Synthetic study of biphenylquinolizidine alkaloids I. Asymmetric total synthesis of lasubine I featuring organocatalyzed asymmetric intramolecular aza-Michael addition

Article abstract of DOI:10.1016/j.tetlet.2016.12.008

A new procedure for the asymmetric total synthesis of lythraceous alkaloids with a 4-arylquinolizidine skeleton was developed, which involved an organocatalyzed asymmetric intramolecular aza-Michael addition.

Full text of DOI:10.1016/j.tetlet.2016.12.008

Accepted Manuscript
Synthetic study of biphenylquinolizidine alkaloids I. Asymmetric total synthesis
of lasubine I featuring organocatalyzed asymmetric intramolecular aza-Michael
addition
Taku Hirama, Takayuki Umemura, Noriyuki Kogure, Mariko Kitajima,
Hiromitsu Takayama
PII:
S0040-4039(16)31639-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.12.008
TETL 48420
Reference:
Tetrahedron Letters
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3 November 2016
1 December 2016
5 December 2016
Please cite this article as: Hirama, T., Umemura, T., Kogure, N., Kitajima, M., Takayama, H., Synthetic study of
biphenylquinolizidine alkaloids I. Asymmetric total synthesis of lasubine I featuring organocatalyzed asymmetric
intramolecular aza-Michael addition, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.
2016.12.008
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Synthetic study of biphenylquinolizidine alkaloids I.
Asymmetric total synthesis of lasubine I featuring
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organocatalyzed asymmetric intramolecular aza-Michael addition
Taku Hirama, Takayuki Umemura, Noriyuki Kogure, Mariko Kitajima, Hiromitsu Takayama*

1
Tetrahedron Letters
Synthetic study of biphenylquinolizidine alkaloids I. Asymmetric total synthesis of
lasubine I featuring organocatalyzed asymmetric intramolecular aza-Michael addition
Taku Hirama, Takayuki Umemura, Noriyuki Kogure, Mariko Kitajima, Hiromitsu Takayama
Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A new procedure for the asymmetric total synthesis of lythraceous alkaloids with a 4-
arylquinolizidine skeleton was developed, which involved an organocatalyzed asymmetric
intramolecular aza-Michael addition.
2016 Elsevier Ltd. All rights reserved.
Available online
Keywords:
Quinolizidine alkaloid
Lasubine I
Organocatalyst
aza-Michael addition
Asymmetrtic synthesis
Heimia salicifolia (Family Lythraceae) is the main ingredient
of the law-evading drug “sinicuichi”. When consumed, sinicuichi
causes exhilarating feelings and alteration of awareness
accompanied by bradycardia, hypomyotonia, and pleasant
faintness.1 To date, the active principles and the mechanism of
action underlying the neurotropic effects of this drug have not
been clarified. In the course of our investigation of bioactive
alkaloids in medicinal plants,2 we have isolated a number of
biphenylquinolizidine alkaloids,3 such as vertine (1),4 lythrine
(2),5 and heimidine (3),6 from H. salicifolia (Fig. 1). In order to
evaluate their biological activities in detail, we have embarked on
the development of an efficient method for the synthesis of
biphenylquinolizidine alkaloids and their derivatives. In this
letter, we report our efforts towards the asymmetric total
synthesis of these alkaloids using the organocatalyzed
asymmetric intramolecular aza-Michael addition to construct the
phenylquinolizidine ring, and its application to the novel total
synthesis of lasubine I (22).7
The synthetic targets of biphenylquinolizidine alkaloids
consist of a quinolizidine ring with three chiral centers at C2, C4,
and C10 positions and a macrolactone with a 12-membered ring
that includes a biphenyl moiety. Our retrosynthetic analysis of
Scheme 1. Retrosynthetic analysis.
Figure 1. Biphenylquinolizidine alkaloids isolated from Heimia
salicifolia.
these alkaloids is shown in Scheme 1. Common skeleton 4 could
be prepared from arylquinolizidinone 5 by installation of a
———
 Corresponding author. E-mail: takayamah@faculty.chiba-u.jp (H. Takayama)

