Asymmetric total synthesis of (-)-deoxoprosophylline

Article abstract of DOI:10.1016/S0040-4039(01)00483-X

Asymmetric syntheses of (-)-deoxoprosophylline from chiral L-N,N-dibenzyl serine (TBDMS) aldehyde is reported. A highly diastereoselective intramolecular reductive amination of ω-oxo amino diol is a key step of the present synthesis.

Full text of DOI:10.1016/S0040-4039(01)00483-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3431–3434
Asymmetric total synthesis of (−)-deoxoprosophylline
Ange´lique Jourdant and Jieping Zhu*
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette, France
Received 20 March 2001; accepted 22 March 2001
Abstract—Asymmetric syntheses of (−)-deoxoprosophylline from chiral L-N,N-dibenzyl serine (TBDMS) aldehyde is reported. A
highly diastereoselective intramolecular reductive amination of v-oxo amino diol is a key step of the present synthesis. © 2001
Elsevier Science Ltd. All rights reserved.
2,6-Dialkylated piperidine alkaloids have been found
abundantly in nature and are key structural units in
many medicinally important compounds.1 Prosopis
alkaloids, isolated from Prosopis africana, forms a sub-
group possessing a characteristic 3-hydroxy function.2
Structurally, these compounds, possessing a polar head
group and a hydrophobic aliphatic tail, can be consid-
ered as cyclic analogues of membrane lipid sphin-
gosine.3 Indeed, interesting bioactivities including
analgesic, anaesthetic and antibiotic have been reported
for prosophylline, prosopinine and their deoxygenated
derivatives (1–4, Fig. 1). Although many elegant syn-
theses of piperidine alkaloids have been developed,4
asymmetric syntheses of optically pure prosopis alka-
loids appeared only recently.5 As an extension of our
of dioxolane followed by reduction of ester gave the
primary alcohol 15. The one-step transformation of
hydroxyl function to bromide was best realized using a
couple (Ph3P–CBr4) in the presence of a base (Et3N).
Without adding Et3N, the reaction was low-yielding
due to probably the in situ generation of hydrogen
bromide, that can hydrolyze the dioxolane function and
provoke side-reactions thereof.10 Unfortunately, under
diverse reaction conditions varying the magnesium
sources, the equivalents of dibromoethane and the tem-
perature, we were unable to convert 16 into the adduct
17. When the reaction was carried out at or below
room temperature, no addition reaction occurred and
only a proto-debromination product of 16 was isolated
after aqueous workup. To probe the reactivity of this
magnesium, we investigated its reaction with heptanal
and benzaldehyde. However, in neither of these two
cases was the secondary alcohol produced. The low
reactivity of this type of Grignard reagent has been
observed previously and has been explained by an
work on the
aldehyde (
L-(N,N-dibenzylamino)serine (TBDMS)
L
-6),6–8 we thought to synthesize both deoxo-
prosophylline 1 and deoxoprosopinine 3 from v-oxo-
amino diol 7 featuring a key intramolecular reductive
amination. Compound 7 can be synthesized by a nucleo-
philic addition of Grignard reagent 8 to the serine
aldehyde
L
-6. Alternatively, it can be obtained by a
X
H
N
H2N
stepwise homologation of the same starting chiral pool
via an aldehyde 10 (Scheme 1). We report herein a
concise synthesis of (−)-deoxoprosophylline (1) accord-
ing to the latter strategy.
OH
OH
OH
OH
8
12
1 X = H, H, (-)-deoxoprosophylline
2 X = O, (-)-prosophylline
5 sphingosine
Bromide 16, a precursor of Grignard reagent 8, was
synthesized as shown in Scheme 2. Mono alkylation of
methyl acetoacetate by 1-bromoundecane gave the
homologated b-keto ester (13) in 70% yield.9 Formation
X
H
N
OTBDMS
OH
O
H
8
Bn2N
OH
Keywords: hydroxypiperidine; deoxoprosophylline; N,N-dibenzyl ser-
ine (OTBS) aldehyde; facial selectivity; intramolecular reductive ami-
nation.
3 X = H, H, (-)-deoxoprosopinine
4 X = O, (-)-prosopinine
L-6
* Corresponding author. Fax: 33 1 69 07 72 47; e-mail: zhu@
icsn.cnrs-gif.fr
Figure 1.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00483-X

