Jaspine B (pachastrissamine) and 2-epi-jaspine B: synthesis and structural assignment

Article abstract of DOI:10.1016/j.tetasy.2008.04.017

Jaspine B (pachastrissamine), which was isolated in 2002, is a naturally occurring anhydrophytosphingosine which displays potent biological activity, and as such has attracted much attention from synthetic chemists in recent years, with 14 syntheses reported to date. This review delineates the isolation of jaspine B, and laboratory total syntheses of jaspine B, 2-epi-jaspine B and analogues, which serves to confirm their structure and stereochemistry.

Full text of DOI:10.1016/j.tetasy.2008.04.017

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 19 (2008) 1027–1047
Tetrahedron: Asymmetry Report number 101
Jaspine B (pachastrissamine) and 2-epi-jaspine B:
synthesis and structural assignment
Elin Abraham, Stephen G. Davies,* Paul M. Roberts,
Angela J. Russell and James E. Thomson
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
Received 25 March 2008; accepted 14 April 2008
Available online 14 May 2008
Abstract—Jaspine B (pachastrissamine), which was isolated in 2002, is a naturally occurring anhydrophytosphingosine which displays
potent biological activity, and as such has attracted much attention from synthetic chemists in recent years, with 14 syntheses reported
to date. This review delineates the isolation of jaspine B, and laboratory total syntheses of jaspine B, 2-epi-jaspine B and analogues,
which serves to confirm their structure and stereochemistry.
Ó 2008 Elsevier Ltd. All rights reserved.
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1028
2. Syntheses of anhydrophytosphingosines prior to the isolation of jaspine B . . . . . . . . . . . . . . . . . . . . 1028
3. Isolation of jaspine B (pachastrissamine) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1029
3.1. Stereochemical assignment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1029
4. Syntheses of jaspine B (pachastrissamine) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1030
4.1. Synthesis of jaspine B via lithium amide conjugate addition . . . . . . . . . . . . . . . . . . . . . . . . . . 1030
4.2. Enantiospecific syntheses of jaspine B . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1032
4.2.1. Manipulation of D-ribo-phytosphingosine: stereodivergent syntheses to both jaspine B and
2-epi-jaspine B . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1032
4.2.2. Manipulation of L-serine derivatives. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1034
4.2.3. Manipulation of carbohydrate derivatives. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1035
4.2.4. Syntheses based on manipulation of other chiral pool starting materials . . . . . . . . . . . 1038
4.3. Other asymmetric syntheses of jaspine B . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1040
4.4. Synthesis with inconsistent data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1041
5. Comparison of spectroscopic data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1042
5.1. Specific rotation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1042
5.2. 1H and 13C NMR spectroscopic data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1042
6. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1046
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1046
*
Corresponding author. E-mail: steve.davies@chem.ox.ac.uk
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.04.017

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E. Abraham et al. / Tetrahedron: Asymmetry 19 (2008) 1027–1047
1. Introduction
2. Syntheses of anhydrophytosphingosines prior to the
isolation of jaspine B
Phytosphingosines 1–4 are a sub-class of the sphingoid
bases, and consist of a 1,3,4-trihydroxy-2-amino unit at
the head of a long hydrocarbon chain. By far the most
abundant phytosphingosine is D-ribo-phytosphingosine 1,
with 18 carbon atoms in the hydrocarbon chain, although
smaller amounts of other chain lengths have been detected.
Sphingolipids are essential components of eukaryotic cells1
and phytosphingolipids exhibit important physiological
properties.2,3 As a result, there has been much interest in
their synthesis, and this was the subject of a review in
2002.4 Jaspine B 5, also know as pachastrissamine, was
the first naturally occurring anhydrophytosphingosine iso-
lated,5 which also displays potent biological activity (vide
infra). Since its isolation in 2002, there has been a great
deal of interest from synthetic chemists concerning the to-
tal synthesis of jaspine B 5, its C(2)-epimer (2-epi-jaspine B
6) and their analogues (Fig. 1).
In 1959 the first report of an anhydrophytosphingosine 7
appeared, although a stereochemical assignment was not
given.6 Subsequently, its structure and relative configura-
tion were assigned by analogy with the ‘truncated’ ana-
logue 16, bearing a C12H25 side chain. In this synthesis
allylic alcohol 8, which was prepared from Grignard addi-
tion of dodecylmagnesium bromide to crotonaldehyde, was
kinetically resolved under Sharpless asymmetric epoxida-
tion conditions with (+)-diisopropyl tartrate [(+)-DIPT]
to afford an enantioenriched sample of (R)-8 in 97% ee,7
which upon O-silylation afforded (R)-9 in 41% yield over
two steps. Ozonolysis of (R)-9 followed by Horner–Wads-
worth–Emmons olefination of the resultant aldehyde 10
gave 11 in 60% overall yield over two steps. Reduction of
the ester functionality within 11 was achieved with diisobut-
ylaluminium hydride (DIBAL-H) to give allylic alcohol 12
in 90% yield, which was oxidised under Sharpless asymmet-
ric epoxidation conditions with (ꢀ)-DIPT to give epoxide
13 in 97% yield and 96% de. Treatment of 13 with benzy-
lisocyanate gave urethane 14 in 98% yield, and subsequent
base-mediated epoxide opening gave tetrahydrofuran
derivative 15 in 67% yield. The configuration of 15 was
determined by conversion to the corresponding N,O-diace-
tyl derivative 17 by sequential desilylation, debenzylation
and acetylation with Ac2O to give 17 in 75% yield over
NH2 OH
OH
NH2 OH
OH
HO
HO
C14H29
C14H29
D-ribo-phytosphingosine 1
D-lyxo-phytosphingosine 2
1
two steps; subsequent H NMR NOE studies on 17 sup-
NH2 OH
NH2 OH
ported a (2R,3S,4S)-configuration (Scheme 1).8
HO
HO
C14H29
C14H29
More recently (2001), the synthesis of an authentic sample
of 2-epi-jaspine B 6 was reported by Kim et al., starting
from D-ribo-phytosphingosine 1.9 Initial treatment of 1
with 3-nitrophthalic acid at reflux under Dean–Stark con-
ditions is reported to give tetrahydrofuran derivative 18
in 67% isolated yield, with hydrazine-mediated N-deprotec-
tion giving 6 in 62% yield. In order to produce a crystalline
derivative, tetrahydrofuran 18 was also treated with so-
dium p-tolylthiolate via nucleophilic displacement of the
aromatic nitro group to give 19,10 the structure of which
was established by X-ray crystallography. Kim et al. also
OH
OH
D-xylo-phytosphingosine 3
D-arabino-phytosphingosine 4
H2N
OH
H2N
OH
C14H29
jaspine B
C14H29
2-epi-jaspine B 6
O
O
(pachastrissamine) 5
Figure 1. Structures of the C18 phytosphingosines 1–4 and the anhydro-
phytosphingosines jaspine B 5 and 2-epi-jaspine B 6.
OH
OH
OTBDMS
OTBDMS
CHO
OTBDMS
H2N
(i), (ii)
(iii)
(iv)
(vi)
C12H25
Me
C12H25
Me
C12H25
C12H25
CO2Et
C14H29
O
7
(R)-9, 97% ee
11, 60% (2 steps)
8
10
41% (2 steps)
(v)
OR'
RHN
OTBDMS
OTBDMS
O
OTBDMS
(viii)
(vii)
OR
OH
OH
C12H25
C12H25
C12H25
C12H25
O
O
15 R = Bn, R' = TBDMS, 67%
14, 98%
13, 97%, 96% de
12, 90%
(ix)
(x)
16 R = R' = H, 78%
R = CONHBn
17 R = R' = Ac, 96%
t
Scheme 1. Reagents and conditions: (i) Ti(OiPr)4, (+)-DIPT, BuO2H, CH2Cl2, ꢀ20 °C, 15 h; (ii) TBDMSOTf, 2,6-lutidine, CH2Cl2, 0 °C, 12 h; (iii) O3,
CH2Cl2, ꢀ78 °C then Me2S, ꢀ78 °C to rt; (iv) (EtO)2P(O)CH2CO2Et, NaH, C6H6, 60 °C to rt, 15 min; (v) DIBAL-H, hexane, 0 °C to rt, 12 h; (vi)
t
Ti(OiPr)4, (ꢀ)-DIPT, BuO2H, CH2Cl2, ꢀ20 °C, 21 h; (vii) BnNCO, Et3N, CH2Cl2, rt, 12 h; (viii) NaH, THF, rt, 12 h; (ix) HF, H2O, MeCN, 70 °C, 2 h
then Pd/C, cyclohexene, HCl (1 M, aq), MeOH, reflux, 2 h; (x) Ac2O, pyridine, 70 °C, 1.5 h.

E. Abraham et al. / Tetrahedron: Asymmetry 19 (2008) 1027–1047
1029
report that treatment of N-trifluoroacetyl D-ribo-phyto-
sphingosine 20 with p-toluenesulfonyl chloride (TsCl) in
pyridine effected cyclisation to tetrahydrofuran derivative
21 in 75% yield, which upon deprotection also gave 6 in
67% yield, with identical spectroscopic data (Scheme 2).9
Debitus and co-workers reported the isolation of two
anhydrophytosphingosines from the marine sponge Jaspis
sp.,11 which they named jaspines A 22 and B 5; pachastriss-
amine and jaspine B being identical (Fig. 2). Both jaspines
A 22 and B 5 display biological activity;5 jaspine B 5 in par-
ticular being the most potent compound isolated from the
Jaspis genus to date against the A549 human lung carci-
noma cell line. At the present time 11 enantiospecific syn-
theses of jaspine B 5 have been reported, utilising D-ribo-
phytosphingosine,12 L-serine,13 D-galactose,14 D-xylose,15
D-glucose,16 (R)-glycidol17 and D-tartaric acid,18 as the
sources of chirality. Three asymmetric syntheses of jaspine
B 5 have also been disclosed: in addition to the procedure
reported by us (employing a diastereoselective lithium
amide conjugate addition),19 two other strategies have ap-
peared which both employ the Sharpless asymmetric
dihydroxylation reaction.20 Two syntheses of ‘truncated’
analogues 23 and 24 (bearing C5H11 and C8H17 side chains)
have also emerged, based upon manipulation of L-xylose21
and Sharpless asymmetric epoxidation,22 respectively. Sev-
eral syntheses of the C(2)-epimeric analogues, with C8H17,
C12H25 and C14H29 side chains, 25,22 168a,b and 6,9,12,19 are
also known (Fig. 2).
O
R
(i)
OH
N
O
C14H29
O
18 R = NO2, 67%
(iii)
19 R = S(p-MeC6H4), 75%
(ii)
NH2 OH
OH
H2N
HO
C14H29
C14H29
O
OH
1
6, 62% from 18
67% from 21
(iv)
(vi)
3.1. Stereochemical assignment
O
O
OH
In their original isolation paper, Higa et al. reported exten-
sive NMR analyses suggesting a 2-alkyl-3-hydroxy-4-ami-
no moiety. Importantly, in the key region of the H and
NH
(v)
F3C
HO
NH
OH
F3C
1
C14H29
C14H29
13C NMR spectra corresponding to the tetrahydrofuran
ring (dH 3.3–4.2 ppm and dC 51–86 ppm), the naturally
occurring sample of jaspine B 5 did not match the data
for the C(2)-epimer 6 (2-epi-jaspine B) or the C12H25
side-chain analogue 16 that had been reported previously,8a
and in fact showed marked differences. After the conver-
sion of jaspine B 5 to the corresponding N-acetyl and
N,O-diacetyl derivatives 26 and 27, Higa et al. determined
the relative configuration of jaspine B 5 by 1H NMR NOE
analysis of the N,O-diacetyl derivative 27, which indicated
the all-cis relationship of the substituents around the tetra-
hydrofuran ring. The (2S,3S,4S)-absolute configuration of
the natural product was then established using the Mosher
method, by conversion of N-acetyl jaspine B 26 to the
corresponding (R)- and (S)-2-methoxy-2-trifluoromethyl-
phenylacetyl (MTPA) derivatives.23 In their independent
O
OH
20
21, 75%
Scheme 2. Reagents and conditions: (i) 3-nitrophthalic acid, PhMe, reflux,
3 h; (ii) NH2NH2, H2O, EtOH reflux, 2 h; (iii) NaH, HS(p-MeC6H4),
DMF, 25 °C, 2 h; (iv) F3CCO2Et, EtOH, 25 °C, 16 h; (v) TsCl, pyridine,
25 °C, 16 h; (vi) K2CO3, MeOH, 25 °C, 16 h.
3. Isolation of jaspine B (pachastrissamine)
In 2002, studies on the marine sponge Pachastrissa sp. by
Higa and co-workers5 led to the isolation of an anhydro-
phytosphingosine derivative which they named pachastriss-
amine 5 (Fig. 2). Shortly after, in an independent study,
OH
H2N
OH
RHN
OR'
HN
O
C14H29
O
C14H29
O
5
R = R' = H
C14H29
jaspine A 22
O
jaspine B
(pachastrissamine) 5
26 R = Ac, R' = H
27 R = R' = Ac
H2N
OH
H2N
OH
RHN
OR'
RHN
OR'
R
R
C14H29
C12H25
O
O
O
O
6 R = R' = H
16 R = R' = H
23 R = C5H11
24 R = C8H17
R = C8H17
25
28 R = R' = Ac
17 R = R' = Ac
16 R = C12H25
6
R = C14H29
Figure 3. Structures of jaspine B 5, 2-epi-jaspine B 6, the ‘truncated’
12H25 side-chain analogue 16 and the corresponding acetate derivatives
17 and 26–28.
Figure 2. Structures of jaspines A 22 and B (pachastrissamine) 5 and other
synthetic analogues 6, 16 and 23–25.
C