2
Tetrahedron Letters
phenylpropanoid residue followed by macrolactonization.
We prepared sulfonamides 7d with a nosyl (Ns) group and 7e
with a 2-(trimethylsilyl)ethanesulfonyl (SES) group by applying
another procedure (Scheme 4) to avoid the spontaneous aza-
Michael addition of HWE products 7d and 7e under the basic
condition. Thus, the HWE reaction between aromatic aldehyde 8
and phosphonate 9 was initially carried out to give dienone 16,
which was then treated with alkene 10d or 10e in the presence of
2nd generation Hoveyda-Grubbs catalyst to furnish corresponding
dienone 7d or 7e in moderate yield, respectively.
Arylquinolizidinone 5 could be constructed from linear dienone 7
via a double intramolecular aza-Michael addition. In this process,
we have designed induction of chirality through the asymmetric
cyclization of 7 using a chiral organocatalyst.8 Substrate 7 could
be prepared by the condensation of three units, i.e., aromatic
aldehyde 8, known phosphonate 9,9 and alkene 10, via the
Horner-Wadsworth-Emmons (HWE) reaction10 and olefin cross-
metathesis.
Initially, we prepared aromatic aldehyde 8 from isovanillin
(11) (Scheme 2). Protection of the phenol in 11 with a
methoxymethyl (MOM) group followed by reduction of the
aldehyde with sodium borohydride gave alcohol 12. Treatment of
12 with N-iodosuccinimide (NIS) afforded iodination product 13
regioselectively, which was then converted into aldehyde 14 by
the Swern oxidation11 (in 89% yield over 2 steps). Finally,
replacement of the MOM group with a mesyl (Ms) group gave
aromatic aldehyde 8 in 81% total yield over 6 steps from 11.
Scheme 4. Synthesis of cyclization precursors 7d-e.
With cyclization precursors 7a-7e in hand, we next examined
the asymmetric intramolecular aza-Michael addition using chiral
organocatalyst 1714 (Table 1). In the case of N-Boc dienone 7a,
the reaction did not proceed and the starting material was
recovered (entry 1). Although the cyclization using sulfoxide-
protected substrate 7b proceeded, the product was a racemate
(entry 2). Based on these results, we considered that the acidity
of the amide proton of 7a or 7b was so low that catalyst 17 did
not participate in the cyclization. On the other hand, sulfonamide
dienones 7c-e gave desired products 6c-e in good yields with
high enantioselectivities (91% to 96% ee), respectively (entries
3-5). The absolute configuration of the newly formed chiral
center at C10 in 6 was determined at a later stage as described
below. This is the first report of the successful intramolecular
asymmetric aza-Michael addition of the linear dienone
compound catalyzed by a chiral organocatalyst.
Scheme 2. Synthesis of aromatic unit 8.
Next, we synthesized cyclization precursors 7a-e (Scheme 3).
Coupling of phosphonate 9 and alkene 10a or 10b with 2nd
generation Hoveyda-Grubbs catalyst in the presence of
Ti(OiPr)412 produced alkene 15a or 15b in good yield,
respectively. Cyclization precursors 7a and 7b were obtained by
the HWE reaction of aromatic aldehyde 8 with corresponding
HWE reagents 15a and 15b in good yield with high E/Z
selectivity. In this reaction, the electron-withdrawing Ms group
was necessary to realize good E/Z selectivity of the product.13
Next, oxidation of the sulfinamide group in 7b with m-CPBA
gave precursor 7c having a tert-butylsulfonyl (Bus) group in a
quantitative yield.
Table 1. Organocatalyzed asymmetric intramolecular aza-Michael
addition.
Scheme 3. Synthesis of cyclization precursors 7a-c.

