Asymmetric synthesis of Pachastrissamine (Jaspine B) and its diastereomers via η3-allylpalladium intermediates

Article abstract of DOI:10.1039/c0ob00643b

A short route for the synthesis of Pachastrissamine (Jaspine B), an anhydrosphingosine derivative, and all three of its diastereomers is presented. The route consists of only 9 steps from the commercially available Garner's aldehyde. The furan framework is formed via an η³-allylpalladium intermediate.

Full text of DOI:10.1039/c0ob00643b

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PAPER
Asymmetric synthesis of Pachastrissamine (Jaspine B) and its diastereomers
via g3-allylpalladium intermediates
Mikko Passiniemi and Ari M. P. Koskinen*
Received 30th August 2010, Accepted 25th November 2010
DOI: 10.1039/c0ob00643b
A short route for the synthesis of Pachastrissamine (Jaspine B), an anhydrosphingosine derivative, and
all three of its diastereomers is presented. The route consists of only 9 steps from the commercially
3
available Garner’s aldehyde. The furan framework is formed via an h -allylpalladium intermediate.
Introduction
Polysubstituted tetrahydrofurans are common structural motifs
found in natural products and biologically active molecules such
as annonaceous acetogenins,1 lignans,2 polyether ionophores3
and macrodiolides.4 Due to their biological activities including
antitumour, antihelmic, antimalarial, antimicrobial and antipro-
tozoal activity as well as challenging structures, development
of methods for synthesizing differently substituted tetrahydrofu-
rans stereoselectively have become important. There are many
approaches described in the literature for the formation of
tetrahydrofuran ring systems.5 They include oxidative cyclisation,6
Fig. 2 Structure of Pachastrissamine and its diastereomers.
radical cyclisation,7 cycloisomerisation,8 Prins/Prins-Pinacol type
cytotoxic properties. Pachastrissamine (Jaspine B) 1 (Fig. 2),
the first naturally occurring anhydrosphingosine derivative, was
isolated in 2001 by Higa and co-workers11 from an Okinawan
marine sponge Pachastrissa sp. (family calthropellidae). Later
in 2003 Debitus and co-workers12 isolated the same compound
from a Vanuatuan marine sponge genus Jaspis. It was found to
possess marked cytotoxicity at a level of IC50 0.01 mg mL-1 against
P388, A549, HT29 and Mel 28 cell lines. Due to the biological
cyclisation,9 Palladium mediated Tsuji–Trost allylation reaction10
among others (Fig. 1).
The marine environment has frequently afforded a variety
of biologically active compounds with strong anticancer and
Department of Chemistry, School of Chemical Technology, Aalto Univer-
sity, P.O. Box 16100 (Kemistintie 1), FI-00076, Aalto, Finland. E-mail:
ari.koskinen@tkk.fi
Fig. 1 Some examples for the preparation of tetrahydrofuran/dihydrofuran ring systems.
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Scheme 1 Retrosynthetic analysis.
Scheme 2 a) TBSCl, imidazole, DMF, 0 ◦C → rt; b) I2, n-BuLi, THF, -78 ◦C; c) KO2CN NCO2K, AcOH, MeOH; d) I2, KOH, MeOH–H2O.
activity and challenging chemical structure, a great deal of effort
has been devoted to the synthesis of Pachastrissamine13 including
our own.14 Lesser, but lately increasing, attention has been paid
to the synthesis of other diastereomers of Pachastrissamine.
Delgado and co-workers13q and Ohno and co-workers13x have both
synthesized four diastereomers of Pachastrissamine (1, C2 epimer
2, C2&C3 epimer 3 and C3 epimer 4) and other groups only the
epimer 2.13c,k,n,s Herein, we report a short synthesis of all four
diastereomers of Pachastrissamine from Garner’s aldehyde.
volatility of the iodide 10 (despite it being crystalline). This iodide
can be distilled under vacuum (10–15 mmHg). N.B. Iodide 10 is
explosive at high temperatures! Diimide reduction of 10 proceeded
smoothly to provide the Z-alkene 1120 in a fairly good yield (65%).
TBS protection proceeded with ease providing the Z-iodide 621
in almost quantitative yield (96%). This three step procedure can
be performed with a single purification process, distillation of the
final Z-iodide 6.
Nucleophilic addition to Garner’s aldehyde has been very
thoroughly studied.22 Pioneering research was done separately
by Herold22a and Garner.22b The stereochemical outcome can
be controlled either through the use of additives or chelating
agents. HMPA is known to solvate lithium cations very well.
This coordination enhances the nucleophilicity of the lithiated
species, which favours the attack of the nucleophile from the
least hindered side via a Felkin–Ahn transition state (leading to
anti-diastereomer). Bidentate metal cations (e.g. Mg, Zn) tend
to chelate to the carbonyl groups and affect the stereochemical
outcome. Under chelation control syn-diastereomers are produced
as major products. Iodide 6 was then coupled with Garner’s alde-
hyde 5 (Scheme 3). anti/syn-Selectivities are reported in Table 1.
High anti-selectivity (upto 17 : 1 anti/syn) was best achieved with
DMPU or HMPA as an additive. Without additives the selectivity
Results and discussion
Our synthetic plan is depicted in Scheme 1. Retrosynthetically
the carbon skeleton of 1 can be considered to arise from a
cross metathesis reaction of a vinyltetrahydrofuran and a terminal
alkene. We anticipated that the (2,3,4)-substituted tetrahydrofuran
framework, the key intermediate of our route, could be achieved
3
via an h -allylpalladium intermediate. Depending on the selectivity
of the cyclization step both isomers at C2 should be achievable.
After simple functional group manipulations the synthon for the
tetrahydrofuran framework can be envisaged to arise from an
allylic oxazoline, which itself can be derived from a stereoselec-
tive coupling of Garner’s aldehyde 5 with a suitably protected
vinyliodide 6.
The synthesis commenced with the preparation of Z-iodide 6
(Scheme 2). We first attempted a route first published by Luithle
and Pietruszka.15 Propargyl alcohol 7 was protected as a silyl
ether with TBSCl (93%).16 The TBS ether◦8 was then subjected
to iodination with elemental iodine at -78 C (61%).17 The triple
bond of 9 was reduced with diimide (HN NH)18 to give the
Z-double bond in a modest yield (30%) with the overall yield
being just 17% (over three steps). The poor yield of the reduction
reaction is partly explained by overreduction of the triple bond to
single bond. By simply changing the order of reactions the overall
yield improved to 51%. Iodination of propargyl alcohol 7 provided
iodide 1019 in good yield (82%). The yield is lowered due to the high
Scheme 3 Coupling reaction.
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Table 1 Diastereoselectivity of the addition of (Z)-iodoalkene 6 to
Garner’s aldehyde 5
95%). Cleavage of the N,O-acetal was best achieved with FeCl3
adsorbed on silica gel in CHCl3.23 80% AcOH at 50 ◦C can also be
used, but on larger scales this reagent esterifies the newly formed
free alcohol to some extent.
Entry
Additive
Solvent
anti : syna
Conversion
The key reaction, cyclization into a furan ring, we had en-
visioned to proceed via an allylpalladium intermediate.10,24 It is
known that with chiral allylic acetates (or esters in general) in the
formation of the allylpalladium complex, the initial attack of Pd0
occurs from the least hindered side (anti-attack) thus inverting
the stereochemistry of the complex. Soft carbon nucleophiles and
heteroatoms (such as N and O) attack in a SN2 type manner
inverting the stereochemistry of the allylpalladium complex. The
overall outcome of the reaction is retention of stereochemistry.
We anticipated that the stereogenic center at C4 (the allylic benzyl
ether would provide enough internal asymmetric induction for
the cyclization. With 16b, the Pd catalyst would coordinate to the
allylic system from the least hindered side forcing the nucleophile
to replace Pd from the backside (TSanti in Scheme 5). With the
anti-isomer 16a the cyclization reaction proceeded smoothly with
catalytic Pd(PPh3)4/PPh3 in THF at 55 ◦C. It became immediately
evident that the selectivity of the cyclisation was modest. Crude
1H NMR showed that a ~2 : 1 mixture of 17a and 17b had
formed favoring the all syn (3S,4S,5S) configuration. With the syn-
isomer 16b the selectivity rose substantially to over 9 : 1 (17c : 17d)
favoring the (3S,4R,5R) configuration (overall yield 88%). The
lower selectivity of 16a can possibly be explained by p-s-p-
isomerization of the Pd intermediate. This kind of isomerization
could be feasible due to the lower energy difference between the
Pd intermediates, i.e. the intermediates equilibrate more rapidly
than cyclize. Hence the lower selectivity from the cyclization. Both
1
2
3
4
5
6
HMPT
DMPU
no additive
SnCl4
ZnCl2
BF3·Et2O
Toluene
Toluene
Toluene
Toluene
Toluene/Et2O
Toluene
12 : 1
16.9 : 1
4 : 1
1 : 1.8
1 : 5.7
1 : 6
55%
57%
63%
41%
72%
70%
a anti/syn selectivity was checked by chiral HPLC (column: Supelco
Cyclodextrin g)
was 4 : 1 (anti/syn), which manifests the enantioface controlling
effect of the N-Boc protected dimethyloxazolidine ring unit.