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E. Abraham et al. / Tetrahedron: Asymmetry 19 (2008) 1027–1047
study, Debitus et al. also converted jaspine B 5 to the cor-
responding N-acetyl and N,O-diacetyl derivatives 26 and
of alcohols, with the major diastereoisomer (4S,5S,10S)-
36 isolated in 51% yield and >98% de.26 The preferential
addition of tetradecylmagnesium bromide to the Si face
of aldehyde 34, giving alcohol (4S,5S,10S)-36 as the major
diastereoisomeric product, is consistent with the 1,2-addi-
tion reaction proceeding via a chelated Cram model 35.28
Desilylation of 36 with tetrabutylammonium fluoride
(TBAF) gave diol 37 in 95% isolated yield. Optimum con-
ditions for the selective formation of tetrahydrofuran 38
from diol 37 were heating at 80 °C with 3 equiv of tosyl
chloride and 4-dimethylaminopyridine (DMAP) for 8 h,
which gave quantitative conversion to an 82:18 mixture
of diastereoisomeric tetrahydrofurans, with subsequent
chromatographic separation giving the major diastereoiso-
mer 38 in 52% yield and >98% de. Subsequent global
deprotection of 38 and recrystallisation gave jaspine B 5
in 79% yield (10% overall yield in nine steps from a,b-
unsaturated ester 29) (Scheme 3). Our synthetic sample of
jaspine B 5 showed good agreement with the isolation data,
although there were significant discrepancies with some
reported syntheses of jaspine B 5. To facilitate a full
comparison with all the existing literature data (including
2-epi-jaspine B 6 and the N,O-diacetyl derivatives of both
diastereoisomers 27 and 28), authentic samples of these
compounds were synthesised. 2-epi-Jaspine B 6 was synthe-
sised from intermediate alcohol 36 via initial mesylation
with methanesulfonyl chloride (MsCl) to give 39, followed
by desilylation with TBAF and in situ cyclisation of the
1
27, and compared the H and 13C NMR data with that
of the known C12H25 side-chain N,O-diacetyl derivative
17,8a,b which also indicated an all-cis relationship of the
substituents around the tetrahydrofuran ring. The absolute
configuration of the natural product was then determined,
also by the Mosher method, as (2S,3S,4S) (Fig. 3).
4. Syntheses of jaspine B (pachastrissamine)
4.1. Synthesis of jaspine B via lithium amide conjugate
addition
We have recently reported an asymmetric synthesis of
jaspine B 5, which employs the conjugate addition of a
homochiral lithium amide as the key step.19b,c,24 Thus,
a,b-unsaturated ester 29 was treated with lithium (S)-N-
benzyl-N-(a-methylbenzyl)amide, with subsequent enolate
oxidation with (+)-(camphorsulphonyl)-oxaziridine [(+)-
CSO]25 affording a-hydroxy-b-amino ester 30 in 75% yield
and >98% de. Protecting group manipulation furnished
oxazolidine ester 32 in 71% yield over two steps. Reduction
of 32 with DIBAL-H, followed by re-oxidation with 2-
iodoxybenzoic acid (IBX), gave aldehyde 34 which was
immediately treated with tetradecylmagnesium bromide.
This gave a chromatographically separable 90:10 mixture
Ph
Boc
Boc
NH
N
(i)
(ii)
(iii)
Ph
N
TIPSO
CO2Me
O
TIPSO
CO2Me
TIPSO
TIPSO
CO2Me
OH
CO2Me
OH
29
30, 75% yield
31, 94% yield
32, 75% yield
>98% de
>98% de
>98% de
(iv)
Boc
Boc
N
OTIPS
Boc
N
Mg2+
N
O
N
Boc
(vi)
(v)
O
O
O
TIPSO
TIPSO
O
TIPSO
90:10 dr
H
CHO
34, quant yield
HO
C14H29
OH
C14H29MgBr
36, 51% yield
33, 98% yield
>98% de
>98% de
>98% de
35
(vii)
Boc
N
Boc
H2N
OH
AcHN
OAc
N
O
(viii)
(ix)
(x)
O
HO
82:12 dr
C14H29
C14H29
O
O
C14H29
O
HO
C14H29
37, 95% yield
38, 52% yield
5, 79% yield
27, 95% yield
>98% de
>98% de
>98% de
>98% de
Scheme 3. 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, BF3ꢁEt2O, acetone, reflux, 12 h; (iv) DIBAL-H, CH2Cl2, 0 °C, 6 h; (v) IBX,
DMSO, rt, 12 h; (vi) C14H29MgBr, THF, 0 °C to rt, 6 h; (vii) TBAF, THF, rt, 12 h; (viii) TsCl, DMAP, pyridine, reflux, 8 h; (ix) HCl (2 M, aq), MeOH,
50 °C, 6 h, then KOH (2 M, aq); (x) Ac2O, DMAP, pyridine, rt, 12 h.

E. Abraham et al. / Tetrahedron: Asymmetry 19 (2008) 1027–1047
1031
resultant primary oxyanion species to give tetrahydrofuran
40. Tetrahydrofuran 40 proved inseparable by chromato-
graphy from the silicon-containing by-products formed in
the desilylation reaction and therefore acidic hydrolysis
was undertaken giving 2-epi-jaspine B 6, after basification
and recrystallisation, in 70% yield (14% overall yield in
10 steps from a,b-unsaturated ester 29) and >98% de
(Scheme 4). The corresponding N,O-diacetyl derivatives
of both jaspine B 5 and 2-epi-jaspine B 6 were generated
upon the treatment of the free bases with Ac2O in pyridine
to give 27 and 28 in 95% and 81% yields, respectively
(Schemes 3 and 4).
Our spectroscopic data for these compounds revealed that
there are clear differences between the 1H NMR spectra for
1
jaspine B 5 and 2-epi-jaspine B 6, and also between the H
NMR spectra for the corresponding N,O-diacetyl deriva-
tives 27 and 28. One characteristic difference between the
spectra for jaspine B 5 and 2-epi-jaspine B 6 is that the nat-
ural product 5 has a peak at 3.91 ppm for one of the C(5)
protons, whereas 2-epi-jaspine B 6 has a corresponding res-
onance at 4.11–4.15 ppm: there are no peaks in the 1H
NMR spectrum of jaspine B 5 above 4 ppm (Fig. 4). The
most striking difference between the two diastereoisomeric
N,O-diacetyl derivatives 27 and 28 concerns the peaks cor-
responding to C(3)H: for the N,O-diacetyl jaspine B 27 this
appears at 5.38 ppm, whereas for the corresponding C(2)-
epimer 28 the peak is observed at 4.95–4.97 ppm (Fig. 5).
Boc
Boc
N
N
(i)
O
O
TIPSO
TIPSO
HO
36
C14H29
MsO
C14H29
39, 75%, >98% de
(ii)
1
Within our laboratory, H NMR NOE analyses of N,O-
diacetyl derivatives 27 and 28 were supportive of the as-
signed relative configurations of the tetrahydrofuran rings.
Furthermore, single crystal X-ray analysis of 27 unambig-
uously confirmed the all-cis relationship of the substituents
around the ring,19a and determination of a Flack parame-
ter29 for the structure of ꢀ0.04(15), which satisfies the cri-
terion for a reliable assignment of absolute configuration of
a material known to be homochiral,29 confirmed the re-
ported absolute (2S,3S,4S)-configuration of the natural
product (originally determined by Higa et al.5 using the
Mosher method)23 unambiguously (Fig. 6).
RHN
OR'
Boc
N
O
(iii)
C14H29
O
C14H29
O
40
6 R = R' = H, 70%, >98% de
28 R = R' = Ac, 81%, >98% de
(iv)
Scheme 4. Reagents and conditions: (i) MsCl, Et3N, CH2Cl2, rt, 12 h; (ii)
TBAF, THF, rt, 12 h; (iii) HCl (2 M, aq), MeOH, 50 °C, 6 h, then KOH
(2 M, aq); (iv) Ac2O, DMAP, pyridine, rt, 12 h.
C(2)H, C(3)H
C(5)HA
C(5)HB
C(4)H
B
C(5)HA
C(3)H
C(2)H
C(4)H
C(5)HB
A
H2N
OH
4.1
4.0
3.9
3.8
3.7
3.6
3.5
3.4
4
3
5
2
C14H29
O
2-epi-jaspine B 6
B
A
H2N
OH
4
3
5
2
C14H29
O
jaspine B 5
ppm
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
Figure 4. 400 MHz 1H NMR spectra for (A) jaspine B 5 and (B) 2-epi-jaspine B 6 in CDCl3.

