Asymmetric synthesis of N,O,O,O-tetra-acetyl d-lyxo-phytosphingosine, jaspine B (pachastrissamine), 2-epi-jaspine B, and deoxoprosophylline via lithium amide conjugate addition

Article abstract of DOI:10.1039/b801671b

The highly diastereoselective anti-aminohydroxylation of (E)-γ-tri-iso-propylsilyloxy-α,β-unsaturated esters, via conjugate addition of lithium (S)-N-benzyl-N-(α-methylbenzyl)amide and subsequent in situ enolate oxidation with (+)-(camphorsulfonyl)oxaziri

Full text of DOI:10.1039/b801671b

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Asymmetric synthesis of N,O,O,O-tetra-acetyl D-lyxo-phytosphingosine,
jaspine B (pachastrissamine), 2-epi-jaspine B, and deoxoprosophylline via
lithium amide conjugate addition†
Elin Abraham, E. Anne Brock, Jose´ I. Candela-Lena, Stephen G. Davies,* Matthew Georgiou, Rebecca L.
Nicholson, James H. Perkins, Paul M. Roberts, Angela J. Russell, Elena M. Sa´nchez-Ferna´ndez, Philip M.
Scott, Andrew D. Smith and James E. Thomson
Received 30th January 2008, Accepted 20th February 2008
First published as an Advance Article on the web 19th March 2008
DOI: 10.1039/b801671b
The highly diastereoselective anti-aminohydroxylation of (E)-c-tri-iso-propylsilyloxy-a,b-unsaturated
esters, via conjugate addition of lithium (S)-N-benzyl-N-(a-methylbenzyl)amide and subsequent in situ
enolate oxidation with (+)-(camphorsulfonyl)oxaziridine, has been used as the key step in the
asymmetric synthesis of N,O,O,O-tetra-acetyl D-lyxo-phytosphingosine (20% yield over 7 steps), the
anhydrophytosphingosine jaspine B (10% yield over 9 steps), 2-epi-jaspine B (14% yield over 9 steps),
and the Prosopis alkaloid deoxoprosophylline (26% yield over 7 steps).
reported the isolation of two anhydrophytosphingosines from
Introduction
the marine sponge Jaspis sp.,8 which they named jaspine A 5
The phytosphingosines are a sub-class of the sphingoid bases that
consist of a 1,3,4-trihydroxy-2-amino unit at the head of a long
hydrocarbon chain. By far the most abundant phytosphingosine
and B 6; pachastrissamine and jaspine B being identical (Fig. 2).
To date, eleven enantiospecific syntheses of jaspine B 6 have
been reported,9–15 utilizing L-serine,9 D-xylose,10 (R)-glycidol,11
D-ribo-phytosphingosine,12 D-glucose,13 D-galactose,14 and
D-tartaric acid15 as the sources of chirality. Three asymmetric
syntheses of jaspine B 6 have also been disclosed:16,17 in addition
to the procedure communicated by us (employing lithium amide
conjugate addition),16 two other strategies have been reported
which both employ the Sharpless asymmetric dihydroxylation
reaction.17 Two syntheses of ‘truncated’ analogues (bearing C5
and C8 side-chains), based upon manipulation of L-xylose,18 and
Sharpless asymmetric epoxidation,19 have also appeared.
is D-ribo-phytosphingosine 1, with 18 carbon atoms in the
hydrocarbon chain, although smaller amounts of other chain
lengths have been detected (Fig. 1). Sphingolipids are essential
components of eukaryotic cells1 and phytosphingolipids exhibit
important physiological properties.2,3 As such, there has been
much interest in their synthesis, and this was the subject of a
review in 2002.4 The majority of routes to this molecular class are
enantiospecific, utilising starting materials from the chiral pool;5
in comparison asymmetric routes are relatively rare.6
Fig. 2 Jaspine A 5 and jaspine B (pachastrissamine) 6.
Previous investigations from this laboratory have demon-
strated that the conjugate addition of homochiral, secondary
lithium amides (derived from a-methylbenzylamine)20 to a,b-
unsaturated esters and in situ enolate oxidation with (camphor-
sulfonyl)oxaziridine (CSO) represents an efficient entry to anti-
a-hydroxy-b-amino esters.21 This methodology has been used as
the key step in a number of natural product syntheses22 and
was applied by us as described in the preceding manuscript to
the asymmetric synthesis of the sphingoid bases sphinganine
and sphingosine.23 In this manuscript we report the further
application of this versatile methodology to encompass the
asymmetric syntheses of the N,O,O,O-tetra-acetyl derivative of
D-lyxo-phytosphingosine 2, jaspine B (pachastrissamine) 6 and
Fig. 1 Diastereoisomers of C18 phytosphingosine 1–4.
Recent studies on the marine sponge Pachastrissa sp.
by Higa and co-workers7 led to the isolation of a cyclic
anhydrophytosphingosine, which they named pachastrissamine
6. Shortly after, in an independent study, Debitus and co-workers
Department of Chemistry, Chemistry Research Laboratory, University of
Oxford, Mansfield Road, Oxford, UK OX1 3TA. E-mail: steve.davies@
chem.ox.ac.uk
† Electronic supplementary information (ESI) available: Full experimental
details. See DOI: 10.1039/b801671b
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2-epi-jaspine B 7, as well as its extension to the asymmetric
synthesis of the Prosopis alkaloid deoxoprosophylline. Part of this
work has been communicated previously.16
Results and discussion
Retrosynthetic analysis of jaspine B 6 and 2-epi-jaspine B 7
proceeded via initial disconnection of either endocyclic O–C bond
of the THF skeleton to give a protected phytosphingosine 8 (with
either the D-lyxo- or D-ribo-configuration). It was anticipated that
phytosphingosine derivative 8 could result from diastereoselective
addition of an organometallic reagent to aldehyde 9. In turn,
aldehyde 9 could be derived from anti-a-hydroxy-b-amino ester
10 (Fig. 3).
Scheme
1
Reagents and conditions: (i) lithium (S)-N-benzyl-N-(a-
methylbenzyl)amide, THF, −78 ◦C, 2 h, then (+)-CSO, −78 ◦C to
rt, 12 h; (ii) H2 (5 atm), Pd(OH)2/C, Boc2O, EtOAc, rt, 12 h; (iii)
2,2-dimethoxypropane, BF3·Et2O, acetone, reflux, 12 h; (iv) DIBAL-H,
DCM, 0 ◦C, 6 h; (v) IBX, DMSO, rt, 12 h.
upon treatment with HCl in MeOH–H2O, with subsequent
acetylation giving N,O,O,O-tetra-acetyl D-lyxo-phytosphingosine
19 with spectroscopic properties in excellent agreement with
those previously reported {[a]2D1 −3.1 (c 0.7 in CHCl3); lit.25
[a]2D2 −3.1 (c 1.1 in CHCl3)}. Analogous treatment of the minor
diastereoisomeric alcohol (4S,5S,1ꢀR)-18 gave N,O,O,O-tetra-
acetyl D-ribo-phytosphingosine 20 {[a]2D2 +18.2 (c 1.0 in CHCl3);
lit.25 [a]2D2 +21.9 (c 1.1 in CHCl3)}. The preferential addition of
tetradecylmagnesium bromide to the Si face of aldehyde 16, giving
alcohol (4S,5S,1ꢀS)-17 as the major diastereoisomeric product, is
therefore consistent with the 1,2-addition reaction proceeding via
a chelated Cram model26 (Scheme 2).
Fig. 3 Retrosynthetic analysis of jaspine B 6 and 2-epi-jaspine B 7.
It was therefore envisaged that the development of an efficient
asymmetric route to either D-lyxo- or D-ribo-phytosphingosine 1
or 2, coupled with subsequent ring closure, would facilitate an
entry to jaspine B 6 and 2-epi-jaspine B 7.