For syn-selective coupling we turned to chelating metals/Lewis
acids. Best results were obtained with ZnCl2 dissolved in Et2O or
BF3·Et2O (1 : 6 anti/syn). Yields of these coupling reactions varied
between 40–70% depending on the reaction conditions.
Alcohols 12a and 12b were protected as benzyl ethers with BnBr,
TBAI and NaH in refluxing THF in a good yield (for 13a 96%
and for 13b 92%). Removal of the TBS protecting groups from
13a/b with TBAF proceeded quickly and smoothly providing
alcohols 14a (90%) or 14b (92%) in excellent yields (Scheme 4).
The reaction was instantly over with both diastereomers 13a/b
as soon as 100 mol% of TBAF had been added. Free alcohols
14a/b were esterified with Ac2O, DMAP/Et3N in CH2Cl2. Again,
this reaction proved to be fast and efficient Full conversion was
reached with both diastereomers 14a/b within 5 min after the
addition of the anhydride (isolated yield with both 15a and 15b
Scheme 4 a) BnBr, TBAI, NaH, THF, reflux; b) TBAF, THF, rt; c) Ac2O, DMAP, Et3N, CH2Cl2, rt; d) FeCl3-SiO2, CHCl3, rt.
Scheme 5 Proposed transition states leading to diastereomers 17a and 17c.
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Scheme 6 a) cat. Pd(PPh3)4, PPh3, THF, 55 ◦C; b) cat. Grubbs’ 2nd gen., 1-tetradecene, CH2Cl2, 45 ◦C; c) (i) cat. Pd/C, H2 (1 atm), MeOH, rt; (ii) HCl
(g), MeOH, 0 ◦C → rt.
cyclizations proceeded with high overall yields (varying between
87–95% for 17a/17b and 89–95% for 17c/17d, respectively). The
relative stereochemistry of all four diastereomers were elucidated
based on 1H, 13C & 2D NMR studies and later confirmed by the
physical data of free amines 1, 2, 3 and 4.
Garner’s aldehyde has been also used by others for the synthesis of
epi-pachastrissamines: overall yields have been 10%13a and 43%13x
for 2, 17% for 3 and 20% for 4.13x
Experimental
With means of synthesizing all four diastereomers 17a–d
(Scheme 6), we then investigated the cross-metathesis reaction.25
Highest conversions (78–87%) were obtained with Grubbs’ 2nd
generation catalyst26 and a 10-fold excess of 1-tetradecene in
CH2Cl2 at 45 ◦C (closed vessel). The catalyst loading had to be at
least 10 mol%, otherwise the metathesis reaction did not proceed
as efficiently and we could detect and isolate unreacted starting
materials. The final hydrogenation and global deprotection was
performed in two steps. First the double bond and benzyl ether
were hydrogenated over Pd/C at an atmospheric pressure of H2
gas. Next the t-butyl carbamate was cleaved off with HCl in MeOH
at 0 ◦C and after basic work up Pachastrissamine 1 and its three
diastereomers 2, 3 and 4 were isolated as free bases.
General Experimental
All reactions were carried out under argon atmosphere in flame-
dried glassware unless otherwise noted. Non-aqueous reagents
were transferred under argon via syringe or cannula and dried
prior to use. Et3N, benzene and toluene were distilled from
metallic Na. THF was distilled from Na/benzophenone, CH2Cl2
˚
from CaH2 and DMF from molecular sieves (4 A)/ninhydrin.
Other solvents and reagents were used as obtained from supplier.
Analytical TLC was performed using Merck silica gel F254 (230–
400 mesh). Column chromatography was performed using Merck
silica gel 60 (230–400 mesh) and p.a. grade solvents. 1H and
13C NMR spectra were recorded on a Bruker Avance 400 (1H
399.98 MHz; 13C 100.59 MHz) spectrometer. The chemical shifts
Conclusion
1
are reported in ppm relative to CHCl3 (d 7.26 ppm for H and
77.0ppmfor 13C) or CHCl2CHCl2 (d 5.96ppmfor 1Hand73.7ppm
for 13C). Melting points were determined in open capillaries using
Stuart SMP3 melting point apparatus. Optical rotations were
obtained with Perkin–Elmer 343 polarimeter. High resolution
mass spectrometric data were measured using MicroMass LCT
Premier spectrometer.
In summary, we have shown that the coupling reaction of Garner’s
aldehyde 5 with the vinyl lithium compound derived from the Z-
alkene 6 can be controlled to give either the anti or syn diastere-
omer in high diastereoselectivity. The open-chain allyl acetates
3
16a and 16b cyclise through an h -allylpalladium intermediate
with moderate to good stereoselectivities to tetrahydrofurans. The
method presented gives easy access to Pachastrissamine 1 and
all three of its diastereomers 2, 3, 4 in 9 steps starting from
commercially available Garner’s aldehyde 5.
3-Iodoprop-2-yn-1-ol 10
Our nine step procedure provides Pachastrissamine 1 in a total
yield of 13%. In comparison 1 has been synthesized from Garner’s
aldehyde in ten (overall yield 22%, TFA salt),13a eleven (overall
yield 11%),13t seven (overall yield 26%)13v and five (38%)13x steps.
Overall yields for 2, 3 and 4 were 6%, 23% and 2% respectively.
Propargyl alcohol 7 (5.71 g, 102 mmol, 100 mol%) was dissolved
in MeOH (100 mL) and cooled to 0 ◦C. KOH (14.36 g, 256 mmol,
251 mol%) dissolved in H2O (20 mL) was added in one portion to
the solution. After 10 min, iodine (28.46 g, 112 mmol, 110 mol%)
was added to the solution. The mixture was stirred at 0 ◦C for
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5 min before it was allowed to warm to room temperature. MeOH
was removed under reduced pressure and the crude product was
partitioned between H2O (100 mL) and Et2O (100 mL). The
aqueous layer was extracted withEt2O (3 ¥ 100 mL). The combined
organic layers were washed with sat. Na2SO3, dried (Na2SO4) and
concentrated in vacuo. The iodide 10 was collected as white crystals
and concentrated in vacuo. The crude product was purified by
Kugelrohr distillation to afford the fully protected (Z)-iodide 6 as
a colorless oil (30.15 g, 96%); b. 65 ◦C (0.15 mmHg); dH (400 MHz,
CDCl3) 0.11 (6H, s), 0.93 (9H, s), 4.26 (2H, dd, J 1.8, 5.3 Hz), 6.25
(1H, td, J 1.8, 7.7 Hz), 6.43 (1H, td, J 5.3, 7.7 Hz); dC (100 MHz,
CDCl3) -5.2, 18.2, 25.8, 66.8, 80.0, 141.3; EI-MS m/z 299 (M +
1)+, 143, 131, 115, 73.
◦
(15.25 g, 82%), mp 47–49 C. N.B. The iodide 10 can be purified
by vacuum distillation (bp 80–90 ◦C, 15 mmHg), but 10 is also
explosive at high temperatures! dH (400 MHz, CDCl3) 1.85 (1H, t,
J 6.1 Hz), 4.42 (2H, d, J 6.0 Hz); dC (100 MHz, CDCl3) 2.6, 52.6,
92.5; EI-MS m/z 182 M+, 165, 152, 139, 127, 55.
(S)-4-[(Z)-(R)-4-(tert-Butyldimethylsilanyloxy)-1-hydroxybut-2-
enyl]-2¢,2¢-dimethyloxazolidine-3¢-carboxylic acid tert-butyl ester
12a
Preparation of potassium (E)-diazene-1,2-dicarboxylate27
The (Z)-iodide 6 (2.490 g, 8.34 mmol, 200 mol%) was dissolved
in dry toluene (36 mL). The flask was cooled to -78 ◦C and n-
BuLi (2.00 M in hexanes, 4.2 mL, 8.4 mmol, 201 mol%) was
added dropwise. This mixture was stirred for 45 min before DMPU
(1.02 mL, 8.5 mmol, 203 mol%) was added. Another 45 min later
serinal 5 (957 mg, 4.18 mmol, 100 mol%) dissolved in toluene
(6 mL) was added at -95 ◦C. The mixture was allowed to react
for 2 h before it was quenched with saturated NH4Cl solution
(20 mL). The aqueous layer was diluted with distilled H2O (15 mL)
and extracted with EtOAc (3 ¥ 10 mL). The combined organic
extracts were washed with brine, dried (Na2SO4) and concentrated.