1032
E. Abraham et al. / Tetrahedron: Asymmetry 19 (2008) 1027–1047
C(5)HA
C(5)HB
C(3)H
C(2)H
C(4)H
NH
D
C
C(5)HB
C(2)H
C(5)HA
C(3)H
C(4)H
NH
AcHN
OAc
5.5
5.0
4.5
4.0
3.5
4
3
5
2
C14H29
2-epi-jaspine B 28
O
D
AcHN
OAc
4
3
5
2
C14H29
jaspine B 27
O
C
ppm
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
1
Figure 5. 400 MHz H NMR spectra for (C) N,O-diacetyl jaspine B 27 and (D) N,O-diacetyl-2-epi-jaspine B 28 in CDCl3. [1H NMR NOE studies have
determined that for N,O-diacetyl jaspine B 27 C(5)HA is anti to the N-acetylamino group and for N,O-diacetyl-2-epi-jaspine B 28 C(5)HA is syn to the N-
acetylamino group.]
although directed C–H amination has also been
employed.20a
4.2.1. Manipulation of D-ribo-phytosphingosine: stereo-
divergent syntheses to both jaspine B and 2-epi-jaspine
B. Overkleeft et al. have reported the synthesis of jaspine
B 5 and 2-epi-jaspine B 6, and their derivatisation to the
corresponding N,O-diacetyl derivatives 27 and 28, all based
Figure 6. Chem 3 D representation of the X-ray crystal structure of N,O-
upon manipulation of D-ribo-phytosphingosine 1. Thus,
diacetyl jaspine B 27 (some H atoms omitted for clarity; CCDC deposition
treatment of 1 with triflic azide (TfN3) resulted in efficient
number 616170). A crystal structure of N,O-diacetyl jaspine B 27 has also
diazotransfer to produce azide 41 in 96% yield. Subsequent
Lewis acid-promoted cyclisation upon treatment with BF3
and trimethylorthoacetate (TMOA) gave tetrahydrofuran
derivative 43 in 92% yield, presumably via oxonium ion
42. Removal of the acetate group was followed by Stau-
dinger reduction of the azide group to give jaspine B 5 in
82% yield over the two steps (Scheme 5). The synthesis of
2-epi-jaspine B 6 from 1 was achieved via initial N-Boc pro-
tection, followed by selective tosylation of the primary
C(1)-hydroxyl and concomitant cyclisation to give 45 in
76% yield over two steps, with N-Boc deprotection giving
2-epi-jaspine B 6 in 95% yield. Both jaspine B 5 and
2-epi-jaspine B 6 were converted into the corresponding
N,O-diacetyl derivatives 27 and 28 by treatment with
Ac2O and pyridine (98% yield in both cases). Full charac-
terisation data are reported for jaspine B 5, 2-epi-jaspine
B 6 and their corresponding N,O-diacetyl derivatives 27
and 28: these data are in good agreement with both the
data reported by Debitus et al.11 for 5 and 27, and the data
obtained in our laboratory (Scheme 5).12a
been reported by Ramana et al. (CCDC deposition number 617243).16
4.2. Enantiospecific syntheses of jaspine B
In addition to our synthesis, 13 independent syntheses of
jaspine B 5 have been reported. A number of enantiospec-
ific syntheses were first to appear following the isolation of
jaspine B 5, with asymmetric approaches being disclosed
later. Several different chiral pool starting materials have
been used in the enantiospecific syntheses, including
D-ribo-phytosphingosine,12 L-serine,13 D-xylose,15 D-glu-
cose,16 D-galactose,14 D-tartaric acid18 and (R)-glycidol.17
The strategies employed have used both starting materials
that contain the desired stereochemistry at the N-bearing
centre, such as D-ribo-phytosphingosine and L-serine, or in-
stalled this stereochemistry at a later stage in the synthesis,
for example, by manipulation of a carbohydrate deriva-
tive.14–16 This is most frequently achieved by SN2 displace-
ment with a nitrogen nucleophile (e.g., azide),14–16,18,20b

E. Abraham et al. / Tetrahedron: Asymmetry 19 (2008) 1027–1047
1033
N3
O
N3
OH
NH2 OH
BocHN
HO
OH
BocHN
OH
(ii)
(i)
(vi)
(vii)
HO
HO
O
C14H29
C14H29
C14H29
C14H29
O
C14H29
O
OH
OH
OH
44, 92%
H
42
D-ribo-phytosphingosine 1
41, 96%
45, 83%
(viii)
N3
RHN
RHN
OAc
OR'
OR'
(iii), (iv)
(v)
C14H29
43, 92%
C14H29
C14H29
6 R = R' = H, 95%
O
O
O
5 R = R' = H, 82% (2 steps)
27 R = R' = Ac, 98%
(v)
28 R = R' = Ac, 98%
Scheme 5. Reagents and conditions: (i) TfN3, Na2CO3, CuSO4, CH2Cl2, MeOH, H2O, rt, 16 h; (ii) TMOA, BF3ꢁEt2O, CH2Cl2, 0 °C to rt, 16 h; (iii)
KOtBu, MeOH; (iv) Me3P, PhMe/H2O (24:1), rt, 16 h; (v) Ac2O, pyridine, rt, 16 h; (vi) (Boc)2O, Et3N, THF, rt, 30 min; (vii) TsCl, pyridine/CH2Cl2 (1:1),
rt, 16 h; (viii) TFA, CH2Cl2, rt, 3 h.
Kim et al. also report a stereodivergent synthesis of jaspine
B 5 and 2-epi-jaspine B 6 from D-ribo-phytosphingosine 1
via the key cyclic sulfate intermediate 47.30 Initial protec-
tion of the amino and primary hydroxyl groups of
D-ribo-phytosphingosine 1 was achieved by sequential
treatment with TfN3 and CuSO4, then tert-butyldiphenyl-
silyl chloride (TBDPSCl) and DMAP to give azido O-
TBDPS ether 46 in 78% yield. Subsequent treatment with
SOCl2 gave the corresponding cyclic sulfite, and oxidation
with RuCl3 and NaIO4 afforded cyclic sulfate 47 in 90%
overall yield for two steps, from which both jaspine B 5
and 2-epi-jaspine B 6 are derived. Desilylative cyclisation
of 47 with TBAF resulted in the desired formation of the
tetrahydrofuran core to give 48, with subsequent reduction
yielding jaspine B 5 in 56% overall yield from D-ribo-phyto-
sphingosine 1. In order to access 2-epi-jaspine B 6, Kim
et al. report the regioselective ring-opening of cyclic sulfate
intermediate 47 with iodide, followed by acid-catalysed
hydrolysis which is reported to give iodo alcohol 49 in
94% yield. Treatment of 49 with K2CO3 in MeOH followed
by TBAF afforded epoxy alcohol 50 in 98% yield for two
steps. Subsequent treatment of 50 with a catalytic amount
NH2 OH
N3
OH
N3
OH
(ii)
(i)
C14H29
C14H29
C14H29
OH
OH
OH
41, >90%
OH
TBDPSO
OH
D-ribo-pyhtosphingosine 1
46, 87%
(iii), (iv)
N3
C14H29
H2N
OH
N3
OH
(vii)
(v), (vi)
TBDPSO
O
C14H29
C14H29
48, 86% (2 steps)
O
O
O
SO2
47, 90% (2 steps)
5, 93%
(viii), (ix)
C14H29
N3
I
N3
C14H29
OTs
N3
(xii)
(x), (xi)
C14H29
O
HO
TBDPSO
OH
OH
OH
50, 98%
49, 94% (2 steps)
51
N3
OH
H2N
OH
(vii)
C14H29
C14H29
O
O
6, 94%
52, 79%
Scheme 6. Reagents and conditions: (i) TfN3, K2CO3, CuSO4, MeOH/H2O/CH2Cl2, rt, 3 h; (ii) TBDPSCl, Et3N, DMAP, CH2Cl2, rt, 24 h; (iii) SOCl2,
Et3N, CH2Cl2, 0 °C, 30 min; (iv) RuCl3ꢁ3H2O, NaIO4, CCl4/MeCN/H2O, rt, 2 h; (v) TBAF, THF, rt, 1 h; (vi) H2SO4/H2O, THF, rt, 1 h; (vii) H2, Pd/C,
MeOH, rt, 3 h; (viii) Bu4NI, THF, 40 °C, 1 h; (ix) H2SO4, H2O, THF; (x) K2CO3, MeOH, rt, 2 h; (xi) TBAF, THF, rt, 2 h; (xii) TsOH, PhMe, reflux, 12 h.

1034
E. Abraham et al. / Tetrahedron: Asymmetry 19 (2008) 1027–1047
of p-toluenesulfonic acid (TsOH) at reflux promoted cycli-
sation to tetrahydrofuran derivative 52 in 79% yield, with
hydrogenation giving 2-epi-jaspine B 6 in 94% yield (48%
yield in ten steps from D-ribo-phytosphingosine 1). The
mechanism of cyclisation to 52 is proposed by the authors
to proceed via an unusual regioselective epoxide ring-open-
ing31 with TsOH to give b-hydroxytosylate 51, which
cyclises in situ to give 52. In support of this mechanism,
the authors report the isolation of b-hydroxytosylate 51
upon treatment of 50 with stoichiometric TsOH at rt
(Scheme 6).12b
mary hydroxy with TBDMSCl giving a 70:30 mixture of
diastereoisomeric O-silyl protected amino alcohols 58 in
86% yield. Mesylation followed by treatment of the corre-
sponding mesylates with TBAF promoted desilylation and
concomitant cyclisation to a separable 70:30 mixture of tet-
rahydrofurans, from which the all-cis diastereoisomer 59
was isolated in 28% yield and its C(2)-epimer 60 was iso-
lated in 12% yield. Subsequent debenzylation and diacety-
lation of 59 and 60 gave N,O-diacetyl jaspine B 27 in 82%
yield and N,O-diacetyl 2-epi-jaspine B 28 in 84% yield,
respectively (Scheme 7).
Passiniemi and Koskinen report a synthesis of jaspine B
hydrochloride 75 using L-serine-derived Garner’s aldehyde
53 as the source of chirality, with Pd(0)-mediated cyclisa-
tion and Ru-mediated cross-metathesis reactions as the key
steps in the synthesis. Iodide 66 was coupled with Garner’s
aldehyde 53 by treatment with BuLi and N,N0-dimethyl-
N,N0-propylene urea (DMPU) to give a separable 92:8 mix-
ture of diastereoisomers, with the major isomer 67 isolated
in 63% yield. Subsequent benzylation, O-TBDMS depro-
tection and acetylation gave acetate 70 in 81% overall yield
over three steps. Hydrolysis of the N,O-acetal followed by
Pd(0)-mediated intramolecular 1,5-cyclisation33 gave a sep-
arable 67:33 mixture of diastereoisomeric tetrahydrofuran
derivatives in 95% combined yield. The all-cis isomer 72
was then coupled with 1-tetradecene (10 equiv) via a
4.2.2. Manipulation of L-serine derivatives. The synthesis
of jaspine B 5 reported by Rao and co-workers in 2005
used L-serine derived Garner’s aldehyde 53 as the source
of chirality.13a Addition of vinylmagnesium bromide to
aldehyde 53 gave a separable 86:14 mixture of diastereoiso-
meric alcohols in accordance with the well-known modified
Felkin–Ahn selectivity for addition.32 The major diastereo-
isomer 54 was protected as the corresponding benzyl ether
to give 55 in 92% isolated yield. Ozonolysis of 55 was fol-
lowed by addition of tetradecylmagnesium bromide to give
an inseparable 70:30 mixture of the diastereoisomeric alco-
hols 56 in 83% yield over two steps. Deprotection of the
acetonide protecting group gave a 70:30 mixture of pro-
tected D-ribo- and D-lyxo-phytospingosine derivatives 57
in 91% yield, with subsequent selective silylation of the pri-
(i)
(ii)
NBoc
NBoc
NBoc
CHO
O
O
O
86:14 dr
OH
54 no yield given
OBn
55, 92%
53
(iii), (iv)
BocHN
OH
BocHN
HO
OH
(vi)
C14H29
NBoc OH
(v)
O
TBDMSO
C14H29
C14H29
OBn
OBn
OBn
56, 83% (2 steps)
58, 86%
57, 91%
70:30 dr
70:30 dr
70:30 dr
70:30 dr
(vii), (viii)
(59:60)
BocHN
OBn
H3N
TFA
OH
AcHN
OAc
(ix), (x)
(xi)
C14H29
O
for 59
C14H29
C14H29
O
O
59, 28% (2 steps)
61, 87%
27, 94%
+
BocHN
OBn
H3N
TFA
OH
AcHN
OAc
(ix), (x)
(xi)
for 60
C14H29
60, 12% (2 steps)
C14H29
62, 89%
C14H29
O
O
O
28, 94%
Scheme 7. Reagents and conditions: (i) vinylmagnesium bromide, THF, 0 °C to rt, 12 h; (ii) BnBr, THF, NaH, 0 °C to rt, 12 h; (iii) O3, CH2Cl2, ꢀ78 °C
1 h, Me2S; (iv) C14H29MgBr, THF, 12 h, rt; (v) AcOH, 0 °C to rt, 12 h; (vi) TBDMSCl, imidazole, CH2Cl2, DMAP, 0 °C to rt, 12 h; (vii) MsCl, Et3N,
CH2Cl2, 0 °C to rt 12 h; (viii) TBAF, THF, rt, 2 h; (ix) Na, NH3, THF, ꢀ78 °C, 30 min; (x) TFA:CH2Cl2 (1:1), rt, 6 h; (xi) Et3N, Ac2O, CH2Cl2, 0 °C to rt,
4 h.