Asymmetric synthesis of N,O,O,O-tetra-acetyl
D-lyxo-phytosphingosine
Aldehyde 16 was reported by us in the preceding manuscript as an
intermediate in the synthesis of sphinganine and sphingosine,23
and therefore its utility in the proposed synthesis of D-lyxo-
or D-ribo-phytosphingosine was examined. Conjugate addition
of lithium (S)-N-benzyl-N-(a-methylbenzyl)amide to c-tri-iso-
propylsilyloxy-a,b-unsaturated ester 11 and enolate oxidation with
(+)-CSO21 gave a-hydroxy-b-amino ester 12 which, after protecting
group manipulation, furnished oxazolidine ester 14. Reduction
of 14 with DIBAL-H, followed by re-oxidation with IBX, gave
aldehyde 16 which was used immediately (Scheme 1).16,23
Aldehyde 16 was treated with a solution of tetradecylmagne-
sium bromide in THF (prepared from 1-bromotetradecane and
magnesium turnings in the presence of iodine). It was found that
an excess of Grignard reagent (5 eq, based on 1-bromotetradecane)
was required to drive the addition reaction to completion, giving
a chromatographically separable 90 : 1024 mixture of alcohols
(4S,5S,1ꢀS)-17 and (4S,5S,1ꢀR)-18, isolated in 51 and 4% yield
respectively, and in >98% de in both cases. The configurations
of the newly formed C(1ꢀ)-stereocentres within alcohols 17 and 18
could not be assigned a priori; they were established via conversion
to the corresponding N,O,O,O-tetra-acetyl phytosphingosines
19 and 20. Global hydrolysis of the protecting groups within
the major diastereoisomeric alcohol (4S,5S,1ꢀS)-17 was achieved
Scheme 2 Reagents and conditions: (i) C14H29MgBr, THF, 0 ◦C to rt, 6 h;
(ii) HCl (3 M, aq), MeOH, 50 ◦C, 3 h, then Ac2O, DMAP, pyridine, rt,
12 h.
Asymmetric synthesis of jaspine B and 2-epi-jaspine B
With samples of epimeric alcohols 17 and 18 in hand their
conversion to jaspine B 6 and 2-epi-jaspine B 7 was investigated.
It was anticipated that activation of the C(1ꢀ)-hydroxyl within the
major diastereoisomeric alcohol (4S,5S,1ꢀS)-17 as a leaving group,
followed by sequential desilylation and SN2-type ring closure
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would give the tetrahydrofuran skeleton. Subsequent deprotection
would then furnish 7.27 Thus, mesylation of alcohol (4S,5S,1ꢀS)-
17 gave mesylate 21 in 75% yield. Subsequent desilylation of 21
with TBAF was followed by in situ cyclisation of the resultant
primary oxyanion species 22, giving tetrahydrofuran 23. Tetrahy-
drofuran 23 proved inseparable by chromatography from the
silicon-containing by-products formed in the desilylation reaction
and therefore acidic hydrolysis was undertaken, giving 24 in
quantitative yield and >98% de from 21. Subsequent basification
and recrystallisation gave 7 in 70% yield (14% overall yield in 10
steps from c-tri-iso-propylsilyloxy-a,b-unsaturated ester 11) and
>98% de, with spectroscopic data in excellent agreement with that
of the literature {[a]D24 +16.4 (c 0.85 in MeOH); lit.12a [a]2D2 +15.0 (c
1.0 in MeOH)} (Scheme 3).
Scheme 4 Reagents and conditions: (i) MsCl, DMAP, pyridine, 0 ◦C to
rt, 12 h; (ii) TBAF, THF, rt, 30 min; (iii) HCl (3 M, aq), MeOH, 50 ◦C,
3 h; (iv) KOH (2 M, aq), then recrystallisation.
desilylation of (4S,5S,1ꢀS)-17 with TBAF gave diol 29 in 95%
isolated yield. Attempted selective mesylation of the primary
hydroxyl group of diol 29 under a variety of conditions was
unsuccessful due to competing mesylation of the secondary
hydroxyl group, forming a mixture of mono- and dimesylated
species. Competitive mesylation of the secondary hydroxyl group
could not be prevented even at −78 ◦C and employing a
sub-stoichiometric amount of mesyl chloride (0.5 eq). It was
therefore proposed that treatment of diol 29 with a more bulky
activating agent would increase the selectivity for activation of the
primary over the secondary hydroxyl. Unfortunately, treatment of
diol 29 with triphenylphosphine and N-iodosuccinimide gave a
complex mixture of products, whilst attempted tosylation at room
temperature returned only starting material, even after extended
reaction times (5 days) and in the presence of a stoichiometric
amount of DMAP. At reflux in pyridine, however, a mixture
of tetrahydrofurans 27 and 23, resulting from tosylation of the
primary and secondary hydroxyl groups, respectively, and in situ
cyclisation, was observed. The effect of reaction temperature
on the formation of these two diastereoisomers was therefore
investigated, and revealed that no tosylated or cyclised products
appeared until above 60 ◦C; however, at this temperature both
27 and 23 were observed. Optimum conditions for the selective
formation of tetrahydrofuran 27 from diol 29 were heating at
80 ◦C with 3 equivalents of tosyl chloride and catalytic DMAP for
8 hours, which gave quantitative conversion to an 82 : 18 mixture
of 27 : 23, with subsequent chromatographic separation giving 27
in 52% yield and >98% de, and 23 in 15% yield and >98% de.
Subsequent global deprotection of 27 and recrystallisation gave
jaspine B 6 in an improved 10% overall yield in 9 steps from c-tri-
iso-propylsilyloxy-a,b-unsaturated ester 11 (Scheme 5).
Scheme 3 Reagents and conditions: (i) MsCl, DMAP, Et3N, DCM, 0 ◦C,
3 h; (ii) TBAF, THF, rt, 30 min; (iii) HCl (3 M, aq), MeOH, 50 ◦C, 3 h;
(iv) KOH (2 M, aq), then recrystallisation.
Following the successful synthesis of 7 from the major
diastereoisomeric alcohol (4S,5S,1ꢀS)-17 resulting from addition
of tetradecylmagnesium bromide to aldehyde 16, it was pre-
dicted that a similar sequence of reactions applied to the minor
diastereoisomeric alcohol (4S,5S,1ꢀR)-18 would give jaspine B 6.
In accordance with this hypothesis, mesylation of (4S,5S,1ꢀR)-18
gave mesylate 25, with subsequent desilylation upon treatment
with TBAF accompanied by cyclisation to 27. Hydrolysis of 27,
basification and recrystallisation gave jaspine B 6 as a white solid,
in 58% overall yield from alcohol 18 (Scheme 4).
The overall yield of jaspine B 6 from c-tri-iso-propylsilyloxy-a,b-
unsaturated ester 11, however, was unacceptably low (1.1%) due
to the use of alcohol (4S,5S,1ꢀR)-18 (the minor diastereoisomer
resulting from Grignard addition to aldehyde 16, isolated yield
4%) in the synthesis. An alternative approach to the natural
product from the major diastereoisomeric alcohol (4S,5S,1ꢀS)-
17 was therefore envisaged. It was proposed that desilylation
of (4S,5S,1ꢀS)-17 would give the corresponding diol 29, which
could be selectively activated at the primary hydroxyl group,
with subsequent ring closure giving tetrahydrofuran 27. Thus,
The samples of jaspine B 6 prepared independently from
both alcohols (4S,5S,1ꢀS)-17 and (4S,5S,1ꢀR)-18 (Scheme 4 and
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Fig. 4 Selected 1H NMR NOE enhancements for N,O-diacetyl jaspine B
30.
Scheme 5 Reagents and conditions: (i) TBAF, THF, rt, 30 min; (ii) TsCl,
DMAP, pyridine, reflux, 8 h; (iii) HCl (3M, aq), MeOH, 50 ◦C, 3 h, then
KOH (2M, aq), then recrystallisation.