3
Next, the construction of the quinolizidinone ring from 6 was
investigated (Scheme 5). N-Bus enone 6c with 95% ee was
treated with TFA in the presence of anisole15 followed by
cyclization under the basic condition to afford quinolizidinone 19
in 67% yield. The relative configuration at C4 and C10 in 19 was
determined from the nOe correlation between H-10 and H-6’.
Although the second aza-Michael addition proceeded in a highly
diastereoselective manner to give 19, the enantiomeric excess of
the product was 74% ee. The decrease of the enantiomeric excess
in the course of the reaction was probably caused by the partial
racemization via the retro aza-Michael addition under the strong
acidic condition to remove the Bus group or under the basic
condition (K2CO3 in EtOH). Deprotection of the Ns group in 6d
under the basic condition gave desired quinolizidinone 19 in 58%
yield, but the decrement of the enantiomeric excess was also
observed (69% ee).16 Nevertheless, thus-obtained compound 19
should play an important role as a synthetic intermediate of
several biphenylquinolizidine alkaloids.
In conclusion, we have developed a novel organocatalyzed
asymmetric intramolecular aza-Michael addition of linear
dienone and succeeded in the asymmetric synthesis of
quinolizidinone 19, which is a key intermediate in the synthesis
of lythraceous biphenylquinolizidine alkaloids and the
phenylquinolizidine alkaloid lasubine
I
(22). Further
investigations of improvement of reaction conditions from enone
6 to 19 to avoid the partial racemization and the total syntheses of
biphenylquinolizidine alkaloids using this strategy are ongoing in
our laboratory.
Acknowledgments
This work was supported by JSPS KAKENHI Grant Numbers
16H05094 and 26293023.
Supplementary data
Supplementary data (full experimental procedures and
characterization data for new compounds) associated with this
article can be found in the online version at ~.
References and notes
1.
2.
Kempf, J.; Stedtler, U.; Neusü, C.; Weinmann, W.; Auwärter, V.
Forensic Sci. Int. 2008, 179, e57–e61.
(a) Kitajima, M.; Nakazawa, M.; Wu, Y.; Kogure, N.; Zhang, R.;
Takayama, H. Tetrahedron 2016, 72, 6692–6696; (b) Tokuda, R.;
Okamoto, Y.; Koyama, T.; Kogure, N.; Kitajima, M.; Takayama,
H. Org. Lett. 2016, 18, 3490–3493; (c) Kogure, N.; Maruyama,
M.; Wongseripipatana, S.; Kitajima, M.; Takayama, H. Chem.
Pharm. Bull. 2016, 64, 793–799; (d) Kitajima, M.; Murakami, Y.;
Takahashi, N.; Wu, Y.; Kogure, N.; Zhang, R.; Takayama, H.
Org. Lett. 2014, 16, 5000–5003; (e) Kitajima, M.; Anbe, M.;
Kogure, N.; Wongseripipatana, S.; Takayama, H. Tetrahedron
2014, 70, 9099-9106.
Scheme 5. Synthesis of chiral quinolizidinone 19 from 6c or 6d.
3.
(a) Michael, J. P. In The Alkaloids, Knölker, H.-J. Ed.; Academic
Press: San Diego, 2016; Vol. 75, 1–498, and references cited
therein; (b) Michael, J. P. In The Alkaloids, Knölker, H.-J. Ed.;
Academic Press: San Diego, 2001; Vol. 55, 91–258, and
references cited therein.
Ferris, J. P. J. Org. Chem. 1962, 27, 2985–2990.
Blomster, R. N.; Schwarting, A. E.; Bobbitt, J. M. Lloydia 1964,
27, 15–24.
The absolute configuration of the major enantiomer in 19
(74% ee) was determined by conversion into known natural
alkaloid lasubine I (Scheme 6). Diastereoselective reduction of
the ketone in 19 with L-selectride followed by alkaline
hydrolysis of the Ms group gave alcohol 20 in 97% yield (2
steps). Subsequently, methylation of phenol in 20 using
trimethylsilyldiazomethane gave 21.17 Finally, deiodination of 21
with Mg metal afforded (–)-lasubine I (22). Synthetic 22 was
identical in all respects with the natural product, including the
4.
5.
6.
7.
El-Olemy, M. M.; Stohs, S. J.; Schwarting, A. E. Lloydia 1971,
34, 439–441.
(a) Isolation: Fuji, K.; Yamada, T.; Fujita, E.; Murata, H. Chem.
Pharm. Bull. 1978, 26, 2515–2521; (b) Total synthesis: Iida, H.;
Tanaka, M.; Kibayashi, C. J. Chem. Soc., Chem. Commun. 1983,
1143 (racemate); (c) Total synthesis: Comins, D. L.; LaMunyon,
D. H. J. Org. Chem. 1992, 57, 5807–5809 (asymmetric); (d)
Formal synthesis: Li, H.; Wu, J. Org. Lett. 2015, 17, 5424–5427
(racemate); (e) Formal synthesis: Reddy, A. A.; Reddy, P. O.;
Prasad, K. R. J. Org. Chem. ASAP (asymmetric).
26
18
optical property: synthetic, []D –6.7 (c 0.20, MeOH)
;
23
natural,7a []D
–8.8 (c 0.34, MeOH). Therefore, the
stereochemistry including the absolute configuration of product
19 obtained by the organocatalyzed asymmetric aza-Michael
addition/second aza-Michael addition was clarified.
8.
9.
Examples of organocatalyzed intramolecular aza-Michael reaction,
see (a) Gu, Q.; You, S. L. Chem. Sci. 2011, 2, 1519–1522; (b) Liu,
J.-D.; Chen, Y.-C.; Zhang, G.-B.; Li, Z.-Q.; Chen, P.; Du, J.-Y.;
Tu, Y.-Q.; Fan, C.-A. Adv. Synth. Catal. 2011, 353, 2721–2730;
(c) Fukata, Y.; Asano, K.; Matsubara, S. J. Am. Chem. Soc. 2013,
135, 12160–12163.
Yang, H.; Hong, Y.-T.; Kim, S. Org. Lett. 2007, 9, 2281–2284.
10. William, S.; Wadsworth, J. R.; Emmons, W. D. J. Am. Chem. Soc.
1961, 83, 1733–1738.
11. Huang, S. L.; Omura, K.; Swern, D. J. Org. Chem. 1976, 41,
3329–3331.
12. Fustero, S.; Monteagudo, S.; Sánchez-Roselló, M.; Flores, S.;
Barrio, P.; del Pozo, C. Chem. Eur. J. 2010, 16, 9835–9845.
13. In the case of HWE reaction using aromatic aldehyde protected by
MOM group, the product containing Z olefin (E/Z = 6.7:1) was
obtained.
14. Vakulya, B.; Varga, S.; Csámpai, A.; Soós, T. Org. Lett. 2005, 7,
1967–1969.
Scheme 6. Determination of absolute configuration of key
intermediate 19.