E. Abraham et al. / Tetrahedron: Asymmetry 19 (2008) 1027–1047
1035
(iii)
(ii)
(i)
OH
OH
I
OH
65, 65%
I
OTBDMS
66, 96%
I
63
64, 82%
92:8
(iv)
(anti:syn)
Boc
N
Boc
N
Boc
(v)
OBn
OBn
OH
(vi)
N
OH
OTBDMS
OTBDMS
O
O
O
69, 85% (2 steps)
68
67, 63%
(vii)
OBn
BocHN
Boc
(viii)
OBn
BocHN
HO
OBn
(ix)
N
OAc
OAc
O
O
67:33 dr
95% combined yield
70, 95%
72
71, 94%
(x)
OBn
MesN
NMes
Boc
N
OH
BocHN
H3N
Cl
Cl
Cl
(xi)
CHO
Ru
O
Ph
Pcy3
C12H25
C14H29
75, 76%
O
O
53
73
74, 87%
Scheme 8. Reagents and conditions: (i) I2, KOH, MeOH; (ii) KO2CN@NCO2K, AcOH, MeOH; (iii) TBDMSCl, imidazole, DMF; (iv) BuLi, DMPU,
PhMe, ꢀ78 °C then 53, PhMe, ꢀ95 °C; (v) BnBr, TBAI, NaH, THF, 0 °C then D; (vi) TBAF, CH2Cl2, rt; (vii) Ac2O, DMAP, Et3N, CH2Cl2, rt; (viii)
FeCl3–SiO2, CHCl3, rt; (ix) Pd(PPh3)4, PPh3, THF, 55 °C; (x) Grubbs II 73, 1-tetradecene, CH2Cl2, 40 °C; (xi) H2, Pd(OH)2, MeOH/EtOAc (1:1), rt then
HCl, MeOH/EtOAc (1:1).
cross-metathesis reaction with Grubbs II 73 to give 74 as
the only diastereoisomer in 87% yield. Tandem hydrogena-
tion/hydrogenolysis of 74 with Pd(OH)2/C under H2,
followed by treatment with HCl gas was reported to afford
jaspine B hydrochloride 75 in 76% yield (Scheme 8).13c
hydroxyl group and benzylated with benzyl trichloro-
acetimidate and trimethylsilyltriflate (TMSOTf) to give
tosylate 88 in 57% overall yield for three steps. Subsequent
treatment with HCl in EtOH gave 89, then mesylation and
exposure to NaN3 generated tetrahydrofuran derivative 91
in 63% yield. Hydrolysis of 91 with aqueous TFA afforded
aldehyde 83, which was then subjected to Wittig olefination
giving an inseparable mixture of (E)- and (Z)-isomers of
the corresponding olefin 84 in 77% yield. Finally, 84 was
fully reduced under hydrogenation conditions to reportedly
give jaspine B 5 in 92% yield as the free base, although the
data quoted actually correspond to those of jaspine B TFA
salt 61 (Scheme 10).15a Subsequently, an improved and
scaleable synthesis was reported by Du et al., also starting
from D-xylose 85.15b In this approach, protected D-xylose
derivative 92 was treated with NaIO4 to generate aldehyde
93, which was immediately subjected to a Wittig reaction to
produce 94 in 82% yield over two steps. Iodine-promoted
cyclofunctionalisation/debenzylation of 94 afforded iodide
95,35 and subsequent oxidation of the iodomethyl group
with DMSO followed by treatment with MsCl gave
mesylate 96 in 74% yield over two steps from 95. Wittig
olefination of 96 resulted in the generation of an insepara-
ble mixture of (E)- and (Z)-isomers 97, which upon treat-
ment with NaN3 gave 84 in 72% yield over two steps
(Scheme 11). Subsequent elaboration of 84 to jaspine B
TFA salt 61 was reported to be directly analogous to the
previous synthesis, affording jaspine B TFA salt 61 in
4.2.3. Manipulation of carbohydrate derivatives. Several
carbohydrate starting materials have also been employed
for enantiospecific syntheses of jaspine B 5. Shaw et al.
have reported a synthesis of jaspine B 5 using D-galactose
as the source of chirality. Initial treatment of tri-O-
benzyl-D-galactal 76 under Perlin hydrolysis conditions
gave a,b-unsaturated aldehyde 77, which was immediately
reduced under Luche conditions to afford allylic alcohol 78
in 65% yield over two steps. Allylic alcohol 78 was then
treated under Sharpless asymmetric epoxidation conditions
with (+)-diethyl tartrate [(+)-DET] to generate diol 79, via
an intramolecular asymmetric ring-opening process,34 with
subsequent isopropylidene protection giving tetrahydro-
furan derivative 80 in 48% yield over two steps.35 Mesyla-
tion of 80 followed by SN2 displacement with NaN3 gave
azide 82 in 62% yield. Hydrolysis of the acetonide function-
ality within 82 and periodate cleavage of the resultant diol
was followed by Wittig olefination to give 84 as a mixture
of geometic isomers, in 82% yield. Global reduction was
then achieved via transfer hydrogenation with HCO2NH4
in refluxing MeOH to yield jaspine B 5 in 72% yield
(Scheme 9).14
1
95% yield (Scheme 10). The H and 13C NMR spectro-
Du and co-workers initially communicated their synthesis
of jaspine B 5 in 2006 in which D-xylose 85 was protected
as acetal 86, regioselectively tosylated on the primary
scopic data reported in this article (for jaspine B TFA salt
61) are in excellent agreement with those reported by Higa
et al. for the TFA salt of the natural product.5

1036
E. Abraham et al. / Tetrahedron: Asymmetry 19 (2008) 1027–1047
OBn
O
OH
OH
(i)
(ii)
OBn
OBn
BnO
CHO
BnO
OH
OBn
OBn
77
78, 65% (2 steps)
76
(iii)
N3
OBn
MsO
OBn
HO
OBn
HO
OBn
(vi)
(v)
(iv)
O
O
O
OH
O
O
O
O
O
O
O
OH
82, 62% (2 steps)
81
80, 48% (2 steps)
79
(vii)
N3
OBn
N3
OBn
H2N
(ix)
OH
(viii)
C12H25
CHO
C14H29
O
O
O
83
84, 82% (2 steps)
5, 72%
Scheme 9. Reagents and conditions: (i) HgSO4 (cat.), H2SO4 (0.01 M, aq), 1,4-dioxane, 0 °C to rt, 8 h; (ii) NaBH4, (0.5 equiv), CeCl3ꢁ7H2O (1.0 equiv),
i
t
˚
EtOH, 0 °C to rt, 3 h; (iii) Ti(O Pr)4 (1.0 equiv), (+)-DET (1.2 equiv), BuO2H (2.0 equiv), 4 A MS, CH2Cl2, ꢀ25 °C to 0 °C, 2.5 h (iv) satd citric acid in
acetone, 2 h; (v) MsCl, Et3N, CH2Cl2, 0 °C to rt, 1.5 h; (vi) NaN3, Bu4NCl (cat.), DMF, 120 °C, 3 days; (vii) H5IO6 (1.3 equiv), EtOAc, rt, 3 h; (viii)
[C13H27PPh3]+[Br]ꢀ, BuLi, THF, ꢀ78 °C; (ix) HCO2NH4, MeOH, Pd/C, D, 18 h.
OH
HO
RO
O
O
(i)
(ii)
HO
OH
OH
HO
TsO
O
O
O
O
O
D-xylose 85
86, 82%
87 R = H
(iii)
88 R = Bn, 70% (2 steps)
(iv)
N3
OBn
MsO
OBn
HO
OBn
(vi)
(v)
OEt
OEt
OEt
O
O
O
OEt
OEt
OEt
91, 71% (2 steps)
90
89, 89%
(vii)
N3
OBn
N3
OBn
H2N
OH
(viii)
(ix)
CHO
83, 90%
C12H25
C14H29
O
O
O
84, 86%
5, 92%
>10:1 [(Z):(E)]
Scheme 10. Reagents and conditions: (i) acetone, H2SO4 (concd), then Na2CO3; (ii) tosylimidazolide, MeOTf, N-methylimidazole, THF; (iii) benzyl
trichloroacetimidate, TMSOTf (1 mol %), CH2Cl2, ꢀ40 °C; (iv) HCl (5% in EtOH, v/v), D, 3 h; (v) MsCl, pyridine, rt, 4 h; (vi) NaN3, NH4Cl, DMF,
120 °C, 20 h; (vii) TFA (50% aq), CH2Cl2, rt, 30 min; (viii) [C13H27PPh3]+[Br]ꢀ, BuLi, THF, ꢀ40 °C; (ix) H2, Pd(OH)2/C, MeOH/EtOAc, 5 h.
Ramana et al. have reported a stereodivergent synthesis of
jaspine B 5 and ent-jaspine B ent-5 starting from D-glucose
98,16 in a directly analogous fashion to that reported by Du
and co-workers.15a Conversion of D-glucose 98 to aldehyde
99 (according to a literature procedure)36 was followed by
reduction with NaBH4 and treatment with TsCl to give tos-
ylate 88 in 83% yield (over two steps from aldehyde 99).
Subsequent acid-mediated acetonide deprotection with
concomitant cyclisation gave dimethylacetal 101 in 81%
yield. Acid catalysed hydrolysis gave aldehyde 102, which
was then subjected to Ohira–Bestmann alkynylation to af-
ford alkynol 103 in 54% yield. Conversion of 103 to the

E. Abraham et al. / Tetrahedron: Asymmetry 19 (2008) 1027–1047
1037
OH
OBn
CHO
BnO
OH
(i)
HO
OH
OH
BnO
BnO
OH
O
OH
93
O
D-xylose 85
92, 72%
(ii)
OBn
MsO
OBn
HO
OBn
(iv), (v)
(iii)
BnO
CHO
CH2I
OH
O
O
96, 74% (2 steps)
95, 80%
94, 82% (2 steps)
(vi)
MsO
OBn
N3
OBn
H3N
TFA
OH
(vii)
(viii)
C12H25
C14H29
C12H25
O
O
O
97, 90%
84, 80%
61, 95%
>10:1 [(Z):(E)]
Scheme 11. Reagents and conditions: (i) NaIO4, MeOH, H2O; (ii) [CH3PPh3]+[Br]ꢀ, BuLi, THF, ꢀ40°C to rt; (iii) I2, NaHCO3, MeCN; (iv) NaHCO3,
DMSO, 150°C, 6 min; (v) MsCl, pyridine, rt, 30 min; (iv) [C13H27PPh3]+[Br]ꢀ, BuLi, THF, ꢀ40 °C to rt; (vii) NaN3, NH4Cl, DMF, 120 °C, 20 h; (viii) Pd/
C, H2, MeOH, TFA, 5 h.
corresponding azidoalkyne 104 was achieved by treatment
with triflic anhydride (Tf2O) in pyridine, followed by reac-
tion with LiN3 in DMF to give 104 in 81% yield over two
steps. Alkylation of the terminal acetylene 104 with BuLi,
hexamethylphosphoramide (HMPA) and C12H25Br gave
105, which was reduced under transfer hydrogenolysis con-
ditions to give jaspine B 5 in 41% yield over two steps.
Whilst no data are reported for the natural product, full
characterisation data for the N,O-diacatate derivative 27,
including X-ray crystal structure data, are given (Scheme
12). Aldehyde 99 was also converted into ent-jaspine B
ent-5 by first subjecting it to Ohira–Bestmann alkynylation
OH
BnO
O
BnO
BnO
O
O
(i)
(ii)
HO
HO
OH
HO
TsO
O
O
O
OHC
O
O
O
O
CH2OH
D-glucose 98
99
100, 89%
88, 93%
(iii)
HO
HO
OBn
OBn
N3
HO
OBn
OBn
(vi), (vii)
(v)
(iv)
OMe
OMe
101, 81%
O
O
O
O
O
104, 81% (2 steps)
103, 67%
102, 81%
(viii)
N3
OBn
RHN
OR'
(ix)
(x)
O
C14H29
O
C12H25
105, 61%
5 R = R' = H, 67%
27 R = R' = Ac, 91%
Scheme 12. Reagents and conditions: (i) NaBH4, MeOH, 0 °C, 2 h; (ii) TsCl, pyridine, DMAP, CH2Cl2, 5 h; (iii) TsOH, MeOH, D, 6 h; (iv) H2SO4 (2.0 M,
aq), AcOH (50% aq), 9 °C, 2 h; (v) (MeO)2P(O)C(N2)COCH3, MeOH, K2CO3, rt, 8 h; (vi) Tf2O, pyridine, CH2Cl2, 0 °C, 6 h; (vii) LiN3, DMF, rt, 12 h;
(viii) BuLi, THF/HMPA (7:1), C12H25Br, ꢀ78 °C to ꢀ40 °C, 1 h; (ix) Pd/C (10% w/w), HCO2NH4, MeOH, D, 10 h; (x) Ac2O, Et3N, DMAP, CH2Cl2, rt,
6 h.

