Asymmetric synthesis of (+)-abresoline

Article abstract of DOI:10.1016/j.tetlet.2005.02.110

The first asymmetric synthesis of (+)-abresoline has been achieved starting from the (S)-1-(aryl)homoallylic amine, which was prepared enantioselectively by the method based on allylation of the (R)-2′-(2-naphthyl)-bearing hydroxyoxime ether. This synthetic route employs the TiCl₄-induced intramolecular Mannich-type cyclization of the 1-azadiene-bearing ketal amine as the key steps to afford stereoselectively the cis-2,6-disubstituted piperidine, followed by CBr₄/PPh₃-induced dehydrocyclization for the elaboration of the amino alcohol to the trans-4-arylquinolizidine.

Full text of DOI:10.1016/j.tetlet.2005.02.110

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2669–2673
Asymmetric synthesis of (+)-abresoline
Masakazu Atobe, Naoki Yamazaki and Chihiro Kibayashi*
School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Received 5 January 2005; revised 7 February 2005; accepted 10 February 2005
Abstract—The first asymmetric synthesis of (+)-abresoline has been achieved starting from the (S)-1-(aryl)homoallylic amine, which
was prepared enantioselectively by the method based on allylation of the (R)-20-(2-naphthyl)-bearing hydroxyoxime ether. This
synthetic route employs the TiCl4-induced intramolecular Mannich-type cyclization of the 1-azadiene-bearing ketal amine as the
key steps to afford stereoselectively the cis-2,6-disubstituted piperidine, followed by CBr4/PPh3-induced dehydrocyclization for
the elaboration of the amino alcohol to the trans-4-arylquinolizidine.
Ó 2005 Elsevier Ltd. All rights reserved.
The 4-arylquinolizidin-2-ol (1)1 and its ferulate abreso-
line (2),2 both isolated from young seedlings of Heimia
salicifolia,1 are members of the arylquinolizidine class
of lythraceae alkaloids.3 This class of alkaloids including
lasubine I (3) and II (5),4 and their 3,4-dimethoxycinn-
amate esters subcosine I (4) and II (6)4 have attracted
increasing interest as synthetic targets, and numerous
syntheses of these alkaloids in either racemic or enantio-
merically pure form have been reported.5–8 However,
there have been no reports dealing with the asymmetric
synthesis of abresoline, though its racemic syntheses
have been reported.5b,c
No description of the optical rotation data for the quin-
olizidol 1 and abresoline (2) has been given in the litera-
ture,1,2 and their absolute stereochemistries have not
been established but were assumed to have the configu-
ration depicted in Figure 1 by analogy with the closely
Ph
OH
HO
7
O
O
Ph
Ar
N
Ar
N
Recently, we have reported9 that the arylaldehyde oxime
ethers 8 and 9 bearing (10S)-20-hydroxy-10-phenylethyl
and (20R)-20-hydroxy-20-phenylethyl groups, respec-
tively, as chiral auxiliaries both derived from (R)-1-
phenyl-1,2-ethanediol (7) underwent nucleophilic addi-
tion of organolithium reagents to the re-and si-faces of
the C@N bonds of six-membered chelation intermedi-
ates 10 and 11, leading to the (R)- and (S)-adducts 12
and 13, respectively (Scheme 1). After removal of the
chiral auxiliary by reductive N–O bond cleavage, the
EPC preparation of both enantiomers of primary
1-(aryl)alkylamine 14 has thus been established in an
enantiodivergent fashion. On the basis of this hydroxy-
oxime ether-based protocol herein, we report the first
enantioselective total synthesis of (+)-abresoline (2).