Scheme 5) were identical by 1H NMR and displayed physical and
spectroscopic properties in excellent agreement with those origi-
nally reported for the natural product by Higa et al. {[a]2D3 +17.5 (c
0.3 in EtOH); lit.7 [a]D25 +18.0 (c 0.1 in EtOH)}. In order to further
confirm the relative stereochemistry of our samples of jaspine B 6
and 2-epi-jaspine B 7, both were derivatised to the corresponding
N,O-diacetates 30 and 31 upon treatment with Ac2O and DMAP
in pyridine (Scheme 6). The spectroscopic properties of 30 and
31 were in excellent agreement with those of the literature {30
[a]2D3 −26.4 (c 0.5 in CHCl3); lit.12a [a]2D5 −22.6 (c 1.0 in CHCl3); 31
[a]2D1 −14.6 (c 0.5 in CHCl3); lit.12a [a]2D2 −15.4 (c 1.0 in CHCl3)}.
Fig. 5 Selected 1H NMR NOE enhancements for N,O-diacetyl-2-
epi-jaspine B 31.
of absolute configuration of a material known to be homochiral,29
and allowed the reported absolute (2S,3S,4S)-configuration of the
natural product (originally determined by Higa et al.7 using the
Mosher method)30 to be confirmed unambiguously.
Asymmetric synthesis of deoxoprosophylline
In order to further demonstrate the versatility of this lithium amide
methodology for the synthesis of natural products containing an
amino diol motif, application to the synthesis of the Prosopis
alkaloid deoxoprosophylline 32 was examined. The Prosopis alka-
loids, isolated from Prosopis africana Taub.,31 possess a polar head
group and a hydrophobic tail and are therefore often considered
as cyclic analogues of the sphingoid bases.32 These polysubstituted
piperidine alkaloids33 exhibit a range of useful pharmacological
properties, such as anesthetic, analgesic and antibiotic activity.34
There has thus been considerable synthetic interest in this sub-
group of piperidine alkaloids and several syntheses producing
the natural products in both racemic and homochiral forms have
appeared in the literature.35,36
Retrosynthetic analysis of deoxoprosophylline 32 revealed that
disconnection of the N(1)–C(6) bond gave ketone 33. Functional
group manipulation and further disconnection across the double
bond of 34 gave aldehyde 9, an intermediate in the retrosynthesis
of jaspine B 6 (vide supra, Fig. 3). In the forward direction,
it was anticipated that hydrogenation of the alkene within 34
and hydrogenolysis of the N-benzyl-N-a-methylbenzyl protecting
groups could be achieved in one pot to liberate the corresponding
primary amine, which was expected to undergo spontaneous
cyclisation to the corresponding imine,37 with subsequent in situ
imine reduction giving deoxoprosophylline 32 (Fig. 6).
Scheme 6 Reagents and conditions: (i) Ac2O, DMAP, pyridine, rt, 12 h.
1H NMR NOE analyses conducted on these samples were in
accordance with the original data reported by Higa7 and Debitus.8
For N,O-diacetyl jaspine B 30, a series of enhancements between
C(2)H, C(3)H, C(4)H, and C(5)HA, suggested that they all occupy
the same face of the tetrahydrofuran ring (Fig. 4) whilst in N,O-
diacetyl-2-epi-jaspine B 31 a series of strong enhancements
between C(3)H, C(4)H and C(1ꢀ)H2 suggest that these protons
occupy the same face of the tetrahydrofuran core. Other NOE en-
hancements to C(5)H2 served to confirm this assignment (Fig. 5).
Subsequent recrystallisation of N,O-diacetyl jaspine B 30 from
CHCl3–heptane gave colourless prisms which proved suitable for
single crystal X-ray structural analysis.28 This unambiguously
confirmed the all cis relationship of the substituents around
the ring. An extended data collection using Cu-Ka radiation
allowed determination of a Flack parameter29 for the structure
of −0.04(15), which satisfies the criterion for a reliable assignment
The synthesis of deoxoprosophylline 32 therefore began with N-
benzyl-N-a-methylbenzyl protected a-hydroxy-b-amino ester 36,23
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employing acetic acid as co-solvent, complete conversion to
a single diastereoisomer of piperidine 43 was observed, with
subsequent desilylation and recrystallisation furnishing deoxo-
prosophylline 32 in >98% de and 26% overall yield in 7 steps from
35, with spectroscopic properties in excellent agreement with those
of the literature {[a]D22 +13.5 (c 0.3 in CHCl3); lit. for enantiomer35a
[a]D −14.0 (c 0.2 in CHCl3); lit.35k [a]D20 +13.0 (c 0.2 in CHCl3)}
(Scheme 8).
Fig. 6 Retrosynthetic analysis of deoxoprosophylline 32.
prepared via the conjugate addition of lithium (S)-N-benzyl-N-
(a-methylbenzyl)amide to c-tri-iso-propylsilyloxy-a,b-unsaturated
ester 35 and in situ enolate oxidation with (+)-CSO.21 Attempted
protection of the hydroxyl group within 36 with either TBDMSCl
or TIPSCl was unsuccessful and returned starting material in
both cases. O-Benzyl protection was therefore investigated, and
benzylation of 36 was achieved upon treatment with NaH,
15-crown-5 and BnBr, giving 37 in 83% yield and >98% de.
Subsequent reduction of 37 with DIBAL-H gave alcohol 38 in 83%
yield and >98% de, with re-oxidation with IBX giving aldehyde
39 in quantitative yield and >98% de.38 Wadsworth–Emmons
olefination of aldehyde 39 was effected utilizing the lithium anion
Scheme 8 Reagents and conditions: (i) Pd/C, H2 (5 atm), EtOAc, 24 h; (ii)
Pd/C, H2 (5 atm), EtOAc–AcOH (1 : 1), 48 h; (iii) TBAF, THF, rt, 12 h.
Conclusion
of dimethyl 2-oxotetradecylphosphonate 40, giving (E)-41 (J4,5
16.2 Hz) as a single diastereoisomer, isolated in 61% yield and
=
In conclusion, the highly diastereoselective anti-amino-
hydroxylation of readily available a,b-unsaturated esters, via con-
jugate addition of lithium (S)-N-benzyl-N-(a-methylbenzyl)amide
and in situ enolate oxidation with (+)-CSO, has been used as
the key step for asymmetric synthesis of N,O,O,O-tetra-acetyl
D-lyxo-phytosphingosine, the anhydrophytosphingosine jaspine B
(pachastrissamine) and 2-epi-jaspine B, and the Prosopis alkaloid
deoxoprosophylline. This synthetic strategy should be widely
applicable to the generation of homologues of these natural
product families with different side chain lengths and substituents.
>98% de after chromatography (Scheme 7).
Experimental
General experimental
All reactions involving organometallic or other moisture-sensitive
reagents were carried out under a nitrogen or argon atmosphere
using standard vacuum line techniques and glassware that was
flame dried and cooled under nitrogen before use. Solvents were
dried according to the procedure outlined by Grubbs and co-
R
workers.39 Water was purified by an Elixꢀ UV-10 system. All other
solvents were used as supplied (analytical or HPLC grade) without
prior purification. Organic layers were dried over MgSO4. Thin
layer chromatography was performed on aluminium plates coated
with 60 F254 silica. Plates were visualised using UV light (254 nm),
iodine, 1% aq KMnO4, or 10% ethanolic phosphomolybdic acid.
Flash column chromatography was performed on Kieselgel 60
silica.