Purification of the crude with column chromatography (20%
EtOAc/hexanes) provided a mixture of alcohols 12a/12b as a
colourless oil (922.0 mg, 55%, anti/syn ratio 16.9 : 1); [a]D -36.7 (c
1.02, CHCl3); IR (neat) 3410, 2978, 2932, 2870, 2850, 1698 cm-1;
dH (400 MHz, CDCl2CDCl2, 90 ◦C) 0.10 (6H, s), 0.93 (9H, s),
1.51 (12H, s), 1.58 (3H, s), 3.05 (1H, bs), 3.92–4.02 (3H, m), 4.28
(1H, ddd, J 1.5, 5.7, 13.5 Hz), 4.37 (1H, ddd, J 1.5, 6.2, 13.5 Hz),
4.59 (1H, m), 5.48 (1H, tdd, J 1.7, 8.0, 11.4 Hz), 5.70 (1H, tdd,
KOH (59.8 g, 1.07 mol, 250 mol%) was dissolved in distilled
H2O (110 mL). The solution was stirred vigorously and cooled
to 0 ◦C. Azodicarbonamide (49.7 g, 0.43 mol, 100 mol%) was
added in small portions to the solution (3–5 g each). After the
addition of azodicarbonamide the mixture was stirred for 30 min
before the azodicarbocylate salt was collected as a bright yellow
precipitate by filtration (79.2 g, 95%). The filtrate was washed with
cold H2O until washings were neutral, then with MeOH and finally
with Et2O.
(Z)-3-Iodoprop-2-en-1-ol 11
Iodide 10 (30.0 g, 0.165 mol, 100 mol%) was dissolved in
MeOH (400 mL) and the dipotassium diazocarboxylate (68.7 g,
0.354 mmol, 215 mol%) was added to the reaction flask. Glacial
acetic acid (40.5 mL, 0.707 mmol, 430 mol%) in MeOH (100 mL)
was slowly added to the solution. The rate of addition was
controlled so that the solvent didn’t start to boil. Gas evolution
was immediate when the addition of AcOH was started and
the evolved gas was released through a three-way tap. After the
addition of acetic acid the contents of the flask were allowed to
react for 1.5 h. MeOH was evaporated in vacuo and the residue
was partitioned between H2O (200 mL) and CH2Cl2 (100 mL).
The aqueous layer was extracted with CH2Cl2 (3 ¥ 100 mL). The
combined organic extracts were dried (Na2SO4) and concentrated.
The residue was stirred in n-butylamine (50 mL) for 16 h. The
solution was partitioned between distilled H2O (100 mL) and
CH2Cl2 (100 mL). The aqueous layer was extracted with CH2Cl2
(2 ¥ 100 mL) and the combined organic layers were washed with
1 M HCl solution (200 mL). Drying of the solvents (Na2SO4) was
followed by concentration. The crude (Z)-iodide 11 was purified
by filtering through a short pad (~5 cm) of silica. The iodide was
collected as a pale yellow oil (19.6 g, 65%); dH (400 MHz, CDCl3)
1.91 (1H, br s), 4.24 (2H, dd, J 1.5, 5.7 Hz), 6.36 (1H, td, J 1.6,
7.6 Hz), 6.49 (1H, td, J = 5.8, 7.7 Hz); dC (100 MHz, CDCl3) 65.7,
82.6, 140.0; EI-MS m/z 184 M+, 183, 167, 153, 127, 55.
◦
J 0.9, 5.8, 11.5 Hz); dC (100 MHz, CDCl2CDCl2, 90 C) -5.41,
-5.37, 17.9, 24.0, 25.7, 26.3, 28.2, 59.5, 61.8, 64.2, 68.5, 80.4, 94.2,
129.1, 132.9, 152.9; HRMS (M + Na)+ calcd for C20H39NO5NaSi
424.2495, found 424.2516.
(S)-4-[(Z)-(S)-4-(tert-Butyldimethylsilanyloxy)-1-hydroxybut-2-
enyl]-2¢,2¢-dimethyloxazolidine-3¢-carboxylic acid tert-butyl ester
12b
The (Z)-iodide 6 (2.42 g, 8.11 mmol, 201 mol%) was dissolved
in dry toluene (38 mL). The flask was cooled to -78 ◦C and n-
BuLi (2.28 M in hexanes, 3.6 mL, 8.21 mmol, 203 mol%) was
added dropwise. After an hour the flask was cooled to -95 ◦C
and BF3·Et2O (820 mL, 6.47 mmol, 160 mol%) was added. The
reaction mixture was stirred for another 30 min before the serinal
5 (926.6 mg, 4.04 mmol, 100 mol%) dissolved in toluene (6 mL)
was added. The mixture was stirred at -95 ◦C for 2.5 h before
the reaction was quenched with saturated NH4Cl (20 mL). The
aqueous layer was extractedwithEtOAc (2¥ 20mL)andcombined
organic phases dried (Na2SO4) and concentrated. Purification by
column chromatography (15% EtOAc : hexanes) afforded 1.26 g
(3.12 mmol, 77%) of 12b (syn/anti ratio 6.2 : 1); [a]D -28.1 (c 1.00,
CHCl3); IR (neat) 3436, 2956, 2932, 2885, 2858, 1695 cm-1; dH
(Z)-tert-Butyl(3-iodoallyloxy)dimethylsilane 6
(Z)-iodide 11 (13.30 g, 0.105 mol, 100 mol%) was dissolved in dry
DMF (50 mL). Imidazole (15.80 g, 0.232 mol, 220 mol%) was
added and allowed to dissolve before TBSCl (16.60 g, 0.105 mol,
100 mol%) was added. The reaction was complete in 30 min and
pentane (100 mL) was added. Phases were separated and the DMF
layer was extracted with pentane (2 ¥ 50 mL). The combined
organic extracts were washed with H2O (50 mL), dried (Na2SO4)
◦
(400 MHz, CDCl2CDCl2, 90 C) 0.09 (6H, s), 0.92 (9H, s), 1.51
(12H, s), 1.57 (3H, s), 3.36 (1H, bs), 4.00–3.85 (3H, m), 4.23 (1H,
ddd, J 1.6, 5.7, 13.5 Hz), 4.34 (1H. ddd, J 1.7, 6.5, 13.6 Hz), 4.60
(1H, app. t, J = 8.0 Hz), 5.47 (1H, m), 5.73 (1H, m); dC (100 MHz,
CDCl2CDCl2, 90 ◦C) -5.42, -5.38, 17.9, 23.9, 25.7, 26.4, 28.2,
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59.3, 61.7, 64.8, 69.3, 80.2, 94.0, 129.4, 133.7, 153.6; HRMS (M +
Na)+ calcd for C20H39NO5NaSi 424.2495, found 424.2511.
(S)-tert-Butyl 4-((R,Z)-1-(benzyloxy)-4-hydroxybut-2-en-1-yl)-
2,2-dimethyloxazolidine-3-carboxylate 14a
Benzyl ether 13a (1.40 g, 2.85 mmol, 100 mol%) was dissolved in
THF (20 mL). To this solution was added TBAF (1 M in THF,
3.0 mol, 3.0 mmol, 105 mol%). The reaction was complete in
15 min and the solvent was evaporated in vacuo. The crude alcohol
was purified by column chromatography (30% EtOAc : hexanes)
to afford the anti-acohol 14a as a viscous oil (966 mg, 90%); [a]D
-40.3 (c 1.88, CH2Cl2); IR (neat) 3449, 3089, 3064, 2979, 2935,
(S)-tert-Butyl 4-((R,Z)-1-(benzyloxy)-4-((tert-
butyldimethylsilyl)oxy)but-2-en-1-yl)-2,2-dimethyloxazolidine-3-
carboxylate 13a
anti-Alcohol 12a (1.205 g, 3.00 mmol,◦100 mol%) was dissolved
in dry THF (20 mL) and cooled to 0 C. NaH (60% dispersion
in oil, 170 mg, 4.25 mmol, 142 mol%) was added and the mixture
was stirred for 15 min before TBAI (111 mg, 0.30 mmol, 10 mol%)
followed by BnBr (476 mL, 4.00 mmol, 133 mol%) were added.
The mixture was heated to reflux for 16 h. When the reaction
was complete, the mixture was cooled to 0 ◦C and quenched
with saturated NH4Cl solution (10 mL). The mixture was diluted
with H2O (5 mL) and EtOAc (10 mL) and phases were separated.