HO
Ph
HO
8
9
RLi
RLi
H
Li
O
Ar
N
R
R
O
Li
Ph
Ph
O
re
si
Li
Li
N
H
O
11
10
Ar
R
R
O
Ph
O
Ar
N
Ar
N
H
H
HO
HO
Ph
12
13
R
R
Ar
NH2
(R)-14
Ar
NH2
(S)-14
*
Corresponding author. Tel.: +81 426 76 3275; fax: +81 426 76
4475; e-mail: kibayasi@ps.toyaku.ac.jp
Scheme 1. Enantiodivergent synthesis of 1-(aryl)alkylamines 14.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.02.110

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M. Atobe et al. / Tetrahedron Letters 46 (2005) 2669–2673
O
O
O
N
O
O
OH
N
H
2
OMe
N
H
H
H
OR
N
MeO
MeO
HO
OR
15
OR
MeO
1 R = H
MeO
16
OR
OR
abresoline (2) R = H
(+)-subcosine II (6) R = Me
(–)-lasubine II (5) R = Me
O
O
O
O
Me
OH
NH2
N
OMe
MeO
H
H
MeO
R'O
OMe
OR
18
N
N
OR
17
MeO
MeO
OMe
(–)-lasubine I (3)
OMe
(+)-subcosine I (4)
Scheme 2.
Figure 1. Structures of 4-arylquinolizidine alkaloids.
as a major isomer but with low diastereoselectivity of
2:1. When the hydroxyoxime ether 19b bearing a 10-(2-
naphthyl) group was subjected to the same conditions,
the allylation reaction proceeded but led to the loss of
diastereoselectivity (20b/21b = 1:1, entry 2). Reversal of
the diastereoselectivity in allylation was observed for
19c incorporating the 20-phenyl group, resulting in the
allylated product 21c (R1 = H, R2 = Ph) with the desired
S configuration in a 2.5:1 diastereomeric ratio (entry 3).
Use of the oxime ether 19d bearing a 20-(1-naphthyl)
group also led to the (S)-adduct 21d (R1 = H, R2 = 1-
naphthyl) with low diastereoselectivity of 2:1 (entry 4),
but a significant improvement in the diastereoselectivity
(21e/20e = 5:1) was obtained upon using 19e incorporat-
ing a 20-(2-naphthyl) group (entry 5). In all cases, diaste-
reomers were separable by column chromatography,
and the absolute configuration of the major isomers
was determined by N–O bond cleavage (Zn, AcOH) of
the reaction products and comparison of the optical
rotation of the obtained homoallylic amine with the
reported data.10
related lythraceae alkaloids, (ꢀ)-lasubine II (5) and (+)-
subcosine II (6), both belonging to the trans-quinoliz-
idine series. Thus, from the retrosynthetic analysis out-
lined in Scheme 2, we envisioned an enantioselective
approach to 2 utilizing the 1-(aryl)homoallylic amine
18 with the S configuration as the starting material,
which could be prepared by allylation of an appropriate
hydroxyoxime ether. Subsequent elaboration of the (S)-
imine 17 to the cis-2,6-disubstituted piperidine 16 by an
intramolecular Mannich-type cyclization followed by
intramolecular cyclization would provide the quinolizid-
inone 15 as a key precursor to abresoline (2).
On the basis of this analysis, our initial investigation fo-
cused on enantioselective synthesis of the 1-(aryl)homo-
allylic amines by nucleophilic addition of allyllithium to
the hydroxyoxime ethers 19 prepared by condensation
of veratraldehyde with the (S)-2-aryl aminooxy ethanol
(for 19a and 19b) or the (R)-1-aryl aminooxy ethanol
(for 19c–e) according to our previous paper.9 As can
be seen in Table 1 (entry 1) upon treatment with allyl-
lithium (5 equiv) in toluene–Et2O (1:1) at 40 °C for
20 min, the allylation of the hydroxyoxime ether 19a
bearing a 10-phenyl group was found to proceed to
afford the (R)-allylated product 20a (R1 = Ph, R2 = H)
It is interesting that the diastereoselectivity observed in
the allylation is significantly lower (actually not stereo-
selective) for the 10-(2-naphthyl)-bearing hydroxyoxime
ether 19b than for 20-(2-naphthyl)-bearing hydroxy-
oxime ether 19e since in our previous studies9 we recog-
Table 1. Diastereoselective addition of allyllithium to hydroxyoxime ethers 19a–e
MeO
MeO
O
R1
R2
CH2=CHCH2Li
R1
R2
MeO
MeO
O
R1
R2
N
MeO
MeO
O
+
R
S
N
N
toluene–THF (1:1)
20 min
H
H
HO
HO
HO
19a–e
20a–e
21a–e
Entry
Substrate
R1
Ph
R2
H
Temperature (°C)
Yielda (%)
20/21 Ratiob
1
2
3
4
5
19a
19b
19c
19d
19e
40
40
45
45
45
63
73
70
77
75
2:1
1:1
2-Naphthyl
H
Ph
H
H
H
1:2.5
1:2
1-Naphthyl
2-Naphthyl
1:5
a Isolated yield.
b Ratio determined by 1H NMR spectroscopy on the crude products mixture.