Melting points were recorded on a Gallenkamp Hot Stage
apparatus and are uncorrected. Optical rotations were recorded
on a Perkin-Elmer 241 polarimeter with a water-jacketed 10 cm
cell. Specific rotations are reported in 10−1 deg cm2 g−1 and
concentrations in g 100 mL−1. IR spectra were recorded on Bruker
Tensor 27 FT-IR spectrometer as either a thin film on NaCl plates
Scheme 7 Reagents and conditions: (i) lithium (S)-N-benzyl-N-(a-methyl-
benzyl)amide, THF, −78 ◦C, 2 h, then (+)-CSO, −78 ◦C to rt, 12 h;
(ii) NaH, THF, 0 ◦C to rt, 1 h, then 15-crown-5, BnBr, 12 h, rt; (iii)
DIBAL-H, DCM, 0 ◦C, 18 h; (iv) IBX, DMSO, rt, 18 h; (v) BuLi,
(MeO)2P(O)CH2COC12H25 40, THF, −78 ◦C, 30 min, then 39, THF,
−78 ◦C to rt, 12.5 h.
With 41 in hand, tandem hydrogenation and hydrogenolysis,
and concomitant cyclisation, was next probed. Treatment of 41
with Pd/C under 5 atmospheres pressure of hydrogen for 24 h
gave incomplete debenzylation, although returned 42 as a single
diastereoisomer in quantitative yield. Over 48 h, however, and
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(film) or a KBr disc (KBr), as stated. Selected characteristic peaks
are reported in cm−1. NMR spectra were recorded on Bruker
Avance spectrometers in the deuterated solvent stated. Spectra
were recorded at rt unless otherwise stated. The field was locked
by external referencing to the relevant deuteron resonance. Low-
resolution mass spectra were recorded on either a VG MassLab
20–250 or a Micromass Platform 1 spectrometer. The ion [M +
59]+ refers to [M + MeCN + NH4]+. Accurate mass measurements
were run on either a Bruker Micro TOF internally calibrated
with polyalanine, or a Micromass GCT instrument fitted with
a Scientific Glass Instruments BPX5 column (15 m × 0.25 mm)
using amyl acetate as a lock mass.
H2O (10 mL). The aqueous layer was separated and extracted with
Et2O (10 mL). The combined organic layers were washed sequen-
tially with sat aq CuSO4 (10 mL), H2O (10 mL) and brine (10 mL),
then dried and concentrated in vacuo to give 20 as gum (45 mg,
80%, >98% de); [a]D22 +18.2 (c 1.0 in CHCl3); {lit.25 [a]2D2 +21.9 (c 1.1
=
=
in CHCl3)}; mmax (KBr) 2915 (C–H), 1734 (C O), 1683 (C O); dH
(400 MHz, CDCl3) 0.88 (3H, t J 7.0, C(18)H3), 1.24–1.31 (24H, m,
C(6)–C(17)H2), 1.60–1.67 (2H, m, C(5)H2), 2.03 (3H, s, COMe),
2.05 (6H, s, 2 × COMe), 2.08 (3H, s, COMe), 4.00 (1H, dd J 11.6,
2.9, C(1)HA), 4.29 (1H, dd J 11.6, 4.7, C(1)HB), 4.44–4.50 (1H,
m, C(2)H), 4.93 (1H, dt J 9.7, 3.1, C(4)H), 5.1 (1H, dd J 8.3,
3.1, C(3)H), 6.01 (1H, br d J 9.4, NH); dC (100 MHz, CDCl3)
14.1 (C(18)), 20.8 (COMe), 20.9 (COMe), 21.0 (COMe), 22.7
(C(17)), 23.3 (COMe), 25.5, 28.1, 29.3, 29.4, 29.5, 29.6, 29.6, 29.6,
29.7, 29.8, 29.9, 31.9 (C(5)–C(16)), 47.6 (C(2)), 62.8 (C(1)), 71.9
(C(3)), 73.0 (C(4)), 169.7 (COMe), 170.1 (COMe), 170.8 (COMe),
171.2 (COMe); m/z (ESI+) 508 ([M + Na]+, 100%), 486 (25);
(2S,3S,4S)-1,3,4-Triacetoxy-2-acetamido-octadecane [N,O,O,O-
tetra-acetyl D-lyxo-phytosphingosine] 19
HRMS (ESI+) C26H48NO7 ([M + H]+) requires 486.3431; found
+
486.3436.
(2R,3S,4S)-2-Tetradecyl-4-amino-tetrahydrofuran-3-ol
hydrochloride 24
A solution of 17 (100 mg, 0.16 mmol) in 3 M aq HCl (1 mL)
and MeOH (5 mL) was heated at 50 ◦C for 3 h. Removal of
the solvent in vacuo gave a white solid which was redissolved in
pyridine (5 mL). Ac2O (80 mg, 0.85 mmol) and DMAP (5 mg, cat.)
were added and the solution was stirred at rt for 12 h. The reaction
mixture was then diluted with Et2O (10 mL) and extracted with
H2O (10 mL). The aqueous layer was separated and extracted
with Et2O (10 mL). The combined organic layers were washed
sequentially with sat aq CuSO4 (10 mL), H2O (10 mL) and brine
(10 mL), then dried and concentrated in vacuo to give 19 as a pale
yellow oil (58 mg, 74%, >98% de); [a]2D1 −3.1 (c 0.7 in CHCl3);
{lit.25 [a]D22 −3.1 (c 1.1 in CHCl3); mmax (film) 2918 (C–H), 1736
TBAF (1 M in THF, 1.4 mL, 1.4 mmol) was added to a stirred
solution of 21 (236 mg, 0.34 mmol) in THF (10 mL) at rt and
stirring was continued for 12 h. H2O (10 mL) was then added, the
organic layer was separated and the aqueous layer was extracted
with Et2O (10 mL). The combined organic layers were washed
sequentially with H2O (20 mL) and brine (20 mL) before being
dried and concentrated in vacuo. The residue was dissolved in
MeOH (10 mL), 3 M aq HCl (1 mL) was added and the solution
was heated at 50 ◦C for 3 h. The reaction mixture was then allowed
to cool to rt and the solvents were removed in vacuo to give 24 as a
white solid (115 mg, quant, >98% de); mp 93–95 ◦C; [a]D21 +15.5 (c
0.9 in MeOH); mmax (KBr) 2917 (C–H), 3302 (O–H), 3060 (N–H);
dH (500 MHz, MeOH-d4) 0.93 (3H, t J 6.4, C(14ꢀ)H3), 1.26–1.46
(20H, m, (C(4ꢀ)H2-C(13ꢀ)H2), 1.46–1.68 (6H, m, C(1ꢀ)H2-C(3ꢀ)H2),
3.70–3.77 (3H, m, C(2)H, C(4)H, C(5)HA), 4.04–4.06 (1H, m,
C(3)H), 4.16–4.19 (1H, m, C(5)HB); dC (125 MHz, MeOH-d4)
13.1 (C(14ꢀ)), 22.7, 25.5, 29.1, 29.16, 29.17, 29.28, 29.33, 29.39,
29.42, 29.45, 31.5, 31.7, 32.7 (C(1ꢀ)–C(13ꢀ)), 52.3 (C(2)), 68.0
(C(5)), 73.0 (C(4)), 83.8 (C(3)); m/z (CI+) 300 ([M − Cl]+, 100%);
=
=
(C O), 1683 (C O); dH (500 MHz, CDCl3) 0.93 (3H, t J 6.6,
C(18)H3), 1.21–1.34 (24H, m, C(6)–C(17)H2), 1.48–1.60 (2H, m,
C(5)H2), 2.03 (3H, s, COMe), 2.12 (3H, s, COMe), 2.14 (3H, s,
COMe), 2.18 (3H, s, COMe), 4.00 (1H, dd J 11.7, 2.7, C(1)HA),
4.29 (1H, dd J 11.7, 4.2, C(1)HB), 4.57–4.61 (1H, m, C(2)H), 5.14–
5.15 (2H, m, C(3)H, C(4)H), 5.80–5.82 (1H, br d J 9.7, NH); dC
(125 MHz, CDCl3) 14.5 (C(18)), 20.8 (COMe), 20.9 (COMe), 21.3
(COMe), 22.7 (C(17)), 23.3 (COMe), 25.2, 25.9, 28.0, 29.4, 29.5,
29.6, 29.7, 30.9, 31.8, 32.4, 32.6 (C(5)–C(16)), 47.3 (C(2)), 63.1
(C(1)), 71.7 (C(3)), 73.0 (C(4)), 169.8 (COMe), 170.4 (COMe),
170.8 (COMe), 171.2 (COMe); m/z (ESI+) 508 ([M + Na]+, 100%),
486 (40); HRMS (ESI+) C26H48NO7+ ([M + H]+) requires 486.3431;
found 486.3439.