The aqueous layer was extracted with EtOAc (2 ¥ 10 mL). The
combined organic phases were washed with brine, dried (Na2SO4)
and concentrated. Purification by column chromatography (20%
EtOAc : hexanes) afforded the benzyl ether 13a as an oil (1.415 g,
96%); [a]D -27.4 (c 1.50, CH2Cl2); IR (neat) 3070, 2940, 2872,
1700, 1605, 1586 cm-1; dH (400 MHz, CDCl3, 50 ◦C) 0.08 (6H, s),
0.93 (9H, s), 1.47 (9H, s), 1.50 (3H, s), 1.56 (3H, s), 3.91 (2H, m),
4.13 (1H, app. d, J 6.3 Hz), 4.19 (1H, dd, J 4.6, 13.1 Hz), 4.33 (1H,
dd, J 6.9, 13.1 Hz), 4.39 (1H, d, J 12.1 Hz), 4.39–4.45 (1H, m), 4.60
(1H, d, J 12.2 Hz), 5.43 (1H, app. t, J 10.8 Hz), 5.80 (1H, app. td,
J 5.8, 11.7 Hz), 7.24–7.40 (5H, m); dC (100 MHz, CDCl3, 50 ◦C)
-5.4, 17.9, 24.3, 25.7, 26.5, 28.2, 59.3, 60.2, 64.3, 70.5, 74.3, 79.6,
94.0, 127.2, 127.4, 128.0, 128.1, 128.3, 134.6, 138.4, 152.0; HRMS
calcd. for C27H45NO5SiNa [M++Na] 514.2965, found 514.2951.
◦
2874, 1698, 1608, 1587 cm-1; dH (400 MHz, CDCl3, 50 C) 1.46
(9H, s), 1.49 (3H, s), 1.57 (3H, s), 2.15 (1H, br s), 3.88–3.98 (2H,
m), 4.12 (1H, ddd, J 1.3, 6.1, 13.0 Hz), 4.15 (1H, m), 4.20 (1H,
ddd, J 1.0, 7.3, 13.1 Hz), 4.39 (1H, d, J 11.9 Hz), 4.52 (1H, m), 4.31
(1H, d, J 11.9 Hz), 5.52 (1H, app. dd, J 9.8, 10.8 Hz), 5.87 (1H,
dddd, J 1.0◦, 6.2, 7.1, 11.3 Hz), 7.23–7.35 (5H, m); dC (100 MHz,
CDCl3, 50 C) 24.6, 26.7, 28.4, 58.6, 60.8, 64.3, 70.9, 74.0, 80.3,
94.3, 127.6, 127.8, 128.3, 130.8, 133.5, 138.3, 152.7; HRMS calcd.
for C21H31NO5Na [M++Na] 400.2100, found 400.2097.
(S)-tert-Butyl 4-((S,Z)-1-(benzyloxy)-4-hydroxybut-2-en-1-yl)-
2,2-dimethyloxazolidine-3-carboxylate 14b
Benzyl ether 13b (1.340 g, 2.73 mmol, 100 mol%) was dissolved in
THF (20 mL). To this solution was added TBAF (1 M in THF,
3.0 mol, 3.0 mmol, 110 mol%). The reaction was complete in
15 min and the solvent was evaporated in vacuo. The crude alcohol
was purified by column chromatography (30% EtOAc : hexanes)
to afford the syn-alcohol 14b as a viscous oil (945 mg, 92%); [a]D
+3.2 (c 1.05, CH2Cl2); IR (neat) 3437, 3060, 2978, 2935, 2875,
1698, 1601, 1585 cm-1; dH (400 MHz, CDCl3, 50 ◦C) 1.46 (9H, s),
1.47 (3H, s), 1.52 (3H, s), 1.75–1.85 (1H, br s), 3.93 (1H, dd, J
6.9, 9.5 Hz), 4.07 (1H, dd, J 5.7, 13.3 Hz), 4.06–4.19 (1H, m), 4.17
(1H, dd, J 7.2, 12.9 Hz), 4.21 (1H, dd, J 1.4, 9.6 Hz), 4.44 (1H, d,
J 12.0 Hz), 4.61 (1H, d, J 12.1 Hz), 4.64–4.72 (1H, m), 5.59 (1H,
app. t, J 10.6 Hz), 5.93 (1H, app. td, J 6.4, 11.6 Hz), 7.25–7.35 (5H,
m); dC (100 MHz, CDCl3, 50 ◦C) 24.3, 26.5, 28.4, 58.7, 59.8, 63.5,
70.9, 72.5, 80.4, 94.3, 127.64, 127.68, 128.4, 128.7, 135.0, 138.5,
152.8; HRMS calcd. for C21H31NO5Na [M++Na] 400.2100, found
400.2094.
(S)-tert-Butyl 4-((S,Z)-1-(benzyloxy)-4-((tert-
butyldimethylsilyl)oxy)but-2-en-1-yl)-2,2-dimethyloxazolidine-3-
carboxylate 13b
syn-Alcohol 12b (1.260 g, 3.14 mmol, 100 mol%) was dissolved in
dry THF (20 mL) and cooled to 0 ◦C. NaH (60% dispersion in oil,
173.3 mg, 4.33 mmol, 138 mol%) was added and the mixture was
stirred for 15 min before TBAI (116 mg, 0.314 mmol, 10 mol%)
followed by BnBr (480 mL, 4.03 mmol, 128 mol%) were added.
The mixture was heated to reflux for 20 h. When the reaction
was complete, the mixture was cooled to 0 ◦C and quenched
with saturated NH4Cl solution (15 mL). The mixture was diluted
with H2O (5 mL) and EtOAc (10 mL) and phases were separated.
The aqueous layer was extracted with EtOAc (2 ¥ 10 mL). The
combined organic phases were washed with brine, dried (Na2SO4)
and concentrated. Purification by column chromatography (20%
EtOAc : hexanes) afforded the benzyl ether 13b as an oil (1.420 g,
92%); [a]D +8.7 (c 1.40, CH2Cl2); IR (neat) 3065, 2928, 2872,
1699, 1603, 1586 cm-1; dH (400 MHz, CDCl3, 60 ◦C) 0.0671 (3H,
s), 0.0716 (3H, s), 0.92 (9H, s), 1.45 (9H, s), 1.47 (3H, s), 1.52 (3H,
s), 3.92 (1H, dd, J 6.5, 9.6 Hz), 4.08 (1H, ddd, J 1.8, 4.5, 13.5 Hz),
4.05–4.20 (1H, m), 4.18 (1H, dd, J 1.4, 9.5 Hz), 4.32 (1H, m), 4.42
(1H, d, J 12.0 Hz), 4.62 (1H, d, J 11.9 Hz), 4.60–4.75 (1H, m), 5.50
(1H, app. tdd, J 1.6, 9.9, 11.4 Hz), 5.89 (1H, app. ddd, J 4.2, 7.3,
11.4 Hz), 7.25–7.38 (5H, m); dC (100 MHz, CDCl3, 60 ◦C) d -5.14,
-5.12, 18.2, 24.3, 25.9, 26.3, 28.5, 59.4, 60.1, 63.6, 70.8, 72.9, 79.9,
94.4, 126.8, 127.5, 127.7, 128.3, 136.6, 138.8, 152.2; HRMS calcd.
for C27H45NO5SiNa [M++Na] 514.2965, found 514.2972.
(S)-tert-Butyl 4-((R,Z)-4-acetoxy-1-(benzyloxy)but-2-enyl)-2,2-
dimethyloxazolidine-3-carboxylate 15a
Alcohol 14a (802 mg, 2.12 mmol, 100 mol%) was dissolved in
CH2Cl2 (20 mL) at room temperature. To this solution were added
DMAP (51.0 mg, 0.42 mmol, 20 mol%), Et3N (592 ml, 4.25 mmol,
200 mol%) and finally Ac2O (324 mL, 3.44 mmol, 162 mol%). The
reaction was complete in 10 min. Solvents were evaporated in vacuo
and the crude acetate was purified by column chromatography
(50% EtOAc : hexanes) to afford the the anti-acetate 15a as a
colourless oil (850 mg, 95%); [a]D -52.4 (c 1.31, CH2Cl2); IR (neat)
3089, 3065, 3030, 2977, 2933, 2873, 1739, 1698, 1607, 1587 cm-1;
dH (400 MHz, CDCl3, 50 ◦C) 1.45 (9H, s), 1.50 (3H, s), 1.56 (3H,
s), 2.05 (3H, s), 3.91 (1H, dd, J 5.8, 9.1 Hz), 3.95 (1H, m), 4.13
(1H, app. dd, J 2.0, 9.0 Hz), 4.39 (1H, d, J 11.7 Hz), 4.42 (1H,
br s), 4.55 (1H, m), 4.60 (1H, d, J 11.8 Hz), 4.74 (1H, ddd, J 1.0,
7.6, 13.0 Hz), 5.64 (1H, app. t, J 10.3 Hz), 5.73–5.85 (1H, br s),
7.26–7.35 (5H, m); dC (100 MHz, CDCl3, 50 ◦C) 20.8, 23.3, 26.1,
28.4, 60.0, 60.3, 64.6, 71.0, 74.3, 80.1, 93.1, 126.8, 127.9, 128.4.,
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129.6, 133.0, 138.4, 152.1, 170.5; HRMS calcd. for C23H33NO6Na
[M++Na] 442.2203, found 442.2206.