3432
A. Jourdant, J. Zhu / Tetrahedron Letters 42 (2001) 3431–3434
MgBr
H
N
Bn2N
L-6
O
O
9
OH
OH
+
OH
OH
10
8
10
O
Bn2N
OTBDM
1 and/or 3
7
MgBr
S
H
+
10
OH
O
9
10
Scheme 1. Retro-synthetic analysis of deoxoprosophylline and deoxoprosopinene.
O
O
O
O
O
O
a
b
c
O
MeO
HO
MeO
MeO
10
10
11
13
14
Bn2N
O
OTBDMS
OH
d
O
O
e
O
O
X
Br
O
10
10
10
15
16
17
Scheme 2. Reagents and conditions: (a) LDA (2.2 equivalents), then C11H23Br (12), THF, 70%; (b) TMSCl, HOCH2CH2OH,
CH2Cl2, 88%; (c) LiBH4, Et2O–MeOH, 97%; (d) PPh3, CBr4, CH2Cl2, 89%; (e) Mg, THF, then -6.
L
internal solvolysis of the magnesium by the dioxolane
oxygen.11 When the reaction was performed at 60°C or
under sonification conditions,12 a complex reaction
mixture was obtained due to probably the degradation
of both the aldehyde and the magnesium.13
amino diol 19 in excellent yield and diastereoselectivity
(anti/syn=15/1). The major stereomer was assumed to
be anti according to the Felkin–Anh model15 and this is
corroborated by the synthesis of the final compound.
Protection of the secondary alcohol as benzyl ether
followed by acidic hydrolysis of dioxolane gave the
aldehyde 21a. Reaction of aldehyde 21a with an excess
of dodecylmagnesium bromide afforded alcohol 22a as
a mixture of two diastereomers in a 1:1 ratio.16 On the
other hand, a moderate diastereoselectivity (dr 7/3) was
Synthesis of (−)-deoxoprosophylline was finally accom-
plished as depicted in Scheme 3. Addition of Bu¨chi’s
Grignard reagent,14 prepared in situ from the corre-
sponding bromide 18, to the aldehyde
L
-6 gave the
Bn2N
Bn2N
OTBDMS
OTBDMS
Br
O
a
b
c
O
O
OBn
OH
O
O
O
18
Bn2N
19
20
Bn2N
Bn2N
OTBDMS
OR
OR
d
e
C12H25
C
12H25
H
OBn
OBn
OBn
O
O
OH
21a R = H
21b R = TBDMS
22a R = H
22b R = TBDMS
23
H
N
f
g
1
OH
8
OBn
24
Scheme 3. Reagents and conditions: (a) Mg, THF, room temperature, then
L
-6, 86%; (b) NaH, BnBr, BuNI, THF, 0°C, then room
temperature, 85%; (c) (i) 3N HCl–THF, (ii) TBDMSCl, imidazole, DMF, room temperature, 90%; (d) C12H25Br, Mg,
dibromoethane, THF, then 21b, 70°C, 80%; (e) DMSO, (COCl2) then Et3N, 84%; (f) Pd(OH)2, cyclohexene, EtOH, reflux, (g)
Pd/C, MeOH, 73%.

A. Jourdant, J. Zhu / Tetrahedron Letters 42 (2001) 3431–3434
3433
H-
HO
BnO
HO
N
N
R
C12H25
R
C12H25
A
B
OBn
R = H or Bn
H-
HO
BnO
HO
N
C12H25
R
N
R
OBn
C12H25
24 R = H
Scheme 4. Stereochemical issue.
observed when the Grignard addition was performed
on the fully protected aldehyde 22b.17 This lack of
diastereoselectivity was nevertheless of no consequence
since the chiral centre in question was anyway thought
to be introduced at the end of the synthesis via reduc-
tion of a cyclic iminium.
Acknowledgements
A doctoral fellowship from the MRES to A.J. is grate-
fully acknowledged.
Swern oxidation of alcohol 22b afforded ketone 23 in
84% yield. Catalytic hydrogenation of 22b under acidic
conditions (3N HCl, MeOH, Pd/C, H2) furnished
directly the (−)-deoxoprosophylline (1) in 63% yield.
However, this process is found to be non-reproducible
and an alternative two-step process was developed.
Thus, under catalytic transfer hydrogenolysis condi-
tions developed recently by Bajwa and co-workers
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