M. Atobe et al. / Tetrahedron Letters 46 (2005) 2669–2673
2671
OH
nized that the diastereoselectivities of the nucleophilic
additions of methyllithium and vinyllithium were gener-
ally higher for the 10-phenyl-bearing hydroxyoxime
ethers (8 in Scheme 1) than for the 20-phenyl-bearing
hydroxyoxime ethers (9 in Scheme 1). The low diastereo-
selectivity for 19b can be rationalized by means of a
six-membered chelate model 22 (Fig. 2), which consti-
tutes a g3-allyl-complex11 with lithium coordination to
the oxime ether oxygen atom in axial mode to avoid
1,3-allylic strain.12 This transition state model 22 pre-
sents an unfavorable steric interaction between the allyl
and the equatorially-oriented 2-naphthyl group, pre-
venting the stereoselective formation of the expected
(R)-allyl adduct 20b (R1 = 2-naphthyl, R2 = H). In the
allylation of 19e, this interaction is avoided in the tran-
sition state 23, leading to the preferential formation of
the (S)-allyl adduct 21e (R1 = H, R2 = 2-naphthyl).
BnO
MeO
CHO
toluene, refl.
98%
ONH2
+
24
25
BnO
MeO
O
N
CH2=CHCH2Li
HO
toluene–Et2O, 45 ˚C
70%
26
BnO
MeO
O
S
N
+
(1'R)-isomer
H
HO
4:1
27
Zn, AcOH
NH2
THF–H2O, 60 ˚C
82%
MeO
O
Having established the protocol for the enantioselective
preparation of the (S)-homoallylic amine 21e via allyl-
ation of the oxime ether 19e incorporating the 20-
(2-naphthyl) group, we sought to use this method for
the synthesis of the (S)-homoallylic amine 28 required
for the synthesis of abresoline (2). The requisite oxime
ether 26 was prepared in 98% yield by condensation of
O-benzylisovanilline (24) with the (R)-1-(2-naphthyl)
aminooxy ethanol 25. Treatment of 26 with allyllithium
under the same conditions used for the allylation of 19e
(Table 1, entry 5) produced the (S)-adduct 27 as a major
isomer in a 4:1 ratio and 70% combined yield (Scheme
3). Removal of the chiral auxiliary was carried out by
reductive N–O bond cleavage with zinc and acetic acid
to yield the (S)-homoallylic amine 28 with the chiral
auxiliary ((1R)-1-naphthalen-2-ylethane-1,2-diol) being
recovered. After protection of the amino group as the
phthalimide, Wacker oxidation of the terminal alkene
of 29 gave the methyl ketone 30, which was then con-
verted to the ketal amine 31 by the standard procedure
involving acetalization followed by phthalimide
cleavage.
OBn
28
PdCl2, CuCl2, O2
phthalic anhydride
N
toluene, refl.
87%
DMF–H2O, 85 ˚C
86%
MeO
O
OBn
29
O
1) ethylene glycol, TsOH
benzene, refl.
2) (NH2)2·H2O, EtOH, refl.
O
O
Me
O
Me
N
NH2
69%
MeO
O
MeO
OBn
OBn
31
30
Scheme 3.
by condensation of the ketal amine 31 with 5-benzyloxy-
pentanal, by acidic treatment (TsOH in benzene at
reflux or TiCl4 in CH2Cl2 at 0 °C) failed to yield the
cis-2,6-disubstituted piperidine 16 (R = Bn) and instead
gave rise to a complex mixture of products, possibly
due to the instability of the iminium intermediate gener-
ated from 17 under the reaction conditions. We then
sought to utilize the 1-azadiene 33 for the cyclization,
in anticipating that its use in the acid-mediated Man-
nich-type cyclization would be effective in stabilizing
the iminium intermediate by mesomeric effect of the
olefinic double bond. Thus, the ketal amine 31 was con-
densed with 5-benzyloxypent-2-enal (32)14 to give 33.