127.8, 127.9, 128.5, 129.1, 131.4, 137.6, 156.2, 170.7; HRMS calcd.
for C20H29NO6Na [M++Na] 402.1893, found 402.1898.
Formation of the furan ring
(S)-tert-Butyl 4-((S,Z)-4-acetoxy-1-(benzyloxy)but-2-en-1-yl)-
2,2-dimethyloxazolidine-3-carboxylate 15b
anti-Alcohol 16a (305 mg, 0.805 mmol, 100 mol%) was dissolved
in dry THF (15 mL). To this solution were added PPh3 (27.2 mg,
0.104 mmol, 12 mol%) and Pd(PPh3)4 (60.0 mg, 0.0519, 6 mol%).
The flask was sealed, placed in an oil bath and heated to
55 ◦C. After 8 h the reaction was complete and the solution
was concentrated. The crude product was purified by column
chromatography (20% EtOAc : hexanes) to afford 17a (152 mg,
59%) and 17b (73 mg, 28%).
Alcohol 14b (925 mg, 2.45 mmol, 100 mol%) was dissolved in
CH2Cl2 (10 mL) at room temperature. To this solution were added
DMAP (20.0 mg, 0.164 mmol, 7 mol%), Et3N (520 mL, 3.68 mmol,
150 mol%) and finally Ac2O (255 mL, 2.70 mmol, 110 mol%). The
reaction was complete in 15 min. Solvents were evaporated in vacuo
and the crude acetate was purified by column chromatography
(50% EtOAc : hexanes) to afford the the syn-acetate 15b as a
colourless oil (980 mg, 95%); [a]D -2.5 (c 1.09, CH2Cl2); IR (neat)
tert-Butyl ((3S,4S,5S)-4-(benzyloxy)-5-vinyltetrahydrofuran-3-
yl)carbamate 17a. [a]D -21.5 (c 1.04, CH2Cl2); IR (neat) 3342,
3065, 3031, 2977, 2931, 2874, 1713, 1604, 1586 cm-1; dH (400 MHz,
CDCl3) 1.43 (9H, s), 3.70 (1H, dd, J 7.3, 8.6 Hz), 4.02 (1H, dd,
J 7.2, 8.5 Hz), 4.02–4.08 (1H, m), 4.38 (2H, m), 4.52 (1H, d,
J 11.7 Hz), 4.65 (1H, d, J = 11.7 Hz), 5.03 (1H, d, J 7.7 Hz),
5.29 (1H, ddd, J 1.1, 1.7, 10.3 Hz), 5.40 (1H, ddd, J 1.3, 1.6,
17.2 Hz), 6.03 (1H, ddd J 7.0, 10.3, 17.2 Hz), 7.30–7.42 (5H, m);
dC (100 MHz, CDCl3) 28.3, 52.8, 70.8, 73.6, 79.63, 79.67, 82.3,
118.2, 127.8, 128.0, 128.5, 134.2, 137.6, 155.5; HRMS calcd. for
C18H25NO4Na [M++Na] 342.1681, found 342.1689.
3065, 3031, 2977, 2930, 2873, 1742, 1699, 1605 cm-1
dH (400 MHz,
CDCl3, 50 ◦C) 1.44 (9H, s), 1.46 (3H, s), 1.51 (3H, s), 2.04 (3H, s),
3.93 (1H, dd, J 6.5, 9.6 Hz), 4.02–4.18 (2H, m), 4.19 (1H, dd, J 1.0,
9.6 Hz), 4.39 (1H, d, J 11.8 Hz), 4.42–4.47 (1H, br s), 4.61 (1H, d,
J 11.9 Hz), 4.73 (1H, dd, J 7.4, 13.1 Hz), 5.69 (1H, tdd, J 1.3, 9.8,
11.3 Hz), 5.87 (1H, m), 7.22–7.38 (5H, m); dC (100 MHz, CDCl3,
50 ◦C) 20.7, 24.1, 25.6, 28.4, 60.0, 60.2, 63.5, 70.9, 72.4, 80.1, 94.5,
127.7, 127.9, 128.4, 130.0, 131.1, 138.5, 152.5, 170.4; HRMS calcd.
for C23H33NO6Na [M++Na] 442.2203, found 442.2209.
(4R,5S,Z)-4-(Benzyloxy)-5-((tert-butoxycarbonyl)amino)-6-
hydroxyhex-2-en-1-yl acetate 16a
tert-Butyl ((3S,4S,5R)-4-(benzyloxy)-5-vinyltetrahydrofuran-3-
yl)carbamate 17b. [a]D +12.5 (c 1.01, CH2Cl2); IR (neat) 3347,
3065, 3032, 2978, 2932, 2875, 1714, 1602, 1585 cm-1; dH (400 MHz,
CDCl3) 1.45 (9H, s), 3.66 (1H, dd, J 7.5, 8.6 Hz), 3.77 (1H, app.
dd, J 4.5, 5.1 Hz), 4.18 (1H, dd, J 7.0, 8.3 Hz), 4.27 (1H, app.
td, J 6.7, 10.3 Hz), 4.35 (1H, m), 4.56 (1H, d, J 11.7 Hz), 4.61
(1H, d, J 11.7 Hz), 5.11 (1H, d, J 7.0 Hz), 5.18 (1H, app. td, J
1.3, 10.5 Hz), 5.33 (1H, app. td, J 1.5, 17.1 Hz), 5.79 (1H, ddd, J
6.0, 10.5, 17.1 Hz), 7.29–7.40 (5H, m); dC (100 MHz, CDCl3) 28.3,
51.3, 71.3, 72.2, 79.7, 81.7, 82.9, 116.8, 127.9, 128.0, 128.5, 136.0,
137.3, 155.6; HRMS calcd. for C18H25NO4Na [M++Na] 342.1681,
found 342.1684.
anti-Acetate 15a (690 mg, 1.65 mmol, 100 mol%) was dissolved
in chloroform (15 mL). To this vigorously stirred solution was
added FeCl3-SiO2 (680 mg). The mixture was stirred for 12 h
before solvents were evaporated. The crude alcohol was purified
by column chromatography to afford 16a as a highly viscous oil
(574.5 mg, 92%); [a]D -48.6 (c 1.11, CH2Cl2); IR (neat) 3423, 3067,
3034, 2976, 2930, 2870, 1741, 1698 cm-1; dH (400 MHz, CDCl3)
1.42 (9H, s), 2.07 (3H, s), 2.33 (1H, br s), 3.58–3.67 (1H, br s), 3.67
(1H, dd, J 3.7, 11.3 Hz), 3.95 (1H, dd, J 3.0, 11.2 Hz), 4.34 (1H, d, J
11.8 Hz), 4.42 (1H, dd, J 5.3, 8.7 Hz), 4.58 (1H, dd, J 6.2, 12.3 Hz),
4.61 (1H, d, J 11.8 Hz), 4.68 (1H, dd, J 7.5, 13.2 Hz), 5.23 (1H,
d, J 3.8 Hz), 5.67 (1H, app. dd, J 9.5, 10.9 Hz), 5.84 (1H, dddd, J
0.8, 6.2, 7.2, 11.3 Hz), 7.27–7.38 (5H, m); dC (100 MHz, CDCl3)
20.9, 28.3, 54.8, 60.0, 62.3, 71.0, 75.8, 79.5, 127.8, 128.0, 128.5,
129.1, 132.0, 137.5, 155.7, 170.8; HRMS calcd. for C20H29NO6Na
[M++Na] 402.1893, found 402.1884.
Formation of the furan ring
syn-Alcohol 16b (200 mg, 0.527 mmol, 100 mol%) was dissolved
in dry THF (10 mL). To this solution were added PPh3 (16.6 mg,
0.063 mmol, 12 mol%) and Pd(PPh3)4 (36.3 mg, 0.031, 6 mol%).
The flask was sealed, placed on oil bath and heated to 55 ◦C. 16 h
later the reaction was complete and the solution was concentrated.
The crude product was purified by column chromatography (20%
EtOAc : hexanes) to afford 17c (138 mg, 81%) and 17d (14.5 mg,
8%).
