Stereoselective allyl amine synthesis via enantioselective addition of diethylzinc and sigmatropic rearrangement; synthesis of lentiginosine

Article abstract of DOI:10.1055/s-2003-39314

A new synthetic method for the preparation of allyl amine derivatives has been developed. The key steps of this method are enantioselective addition of diethylzinc (Soai protocol) and allyl cyanate-to-isocyanate rearrangement. Successful application of th

Full text of DOI:10.1055/s-2003-39314

1034
LETTER
Stereoselective Allyl Amine Synthesis via Enantioselective Addition of
Diethylzinc and Sigmatropic Rearrangement; Synthesis of Lentiginosine
S
ynthesis of Lentig
o
inosine shiyasu Ichikawa,* Takashi Ito, Taihei Nishiyama, Minoru Isobe
Laboratory of Organic Chemistry, School of Bioagricultural Sciences, Nagoya University, Chikusa, Nagoya 464-8601, Japan
Fax +81(52)7894111; E-mail: ichikawa@agr.nagoya-u.ac.jp
Received 6 March 2003
OH
H
HO
Abstract: A new synthetic method for the preparation of allyl
amine derivatives has been developed. The key steps of this method
are enantioselective addition of diethylzinc (Soai protocol) and allyl
cyanate-to-isocyanate rearrangement. Successful application of this
procedure realized the synthesis of lentiginosine (6).
L-tartaric acid
N
Lentiginosine (6)
Key words: stereoselective, asymmetric synthesis, amines, rear-
rangements, natural products
Figure 1
2-yl)methanol (DPMPM) smoothly afforded 9 and its
epimer as an inseparable 93:7 mixture.7 Treatment of 9
with trichloroacetyl isocyanate followed by hydrolysis
with potassium carbonate in aqueous methanol gave the
carbamate 10. Dehydration of 10 with triphenylphos-
phine, carbon tetrabromide and triethylamine at –20 °C
gave the allyl cyanate 11, which underwent [3,3]-sigma-
tropic rearrangement to afford the allyl isocyanate 12.
Since isolation of 12 using an aqueous work-up would
result in a decrease of yield due to the hydrolysis of the
isocyanate group, isocyanate 12 was treated in situ with
2,2,2-trichloroethanol to afford trichloroethoxy (Troc)
carbamate 13 in 86% yield from 10.
In connection with ongoing efforts to explore [3,3]-sigma-
tropic rearrangement of allyl cyanate for the synthesis of
natural products,1 we recently developed a stereoselective
allyl amine synthesis as shown in Scheme 1.
enantioselective
addition of Et2Zn
R
Et
R
Et
*
*
R
H
OH
O
N
C
O
2
1
3
R
H
Et
R
Et
*
*
[3,3]-sigmatropic
rearrangement
ROH
N
N
C
COOR
O
5
4
Scheme 1
Et2Zn, (S)-DPMPM
cyclohexane
O
O
O
O
IBX, DMSO
(90%)
The reaction sequence starts with the preparation of
stereochemically defined allyl alcohol 2 employing an
enantioselective addition of diethylzinc to a,b-unsaturat-
ed aldehyde 1.2 The resulting allyl alcohol 2 is then trans-
formed into allyl cyanate 3 which rearranges into allyl
isocyanate 4 with high degree of 1,3-chirality transfer.3
Finally, treatment of 4 with alcohols furnish a variety of
carbamates 5. This method will offer a useful entry to the
stereoselective synthesis of the protected allyl amine de-
rivatives. In this manuscript, we described successful ap-
plication of this procedure to the synthesis of the most
potent inhibitor of amyloglucosidase, lentiginosine (6),4
from L-tartaric acid (Figure 1).
(93:7, 91%)
TBSO
TBSO
TBSO
OH
CHO
8
7
9
i) CCl3CONCO
O
O
O
O
ii) K2CO3, MeOH,
H2O
TBSO
(95%)
Et
O
Et
10
HO
O
H2N
O
O
C
[3,3]-sigmatropic
rearrangement
PPh3,CBr4,Et3N,
–20 °C to 0 °C
TBSO
Synthesis of lentiginosine (6) began with the o-iodoxy-
benzoic acid (IBX) oxidation of allyl alcohol 7,5 which
was prepared from L-tartaric acid employing known
procedure6 (Scheme 2). Enantioselective addition of di-
ethylzinc to the resulting a,b-unsaturated aldehyde 8
catalyzed by 7 mol% of (S)-diphenyl(1-methylpyrrolidin-
Et
11
N
O
O
O
O
O
TBSO
Cl3CCH2OH
(86%)
TBSO
O
C
NH
Et
O
C
N
Et
OCH2CCl3
Synlett 2003, No. 7, Print: 02 06 2003.
Art Id.1437-2096,E;2003,0,07,1034,1036,ftx,en;U04303ST.pdf.
13
12
© Georg Thieme Verlag Stuttgart · New York
Scheme 2