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Tetrahedron Letters
15. Sun, P.; Weinreb, S. M. J. Org. Chem. 1997, 62, 8604–8608.
16. Treatment of substrate 6e having an SES protecting group with
TAS-F resulted in the decomposition of the starting material.
17. Chausset-Boissarie, L.; Àrvai, R.; Cumming, G. R;. Guénée, L;.
Kündig, E. P. Org. Biomol. Chem. 2012, 10, 6473–6479.
18. The Chiral HPLC analysis of benzoate derivative of synthetic 22
demonstrated 74% ee.

Table 1. Organocatalyzed asymmetric intramolecular aza-Michael
addition.
Entry
Substrate
7a (R = Boc)
7b (R = S(O)tBu)
7c (R = Bus)
7d (R = Ns)
Temp. (°C)
Time (h)
48
Yield (%)
Ee (% ee)*
1
2
3
4
5
50
50
50
0
0
–
48
56
98
86
97
0
84
95
91
96
24
7e (R = SES)
40
22
* Ee was determined by chiral HPLC analysis

5
Research highlights
An organocatalyzed asymmetric intramolecular aza-Michael addition of linear dienone was
developed.
A new synthetic method of chiral 4-arylquinolizidinone was developed.
A novel and efficient total synthesis of lythraceous alkaloid, lasubine I, was accomplished.