(4S,5S,Z)-4-(Benzyloxy)-5-((tert-butoxycarbonyl)amino)-6-
hydroxyhex-2-en-1-yl acetate 16b
syn-Acetate 15b (950 mg, 2.27 mmol, 100 mol%) was dissolved
in chloroform (20 mL). To this vigorously stirred solution was
added FeCl3-SiO2 (1.03 g). The mixture was stirred for 12 h
before solvents were evaporated. The crude alcohol was purified
by column chromatography (30% EtOAc : hexanes) to afford 16b
as a highly viscous oil (740 mg, 86%); [a]D +11.6 (c 1.14, CH2Cl2);
IR (neat) 3445, 3065, 3031, 2978, 2932, 2871, 1739, 1695 cm-1;
dH (400 MHz, CDCl3) 1.43 (9H, s), 2.06 (3H, s), 2.60 (1H, br s),
3.66–3.74 (3H, m), 4.34 (1H, d, J 11.7 Hz), 4.43 (1H, dd, J 1.3,
9.0 Hz), 4.57 (1H, m), 4.59 (1H, d, J 11.6 Hz), 4.64 (1H, ddd,
J 0.9, 7.0, 13.1 Hz), 5.03–5.14 (1H, br s), 5.66 (1H, dd, J 9.8,
11.0 Hz), 5.83 (1H, app. td, J 6.7, 11.5 Hz), 7.27–7.37 (5H, m);
dC (100 MHz, CDCl3) 20.9, 28.3, 55.6, 60.1, 63.3, 70.5, 73.7, 79.7,
tert-Butyl ((3S,4R,5R)-4-(benzyloxy)-5-vinyltetrahydrofuran-3-
yl)carbamate 17c. [a]D -54.8 (c 0.8, CH2Cl2); IR 3345, 3065,
3033, 2977, 2929, 2870, 1709,1603, 1585 (neat) cm-1; dH (400 MHz,
CDCl3) 1.47 (9H, s), 3.61 (1H, dd, J 4.3, 11.3 Hz), 3.89 (1H, d, J
4.4 Hz), 4.22–4.28 (2H, m), 4.38 (1H, dd, J 4.9, 6.0 Hz), 4.62 (1H,
d, J 11.2 Hz), 4.68 (1H, m), 4.77 (1H, d, J 12.1 Hz), 5.27 (1H, ddd, J
1.0, 1.3, 10.3 Hz), 5.34 (1H, app. td, J 1.1, 17.3 Hz), 6.01 (1H, ddd,
J 7.0, 10.3, 17.3 Hz), 7.27–7.36 (5H, m); dC (100 MHz, CDCl3)
28.4, 56.4, 71.1, 71.5, 79.9, 81.8, 84.6, 117.9, 127.58, 127.64, 128.3,
133.5, 138.0, 155.0; HRMS calcd. for C18H25NO4Na [M++Na]
342.1681, found 342.1687.
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tert-Butyl ((3S,4R,5S)-4-(benzyloxy)-5-vinyltetrahydrofuran-3-
yl)carbamate 17d. [a]D -33.2 (c 0.39, CH2Cl2); IR (neat) 3338,
3065, 3031, 2978, 2930, 2872, 1710 cm-1; dH (400 MHz, CDCl3)
1.45 (9H, s), 3.68 (1H, d, J 3.4 Hz), 3.83 (1H, d, J 9.7 Hz), 4.05
(1H, dd, J 4.8, 9.7 Hz), 4.21 (1H, m), 4.25 (1H, m), 4.62 (1H, d, J
12.0 Hz), 4.71 (1H, m), 4.78 (1H, d, J 11.9 Hz), 5.17 (1H, app. td,
J 1.2, 10.4 Hz), 5.35 (1H, app. td, J 1.3, 17.2 Hz), 5.87 (1H, ddd, J
5.9, 10.5, 17.2 Hz), 7.28–7.38 (5H, m); dC (100 MHz, CDCl3) 28.4,
56.5, 71.7, 72.2, 79.8, 85.0, 88.7, 116.3, 127.8, 127.9, 128.4, 136.3,
137.8, 155.0; HRMS calcd. for C18H25NO4Na [M++Na] 342.1681,
found 342.1688.
tert-Butyl ((3S,4R,5R)-4-(benzyloxy)-5-((E)-tetradec-1-en-1-
yl)tetrahydrofuran-3-yl)carbamate 18c
Furan 17c (41 mg, 0.128 mmol, 100 mol%) was dissolved in
dry CH2Cl2 (3 mL). To this solution was added 1-tetradecene
(335 mL, 1.32 mmol, 10 equiv) and 5 min later Grubbs’ catalyst
(2nd generation, 16.7 mg, 0.020, 15 mol%). The flask was sealed,
placed in an oil bath and stirred at 45 ◦C for 18 h. When the
reaction was complete, the mixture was concentrated in vacuo.
The crude product was purified by column chromatography (100%
hexanes → 20% EtOAc : hexanes). Yield of 18c (50.6 mg, 81%);
[a]D -16.8 (c 1.01, CH2Cl2); IR (neat) 3341, 3065, 3030, 2978, 2930,
2862, 1712 cm-1; dH (400 MHz, CDCl3) 0.88 (3H, t, J 6.9 Hz), 1.26
(20H, m), 1.35–1.43 (2H, m), 1.46 (9H, s), 2.08 (2H, app. q, J
6.9 Hz), 3.56 (1H, dd, J 4.5, 11.4 Hz), 3.81 (1H, d, J 4.1 Hz), 4.24
(2H, m), 4.31 (1H, dd, J 4.2, 6.9 Hz), 4.62 (1H, d, J 12.2 Hz),
4.70 (1H, d, J 5.6 Hz), 4.76 (1H, d, J 12.2 Hz), 5.68 (1H, app.
dd, J 7.5, 15.5 Hz), 5.76 (1H, td, J 6.2, 15.5 Hz), 7.26–7.37 (5H,
m); dC (100 MHz, CDCl3) 14.1, 22.7, 28.3, 29.0, 29.2, 29.3, 29.51,
29.57, 29.62, 29.66, 31.9, 32.4, 56.5, 71.0, 71.5, 79.8, 81.8, 84.7,
124.8, 127.47, 127.53, 128.2, 135.8, 138.2, 155.0; HRMS calcd. for
C30H49NO4Na [M++Na] 510.3559, found 510.3555.
tert-Butyl ((3S,4S,5S)-4-(benzyloxy)-5-((E)-tetradec-1-en-1-
yl)tetrahydrofuran-3-yl)carbamate 18a
Furan 17a (43 mg, 0.135 mmol, 100 mol%) was dissolved in
dry CH2Cl2 (4 mL). To this solution was added 1-tetradecene
(350 mL, 1.33 mmol, 10 equiv) and 5 min later Grubbs’ catalyst
(2nd generation, 14.6 mg, 0.017, 13 mol%). The flask was sealed,
placed in an oil bath and stirred at 45 ◦C for 18 h. When the
reaction was complete, the mixture was concentrated in vacuo.
The crude product was purified by column chromatography (100%
hexanes → 20% EtOAc : hexanes). Yield of 18a (57.2 mg, 87%);
[a]D -2.3 (c 1.14, CH2Cl2); IR (neat) 3350, 3032, 2970, 2925, 2854,
1717 cm-1; dH (400 MHz, CDCl3) 0.88 (3H, t, J 7.0 Hz), 1.25 (20H,
m), 1.34–1.43 (2H, m), 1.43 (9H, s), 2.07 (2H, m), 3.65 (1H, dd, J
7.9, 8.2 Hz), 3.95 (1H, t, J 4.7 Hz), 3.99 (1H, dd, J 7.7, 8.2 Hz),
4.32 (1H, dd, J 4.2, 7.7 Hz), 4.32–4.40 (1H, m), 4.51 (1H, d, J
11.7 Hz), 4.66 (1H, d, J 11.7 Hz), 5.04 (1H, d, J 7.7 Hz), 5.65
(1H, app. tdd, J 1.1, 7.7, 15.5 Hz), 5.80 (1H, td, J 6.7, 15.4 Hz),
7.28–7.37 (5H, m); dC (100 MHz, CDCl3) 14.5, 23.1, 28.8, 29.4,
29.7, 29.8, 29.9, 30.00, 30.04, 30.1, 32.3, 32.8, 53.4, 70.9, 74.1, 80.0,
80.3, 83.0, 125.9, 128.2, 128.3, 128.9, 136.2, 138.1, 156.0; HRMS
calcd. for C30H49NO4Na [M++Na] 510.3559, found 510.3580.