HRMS (CI+) C18H38NO2 ([M − Cl]+) requires 300.2903; found
+
300.2902.
(2S,3S,4R)-1,3,4-Triacetoxy-2-acetamido-octadecane [N,O,O,O-
tetra-acetyl D-ribo-phytosphingosine] 20
(2R,3S,4S)-2-Tetradecyl-4-amino-tetrahydrofuran-3-ol 7
A solution of 18 (77 mg, 0.12 mmol) in 3 M aq HCl (1 mL)
and MeOH (5 mL) was heated at 50 ◦C for 3 h. Removal of
the solvent in vacuo gave a white solid which was redissolved in
pyridine (5 mL). Ac2O (80 mg, 0.85 mmol) and DMAP (5 mg, cat.)
were added and the solution was stirred at rt for 12 h. The reaction
mixture was then diluted with Et2O (10 mL) and extracted with
2 M aq KOH (5 mL) and DCM (5 mL) were added to 24 (31 mg,
0.09 mmol) and the mixture was stirred for 1 min. The organic layer
was separated and the aqueous layer was extracted with DCM (3 ×
5 mL). The combined organic extracts were dried and concentrated
in vacuo. Recrystallisation of the residue from CHCl3–heptane
(1 : 1) gave 7 as a white solid (20 mg, 70%, >98% de); mp
1670 | Org. Biomol. Chem., 2008, 6, 1665–1673
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◦
([M + H]+, 100%); HRMS (ESI+) C18H38NO2+ ([M + H]+) requires
300.2897; found 300.2900.
106–108 C (CHCl3–heptane); [a]2D4 +16.4 (c 0.85 in MeOH);
{lit.12a [a]2D2 +15.0 (c 1.0 in MeOH)}; mmax 2918 (C–H); dH
(400 MHz, CDCl3) 0.88 (3H, t J 6.7, C(14ꢀ)H3), 1.26–1.35 (24H, m,
C(2ꢀ)–C(13ꢀ)H2), 1.37–1.49 (1H, m, C(1ꢀ)HA), 1.50–1.64 (1H, m,
C(1ꢀ)HB), 2.08 (1H, br s, OH), 3.37–3.47 (1H, m, C(5)HA), 3.46–
3.49 (1H, m, C(4)H), 3.60–3.64 (2H, m, C(2)H, C(3)H), 4.11–4.15
(1H, m, C(5)HB); dC (100 MHz, CDCl3) 14.1 (C(14ꢀ)), 22.7, 25.9,
29.4, 29.6, 29.61, 29.67, 31.9, 33.8 (C(1ꢀ)–C(13ꢀ)), 52.6 (C(4)), 73.2
(C(5)), 74.8 (C(2)), 85.3 (C(3)); m/z (ESI+) 300 ([M + H]+, 100%);
(2S,3S,4S)-2-Tetradecyl-3-acetoxy-4-acetamido-tetrahydrofuran
[N,O-diacetyl-jaspine B] 30
HRMS (ESI+) C18H38NO2 ([M + H]+) requires 300.2903; found
+
Ac2O (1 mL) and DMAP (2 mg) were added sequentially to a
stirred solution of 6 (67 mg, 0.22 mmol) in pyridine (5 mL) at rt.
After 12 h the reaction mixture was quenched with H2O (2 mL).
The reaction mixture was then diluted with H2O (10 mL) and
extracted with Et2O (3 × 10 mL). The combined organic extracts
were washed sequentially with sat aq CuSO4 solution (2 × 20 mL),
H2O (20 mL) and brine (20 mL), then dried and concentrated in
vacuo to ◦give 30 as a white solid (80 mg, 95%, >98% de); mp
100–102 C (Et2O–heptane); [a]2D3 −26.4 (c 0.5 in CHCl3); {lit.12a
[a]2D5 −22.6 (c 1.0 in CHCl3)}; mmax (KBr) 3295 (N–H), 2921 (C–
300.2902.
(2S,3S,4S)-2-Tetradecyl-4-amino-tetrahydrofuran-3-ol
hydrochloride 28
TBAF (1 M in THF, 1.9 mL, 1.9 mmol) was added to a stirred
solution of 25 (325 mg, 0.47 mmol) in THF (10 mL) at rt and
stirring was continued for 12 h. H2O (10 mL) was then added, the
organic layer was separated and the aqueous layer was extracted
with Et2O (10 mL). The combined organic layers were washed
sequentially with H2O (20 mL) and brine (20 mL) before being
dried and concentrated in vacuo. The residue was dissolved in
MeOH (10 mL), 3 M aq HCl (1 mL) was added and the solution
was heated at 50 ◦C for 3 h. The reaction mixture was then allowed
to cool to rt and the solvents were removed in vacuo to give 28 as
=
=
H), 1733 (C O), 1653 (C O); dH (400 MHz, CDCl3) 0.88 (3H, t,
J 6.0, C(14ꢀ)H3), 1.20–1.32 (24H, m, C(2ꢀ)–C(13ꢀ)H2), 1.35–1.57
(2H, m, C(1ꢀ)H2), 2.00 (3H, s, COMe), 2.19 (3H, s, COMe), 3.60
(1H, t, J 8.1, C(5)HA), 3.91 (1H, ddd, J 7.6, 5.2, 3.6, C(2)H), 4.10
(1H, t, J 8.1, C(5)HB), 4.82 (1H, ddd, J 13.2, 7.6, 5.6, C(4)H),
5.38 (1H, dd, J 5.6, 3.6, C(3)H), 5.60 (1H, br d, J 7.9, NH); dC
(100 MHz, CDCl3) 14.1 (C(14ꢀ)), 20.8 (COMe), 22.7 (C(13ꢀ)), 23.2
(COMe), 26.0, 28.4, 28.5, 29.2, 29.3, 29.4, 29.5, 29.6, 29.7, 31.9
(C(1ꢀ)–C(12ꢀ)), 51.3 (C(4)), 69.8 (C(5)), 73.5 (C(3)), 81.2 (C(2)),
169.9 (COMe), 170.0 (COMe); m/z (ESI+) 442 ([M + 59]+, 100%);
◦
a white solid (157 mg, quant, >98% de); mp 148–150 C; [a]D23
HRMS (ESI+) C22H41NNaO4 ([M + Na]+) requires 406.2933;
+
+2.6 (c 0.38 in MeOH); mmax (film) 3396 (O–H), 2923 (C–H); dH
(400 MHz, MeOH-d4) 0.91 (3H, t, J 6.6, C(14ꢀ)H3), 1.20–1.60
(24H, m, C(2ꢀ)–C(13ꢀ)H2), 1.62–1.80 (2H, m, C(1ꢀ)H2), 3.73 (1H,
ddd, J 10.0, 7.6, 3.6, C(2)H), 3.83 (1H, app q, J 4.0, C(5)HA), 3.88–
3.96 (2H, m, C(4)H, C(5)HB), 4.28 (1H, dd, J 5.2, 3.6, C(2)H);
dC (100 MHz, MeOH-d4) 13.5, 22.8, 26.2, 28.7, 29.5, 29.7, 29.8,
29.9, 32.1, 53.4, 68.0, 69.9, 83.4; m/z (ESI+) 300 ([M − Cl]+,
100%).
found 406.2929.