1038
E. Abraham et al. / Tetrahedron: Asymmetry 19 (2008) 1027–1047
to give 106 and then reductive deketalisation, using excess
triethylsilane in the presence of BF3ꢁEt2O, to give ent-103
in 75% yield over two steps. The subsequent steps in the
synthesis are directly analogous to that of the natural prod-
uct with final diacetylation giving ent-N,O-diacetyl jaspine
B ent-27 in 31% overall yield in five steps from ent-103
(Scheme 13).
4.2.4. Syntheses based on manipulation of other chiral pool
starting materials. In 2006, Marco et al. reported an
enantiospecific synthesis of jaspine B 5 from (R)-glyc-
idol. O-TBDPS protected (R)-glycidol 111 was initially
treated with tridecylmagnesium bromide in the presence
of CuI to afford the corresponding alcohol, which was
then protected as its O-methoxymethyl (O-MOM) deriv-
ative 112. Sequential desilylation, Swern oxidation and
olefination then gave a,b-unsaturated ester (E)-114 in
81% yield over three steps. Ester reduction of 114 with
DIBAL-H gave allylic alcohol 115, which was treated
under Sharpless asymmetric epoxidation conditions, with
(ꢀ)-DET, to provide epoxy alcohol 116 in 85% yield.35
Epoxy alcohol 116 was then treated with trichloroaceto-
nitrile in the presence of DBU to give imino ester deriv-
ative 117, which was then reacted with Et2AlCl to
generate oxazoline 118 in 72% yield. Subsequent hydro-
lysis and N-Boc protection gave diol 119. Removal of
the O-MOM group was achieved with TMSBr to give
triol 120, which was treated with TsCl, followed by
K2CO3 in MeOH to induce cyclisation to give tetrahy-
drofuran derivative 122 in 50% yield over five steps.
N-Boc Deprotection of 122 with TFA and subsequent
basification with NaOH then gave jaspine B 5 in 75%
yield. Full characterisation data for jaspine B 5 and
the N,O-diacetyl derivative 27, which was prepared by
Chandrasekhar et al. have published a synthesis of a ‘trun-
cated’ version of jaspine B with a C5H11 side chain 23,21
based upon manipulation of L-xylose-derived aldehyde
ent-99.37 Aldehyde ent-99 was subjected to Wittig olefin-
ation with [C4H9PPh3]+[Br]ꢀ, hydrolysis and in situ forma-
tion of the methyl glycoside to give 108 in 82% yield over
two steps. Activation of the hydroxyl group as the corre-
sponding imidazole sulfonate ester allowed SN2-displace-
ment with NaN3 to give 109 in 58% yield. Subsequent
reduction of 109 with Et3SiH promoted by BF3, followed
by hydrogenation gave the ‘truncated’ version of the natu-
ral product 23 in 66% yield (Scheme 14). The truncated side
chain has little effect on the dH/dC signals in the 1H and 13
C
NMR spectra for the resonances associated with the tetra-
hydrofuran core and, crucially, the highest field signal is at
3.85–3.95 ppm (dH < 4.0 ppm for all ring protons in
CDCl3), which is in excellent agreement with an all-cis
arrangement.
BnO
BnO
O
O
BnO
OH
(i)
(ii)
O
O
OHC
O
O
O
99
106, 91%
ent-103, 82%
(iii), (iv)
NHAc
HO
BnO
AcO
NH2
N3
(vii)
(v),(vi)
C14H29
C14H29
O
O
O
ent-27, 94%
ent-5, 39%
ent-104, 85%
Scheme 13. Reagents and conditions: (i) (MeO)2P(O)C(N2)COCH3, MeOH, K2CO3, rt, 8 h; (ii) BF3ꢁEt2O, Et3SiH, CH2Cl2, ꢀ20 °C to rt, 6 h; (iii) Tf2O,
pyridine, CH2Cl2, 0 °C, 6 h; (iv) LiN3, DMF, rt, 12 h; (v) BuLi, THF/HMPA (7:1), C12H25Br, ꢀ78 °C to ꢀ40 °C, 1 h; (vi) Pd/C (10% w/w), HCO2NH4,
MeOH, D, 10 h; (vii) Ac2O, Et3N, DMAP, CH2Cl2, rt, 6 h.
OH
OBn
OBn
O
O
(i)
HO
OH
OH
O
O
CHO
C3H7
O
O
O
L-xylose 85
ent-99
107, 86%
(ii)
N3
OBn
HO
OBn
H2N
OH
(vi)
(iii), (iv)
R
C3H7
MeO
C3H7
C5H11
O
O
O
109 R = OMe, 58% (2 steps)
108, 95%
23, 70%
(v)
110 R = H, 94%
Scheme 14. Reagents and conditions: (i) [C4H9PPh3]+[Br]ꢀ, BuLi, THF/HMPA, ꢀ40 °C, 4 h; (ii) AcCl, MeOH, 60 °C, 8 h; (iii) SO2Im2, NaH, DMF,
ꢀ40 °C, 3 h; (iv) NaN3, Bu4NCl, DMF, 110 °C, 12 h; (v) BF3ꢁEt2O, Et3SiH, CH2Cl2, 0 °C to rt, 2 h; (vi) Pd/C, H2, MeOH, rt, 6 h.

E. Abraham et al. / Tetrahedron: Asymmetry 19 (2008) 1027–1047
1039
OMOM
C14H29
OMOM
OMOM
C14H29
(i), (ii)
(iii)
(iv), (v)
O
TBDPSO
111
TBDPSO
HO
C14H29
113, 94%
EtO2C
112, 77% (2 steps)
114, 86% (2 steps)
(vi)
Cl3C
Cl3C
NH
OMOM
C14H29
OMOM
OMOM
N
OMOM
C14H29
(ix)
(viii)
(vii)
HO
O
HO
O
C14H29
C14H29
O
H
O
OH
118, 72% (2 steps)
117
116, 89%
115, 95%
(x), (xi)
BocNH
OMOM
C14H29
BocNH
OH
OH
BocNH
TsO
OH
OR'
RHN
(xii)
(xiii)
(xiv)
C14H29
C14H29
C14H29
R = Boc, R' = H, 70% (2 steps)
O
OH OH
119, 96% (2 steps)
OH
120, 75%
OH
121
122
(xv)
(xvi)
5 R = R' = H, 75%
27
R = R' = Ac, no yield given
Scheme 15. Reagents and conditions: (i) C13H27MgBr, CuI, THF, ꢀ10 to 0 °C; (ii) MOMCl, EtNiPr2, CH2Cl2, rt, 24 h; (iii) TBAF, THF, rt, 3 h; (iv)
(COCl)2, DMSO, Et3N, CH2Cl2, ꢀ78 to ꢀ46 °C, 3 h; (v) (iPrO)2P(O)CH2CO2Et, LiBr, Et3N, THF, rt; (vi) DIBAL-H, hexane, 0 °C, 2.5 h; (vii) tBuO2H,
(ꢀ)-DET, Ti(OiPr)4, CH2Cl2, ꢀ20 °C, 24 h; (viii) Cl3CCN, DBU, CH2Cl2, 0 °C, 30 min; (ix) Et2AlCl, CH2Cl2, 0 °C to rt, 5 h; (x) HCl (1.0 M, aq), THF, rt,
5 h; (xi) Boc2O, NaHCO3, THF, rt, 16 h; (xii) TMSBr, CH2Cl2, ꢀ78 °C, 30 min; (xiii) TsCl, Et3N, DMAP, CH2Cl2, rt, 20 min; (xiv) K2CO3, MeOH, rt,
16 h; (xv) TFA, CH2Cl2, 0 °C to rt, 45 min then NaOH, MeOH, 5 min; (xvi) Ac2O, DMAP, Et3N, CH2Cl2, rt, 16 h.
treatment of the free base with Ac2O, Et3N and
DMAP, are reported (Scheme 15).17
bisdimethylamide 123 gave keto amide 124 in 86% yield,
and stereoselective reduction of ketone 124 under Luche
conditions furnished a mixture of diastereomeric alcohols
(90% de) with 125 as the major diastereoisomer. Subse-
quent reaction of this mixture with excess 2,2-dimethoxy-
Chandrakumar and Prasad have reported a synthesis of
jaspine B 5 starting from D-tartaric acid-derived bisdimeth-
ylamide 123. Addition of tetradecylmagnesium bromide to
propane and TsOH gave
a separable mixture of
O
O
O
(i)
(ii)
O
O
O
CONMe2
CONMe2
CONMe2
CONMe2
O
HO
C14H29
C14H29
123
124, 86%
125, 97%, 90% de
(iii)
OTs
OH
OH
OTBDMS
OH
(v), (vi)
(iv)
O
O
O
O
O
CO2Me
O
C14H29
C14H29
C14H29
126, 86%
128, 90% (2 steps)
127, 94%
(vii), (viii)
N3
N3
H2N
OH
(ix), (x)
(xi), (xii)
OH
HO
HO
OTs
O
O
C14H29
5, 91% (2 steps)
O
C14H29
C14H29
129, 92% (2 steps)
130, 94% (2 steps)
Scheme 16. Reagents and conditions: (i) C14H29MgBr, THF, ꢀ15 °C, 30 min; (ii) NaBH4, CeCl3, MeOH, ꢀ15 °C, 2 h; (iii) 2,2-dimethoxypropane, TsOH,
C6H6, D, 12 h; (iv) NaBH4, MeOH, ꢀ15 °C to rt, 3 h; (v) TBDMSCl, imidazole, DMF, rt, 12 h; (vi) TsCl, DMAP, CH2Cl2, rt, 14 h; (vii) NaN3, DMF,
100 °C, 12 h; (viii) TBAF, THF, 0 °C to rt, 1 h; (ix) TsCl, Et3N, CH2Cl2, 0 °C to rt, 5 h; (x) FeCl3ꢁ6H2O, CH2Cl2, rt, 8 h; (xi) K2CO3, MeOH, 0 °C to rt,
4 h; (xii) H2, Pd/C, MeOH, CH2Cl2, rt, 3 h.