LETTER
Synthesis of Lentiginosine
1035
Since allyl carbamate 13 has three stererogenic centers spectroscopic properties were identical with those previ-
necessary for lentiginosine synthesis, we next turned to ously reported.11
the construction of indolizidine ring system using ring-
closing metathesis (RCM) (Scheme 3).
In summary, a combination of Soai protocol and sigma-
tropic rearrangement for the stereoselective allyl amine
synthesis has been realized in the context of the synthesis
of lentiginosine (6). Further examination to test the gener-
ality of this stereocontrolled ally amine synthesis is now
under way.
Acknowledgment
This research was financially supported by a Grant-In-Aid for
Scientific Research from the Ministry of Education, Science,
Sports and Culture.
References
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Thus, deprotection of 13 with zinc and acetic acid in THF
followed by treatment of the resulting amine with 2-ni-
trobenzenesulfonyl chloride and Et3N furnished the nosyl
amide 15 as crystals.8 Alkylation of 14 with 3-buten-1-ol
Singh, V. K. J. Org. Chem. 2002, 67, 4630. (o) Feng, Z.-X.;
under Mitsunobu condition (PPh3, DEAD, benzene) af-
forded 1,7-diene 15.9 A ruthenium-catalyzed RCM using
Grubbs catalysis (6 mol%) in refluxing benzene gave the
cyclized product 16.10 Removal of the silyl protecting
group in 16 with tetra-n-butylammonium fluoride fol-
lowed by tosylation of the resulting primary alcohol 17
furnished the tosylate 18. Two-step protective group ma-
nipulation involving acetonide hydrolysis (3 N HCl, aq
THF, 50 °C) and MOM protection (dimethoxymethane,
P2O5) gave 20. Deprotection of the nosyl group with con-
comitant cyclisation was achieved by the reaction of 20
with thiophenol and cesium carbonate to afford the cy-
clized product 21. Catalytic hydrogenation of 21 (H2, Pt-
C, EtOH) gave 22, and acid-catalyzed hydrolysis of the
two MOM protecting groups in 22 (3 N HCl, aq MeOH,
55 °C) followed by treatment with ion exchange resin
(Amberlite IRA 410) furnished lentiginosine 6, whose
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(7) In this reaction, it should be noted that we can avoid
matched-mismatched problems when R has stererogenic
centers (Scheme 1), because asymmetric induction is carried
out at the remote position where the effect of R group
becomes negligible. In fact, synthesis of the diastereomer 23
was also achieved with Soai protocol simply employing (R)-
DPMPM to furnish 23 with 93:7 diastereoselecctivity.
Further transformation of 23 using similar procedures in
Scheme 2 afforded the allyl carbamate 24 in good yield
(Scheme 4). For the matched-mismatched problems, see the
reference: Masamune, S.; Choy, W.; Peterson, J. S.; Sita, L.
R. Angew. Chem., Int. Ed. Engl. 1984, 24, 1.
Synlett 2003, No. 7, 1034–1036 ISSN 1234-567-89 © Thieme Stuttgart · New York

1036
Y. Ichikawa et al.
LETTER
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Angew. Chem., Int. Ed. Engl. 1995, 2039. (b) Grubbs, R.
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27
(11) Spectroscopic data of our synthetic lentiginosine(6): [a]D
+1.06 (c 0.47, MeOH). 1H NMR (300MHz, CDCl3): d =
1.14–1.34 (2 H, m, H-8), 1.38–1.69 (2 H, m, H-6), 1.74–1.97
(2 H, m, H-7), 1.88–1.97 (1 H, m, H-8a), 2.04 (1 H, td,
J = 11, 3 Hz, H-5), 2.61 (1 H, dd, J = 11, 7.5 Hz, H-3a), 2.82
(1 H, dd, J = 11, 2 Hz, H-3b), 2.93 (1 H, br d, J = 11 Hz, H-
5), 3.64 (1 H, dd, J = 9, 4 Hz, H-1), 4.06 (1 H, ddd, J = 8, 4,
2 Hz, H-2). 13C NMR (75 MHz, CDCl3): d = 22.8, 23.8, 27.4,
52.4, 60.1, 68.3, 75.5, 82.8.
Scheme 4
(8) The minor isomer produced in the step (8 → 9) was removed
at this stage by recrystallisation of 14.
(9) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett.
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Synlett 2003, No. 7, 1034–1036 ISSN 1234-567-89 © Thieme Stuttgart · New York