(2R,3S,4S)-2-Tetradecyl-3-acetoxy-4-acetamido-tetrahydrofuran
31
(2S,3S,4S)-2-Tetradecyl-4-amino-tetrahydrofuran-3-ol [jaspine B
(pachastrissamine)] 6
Ac2O (1 mL) and DMAP (5 mg) were added sequentially to a
stirred solution of 7 (25 mg, 0.08 mmol) in pyridine (5 mL) at rt.
After 12 h the reaction mixture was quenched with H2O (2 mL).
The reaction mixture was then diluted with H2O (10 mL) and
extracted with Et2O (3 × 10 mL). The combined organic extracts
were washed sequentially with sat aq CuSO4 solution (2 × 20 mL),
H2O (20 mL) and brine (20 mL), then dried and concentrated in
vacuo to give 31 as a white solid (23 mg, 81%, >98% de); mp
65–67 ◦C; [a]2D1 −14.6 (c 0.5 in CHCl3); {lit.12a [a]2D2 −15.4 (c 1.0 in
2 M aq KOH (5 mL) and DCM (5 mL) were added to 28 (157 mg,
0.47 mmol) and the mixture stirred for 1 min. The organic layer
was separated and the aqueous layer was extracted with DCM (3 ×
5 mL). The combined organic extracts were dried and concentrated
in vacuo. Recrystallisation of the residue from Et2O–heptane (1 :
1) gave 6 as a white solid (110 mg, 79%, >98% de); mp 90–92 ◦C
(Et2O–heptane); [a]2D3 +17.5 (c 0.3 in EtOH); {lit.7 [a]2D5 +18.0 (c 0.1
in EtOH)}; mmax (KBr) 3340 (N–H), 3074 (O–H), 2921 (C–H), 2849
(C–H); dH (400 MHz, CDCl3) 0.87 (3H, t, J 6.7, C(14ꢀ)H3), 1.18–
1.50 (24H, m, C(2ꢀ)H2-C(13ꢀ)H2), 1.55–1.70 (2H, m, C(1ꢀ)H2), 3.50
(1H, dd, J 8.4, 7.2, C(5)HA), 3.61–3.69 (1H, m, C(4)H), 3.74 (1H,
td, J 7.2, 4.0, C(2)H), 3.87 (1H, t, J 4.0, C(3)H), 3.91 (1H, t, J
7.7, C(5)HB); dC (100 MHz, CDCl3) 14.1, 22.7, 26.3, 29.3, 29.4,
29.5, 29.6, 29.7, 29.8, 31.9, 54.4, 71.8, 72.4, 83.1; m/z (ESI+) 300
=
=
CHCl3)}; mmax (KBr) 2915 (C–H), 1730 (C O), 1685 (C O); dH
(500 MHz, CDCl3) 0.93 (3H, t, J 7.1, C(14ꢀ)H3), 1.26–1.35 (24H,
m, C(2ꢀ)H2–C(13ꢀ)H2), 1.34–1.68 (2H, m, C(1ꢀ)H2), 2.06 (3H, s,
COMe), 2.18 (3H, s, COMe), 3.55–3.58 (1H, m, C(5)HA), 3.90–
3.93 (1H, m, C(2)H), 4.21–4.24 (1H, m, C(5)HB), 4.67–4.73 (1H,
m, C(4)H), 4.95–4.97 (1H, m, C(3)H), 5.69 (1H, d J 8.2, NH);
dC (125 MHz, CDCl3) 14.2 (C(14ꢀ)), 21.1 (COMe), 22.8 (C(13ꢀ)),
23.2 (COMe), 25.6, 29.4, 29.51, 29.55, 29.60, 29.65, 29.67, 29.70,
29.72, 29.80, 32.0, 33.6 (C(1ꢀ)C(12ꢀ)), 49.9 (C(4)), 69.9 (C(5)), 77.1
(C(3)), 84.2 (C(2)); m/z (ESI+) 442 ([M + 59]+, 100%); HRMS
(ESI+) C22H42NO4+ ([M + H]+) requires 384.2114; found 384.3112.
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(2R,3S,6S)-2-Hydroxymethyl-6-dodecylpiperidin-3-ol
[deoxoprosophylline] 32
9 N. Sudhakar, A. Ravi Kumar, A. Prabhakar, B. Jagadeesh and B.
Venkateswara Rao, Tetrahedron Lett., 2005, 46, 325; P. Bhaket, K.
Morris, C. S. Stauffer and A. Datta, Org. Lett., 2005, 7, 875; M.
Passiniemi and A. M. P. Koskinen, Tetrahedron Lett., 2008, 49, 980.
10 Y. Du, J. Liu and R. J. Linhardt, J. Org. Chem., 2006, 71, 1251; J. Liu,
Y. Du, X. Dong, S. Meng, J. Xiao and L. Cheng, Carbohydr. Res., 2006,
341, 2653.
11 C. Ribes, E. Falomir, M. Carda and J. A. Marco, Tetrahedron, 2006,
62, 5421.
12 (a) R. J. B. H. N. van den Berg, T. J. Boltje, C. P. Verhagen, R. E. J. N.
Litjens, G. A. van der Marel and H. S. Overkleeft, J. Org. Chem., 2006,
71, 836; (b) T. Lee, S. Lee, Y. S. Kwak, D. Kim and S. Kim, Org. Lett.,
2007, 9, 429.
13 C. V. Ramana, A. G. Giri, S. B. Suryawanshi and R. G. Gonnade,
Tetrahedron Lett., 2007, 48, 265.
14 L. V. R. Reddy, P. V. Reddy and A. K. Shaw, Tetrahedron: Asymmetry,
2007, 18, 542.
15 K. R. Prasad and A. Chandrakumar, J. Org. Chem., 2007, 72, 6312.
16 E. Abraham, J. I. Candela-Lena, S. G. Davies, M. Georgiou, R. L.
Nicholson, P. M. Roberts, A. J. Russell, E. M. Sa´nchez-Ferna´ndez,
A. D. Smith and J. E. Thomson, Tetrahedron: Asymmetry, 2007, 18,
2510.
17 T. Yakura, S. Sato and Y. Yoshimoto, Chem. Pharm. Bull., 2007, 55,
1284; K. Venkatesan and K. V. Srinivasan, Tetrahedron: Asymmetry,
2008, 19, 209.
18 S. Chandrasekhar, B. Tiwari and S. J. Prakash, ARKIVOC, 2006, 155.
19 Y. Ge´nisson, L. Lamande´, Y. Salma, N. Andrieu-Abadie, C. Andre´ and
M. Baltas, Tetrahedron: Asymmetry, 2007, 18, 857.
20 For a review see: S. G. Davies, A. D. Smith and P. D. Price, Tetrahedron:
Asymmetry, 2005, 16, 2833.
TBAF (1 M in THF, 0.16 mL, 0.16 mmol) was added to a stirred
solution of 43 (50 mg, 0.11 mmol) in THF (5 mL) at rt and the
resultant solution was stirred for 12 h. The mixture was then
diluted with Et2O (10 mL) and H2O (10 mL). The organic layer
was separated and the aqueous layer was extracted with Et2O (3 ×
10 mL). The combined organic extracts were successively washed
with H2O (10 mL) and brine (10 mL) before being dried and
concentrated in vacuo. Recrystallization from acetone gave 32 as
◦
a white solid (25 mg, 76%, >98% de); mp 84–85 C; {lit.35a mp
90–91 ◦C; lit.35k mp 83 ◦C}; [a]D22 +13.5 (c 0.3 in CHCl3); {lit.35a for
enantiomer [a]D −14.0 (c 0.2 in CHCl3); lit.35k [a]D20 −13.0 (c 0.2
in CHCl3)}; mmax (KBr) 3267 (O–H); dH (400 MHz, CDCl3) 0.89
(3H, t, J 6.9, C(12ꢀ)H3), 1.20–1.32 (24H, m, C(1ꢀ)H2–C(11ꢀ)H2,
C(4)HA, C(5)HA), 1.66–1.79 (1H, m, C(5)HB), 1.96–2.2 (1H, m,
C(4)HB), 2.40–2.70 (2H, m, C(2)H, C(6)H), 3.39–3.53 (1H, ddd, J
10.9, 9.1, 4.7, C(3)H), 3.71 (1H, dd, J 10.8, 5.2, C(2)CHAHBOH),
3.85 (1H, dd, J 10.8, 4.8, C(2)CHAHBOH); dC (100 MHz, CDCl3)
14.1, 22.6, 26.2, 29.3, 29.6, 29.8, 31.2, 31.9, 34.0, 36.6, 55.9, 63.2,
65.0, 70.1.