1040
E. Abraham et al. / Tetrahedron: Asymmetry 19 (2008) 1027–1047
diastereoisomeric alcohols, from which the major diaste-
reoisomer 126 was isolated in 86% yield. Alcohol 126 was
reduced with NaBH4 to afford diol 127, which was first
treated with TBDMSCl, then TsCl to give 128 in 85% yield
(over three steps). Treatment of 128 with NaN3 gave a
mixture of the expected SN2 displacement product and also
resulted in partial desilylation, subsequent treatment with
TBAF afforded azohydrin 129 in 92% yield from 128.
Tosylation of 129 followed by acid-promoted acetonide
hydrolysis, then treatment with K2CO3 in MeOH gave
the corresponding tetrahydrofuran derivative in 91% yield.
Subsequent azide reduction with Pd/C gave jaspine B 5 in
94% yield (Scheme 16).18
Venkatesan and Srinivasan have also reported an asymmet-
ric synthesis of jaspine B 5 which utilises Sharpless asym-
metric dihydroxylation and a chelation-controlled vinyl
Grignard addition as the key steps in the synthetic strategy.
1-Pentadecanol 140 was subjected to oxidation with
pyridinium chlorochromate (PCC), followed by Wittig
olefination to give a,b-unsaturated ester 141 in 92% yield.
a,b-Unsaturated ester 141 was then treated under Sharpless
asymmetric dihydroxylation conditions to give diol 142 in
88% yield and 97% ee. Subsequent O-MOM protection,
reduction and re-oxidation gave aldehyde 145 which was
immediately treated with vinyl magnesium bromide, under
chelation control, to give allylic alcohol 146 in >95% de and
89% yield from alcohol 144. O-Benzyl protection of 146,
oxidative cleavage and reduction then gave alcohol 147 in
71% yield over four steps. Subsequent protecting group
manipulation, tosylation and azide displacement then gave
azide 149 in 75% yield over four steps. Acidic hydrolysis of
149 followed by treatment with TsCl gave tosylate 130
which was reacted according to the procedure outlined by
Chandrakumar and Prasad18 (vide supra) to give jaspine
B 5 (Scheme 18).20b
4.3. Other asymmetric syntheses of jaspine B
In addition to the syntheses of jaspine B 5 highlighted
above, there have also been two further asymmetric synthe-
ses of the natural product, the first of these by Yakura et al.
utilises the Sharpless asymmetric dihydroxylation of a,b-
unsaturated ester 131 to give diol 132 in 98% ee. Subse-
quent acetonide protection, reduction with DIBAL-H
and Wittig olefination gave 135 as a single diastereoisomer
in 85% yield. One-pot removal of the O-p-methoxybenzyl
(O-PMB) group and olefin reduction was then achieved un-
der hydrogenation conditions to give 136, which was trea-
ted with I2 and PPh3 to afford iodide 137 in 87% yield from
olefin 135. Acid-catalysed deprotection of 137 followed by
cyclisation gave tetrahydrofuran 138. Subsequent treat-
ment with trichloroacetyl isocyanate and Rh-mediated C–
H amination gave a mixture of products from which 139
was isolated in 19% yield from 138. Hydrolysis of 139 with
KOH and acetylation with Ac2O in pyridine gave N,O-di-
acetyl jaspine B 27 in 85% yield (Scheme 17).20a
The synthesis of another ‘truncated’ C8H17 side chain ana-
´
logue 24 is reported by Genisson et al., the synthesis of
which is based on Sharpless asymmetric aminohydroxyla-
tion of allylic alcohol 150. Under these conditions, a
70:30 mixture of amino alcohols 151 and 152 is produced;
subsequent treatment with methyl chloroformate generated
a separable mixture of regioisomeric oxazolidinones 153
and 154, which were isolated in 60% and 23% yields,
respectively; the cis-stereochemistry of the major product
153 was established by single crystal X-ray analysis. Oxida-
tion of 153 with Dess–Martin periodinane (DMP) gave
aldehyde 155 in 90% yield. The C8H17 side chain was then
O
OH
(i)
(ii)
O
CO2Me
CO2Me
PMBO
PMBO
PMBO
PMBO
PMBO
CO2Me
OH
131
132, 89%, 98% ee
133, quant.
(iii)
O
O
O
O
(v)
(iv)
O
O
HO
136, 87%
C12H25
CHO
134, 97%
C14H29
135, 88%
(vi)
O
AcHN
OAc
OH
(vii)
(viii), (ix)
(x), (xi)
C14H29
HN
O
O
O
C14H29
O
C14H29
I
O
O
C14H29
137, quant.
27, 85% (2 steps)
138, 79%
139, 19% (2 steps)
Scheme 17. Reagents and conditions: (i) AD-mix-a, BuOH–H2O, 0 °C, 16 h; (ii) Me2C(OMe)2, CSA, rt, 12 h; (iii) DIBAL-H, CH2Cl2, ꢀ80 °C, 1 h; (iv)
[Ph3PC13H27]+[Br]ꢀ, BuLi, THF, ꢀ20 °C, 1 h; (v) H2 (3 atm), Pd/C, EtOAc, rt, 3 h; (vi) I2, PPh3, imidazole, CH2Cl2, rt, 1 h; (vii) concd HCl, THF, rt, 2.5 h
then K2CO3, MeOH, rt, 3 h; (viii) Cl3CCON@C@O, CH2Cl2, rt, 1 h then neutral Al2CO3; (ix) Rh2(OCOCPh3)4 (10 mol %), PhI(OAc)2 (4.2 equiv), MgO
(6.9 equiv ), C6H6, reflux, 13 h; (x) KOH (aq), EtOH, reflux, 3 h; (xi) Ac2O, pyridine, rt, 12 h.

E. Abraham et al. / Tetrahedron: Asymmetry 19 (2008) 1027–1047
1041
OH
MOMO
(i), (ii)
(iii)
(iv)
(vi)
CO2Et
CO2Et
CO2Et
H29C14
OH
H29C14
H29C14
H29C14
MOMO
OH
140
141, 92% (2 steps)
142, 88%, 97% ee
143, 96%
(v)
MOMO
OBn
MOMO
OH
MOMO
MOMO
H29C14
(viii)-(xi)
(vii)
OH
H29C14
MOMO
147, 71% (4 steps)
H29C14
MOMO
146, 89% (2 steps)
H29C14
OH
O
>95% de
MOMO
145
MOMO
144, 96%
(xii), (xiii)
MOMO
OH
MOMO
N3
OH
N3
H2N
OH
(xiv), (xv)
(xvi), (xvii)
(xviii), (xix)
OMOM
OMOM
OTs
H29C14
MOMO
148, 90% (2 steps)
H29C14
MOMO
149, 83% (2 steps)
H29C14
C14H29
5, no yield given
O
OH
130, 80% (2 steps)
Scheme 18. Reagents and conditions: (i) PCC, CH2Cl2, 0 °C, 3 h; (ii) Ph3PCHCO2Et, C6H6, D, 4 h; (iii) (DHQ)2PHAL, K2CO3, K3[Fe(CN)6],
MeSO2NH2, OsO4 (0.1 M in PhMe), tBuOH/H2O (1:1), 0 °C, 24 h; (iv) MOMCl, CH2Cl2, EtNiPr2, 0 °C to rt, 16 h; (v) DIBAL-H, CH2Cl2, ꢀ10 °C, 1 h;
(vi) IBX, EtOAc, D, 3 h; (vii) vinylmagnesium bromide, MgBr2ꢁEt2O, THF, ꢀ78 °C, 45 min; (viii) BnBr, NaH, THF, 0 °C, 4 h; (ix) OsO4 (0.1 M in PhMe),
tBuOH/THF/H2O (3:2:1), N-methylmorpholine-N-oxide (NMO), 16 h; (x) NaIO4, NaHCO3, H2O, rt, 3 h; (xi) NaBH4, MeOH, 0 °C to rt, 1 h; (xii)
MOMCl, CH2Cl2, EtNiPr2, 0 °C to rt, 6 h; (xiii) H2, Pd/C, MeOH, rt, 16 h; (xiv) TsCl, CH2Cl2, Et3N, DMAP, 0 °C to rt, 3 h; (xv) NaN3, DMF, 95 °C,
14 h; (xvi) aq HCl, THF, 0 °C to rt, 5 h; (xvii) TsCl, CH2Cl2, DMAP, 0 °C to rt, 4 h; (xviii) K2CO3, MeOH, 0 °C to rt, 4 h; (xix) H2, Pd/C, MeOH, rt, 3 h.
1
introduced via Grignard addition to aldehyde 155; mesyl-
ation of the resultant alcohol 156 followed by hydro-
genolytic O-debenzylation and in situ cyclisation gave
tetrahydrofuran derivative 158 in 68% yield. N-Debenzyla-
tion of 158 was achieved via Birch reduction, and saponifi-
cation of the resultant oxazolidinone 159 gave the
‘truncated’ version of the natural product 24 in 95% yield,
with H NMR data (dH < 4.0 ppm for all ring protons in
CDCl3) supporting an all-cis arrangement (Scheme 19).22
4.4. Synthesis with inconsistent data
Datta et al. communicated their purported synthesis of
jaspine B 5 in 2005;13b in this synthesis L-serine 160
O
NHBn
HN
OH
O
BnO
BnO
OH
OH
154, 23%
(i)
(ii), (iii)
152
OH
BnO
+
O
+
O
60%
70:30
OH
O
O
150
(iv)
(151:152)
OH
BnN
BnN
OH
H
BnO
NHBn
O
BnO
BnO
151
153, 60%
155, 90%
(v)
O
O
O
H2N
OH
BnN
O
O
H
O
H
(ix)
(vii)
(vi)
BnN
BnN
C8H17
C8H17
C8H17
24, 95%
C8H17
O
O
OMs
157, 90%
OH
BnO
BnO
158 R = Bn, 75%
159 R = H, 83%
156, 56%
(viii)
i
t
i
˚
Scheme 19. Reagents and conditions: (i) Ti(O Pr)4, (ꢀ)-DET, BuO2H, 4 A MS, CH2Cl2, ꢀ23 °C, 3 days then Me2S, rt, 3 h, then, Ti(O Pr)4, BnNH2, rt, 1.5
days; (ii) K2CO3, MeOCOCl, THF, rt, 18 h; (iii) KOH, MeOH, rt, 5 h; (iv) DMP, CH2Cl2, rt, 3 h; (v) C8H17MgBr, CeCl3, THF, ꢀ78 °C, 5 h then 0 °C,
1 h; (vi) MsCl, Et3N, CH2Cl2, 0 °C to rt, 1.5 h; (vii) H2 (10 bar), Pd(OH)2, EtOH, 2 days; (viii) Na/NH3, THF, ꢀ78 °C, 4 h; (ix) KOH, EtOH/H2O, 85 °C,
7 h.