tert-Butyl ((3S,4R,5S)-4-(benzyloxy)-5-((E)-tetradec-1-en-1-
yl)tetrahydrofuran-3-yl)carbamate 18d
Furan 17d (18.5 mg, 0.058 mmol, 100 mol%) was dissolved in dry
CH2Cl2 (2 mL). To this solution was added 1-tetradecene (150
ml, 0.59 mmol, 10 equiv) and 5 min later Grubbs’ catalyst (2nd
generation, 9.3 mg, 0.011, 19 mol%). The flask was sealed, placed
in an oil bath and stirred at 45 ◦C for 16 h. When the reaction
was complete, the mixture was concentrated in vacuo. The crude
product was purified by column chromatography (100% hexanes
→ 20% EtOAc : hexanes). Yield of 18d (22.0 mg, 78%); [a]D -14.9
(c 1.10, CH2Cl2); IR (neat) 3340, 3065, 3030, 2977, 2932, 2860,
1712 cm-1; dH (400 MHz, CDCl3) 0.88 (3H, t, J 6.9 Hz), 1.26 (20H,
m), 1.32–1.39 (2H, m), 1.46 (9H, s), 2.03 (2H, app. q, J 7.0 Hz),
3.63 (1H, app. d, J 3.8 Hz), 3.79 (1H, d, J 9.5 Hz), 4.01 (1H, dd, J
4.8, 9.7 Hz), 4.18 (2H, m), 4.62 (1H, d, J 12.0 Hz),4.76 (1H, d, J
12.0 Hz), 4.72–4.76 (1H, m), 5.44 (1H, app. dd, J 7.0, 15.4 Hz), 5.77
(1H, tdd, J 0.8, 6.9, 15.5 Hz), 7.27–7.39 (5H, m); dC (100 MHz,
CDCl3) 14.1, 22.7, 28.4, 29.0, 29.2, 29.3, 29.49, 29.58, 29.63, 29.67,
31.9, 32.3, 56.7, 71.6, 72.0, 79.7, 85.1, 88.9, 127.7, 127.82, 127.84,
134.3, 137.9, 155.0; HRMS calcd. for C30H49NO4Na [M++Na]
510.3559, found 510.3560.
tert-Butyl ((3S,4S,5R)-4-(benzyloxy)-5-((E)-tetradec-1-en-1-
yl)tetrahydrofuran-3-yl)carbamate 18b
Furan 17b (31.5 mg, 0.099 mmol, 100 mol%) was dissolved in dry
CH2Cl2 (3 mL). To this solution was added 1-tetradecene (250 mL,
0.982 mmol, 10 equiv) and 10 min later Grubbs’ catalyst (2nd
generation, 8.9 mg, 0.010, 11 mol%). The flask was sealed, placed
in an oil bath and stirred at 45 ◦C for 16 h. When the reaction
was complete, the mixture was concentrated in vacuo. The crude
product was purified by column chromatography (100% hexanes
→ 20% EtOAc : hexanes). Yield of 18b (41.0 mg, 85%); [a]D +10.1
(c 1.11, CH2Cl2); IR (neat) 3352, 3065, 3032, 2970, 2930, 2854,
1717 cm-1; dH (400 MHz, CDCl3) 0.88 (3H, t, J 6.8 Hz), 1.26 (20H,
m), 1.31–1.41 (2H, m), 1.45 (9H, s), 2.02 (2H, app. q, J 7.0 Hz),
3.61 (1H, dd, J 7.7, 8.0 Hz), 3.73 (1H, app. t, J 4.9 Hz), 4.16 (1H,
dd, J 7.0, 8.3 Hz), 4.25 (1H, dd, J 6.2, 13.4 Hz), 4.28 (1H, dd, J
4.3, 6.7 Hz), 4.55 (1H, d, J 11.8 Hz), 4.60 (1H, d, J 11.8 Hz), 5.11
(1H, d, J 7.5 Hz), 5.38 (1H, app. tdd, J 1.4, 7.1, 15.3 Hz), 5.74 (1H,
td, J 6.8, 15.4 Hz), 7.28–7.38 (5H, m); dC (100 MHz, CDCl3) 14.1,
22.7, 28.3, 28.9, 29.2, 29.3, 29.48, 29.58, 29.62, 29.67, 31.9, 32.2,
51.4, 71.2, 72.2, 79.6, 81.9, 83.0, 127.6, 127.7, 127.8, 128.0, 134.6,
137.4, 155.7; HRMS calcd. for C30H49NO4Na [M++Na] 510.3559,
found 510.3568.
tert-Butyl ((3S,4S,5S)-4-hydroxy-5-tetradecyltetrahydrofuran-3-
yl)carbamate
Compound 18a (45.0 mg, 0.0923 mmol, 100 mol%) was dissolved
in MeOH (3 mL). To this solution was added 10 wt-% Pd/C
(9.8 mg, 0.0092 mmol, 10 mol%). The flask was evacuated and the
atmosphere was first changed to Ar and finally to H2 (balloon).
The mixture was allowed to react for 8 h before it was filtered
through a pad of Celite, followed by evaporation of solvents. This
Boc-protected compound was used as such in the following step;
[a]D +1.4 (c 1.29, CH2Cl2); dH (400 MHz, CDCl3, 50 ◦C) 0.88
(3H, t, J 6.9 Hz), 1.22–1.35 (24H, br m), 1.45 (9H, s), 1.57–1.65
(2H, m), 2.6 (1H, br s), 3.57 (1H, t, J 8.2 Hz), 3.78 (1H, td, J 2.9,
6.8 Hz), 4.02 (1H, t, J 8.4 Hz), 4.06 (1H, dd, J 3.1, 4.6 Hz), 4.27
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(1H, m), 5.11 (1H, br d, J 7.7 Hz); dC (100 MHz, CDCl3, 50 ◦C)
14.0, 22.6, 26.1, 28.4, 29.3, 29.56, 29.63, 29.66, 29.72, 31.9, 34.8,
54.5, 70.3, 71.9, 79.9, 82.3, 155.8; HRMS calcd. for C23H45NO4Na
[M + Na] 422.3246, found 422.3250.
53.1, 73.5, 75.2, 85.3; HRMS calcd. for C18H37NO2Na [M + Na]
322.2722, found 322.2728.
tert-Butyl ((3S,4R,5R)-4-hydroxy-5-tetradecyltetrahydrofuran-3-
yl)carbamate
(2S,3S,4S)-4-Amino-2-tetradecyltetrahydrofuran-3-ol
Compound 18c (35.0 mg, 0.0072 mmol, 100 mol%) was dissolved
in MeOH (2.5 mL). To this solution was added 10 wt-% Pd/C
(7.4 mg, 0.0070 mmol, 10 mol%). The flask was evacuated and the
atmosphere was first changed to Ar and finally to H2 (balloon).
The mixture was allowed to react for 16 h before it was filtered
through a pad of Celite, followed by evaporation of solvents. This
Boc-protected compound was used as such in the following step;
[a]D -13.7 (c 1.12, CH2Cl2); dH (400 MHz, CDCl3, 50 ◦C) 0.88
(3H, t, J 6.9 Hz), 1.24–1.35 (24H, m), 1.45 (9H, s), 1.58–1.67 (2H,
m), 2.57 (1H, br s), 3.44 (1H, dd, J 3.8, 9.5 Hz), 3.80 (1H, dt,
J 4.2, 6.6 Hz), 3.99 (1H, dd, J 5.7, 8.4 Hz), 4.05 (1H, app. d,
J 2.2 Hz), 4.22 (1H, dd, J 6.3, 9.4 Hz), 4.67 (1H, d, J 4.7 Hz);
(Pachastrissamine) 1
The Boc-protected amine from the previous reaction was dissolved
in MeOH (2 mL) and cooled to 0 ◦C. To this solution was added
MeOH saturated with gaseous HCl (1 mL). The mixture was
stirred at 0 ◦C for 15 min, before it was allowed to warm to room
temperature. After 2 h solvents were evaporated in vacuo and the
crude HCl salt was partitioned between 1 M NaOH (5mL) and
CH2Cl2 (5mL). The aqueous layer was extracted with CH2Cl2 (4 ¥
4 mL). The combined organic phases were dried (Na2SO4) and
concentrated to afford the free base 1 (17.4 mg, 62% from 18a);
[a]D +18.4 (c 1.00, CH2Cl2); IR (neat); 3340, 2919, 2854 cm-1; dH
(400 MHz, CDCl3) 0.88 (3H, t, J 7.0 Hz), 1.25 (24H, br s), 1.67
(2H, m), 2.14 (3H, br s), 3.51 (1H, dd, J 7.3, 8.2 Hz), 3.64 (1H, m),
3.73 (1H, ddd, J 3.5, 6.5, 7.0 Hz), 3.87 (1H, dd, J 3.6, 4.4 Hz), 3.92
(1H, dd, J 7.7, 8.2 Hz); dC (100 MHz, CDCl3) 14.1, 22.7, 26.3, 29.3,
29.4, 29.58, 29.60, 29.7, 29.8, 31.9, 54.3, 71.7, 72.3, 83.2; HRMS
calcd. for C18H37NO2Na [M + Na] 322.2722, found 322.2730.