Upon treatment of 33 with TiCl4 in CH2Cl2 at 0 °C,
the intramolecular Mannich-type cyclization smoothly
occurred15 with accompanying selective cleavage of the
phenolic benzyl ether that afforded the cis-2,6-disubsti-
tuted piperidine 34 in 88% yield as a single isomer
(Scheme 4). The cis stereochemistry of 34 was confirmed
by a NOESY interaction between H-2 and H-6 of the
piperidine ring.
Following the retrosynthetic analysis shown in
Scheme 2, the attempted intramolecular Mannich-type
cyclization13 of the imine 17 (R = R0 = Bn), prepared
19b
19e
H
Ar
N
O
Li
O
Li
O
Li
re
si
Li
N
H
23
O
Ar
22
21e
Ar =
OMe
OMe
20b
Catalytic hydrogenation of the olefin moiety of 34 with
simultaneous cleavage of the benzyl ether afforded the
amino alcohol 35, which upon treatment with CBr4 and
Figure 2.

2672
M. Atobe et al. / Tetrahedron Letters 46 (2005) 2669–2673
anhydride in refluxed pyridine in the presence of 1 equiv
of DMAP. Finally, simultaneous deprotection of the
TBDMS and MOM ethers with BF3ÆOEt2 in acetonitrile
O
O
BnO
CHO
Me
32
31
N
CHCl3, rt
quant.
at 0 °C furnished (+)-abresoline (2) in 84% yield. Our
20
synthetic sample of 3 was found to have ½aꢁ þ 91:1
D
(c 1.2, MeOH) and to be identical with natural abreso-
MeO
BnO
OBn
1
line2 by IR, H NMR, and mass spectra.
33
The first asymmetric synthesis of (+)-abresoline (2) has
thus been achieved starting with the (S)-1-(aryl)homo-
allylic amine 28, which was prepared enantioselectively
by the method based on allylation of the (R)-20-(2-naph-
thyl)-bearing hydroxyoxime ether 26. This synthetic
route employs as the key steps the TiCl4-induced intramo-
lecular Mannich-type cyclization of the 1-azadiene-bear-
ing ketal 33 to afford the cis-2,6-disubstituted piperidine
34, followed by CBr4/PPh3-induced dehydrocyclization
for the elaboration of the amino alcohol 35 to the trans-
4-arylquinolizidine 36. Although the absolute configur-
ation and the optical rotation of natural abresoline have
not yet been determined (no literature data are available),
since the optical rotation value for 2 was first obtained by
the present synthesis, determination of the absolute
configuration of abresoline will become possible by re-
isolation of the natural product and optical rotation
measurement.
O
O
TiCl4, CH2Cl2, 0 ˚C
88%
N
H
MeO
BnO
OH
34
Scheme 4.
Ph3P16 in Et3N/CH2Cl2 at room temperature dehydro-
cyclized to give the trans-quinolizidine 36 [IR (CHCl3)
] in 76% yield
Bohlmann bands, 2885–2778 cmꢀ1
(Scheme 5). Deketalization followed by silyl protection
of the phenolic hydroxyl group gave the quinolizidin-
2-one 37, which was subjected to stereoselective reduc-
tion with LS-SelectrideÒ to produce the quinolizidin-2-
ol 38 as a single isomer. Conversion of 38 to the ferulate
ester 39 (86%) was effected using MOM-protected ferulic
References and notes
1. Rother, A.; Schwarting, A. E. Experientia 1974, 30, 222–
223.