1042
E. Abraham et al. / Tetrahedron: Asymmetry 19 (2008) 1027–1047
Cbz
Cbz
H
HN
H2N
(ii)-(v)
OH
H
(i)
N
NH2
CO2H
O
O
HO
O
O
C14H29
O
O
O
H
160
161, 42%
162, 79%
5
O
O
Cbz
H
Cbz
OBn
O
HN
HN
H
O
HN
O
O
HN
(ii), (iii)
O
O
O
O
O
O
H
H
O
O
162
163
164
165
-H+
O
O
O
O
+H+
HN
O
HN
O
HN
O
HN
O
O
O
O
O
O
O
O
O
169
168
167
166
O
O
HN
O
HN
O
H2N
OH
(iv)
(v)
C11H23
C14H29
171, 90%
C14H29
O
O
O
170, 67%
6, 77%
Scheme 20. Reagents and conditions: (i) HCO2H, CH2Cl2, 0 °C then EtOAc, satd aq NaHCO3; (ii) DIBAL-H, ꢀ78 °C; (iii) [Ph3PC12H25]+[Br]ꢀ, BuLi,
THF, ꢀ78 °C to rt; (iv) Pd/C, H2, EtOAc, rt; (v) aq KOH, EtOH, D.
was converted into butenolide 161, the synthesis of which
had previously been developed in the Datta laborato-
ries.38 Treatment of 161 with formic acid in dichloro-
methane enabled deprotection of the acetonide, with
subsequent Michael addition of the free hydroxyl group
giving cis-fused bicycle 162; the structure of which was
supported by X-ray crystallographic analysis of related
derivatives.13b,39 Subsequent elaboration of this com-
pound was reported to furnish jaspine B 5 as the free
base in 46% yield over four steps. Unfortunately upon
inspection of the spectroscopic data reported by Datta
et al., and comparison with the other natural and syn-
thetic samples of jaspine B 5 discussed in this review,
it is evident that the data are anomalous and in fact clo-
sely resemble those of 2-epi-jaspine B 6; a full compari-
son of the relevant spectroscopic data is given below.
This discrepancy can be accounted for by a retro-Mi-
chael/Michael epimerisation pathway upon treatment of
bicyclic lactone 162 with DIBAL-H and excess Wittig
reagent. Enolate 166, which is generated under these
conditions, may undergo a retro-Michael reaction to
generate a,b-unsaturated aldehyde 167. Recyclisation of
the resultant oxyanion species would generate the ther-
modynamically favoured 2,3-anti-aldehyde 168, which is
trapped out as the corresponding olefin 170. Subsequent
hydrogenation of 170 and cleavage of the resultant oxa-
zolidinone 171 with ethanolic KOH afforded 2-epi-jaspine
B 6 in 77% yield (Scheme 20).
5. Comparison of spectroscopic data
5.1. Specific rotation
A summary of the reported specific rotation data for jaspine
B 5, 2-epi-jaspine B 6 (both free bases and salts) and the cor-
responding N,O-diacetyl derivatives 27 and 28, excluding the
data reported in the anomalous syntheses highlighted
above,13b,15a is given below (Table 1). It is known that hydro-
gen-bonding systems do not always give consistent measure-
ments for specific rotation,40 and as such judgements based
upon specific rotation alone should be regarded with cau-
tion. In this system, specific rotation is not diagnostic of rel-
ative stereochemistry due to the reported similarities
between the specific rotations for jaspine B 5, 2-epi-jaspine
B 6 and their derivatives. There is seemingly only one major
24
inconsistency within this set of data {½aꢂD ¼ þ76:0 (c 0.2,
CHCl3) reported by Kim et al.12b for the free base of jaspine
B 5} otherwise the values for jaspine B 5, 2-epi-jaspine B 6
and the TFA salts of both diastereoisomers are typically in
the range +10 to +20, and upon conversion to the corre-
sponding N,O-diacetyl derivatives, lie approximately within
the range ꢀ15 to ꢀ30 (Table 1).
5.2. H and 13C NMR spectroscopic data
1
A thorough inspection of the 1H and 13C NMR data for all
reported synthetic and the naturally occurring samples of

E. Abraham et al. / Tetrahedron: Asymmetry 19 (2008) 1027–1047
1043
Table 1. Specific rotation data for jaspine B 5, 2-epi-jaspine B 6, and the corresponding N,O-diacetyl derivatives 27 and 28, TFA salts 61 and 62, and HCl
salts 75 and 172
Compound
Source
Specific rotation
Higa (Ref. 5)
Shaw (Ref. 14)
[a]D = +18.0 (c 0.1, EtOH)
28
½aꢂD ¼ þ13:3 (c 0.03, EtOH)
25
Srinivasan (Ref. 20b)
Prasad (Ref. 18)
Davies (Refs. 19a,19c)
½aꢂD ¼ þ17:7 (c 0.4, EtOH)
[a]D = +17.5 (c 0.4, EtOH)
23
½aꢂD ¼ þ17:5 (c 0.3, EtOH)
22
H2N
OH
Overkleeft (Ref. 12a)
Shaw (Ref. 14)
Kim (Ref.12b)
Daviesd
½aꢂD ¼ þ4:8 (c 1.0, MeOH)
28
½aꢂD ¼ þ8:5 (c 0.047, MeOH)
23
½aꢂD ¼ þ19:7 (c 0.5, MeOH)
C14H29
O
18
½aꢂD ¼ þ9:4 (c 0.3, MeOH)
jaspine B 5
25
Marco (Ref. 17)
Debitus (Ref. 11)
Kim (Ref. 12b)a
Daviesd
½aꢂD ¼ þ9:0 (c 1.5, CHCl3)
20
½aꢂD ¼ þ7:0 (c 0.1, CHCl3)
24
½aꢂD ¼ þ76:0 (c 0.2, CHCl3)
18
½aꢂD ¼ þ6:5 (c 0.47, CHCl3)
23
Kim (Ref. 9)
Daviesd
½aꢂD ¼ þ14:8 (c 0.002, EtOH)
18
½aꢂD ¼ þ12:7 (c 0.65, EtOH)
23
H2N
2-
OH
Kim (Ref. 12b)
Overkleeft (Ref. 12a)
Davies (Ref. 19c)
Datta (Ref. 13b)c
Daviesd
½aꢂD ¼ þ23:2 (c 1.0, MeOH)
22
½aꢂD ¼ þ15:0 (c 1.0, MeOH)
21
½aꢂD ¼ þ16:4 (c 0.85, MeOH)
C14H29
O
25
½aꢂD ¼ þ9:6 (c 0.11, CHCl3)
-
jaspine B 6
epi
18
½aꢂD ¼ þ11:8 (c 0.65, CHCl3)
24
Kim (Ref. 12b)
½aꢂD ¼ ꢀ18:5 (c 0.7, CHCl3)
25
Ramana (Ref. 16)
Marco (Ref. 17)
½aꢂD ¼ ꢀ34:6 (c 1.0, CHCl3)
AcHN
AcHN
OAc
25
½aꢂD ¼ ꢀ28:4 (c 1.0, CHCl3)
22
Overkleeft (Ref. 12a)
Davies (Ref. 19c)
Ramana (ent., Ref. 16)
Rao (Ref. 13a)b
½aꢂD ¼ ꢀ22:6 (c 1.0, CHCl3)
C14H29
23
O
½aꢂD ¼ ꢀ26:4 (c 0.5, CHCl3)
27
25
½aꢂD ¼ þ29:0 (c 1.0, CHCl3)
25
½aꢂD ¼ ꢀ28:8 (c 1.1, CHCl3)
OAc
22
Overkleeft (Ref. 12a)
Davies (Ref. 19c)
½aꢂD ¼ ꢀ15:4 (c 1.0, CHCl3)
22
½aꢂD ¼ ꢀ14:6 (c 0.5, CHCl3)
C14H29
O
28
H3N
TFA
OH
25
Rao (Ref. 13a)
Du (Ref. 15b)
½aꢂD ¼ þ17:1 (c 0.4, EtOH)
25
½aꢂD ¼ þ11:0 (c 1.0, CHCl3)
C14H29
O
61
H3N
TFA
OH
25
Rao (Ref. 13a)
½aꢂD ¼ þ14:5 (c 1.5, EtOH)
C14H29
O
62
H3N
Cl
OH
23
Davies (Ref. 19c)
Davies (Ref. 19c)
½aꢂD ¼ þ2:6 (c 0.4, MeOH)
C14H29
O
75
H3N
Cl
OH
21
½aꢂD ¼ þ15:5 (c 0.9, MeOH)
C14H29
O
172
a A personal communication from the corresponding author has confirmed the value for this specific rotation.
b Data kindly supplied in a personal communication from the corresponding author.
c Stereochemistry re-assigned in this review (see Section 4.4).
d Value obtained for this review.

1044
E. Abraham et al. / Tetrahedron: Asymmetry 19 (2008) 1027–1047
Table 2. Comparison of reported 1H NMR data for jaspine B 5, 2-epi-jaspine B 6, and the corresponding N,O-diacetyl derivatives 27 and 28, TFA salts 61
and 62, and HCl salts 75 and 172
Compound
Entry Source
Solvent
C(2)H
C(3)H
C(4)H
C(5)HA
C(5)HB
1
2
3
4
5
6
7
8
9
Higa (Ref. 5)
Shaw (Ref. 14)a
MeOD
MeOD
3.81 dt
3.86 dd
3.92 qt
3.51 dt
3.43 dd
3.90 dd
3.73–3.78 m
3.69–3.75 m
3.75 ddd
3.73 dt
3.73 ddd
3.75 ddd
3.71–3.76 m
3.74 td
3.49–3.69 m 3.49–3.69 m 4.01–4.03 m
Srinivasan (Ref. 20b)a MeOD
3.84–3.88 m 3.63–3.67 m 3.49–3.53 m 3.89–3.94 m
H2N
OH
Debitus (Ref. 11)
Kim (Ref. 12b)a
Marco (Ref. 17)a
Overkleeft (Ref. 12a)
Prasad (Ref. 18)a,b
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
3.88 dd
3.86 dd
3.86 dd
3.87 dd
3.68 dt
3.64 dt
3.65 m
3.54 dd
3.50 dd
3.51 dd
3.53 dd
3.95 dd
3.92 dd
3.92 dd
3.92 dd
4
3
5
2
C14H29
O
3.59 br m
jaspine B 5
3.86–3.88 m 6.62–3.70 m 3.50–3.53 m 3.91–3.95 m
3.87 t
3.87 dd
Davies (Refs. 19a,19c) CDCl3
Koskinen (Ref. 13c)a,c CDCl3
3.61–3.69 m 3.50 dd
3.64 m 3.51 dd
3.91 t
3.92 dd
10
3.73 ddd
11
12
13
14
15
Datta (Ref. 13b)a,d
Kim (Ref. 12b)a
Kim (Ref. 9)a
Davies (Refs. 19a,19c) CDCl3
Overkleeft (Ref. 12a)
CDCl3
CDCl3
CDCl3
Not reported 3.63 m
3.40–3.48 m 3.40–3.48 m 4.14 dd
H2N
OH
3.60 dd
3.62 m
3.45 m
3.39 dd
4.11 dd
4
3
3.58–3.62 m
3.60–3.64 m
3.58–3.62 m 3.45 q
3.60–3.64 m 3.46–3.49 m 3.37–3.47 m 4.11–4.15 m
3.36 ABq
4.20 ABq
5
2
C14H29
2- -jaspine B 6
O
CDCl3/MeOD 3.74 m
4.04 t
3.67 quin
3.75 dd
4.13 dd
epi
16
17
18
19
20
21
22
23
24
Higa (Ref. 5)
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
3.90 ddd
3.93 ddd
3.90 m
3.85–3.93 m
3.90 ddd
3.90 m
3.86–.395 m
3.91 ddd
3.80–3.90 m
5.38 dd
5.42 dd
5.38 dd
5.37 dd
5.40 dd
5.38 dd
5.38 dd
5.38 dd
4.81 dq
4.85 dq
4.81 dddd
4.80 dq
4.83 qd
4.81 ddd
4.82 qd
4.82 ddd
3.60 dd
3.62 dd
3.59 t
3.58 dd
3.60 t
3.59 dd
3.60 t
3.60 t
4.15 dd
4.11 dd
4.07 t
4.06 dd
4.09 t
4.07 dd
4.08 t
4.10 t
Debitus (Ref. 11)
Kim (Ref. 12b)a
Ramana (Ref. 16)a
Marco (Ref. 17)a
Overkleeft (Ref. 12a)
Yakura (Ref. 20a)a
AcHN
AcHN
OAc
4
3
5
2
C14H29
O
27
Davies (Refs. 19a,19c) CDCl3
Rao (Ref. 13a)a,e
CDCl3
5.30–5.40 m 4.70–4.80 m 3.50–3.60 m 4.00–4.10 m
OAc
4
3
25
26
Overkleeft (Ref. 12a)
Davies (Refs. 19a,19c) CDCl3
CDCl3
3.86 m
3.90–3.93 m
4.91 dd
4.65 m
3.52 dd
4.17 dd
5
2
4.95–4.97 m 4.67–4.73 m 3.55–3.58 m 4.21–4.24 m
C14H29
O
28
H3N
TFA
OH
27
28
Higa (Ref. 5)
MeOD
MeOD
MeOD
3.79 dd
3.79 dd
3.75–3.80 m
4.25 dd
4.23 dd
3.91 dd
3.82–3.93 m 3.70 dt
3.71 dt
3.88 m
3.82–3.93 m
4
3
Du (Ref. 15b)a
Rao (Ref. 13a)a,e
5
2
C14H29
O
4.20–4.25 m 3.80–3.90 m 3.65–3.75 m 3.80–3.90 m
61
H3N
TFA
OH
4
3
29
30
Rao (Ref. 13a)a
MeOD
MeOD
3.64–3.75 m
4.10–4.17 m 3.64–3.75 m 3.64–3.75 m 3.98–4.04 m
5
2
C14H29
O
62
H3N
OH
4
3
2
Cl
Davies (Ref. 19c)
3.73 ddd
4.28 dd
3.88–3.96 m 3.83 q
3.88–3.96 m
5
C14H29
O
75
H3N
Cl
OH
4
3
31
Davies (Ref. 19c)
MeOD
3.70–3.77 m
4.04–4.06 m 3.70–3.77 m 3.70–3.77 m 4.16–4.19 m
5
2
C14H29
O
172
a Protons assigned in this review.
b Resonance at 3.62–3.70 ppm confirmed in a personal communication from the corresponding author.
c Data kindly supplied in a personal communication from the corresponding author.
d Stereochemistry re-assigned in this review (see Section 4.4).
e Spectra kindly supplied in a personal communication from the corresponding author (peaks quoted 0.05 ppm).