◦
dC (100 MHz, CDCl3, 50 C) 14.0, 22.6, 26.4, 28.4, 29.3, 29.57,
29.59, 29.64, 29.66, 29.67, 29.76, 31.9, 60.2, 70.5, 77.6, 80.2, 81.5,
155.7;; HRMS calcd. for C23H45NO4Na [M + Na] 422.3246, found
422.3240.
(2S,3R,4R)-4-Amino-2-tetradecyltetrahydrofuran-3-ol 3
tert-Butyl ((3S,4S,5R)-4-hydroxy-5-tetradecyltetrahydrofuran-3-
yl)carbamate
The Boc-protected amine from the previous reaction was dissolved
in MeOH (2 mL) and cooled to 0 ◦C. To this solution was added
MeOH saturated with gaseous HCl (1 mL). The mixture was
stirred at 0 ◦C for 15 min, before it was allowed to warm to room
temperature. After 4 h solvents were evaporated in vacuo and the
crude HCl salt was partitioned between 1 M NaOH (5mL) and
CH2Cl2 (5mL). The aqueous layer was extracted with CH2Cl2 (5 ¥
4 mL). The combined organic phases were dried (Na2SO4) and
concentrated to afford the free base 3 (18.8 mg, 84% from 18c);
[a]D -2.8 (c 0.94, CH2Cl2); IR (neat); 3360, 2960, 2853 cm-1; dH
(400 MHz, CDCl3) 0.87 (3H, t, J 6.8 Hz), 1.25 (24H, br s), 1.52–
1.65 (2H, m), 1.73 (3H, br s), 3.38 (1H, dd, J 3.4, 9.2 Hz), 3.45
(1H, app. t, J 4.2 Hz), 3.80 (1H, dd, J 0.9, 3.2 Hz), 3.88 (1H,
ddd, J 3.3, 6.2, 7.4 Hz), 4.20 (1H, dd, J 5.9, 9.1 Hz); dC (100 MHz,
CDCl3) 14.1, 22.7, 26.4, 29.3, 29.56, 29.57, 29.60, 29.66, 29.8, 31.9,
60.0, 73.8, 79.7, 80.8; HRMS calcd. for C18H37NO2Na [M + Na]
322.2722, found 322.2723.
Compound 18b (40.0 mg, 0.082 mmol, 100 mol%) was dissolved
in MeOH (2.5 mL). To this solution was added 10 wt-% Pd/C
(8.7 mg, 0.0082 mmol, 10 mol%). The flask was evacuated and the
atmosphere was first changed to Ar and finally to H2 (balloon).
The mixture was allowed to react for 12 h before it was filtered
through a pad of Celite, followed by evaporation of solvents. This
Boc-protected compound was used as such in the following step;
[a]D -21.6 (c 1.25, CH2Cl2); dH (400 MHz, CDCl3, 50 ◦C) 0.88
(3H, t, J 6.9 Hz), 1.22–1.36 (24H, br m), 1.45 (9H, s), 1.50–1.58
(2H, m), 2.43 (1H, br s), 3.50 (1H, m), 3.70 (1H, td, J 3.1, 4.4 Hz),
3.91 (1H, t, J 4.1 Hz), 4.10 (1H, m), 4.12 (1H, t, J 7.0 Hz), 5.02
(1H, br s); dC (100 MHz, CDCl3, 50 ◦C) 14.0, 22.6, 25.8, 28.4,
29.3, 29.53, 29.57, 29.60, 29.63, 29.65, 29.67, 31.9, 33.6, 53.2, 70.5,
75.0, 80.0, 85.3, 156.0;; HRMS calcd. for C23H45NO4Na [M + Na]
422.3246, found 422.3252.
(2S,3S,4R)-4-Amino-2-tetradecyltetrahydrofuran-3-ol 2
tert-Butyl ((3S,4R,5S)-4-hydroxy-5-tetradecyltetrahydrofuran-3-
yl)carbamate
The Boc-protected amine from the previous reaction was dissolved
in MeOH (2 mL) and cooled to 0 ◦C. To this solution was added
MeOH saturated with gaseous HCl (1 mL). The mixture was
stirred at 0 ◦C for 15 min, before it was allowed to warm to room
temperature. After 2 h solvents were evaporated in vacuo and the
crude HCl salt was partitioned between 1 M NaOH (5 mL) and
CH2Cl2 (5mL). The aqueous layer was extracted with CH2Cl2 (4 ¥
4 mL). The combined organic phases were dried (Na2SO4) and
concentrated to afford the free base 2 (16.0 mg, 65% from 18b);
[a]D +23.0 (c 1.00, CH2Cl2); IR (neat) cm-1; 3334, 2914, 2853 cm-1;
Compound 18d (24.0 mg, 0.049 mmol, 100 mol%) was dissolved
in MeOH (2 mL). To this solution was added 10 wt-% Pd/C
(5.4 mg, 0.0051 mmol, 10 mol%). The flask was evacuated and the
atmosphere was first changed to Ar and finally to H2 (balloon).
The mixture was allowed to react for 16 h before it was filtered
through a pad of Celite, followed by evaporation of solvents. This
Boc-protected compound was used as such in the following step;
[a]D -18.4 (c 0.90, CH2Cl2); dH (400 MHz, CDCl3, 50 ◦C) 0.89
(3H, t, J 6.9 Hz), 1.24–1.36 (24H, m), 1.46 (9H, s), 1.55–1.70 (2H,
m), 3.35 (1H, br s), 3.60 (1H, m), 3.63 (1H, dd, J 4.1, 9.6 Hz), 3.77
(1H, dd, J 3.8, 5.9 Hz), 3.91 (1H, m), 4.05 (1H, dd,◦J 6.6, 9.5 Hz),
4.75 (1H, br d, J 3.4); dC (100 MHz, CDCl3, 50 C) 14.0, 22.7,
25.9, 28.4, 29.3, 29.55, 29.58, 29.64, 29.66, 29.68, 31.9, 33.7, 60.5,
d
H (400 MHz, CDCl3) 0.86 (3H, t, J 6.5 Hz), 1.24 (24H, br s), 1.54
(2H, m), 2.22 (3H, br s), 3.39 (1H, app. t, J 6.1 Hz), 3.41–3.55 (1H,
m), 3.61 (2H, m), 4.11 (1H, app. t, J 5.9 Hz); dC (100 MHz, CDCl3)
14.0, 22.6, 25.8, 29.3, 29.55, 29.58, 29.63, 29.65, 29.67, 31.9, 33.8,
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70.5, 80.3, 82.9, 85.0, 156.5; HRMS calcd. for C23H45NO4Na [M +
Na] 422.3246, found 422.3251.
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(2S,3R,4S)-4-Amino-2-tetradecyltetrahydrofuran-3-ol 4
The Boc-protected amine from the previous reaction was dissolved
in MeOH (1 mL) and cooled to 0 ◦C. To this solution was added
MeOH saturated with gaseous HCl (1 mL). The mixture was
stirred at 0 ◦C for 15 min, before it was allowed to warm to room
temperature. After 4 h solvents were evaporated in vacuo and the
crude HCl salt was partitioned between 1 M NaOH (5mL) and
CH2Cl2 (5mL). The aqueous layer was extracted with CH2Cl2 (5 ¥
4 mL). The combined organic phases were dried (Na2SO4) and
concentrated to afford the free base 4 (11.8 mg, 80% from 18d);
[a]D -3.2 (c 0.88, CH2Cl2); IR (neat); 3359, 2924, 2850 cm-1; dH
(400 MHz, CDCl3) 0.87 (3H, t, J 6.7 Hz), 1.25 (24H, br s), 1.55–
1.67 (2H, m), 2.13 (3H, br s), 3.33 (1H, dd, J 4.9, 6.6 Hz), 3.59 (1H,
dd, J 4.8, 9.4 Hz), 3.62 (2H, m), 4.00 (1H, dd, J 5.9, 9.1 Hz); dC
(100 MHz, CDCl3) 14.0, 22.7, 26.0, 29.3, 29.57, 29.60, 29.65, 29.67,
31.9, 34.0, 60.5, 73.6, 84.1, 85.2; HRMS calcd. for C18H37NO2Na
[M + Na] 322.2722, found 322.2725.
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This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 1774–1783 | 1783
©