Asymmetric synthesis of (-)-lentiginosine by double aza-michael reaction

Article abstract of DOI:10.1002/ejoc.201000691

Total synthesis of (-)-lentiginosine (1) was achieved in nine steps from (3R,4R)-3,4-dihydroxy-l,5-hexadiene (2). Cross metathesis, vinyl addition and DDQ oxidation were applied to generate the key 3-oxonona-1,4,8-triene 6, which was cyclised to 4-oxopipe

Full text of DOI:10.1002/ejoc.201000691

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201000691
Asymmetric Synthesis of (–)-Lentiginosine by Double Aza-Michael Reaction
Sin-Wei Liu,[a] He-Chu Hsu,[a] Chiao-Hsin Chang,[a] Hui-Hsu Gavin Tsai,[a] and
Duen-Ren Hou*[a]
Keywords: Aza-Michael reaction / Alkaloids / Asymmetric synthesis / Metathesis
Total synthesis of (–)-lentiginosine (1) was achieved in nine
steps from (3R,4R)-3,4-dihydroxy-1,5-hexadiene (2). Cross
metathesis, vinyl addition and DDQ oxidation were applied
to generate the key 3-oxonona-1,4,8-triene 6, which was
cyclised to 4-oxopiperidine 7 by diastereoselective double
aza-Michael reaction. Both theoretical and empirical studies
support that the stereochemical assignment of the major
Michael adduct is the desired (2R)-4-oxopiperidine 7.
Introduction
A variety of polyhydroxylated indolizidines, such as lenti-
ginosine, castanospermine, swainsonine and slaframine, are
naturally occurring alkaloids[1] and effective glycosidase in-
hibitors.[2] Due to the potential use of glycosidase inhibitors
as antifungal agents, insecticides, antidiabetics and anti-
obesities, antivirals, and therapeutic agents for some genetic
disorders, syntheses of these polyhydroxylated indolizidines
have attracted the attention of chemists.[3,4] For example,
lentiginosine, isolated from the plant Astragalus lentiginosus
in 1990 and later found as the most powerful, competitive
inhibitor of amyloglucosidases known so far,[5,6] has been
the subject of a considerable number of synthetic studies.[7,8]
Most of the reported syntheses utilized or constructed the
five-membered pyrrolidines as the precursors to indolizid-
ines.[7] Recently, Bischoff and Fruit’s group efficiently pre-
pared lentiginosine by hydrogenating the corresponding
pyridinium cation to the piperidine/lentiginosine in spite of
the low stereoselectivity.[8a] However, several examples have
Scheme 1. Proposed retrosynthesis of (–)-lentiginose.
Results and Discussion
Dienediol 2 was first protected as silyl ether 3.[12] Cross
shown that a stereocontrolled formation of piperidines metathesis (CM) between 3 and acrolein provided the trans-
could be achieved by double aza-Michael reaction between α,β-unsaturated aldehyde 4, which was converted into the
dienones and amines.[9] As part of our current interest in dienone 6 after a sequence of protection with chloromethyl
aza-Michael reactions[10] and the use of (3R,4R)-3,4-dihy- methyl ether, addition of vinyl Grignard reagent and oxi-
droxy-1,5-hexadiene (2) as a versatile synthetic block,[11] we dation (Scheme 2). We noticed that the use of Hoveyda–
envisioned the double aza-Michael reaction as a new entry Grubbs catalyst[13] gave a better yield than the Grubbs cata-
into lentiginosine (Scheme 1). We planned to prepared the lyst in this CM reaction (75 and 37%, respectively).
core structure of the indolizidine by reductive amination of
Double aza-Michael reaction of 6 and benzylamine gen-
the intermediate A. The 4-oxopiperidine (intermediate B) erated the 4-oxopiperidines 7 and 8 (Scheme 3). Solvent and
could be prepared by diastereoselective double aza-Michael temperature have modest effects on the diastereomeric ratio
reaction of benzylamine and the dienone C, which was gen- (Table 1), and acetonitrile is the solvent of choice, which is
erated by cross metathesis between acrolein and 2.
in agreement with related examples.[9a] Although this
Michael reaction is sluggish in nonpolar solvents (En-
tries 4–7), we found that adding 10 mol-% of trifluoroacetic
acid accelerated the reaction in dichloromethane and gave
the most clean product under the reaction conditions scre-
ened (Entry 8). The two diastereomers were separated by
column chromatography, and the major isomer was tempo-
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[a] Department of Chemistry, National Central University,
300 Jhong-Da Rd., Jhong-Li City, Taoyuan 32001, Taiwan
Fax: +886-3-4227664
E-mail: drhou@ncu.edu.tw
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000691.
wileyonlinelibrary.com
Eur. J. Org. Chem. 2010, 4771–4773
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4771