E. Abraham et al. / Tetrahedron: Asymmetry 19 (2008) 1027–1047
1045
jaspine B 5 and comparison with that of 2-epi-jaspine B 6
reveals that Datta’s proposed data for the natural product
(Tables 2 and 3, entry 11 ) in fact bears close resemblance
to that of the 2-epi-jaspine B 6 (Tables 2 and 3, entries 12–
14) and displays a characteristic peak at 4.14 ppm in the 1H
NMR spectrum corresponding to one of the C(5) protons;
the all-cis stereochemistry of 2-alkyl-3-hydroxy-4-amino-
tetrahydrofuran derivatives is characterised by the absence
Table 3. Comparison of reported 13C NMR data for jaspine B 5, 2-epi-jaspine B 6, and the corresponding N,O-diacetyl derivatives 27 and 28, TFA salts 61
and 62, and HCl salts 75 and 172
Compound
Entry
Source
Solvent
C(2)
C(3)
C(4)
C(5)
1
2
3
4
5
6
7
8
9
Higa (Ref. 5)
MeOD
MeOD
MeOD
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
84.3
83.5
83.2
83.1
83.2
83.3
82.9
84.3
83.1
83.2
73.3
71.3
72.3
72.2
72.3
72.4
71.8
70.9
72.4
72.3
56.0
54.4
54.4
54.2
54.3
54.4
54.3
54.4
54.4
54.3
72.1
70.5
71.8
71.6
71.8
71.8
71.7
68.9
71.8
71.7
Shaw (Ref. 14)a
Srinivasan (Ref. 20b)a
Debitus (Ref. 11)
Kim (Ref. 12b)a
Marco (Ref. 17)a
Overkleeft (Ref. 12a)
Prasad (Ref. 18)a
Davies (Refs. 19a,19c)
Koskinen (Ref. 13c)a,b
H2N
OH
4
3
5
2
C14H29
O
jaspine B 5
10
11
12
13
14
15
Datta (Ref. 13b)a,c
Kim (Ref. 12b)a
CDCl3
CDCl3
CDCl3
CDCl3
85.1
85.2
85.2
85.3
84.4
74.6
74.8
74.7
74.8
73.1
52.5
52.7
52.6
52.6
52.0
73.1
73.1
73.1
73.2
68.0
H2N
2-
OH
4
3
5
2
Kim (Ref. 9)a
C14H29
Davies (Refs. 19a,19c)
Overkleeft (Ref. 12a)
O
-
jaspine B 6
epi
CDCl3/MeOD
16
17
18
19
20
21
22
Kim (Ref. 12b)a
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
81.2
81.2
81.2
81.1
81.2
81.2
81.0
73.5
73.5
73.6
71.4
73.6
73.5
73.5
51.3
51.3
51.4
51.2
51.3
51.3
51.5
69.9
69.9
70.0
69.7
70.0
69.8
70.0
Ramana (Ref. 16)a
Marco (Ref. 17)a
AcHN
OAc
Overkleeft (Ref. 12a)a
Yakura (Ref. 20a)a
Davies (Refs. 19a,19c)
Rao (Ref. 13a)a,d
4
3
5
2
C14H29
O
27
AcHN
OAc
23
24
Overkleeft (Ref. 12a)a
Davies (Refs. 19a,19c)
CDCl3
CDCl3
84.0
84.2
76.6
77.1
49.8
49.9
69.7
69.9
4
3
5
2
C14H29
O
28
H3N
TFA
OH
25
26
Higa (Ref. 5)a
Du (Ref. 15b)a
Rao (Ref. 13a)a,d
MeOD
MeOD
MeOD
84.3
84.4
85.0
70.9
70.9
71.5
54.3
54.3
55.0
68.9
68.9
69.5
4
3
5
2
C14H29
O
61
H3N
TFA
OH
4
3
27
28
Rao (Ref. 13a)a
MeOD
MeOD
85.2
83.4
74.3
69.9
53.7
53.4
69.4
68.0
5
2
C14H29
O
62
H3N
OH
4
3
2
Cl
Davies (Ref. 19c)
5
C14H29
O
75
H3N
Cl
OH
4
3
29
Davies (Ref. 19c)
MeOD
83.8
73.0
52.3
68.0
5
2
C14H29
O
172
a Carbons assigned in this review.
b Data kindly supplied in a personal communication from the corresponding author.
c Stereochemistry re-assigned in this review (see Section 4.4).
d Spectra kindly supplied in a personal communication from the corresponding author (peaks quoted 0.5 ppm).

1046
E. Abraham et al. / Tetrahedron: Asymmetry 19 (2008) 1027–1047
of peaks above 4 ppm in the 1H NMR spectra in CDCl3, as
found for jaspine B 5 (Table 2, entries 4–10).
16. Ramana, C. V.; Giri, A. G.; Suryawanshi, S. B.; Gonnade, R.
G. Tetrahedron Lett. 2007, 48, 265.
17. Ribes, C.; Falomir, E.; Carda, M.; Marco, J. A. Tetrahedron
2006, 62, 5421.
6. Conclusion
18. Prasad, K. R.; Chandrakumar, A. J. Org. Chem. 2007, 72,
6312.
19. (a) Abraham, E.; Candela-Lena, J. I.; Davies, S. G.;
Georgiou, M.; Nicholson, R. L.; Roberts, P. M.; Russell,
Since the isolation of jaspine B (pachastrissamine) was first
communicated (2002), there have been 13 independent syn-
theses of this natural product. This review has highlighted
some inconsistencies between the data reported for some
synthetic samples of jaspine B and that of the naturally
occurring compound. However, the majority of syntheses
(including those of 2-epi-jaspine B) corroborate the original
structural assignment. The wealth of data summarised in
this review serves to confirm the structure and
(2S,3S,4S)-absolute configuration of this natural product,
which was correctly assigned by Higa et al. in the first in-
stance and then independently by Debitus and co-workers.
´
´
A. J.; Sanchez-Fernandez, E. M.; Smith, A. D.; Thomson, J.
E. Tetrahedron: Asymmetry 2007, 18, 2510; (b) Abraham, E.;
Davies, S. G.; Millican, N. L.; Nicholson, R. L.; Roberts, P.
M.; Smith, A. D. Org. Biomol. Chem. 2008. doi:10.1039/
b801357h; (c) Abraham, E.; Brock, E. A.; Candela-Lena, J.
I.; Davies, S. G.; Georgiou, M.; Nicholson, R. L.; Perkins, J.
´
´
H.; Roberts, P. M.; Russell, A. J.; Sanchez-Fernandez, E. M.;
Scott, P. M.; Smith, A. D.; Thomson, J. E. Org. Biomol.
Chem. 2008, 6, 1665.
20. (a) Yakura, T.; Sato, S.; Yoshimoto, Y. Chem. Pharm. Bull.
2007, 55, 1284; (b) Venkatesan, K.; Srinivasan, K. V.
Tetrahedron: Asymmetry 2008, 19, 209.
21. Chandrasekhar, S.; Tiwari, B.; Prakash, S. J. ARKIVOC
2006, 155.
References
´
´
22. Genisson, Y.; Lamande, L.; Salma, Y.; Andrieu-Abadie, N.;
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26. The configurations of the newly formed C(10)-stereocentres
within alcohols (4S,5S,10S)-36 and (4S,5S,10R)-173 could not
be assigned a priori; they were established via conversion to
the corresponding N,O,O,O-tetra-acetyl phytosphingosines
174 and 175. Global hydrolysis of the protecting groups
within the major diastereoisomeric alcohol (4S,5S,10S)-36
was achieved upon treatment with HCl in MeOH/H2O, with
subsequent acetylation giving N,O,O,O-tetra-acetyl D-lyxo-
phytosphingosine 174 with spectroscopic properties in excel-
7. The absolute configuration of (R)-8 was assigned by its
devitalisation to the corresponding (R)- and (S)-MTPA
derivatives see: (a) Dale, J. A.; Dull, D. L.; Mosher, H. S.
J. Org. Chem. 1966, 34, 2543. This result was in accord with
the established mnemonic for the Sharpless asymmetric
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89.
8. (a) Sugiyama, S.; Honda, M.; Komori, T. Liebigs Ann. Chem.
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Ann. Chem. 1990, 1069; Birk, R.; Sandhoff, K.; Schmidt, R.
R. Liebigs Ann. Chem. 1993, 71.
21
lent agreement with those previously reported {½aꢂD ¼ ꢀ3:1
22
(c 0.7 in CHCl3); lit.27 ½aꢂD ¼ ꢀ3:1 (c 1.1 in CHCl3)}.
Analogous treatment of the minor diastereoisomeric alcohol
9. Jo, S. Y.; Kim, H. C.; Jeon, D. J.; Kim, H. R. Heterocycles
2001, 55, 1127.
(4S,5S,10R)-173 gave N,O,O,O-tetra-acetyl D-ribo-hytosp-
22
hingosine 175 {½aꢂD ¼ þ18:2 (c 1.0 in CHCl3); lit.27
10. For other examples of nucleophilic displacement of aromatic
nitro groups see: (a) Beck, J. R. Tetrahedron 1978, 34, 2057;
(b) Benedetti, F.; Marshall, D. R.; Stirling, C. J. M.; Lengb, J.
L. J. Chem. Soc., Chem. Commun. 1982, 1918; (c) Robert, J.;
Anouti, M.; Bosser, G.; Parrain, J.-L.; Paris, J. J. Chem. Soc.,
Perkin Trans. 2 1995, 1639.
22
½aꢂD ¼ þ21:9 (c 1.1 in CHCl3)} (Scheme 21).
11. Ledroit, V.; Debitus, C.; Lavaud, C.; Massoit, G. Tetra-
hedron Lett. 2003, 44, 225.
12. (a) van den Berg, R. J. B. H. N.; Boltje, T. J.; Verhagen, C. P.;
Litjens, R. E. J. N.; Van der Marel, G. A.; Overkleeft, H. S. J.
Org. Chem. 2006, 71, 836; (b) Lee, T.; Lee, S.; Kwak, Y. S.;
Kim, D.; Kim, S. Org. Lett. 2007, 9, 429.
13. (a) Sudhakar, N.; Ravi Kumar, A.; Prabhakar, A.; Jaga-
deesh, B.; Rao, B. V. Tetrahedron Lett. 2005, 46, 325; (b)
Bhaket, P.; Morris, K.; Stauffer, C. S.; Datta, A. Org. Lett.
2005, 7, 875; (c) Passiniemi, M.; Koskinen, A. M. P.
Tetrahedron Lett. 2008, 49, 980.
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Asymmetry 2007, 18, 542.
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1251; (b) Liu, J.; Du, Y.; Dong, X.; Meng, S.; Xiao, J.;
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1047
27. Shirota, O.; Nakanishi, K.; Berova, N. Tetrahedron 1999, 55,
13643.
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