21 M. E. Bunnage, A. N. Chernega, S. G. Davies and C. J. Goodwin,
J. Chem. Soc., Perkin Trans. 1, 1994, 2373.
22 M. E. Bunnage, S. G. Davies and C. J. Goodwin, Synlett, 1993, 731;
M. E. Bunnage, S. G. Davies and C. J. Goodwin, J. Chem. Soc., Perkin
Trans. 1, 1993, 1375; M. E. Bunnage, A. J. Burke, S. G. Davies and
C. J. Goodwin, Tetrahedron:Asymmetry, 1994, 5, 203; M. E. Bunnage,
S. G. Davies and C. J. Goodwin, J. Chem. Soc., Perkin Trans. 1, 1994,
2385; M. E. Bunnage, A. J. Burke, S. G. Davies and C. J. Goodwin,
Tetrahedron: Asymmetry, 1995, 6, 165; A. J. Burke, S. G. Davies and
C. J. R. Hedgecock, Synlett, 1996, 621; M. E. Bunnage, A. J. Burke,
S. G. Davies, N. L. Millican, R. L. Nicholson, P. M. Roberts and A. D.
Smith, Org. Biomol. Chem., 2003, 1, 3708; S. G. Davies, D. G. Hughes,
R. L. Nicholson, A. D. Smith and A. J. Wright, Org. Biomol. Chem.,
2004, 2, 1549.
References
1 B. Cinque, L. Di Marzio, C. Centi, C. Di Rocco, C. Riccardi and M. G.
Cifone, Pharmacol. Res., 2003, 47, 421.
2 T. Ariga, D. W. Jarvis and R. K. Yu, J. Lipid Res., 1998, 1, 1.
3 For a review see: J. Kobayashi and M. Ishibashi, Heterocycles, 1996,
42, 943 and references contained therein.
4 A. R. Howell and A. Ndakala, Curr. Org. Chem., 2002, 6, 365.
5 S.-Y. Luo, S. R. Thopate, C.-Y. Hsu and S.-C. Hung, Tetrahedron Lett.,
2002, 43, 4889; A. J. Ndakala, M. Hashemzadeh, R. C. So and A. R.
Howell, Org. Lett., 2002, 4, 1719; S. H. Kang, Y. S. Hwang and H. S.
Lee, Bull. Korean Chem. Soc., 2002, 23, 1195; R. J. B. H. N. van den
Berg, C. G. N. Korevaar, G. A. van der Marel, H. S. Overkleeft and J. H.
van Boom, Tetrahedron Lett., 2002, 43, 8409; H. K. Lee, E.-K. Kim
and C. S. Pak, Tetrahedron Lett., 2002, 43, 9641; H.-Y. Chiu, D.-L. M.
Tzou, L. N. Patkar and C.-C. Lin, J. Org. Chem., 2003, 68, 5788; C.-C.
Lin, G.-T. Fan and J.-M. Fang, Tetrahedron Lett., 2003, 44, 5281; S.
Raghavan, A. Rajender and J. S. Yadav, Tetrahedron: Asymmetry, 2003,
14, 2093; S. Raghavan and A. Rajender, J. Org. Chem., 2003, 68, 7094;
H.-Y. Chiu, D.-L. M. Tzou, L. N. Patkar and C.-C. Lin, J. Org. Chem.,
2004, 69, 2228; X. Lu, H.-S. Byun and R. Bittman, J. Org. Chem., 2004,
69, 5433; X. Lu and R. Bittman, Tetrahedron Lett., 2005, 46, 3165; M.
Lombardo, M. G. Capdevila, F. Pasi and C. Trombini, Org. Lett., 2006,
8, 3303; H. J. Yoon, Y.-W. Kim, B. K. Lee, W. K. Lee, Y. Kim and H.-J.
Ha, Chem. Commun., 2007, 79; J. Jeon, M. Shin, J. W. Yoo, J. S. Oh,
J. G. Bae, S. H. Jung and Y. G. Kim, Tetrahedron Lett., 2007, 48, 1105;
C.-W. Chang, Y.-N. Chen, A. K. Adak, K.-H. Lin, D.-L. M. Tzou and
C.-C. Lin, Tetrahedron, 2007, 63, 4310; A. S. Kale, P. S. Sakle, V. K.
Gumaste, A. Rakeeb and A. S. Deshmukh, Synthesis, 2007, 2631.
6 R. A. Fernandes and P. Kumar, Synthesis, 2003, 129; S. V. Naidu and P.
Kumar, Tetrahedron Lett., 2003, 44, 1035; O. V. Singh, D. J. Kampf and
H. Han, Tetrahedron Lett., 2004, 45, 7239; D. Y. Jung, S. Kang, S. B.
Chang and Y. H. Kim, Synlett, 2005, 2183; D. Enders, J. Palecˇek and
C. Grondal, Chem. Commun., 2006, 655; Y. Cai, C.-C. Ling and D. R.
Bundle, Org. Biomol. Chem., 2006, 4, 1140; G. Righi, S. Ciambrone, C.
D’Achille, A. Leonelli and C. Bonini, Tetrahedron, 2006, 62, 11821; I.
Kumar and C. V. Rode, Tetrahedron: Asymmetry, 2007, 18, 1975.
7 I. Kuroda, M. Musman, I. I. Ohtani, T. Ichiba, J. Tanaka, D. Garcia-
Gravalos and T. Higa, J. Nat. Prod., 2002, 65, 1505.
23 E. Abraham, S. G. Davies, N. L. Millican, R. L. Nichol-
son, P. M. Roberts and A. D. Smith, Org. Biomol. Chem.,
DOI: 10.1039/b801357h.
24 Due to the rotameric nature of alcohols 17 and 18, and the presence
of alkyl residues resulting from excess Grignard reagent, the direct
determination of the reaction diastereoselectivity by 1H NMR spectro-
scopic analysis of the crude reaction product was not possible. However,
hydrolysis of the crude reaction mixture and subsequent peracetylation
furnished a 90 : 10 mixture of the phytosphingosines 19 and 20.
25 O. Shirota, K. Nakanishi and N. Berova, Tetrahedron, 1999, 55, 13643.
26 D. J. Cram and F. A. A. Elhafez, J. Am. Chem. Soc., 1952, 74, 5828;
D. J. Cram and K. R. Kopecky, J. Am. Chem. Soc., 1959, 81, 2748.
27 For the synthesis of 2-epi-jaspine B see: S. Y. Jo, H. C. Kim, D. J. Jeon
and H. R. Kim, Heterocycles, 2001, 55, 1127; ref. 12a and 12b within.
28 Crystallographic data (excluding structure factors) has been deposited
with the Cambridge Crystallographic Data Centre as supplementary
publication number CCDC 616170; see: E. Abraham, J. I. Candela-
Lena, S. G. Davies, M. Georgiou, R. L. Nicholson, P. M. Roberts, A. J.
Russell, E. M. Sa´nchez-Ferna´ndez, A. D. Smith and J. E. Thomson,
Tetrahedron: Asymmetry, 2007, 18, 2510.
29 H. D. Flack and G. Bernardelli, Acta Crystallogr., 1999, A55, 908.
30 J. A. Dale and H. S. Mosher, J. Am. Chem. Soc., 1973, 95, 512; G. R.
Sullivan, J. A. Dale and H. S. Mosher, J. Org. Chem., 1973, 38, 2143; I.