O
O
H2, Pd/C
CBr4, Ph3P
2. Ho¨rhammer, R. B.; Schwarting, A. E.; Edwards, J. M.
J. Org. Chem. 1975, 40, 656–657.
3. (a) For reviews of the lythraceae alkaloids, see: Golebiew-
34
THF–MeOH
93%
N
Et3N, CH2Cl2, rt
76%
H
MeO
HO
´
ski, W. M.; Wrobel, J. T. In The Alkaloids; Rodrigo, R. G.
OH
35
A., Ed.; Academic: New York, 1981; Vol. 18, Chapter 4;
(b) Fuji, K. In The Alkaloids; Brossi, A., Ed.; Academic:
San Diego, 1989; Vol. 35, Chapter 3.
O
N
O
O
1) HCl, THF, refl.
4. For isolation, see: Fuji, K.; Yamada, T.; Fujita, E.;
Murata, H. Chem. Pharm. Bull. 1978, 26, 2515–2521.
5. For a racemic synthesis of the 4-arylquinolizidin-2-ol (1),
see: (a) Takano, S.; Shishido, K. J. Chem. Soc., Chem.
Commun. 1981, 940–942; For racemic syntheses of abres-
oline, see: (b) Quick, J.; Ramachantra, R. Synth. Commun.
1978, 8, 511–514; (c) Takano, S.; Shishido, K. Heterocy-
cles 1982, 19, 1439–1441.
6. For racemic syntheses of lasubine I, see: (a) Iida, H.;
Tanaka, M.; Kibayashi, C. J. Chem. Soc., Chem. Commun.
1983, 1143; (b) Iida, H.; Tanaka, M.; Kibayashi, C. J. Org.
Chem. 1984, 49, 1909–1912; (c) Ent, H.; De Koning, H.;
Speckamp, W. N. Heterocycles 1988, 27, 237–243; (d)
Beckwith, A. L. J.; Joseph, S. P.; Mayadunne, R. T. A. J.
Org. Chem. 1993, 58, 4198–4199; (e) Bardot, V.; Gardette,
D.; Gelas-Mialhe, Y.; Gramain, J.-C.; Remuson, R.
Heterocycles 1998, 48, 507–518; For asymmetric syntheses
of (ꢀ)-lasubine I, see: (f) Commins, D. L.; LaMunyon, D.
H. J. Org. Chem. 1992, 57, 5807–5809; (g) Chalard, P.;
Remuson, R.; Gelas-Mialhe, Y.; Gramain, J.-C. Tetrahe-
dron: Asymmetry 1998, 9, 4361–4368; (h) Ratoni, H.;
Kuendig, E. P. Org. Lett. 1999, 1, 1997–1999; (i) Davis, F.
A.; Rao, A.; Carroll, P. J. Org. Lett. 2003, 5, 3855–3857.
7. For racemic syntheses of lasubine II, see: Refs. 6a,b and
Pilli, R. A.; Dias, L. C.; Maldaner, A. O. J. Org. Chem.
1995, 60, 717–722, and references cited therein; For
2) TBDMSOTf, Py., 0 ˚C
H
H
N
82%
MeO
MeO
OTBDMS
OH
36
37
O
OH
N
MOMO
MeO
O
LS-Selectride®
H
2
THF, –78 ˚C
83%
DMAP, Py., refl.
86%
MeO
OTBDMS
38
O
O
N
BF3·OEt2
OMe
OMOM
H
MeCN, 0 ˚C
84%
MeO
OTBDMS
(+)-abresoline (2)
39
Scheme 5.

M. Atobe et al. / Tetrahedron Letters 46 (2005) 2669–2673
2673
asymmetric syntheses of (ꢀ)-lasubine II, see: Ref. 6g and
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reference cited therein.
´
Gracias, V.; Zeng, Y.; Desai, P.; Aube, J. Org. Lett. 2003,
5, 4999–5001, and references cited therein.
8. For a racemic synthesis of subcosine I, see: Refs. 6a,b. For
an asymmetric synthesis of (+)-subcosine I, see: Ref. 6f.
For an asymmetric synthesis of (+)-subcosine II, see:
Ref. 6g.
14. Belval, F.; Chavis, C.; Montero, J.; Lucas, M. Synth.
Commun. 1998, 10, 1823–1838.
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refluxing benzene according to reported procedures (Ref.
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