S.-W. Liu, H.-C. Hsu, C.-H. Chang, H.-H. G. Tsai, D.-R. Hou
SHORT COMMUNICATION
ciency. Deprotection of the remaining tert-butyldimethyl-
silyl group provided the title compound 1. The spectro-
scopic data (1H, 13C NMR and optical rotation) of the syn-
thetic (–)-lentiginosine are consistent with those in the lit-
erature;[8] therefore, the stereochemical assignment of the
Michael adduct 7 was confirmed.
Scheme 2. Synthesis of dienone 6.
rarily assigned as (2R)-7, since theoretical calculations sug-
gested that compound 7 is thermodynamically more stable
1
than the (2S) counterpart 8.[14] We observed that the H
NMR spectrum of isolated 7 was unchanged after 72 h in
[D3]acetonitrile at room temperature; however, epimeriz-
ation occurred after adding a trace of benzylamine–tri-
fluoroacetic acid (0.1 equiv.) to the solution, and the final
ratio of 7/8 was 2.4:1. This result supports that the forma-
tion of 7 is both kinetically and thermodynamically favored.
Scheme 4. Synthesis of (–)-lentiginosine from 7.
Conclusions
We have accomplished the total synthesis of (–)-lentigin-
osine in nine steps from (R,R)-3,4-dihydroxy-1,5-hexadiene,
readily available from inexpensive mannitol. This synthesis
utilizes a cross metathesis to prepare the key trienone and a
diastereoselective double aza-Michael reaction to form the
corresponding 4-oxopiperidine, which was converted to the
indolizidine after ozonolysis and reductive amination. This
new approach could be applied to other polyhydroxylated
indolizidines.
Experimental Section
Scheme 3. Double aza-Michael reaction of 6.
(–)-Lentiginosine [(1R,2R,8aR)-1,2-Dihydroxyindolizidine, 1]: Hy-
drochloric acid (3 , 2.5 mL) was added to the solution of 11
(31 mg, 0.12 mmol) and methanol (7.5 mL). The solution was
stirred at 55 °C for 5 h, cooled to room temp. and concentrated to
give the salt of lentiginosine (20 mg, 0.10 mmol, 90%). The salt
was redissolved in satd. KOH(aq) (2 mL), extracted with THF (3ϫ
10 mL), dried with Na2SO4(s), filtered and concentrated to give 1
as a colorless solid. M.p. 106–108 °C. [α]2D0 = –3.00 (c = 0.3,
Table 1. Double aza-Michael reaction of 6 and benzylamine.
Entry
Solvent
T [°C]
Time [h]
7/8[a]
Yield [%][b]
1
2
3
4
5
6
7
8
CH3CN
CH3CN
CH3CN[c]
THF
25
0
0
25
25
25
10
25
16
96
16
96
96
48
48
16
3.0:1
5.2:1
2.0:1
–
4.4:1
2.3:1
4.8:1
2.1:1
54
41
56
0
37
37
26
75
benzene
CH2Cl2
CH2Cl2
1
MeOH). H NMR (D2O, 500 MHz): δ = 1.23–1.28 (t, J = 9.5 Hz,
2 H), 1.42–1.51 (m, 1 H), 1.64–1.66 (d, J = 12 Hz, 1 H), 1.79–1.85
(m, 1 H), 1.92–1.97 (m, 2 H), 2.03–2.08 (dt, J = 3, 12.5 Hz, 1 H),
2.61–2.65 (dd, J = 7.5, 11 Hz, 1 H, 3a-H), 2.82–2.85 (dd, J = 1.5,
11 Hz, 1 H, 3b-H), 2.94–2.96 (d, J = 11 Hz, 1 H, 8a-H), 3.65–3.67
(dd, J = 4, 8.5 Hz, 1 H, 1-H), 4.07–4.10 (m, 1 H, 2-H) ppm. 13C
NMR (D2O, 125 MHz): δ = 22.8, 23.8, 27.4, 52.4, 60.0, 68.3, 75.5,
82.8 ppm.[7v]
[c]
CH2Cl2
[a] Determined by 1H NMR spectroscopy of the crude product. [b]
Isolated yield. [c] Addition of 10 mol-% trifluoroacetic acid.
The major isomer 7 was subjected to ozonolysis and re-
ductive amination to generate the indolizidine 9 (Scheme 4).
We screened several methods to achieve the reduction of
the carbonyl group to a methylene group, and found that
the sequence of the dithiolane formation and Raney nickel
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details for the synthesis of compounds 4–11,
copies of the 1H and 13C NMR spectra of compounds 4–11, 1, and
reduction gave the most satisfactory result in terms of effi- the calculated stationary structures of 7 and 8 (Figure S1).
4772 Eur. J. Org. Chem. 2010, 4771–4773
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Asymmetric Synthesis of (–)-Lentiginosine
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Acknowledgments
This research was supported by the National Science Council, Tai-
wan (NSC 98-2119-M-008-001 and NSC 95-2113-M-008-007). We
are grateful to Ms. Ping-Yu Lin at the Institute of Chemistry, Aca-
demia Sinica, and Valuable Instrument Center in National Central
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Received: May 14, 2010
Published Online: July 29, 2010
Eur. J. Org. Chem. 2010, 4771–4773
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4773