Ohtani, T. Kusumi, Y. Kashman and H. Kakisawa, J. Am. Chem. Soc.,
1991, 113, 4092.
31 G. Ratle, X. Monsieur, B. Das, J. Yassi, Q. Khuong-Huu and R.
Goutrarel, Bull. Soc. Chim. Belg., 1996, 2945.
32 T. Kolter and K. Sandoff, Angew. Chem., Int. Ed., 1999, 38, 1532.
33 The synthesis of piperidines has been extensively reviewed; for instance
see: P. D. Bailey, P. A. Millwood and P. D. Smith, Chem. Commun., 1998,
633; S. Laschat and T. Dickner, Synthesis, 2000, 1781; P. M. Weintraub,
8 V. Ledroit, C. Debitus, C. Lavaud and G. Massoit, Tetrahedron Lett.,
2003, 44, 225.
1672 | Org. Biomol. Chem., 2008, 6, 1665–1673
This journal is
The Royal Society of Chemistry 2008
©

View Article Online
J. S. Sabol, J. M. Kane and D. R. Borcherding, Tetrahedron, 2003, 59,
2953; M. G. P. Buffat, Tetrahedron, 2004, 60, 1701.
34 G. B. Fodor and B. Colasanti, Alkaloids: Chemical and Biological
Perspective, Wiley, New York, 1985, vol. 3, p. 1; B. D. Christie and
H. Rapoport, J. Org. Chem., 1985, 50, 1239; F. Glorius, N. Spielkamp,
S. Holle, R. Goddard and C. W. Lehmann, Angew. Chem., Int. Ed.,
2004, 43, 2850.
Chun and C. S. Pak, Tetrahedron, 2003, 59, 6445; (w) S. P. Chavan and
C. Praveen, Tetrahedron Lett., 2004, 45, 421; (x) A. Jourdant and J.
Zhu, Heterocycles, 2004, 64, 249; (y) J. Cossy, Chem. Rec., 2005, 5, 70;
(z) J. M. Andres, R. Pedrosa and A. Perez-Encabo, Eur. J. Org. Chem.,
2007, 1803.
36 For the synthesis of prosopinine and/or deoxoprosopinine see: A. B.
Holmes, J. Thompson, A. J. G. Baxter and J. Dixon, J. Chem. Soc.,
Chem. Commun., 1985, 37; M. A. Ciufolini, C. W. Hermann, K. H.
Whitmire and N. E. Byrne, J. Am. Chem. Soc., 1989, 111, 3473; G. R.
Cook, L. G. Beholz and J. R. Stille, Tetrahedron Lett., 1994, 35, 1669;
G. R. Cook, L. G. Beholz and J. R. Stille, J. Org. Chem., 1994, 59, 3575;
N. Toyooka, Y. Yoshida and T. Momose, Tetrahedron Lett., 1995, 36,
3715; Y. Yuasa, J. Ando and S. Shibuya, Tetrahedron: Asymmetry, 1995,
6, 1525; Y. Yuasa, J. Ando and S. Shibuya, J. Chem. Soc., Perkin Trans.
1, 1996, 793; Y. Hirai, J. Watanabe, T. Nozaki, H. Yokoyama and S.
Yamaguchi, J. Org. Chem., 1997, 62, 776; I. Kadota, M. Kawada, Y.
Muramatsu and Y. Yamamoto, Tetrahedron Lett., 1997, 38, 7469; C.
Agami, F. Couty and H. Mathieu, Tetrahedron Lett., 1998, 39, 3505;
C. Agami, F. Couty, H. Lam and H. Mathieu, Tetrahedron, 1998, 54,
8783; D. L. Comins, M. J. Sandelier and T. A. Grillo, J. Org. Chem.,
2001, 66, 6829; Q. Wang and N. A. Sasaki, J. Org. Chem., 2004, 69,
4767; ref. 35a, b, d, e, g, h, j and v within.
37 The diastereoselective, intramolecular reductive amination of ad-amino
ketone to form a piperidine ring has been reported extensively in the
literature; for instance see: J. A. Castillo, J. Calveras, J. Casas, M.
Mitjans, M. P. Vinardell, T. Parella, T. Inoue, G. A. Sprenger, J. Joglar
and P. Clapes, Org. Lett., 2006, 8, 6067; S. R. V. Kandula and P. Kumar,
Tetrahedron, 2006, 62, 9942; F. Calderon, E. G. Doyagueez and A.
Fernandez-Mayoralas, J. Org. Chem., 2006, 71, 6258; Y. Nakatani, J.
Oshita, K. Ishigami, H. Watanabe and T. Kitahara, Tetrahedron, 2006,
62, 160.
35 For the synthesis of prosophylline and/or deoxoprosophylline see: (a) Y.
Saitoh, Y. Moriyama, T. Takahashi and Q. Khuong-Huu, Tetrahedron
Lett., 1980, 21, 75; (b) Y. Saitoh, Y. Moriyama, H. Hirota, T. Takahashi
and Q. Khuong-Huu, Bull. Chem. Soc. Jpn., 1981, 54, 488; (c) M.
Natume and M. Ogawa, Heterocycles, 1981, 16, 973; (d) K. Tadano,
K. Takao, Y. Nigawara, E. Nishio, I. Takagi, K. Maeda and S.
Ogawa, Synlett, 1993, 565; (e) K. Takao, Y. Nigawara, E. Nishio,
I. Takagi, K. Maeda, K. Tadano and S. Ogawa, Tetrahedron, 1994,
50, 5681; (f) T. Luker, H. Hiemstra and W. N. Speckamp, J. Org.
Chem., 1997, 62, 3592; (g) I. Kadota, M. Kawada, Y. Muramatsu and
Y. Yamamoto, Tetrahedron: Asymmetry, 1997, 8, 3887; (h) I. Ojima
and E. S. Vidal, J. Org. Chem., 1998, 63, 7999; (i) C.-F. Yang, Y.-M.
Xu, L.-X. Liao and W.-S. Zhou, Tetrahedron Lett., 1998, 39, 9227;
(j) N. Toyooka, Y. Yoshida, Y. Yotsui and T. Momose, J. Org. Chem.,
1999, 64, 4914; (k) C. Herdeis and J. Telser, Eur. J. Org. Chem., 1999,
1407; (l) C. Yang, L. Liao, Y. Xu, H. Zhang, P. Xia and W. Zhou,
Tetrahedron: Asymmetry, 1999, 10, 2311; (m) S. D. Koulocheri and S. A.
Haroutounian, Tetrahedron Lett., 1999, 40, 6869; (n) S. D. Koulocheri
and S. A. Haroutounian, Synthesis, 1999, 1889; (o) A. Datta, J. S. R.
Kumar and S. Roy, Tetrahedron, 2001, 57, 1169; (p) A. Jourdant and
J. Zhu, Tetrahedron Lett., 2001, 42, 3431; (q) J. Cossy, C. Willis and
V. Bellosta, Synlett, 2001, 1578; (r) P. J. Dransfield, P. M. Gore, M.
Shipman and A. M. Z. Slawin, Chem. Commun., 2002, 150; (s) J.
Cossy, C. Willis, V. Bellosta and S. BouzBouz, J. Org. Chem., 2002,
67, 1982; (t) N. Ma and D. Ma, Tetrahedron: Asymmetry, 2003, 14,
1403; (u) P. J. Dransfield, P. M. Gore, I. Prokes, M. Shipman and
A. M. Z. Slawin, Org. Biomol. Chem., 2003, 1, 2723; (v) H. K. Lee, J. S.
38 Aldehyde 39 was partially characterised and used immediately.
39 A. B. Pangborn, M. A. Giardello, R. H. Grubbs, R. K. Rosen and F. J.
Timmers, Organometallics, 1996, 15, 1518.
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The Royal Society of Chemistry 2008
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