A short and efficient total synthesis of (+)-deoxoprosopinine via diastereoselective allylation of the bicyclic N-acyl iminium ion formed in situ with a π-nucleophile

Article abstract of DOI:10.1055/s-0032-1317514

A short and efficient synthesis of (+)-deoxoprosopinine is reported involving Miyashita endoselective epoxide ring-opening reaction, diastereoselective allylation of the bicyclic N-acyl iminium ion formed in situ with a π-nucleophile, and olefin cross-metathesis as the key steps. Copyright

Full text of DOI:10.1055/s-0032-1317514

2814▌
LETTER
lAetteSr hort and Efficient Total Synthesis of (+)-Deoxoprosopinine via Diastereo-
selective Allylation of the Bicyclic N-Acyl Iminium Ion Formed in situ with a
π-Nucleophile
Total Synthesis of (+)-Deoxoprosopinine
Palakodety Radha Krishna,*a Palabindela Srinivas,a Bonepally Karunakar Reddy,a Kakita Veera Mohana Rao,b
Bharatam Jagadeeshb
a
Organic & Biomolecular Chemistry Division, CSIR - Indian Institute of Chemical Technology, Hyderabad 500007, India
Fax +91(40)27160387; E-mail: prkgenius@iict.res.in
b
Centre for Nuclear Magnetic Resonance, CSIR - Indian Institute of Chemical Technology, Hyderabad 500007, India
Received: 30.08.2012; Accepted after revision: 08.10.2012
ly, exploitation of the diastereoselective allylation of bicy-
Abstract: A short and efficient synthesis of (+)-deoxoprosopinine
clic N-acyl iminium ion formed in situ to construct 6-allyl
is reported involving Miyashita endoselective epoxide ring-opening
piperidine derivative 11 and its subsequent transformation
reaction, diastereoselective allylation of the bicyclic N-acyl imini-
into the target molecule 1. There are several reports con-
cerning diastereoselective allylation of N-acyl iminium
ions,5 some of which account for the formation of cis-2,6-
disubstituted piperidines5a,b and a few provide evidence
for the formation of trans-2,6-disubstituted piperidines.5d–f
We describe the total synthesis of 1 (Scheme 1) by utiliz-
ing a one-pot oxidation of 10 and diastereoselective al-
lylation of the bicyclic N-acyl iminium ion5c–e (A) formed
in situ, to furnish the allyl piperidine ring system 11 fol-
lowed by its olefin cross-metathesis6 with 1-undecene, the
other olefinic partner, as the key steps en route to afford
the target molecule. Amino alcohol 10, in turn, could be
derived from epoxy alcohol 6 by applying Miyashita’s en-
doselective epoxide ring-opening reaction with azide nu-
cleophile and subsequent conversion. Thus, it is evident
that trans-2,6-disubstituted piperidine derivative 11 is the
key building block in the synthesis of (+)-deoxoprosopin-
ine 1.
um ion formed in situ with a π-nucleophile, and olefin cross-metath-
esis as the key steps.
Key words: Miyashita epoxide opening, diastereoselectivity, al-
lylation, cross-metathesis, piperidines
Piperidine alkaloids are very common chemical entities
that are found abundantly in Nature and exhibit various
biological activities.1 Prosopis alkaloids are one class
among the various naturally occurring biologically active
piperidine alkaloids. Some of the prosopis alkaloids are:
(+)-prosopinine (2), (+)-prosophylline (4), and their re-
duced analogues (+)-deoxoprosopinine (1), and (+)-de-
oxoprosophylline (3; Figure 1). These alkaloids were
isolated from Prosopis africana2 and exhibit antibiotic
and anaesthetic properties. Structurally, these alkaloids
contain a 2,6-disubstituted 3-piperidinol skeleton bearing
an aliphatic alkyl side chain.
olefin
cross-
metathesis
HO
HO
HO
O
X
HO
N
O
N
N
+
H
7
7
H
Cbz
1 X = H, H, (+)-deoxoprosopinine
2 X = O, (+)-prosopinine
1
11
diastereoselective
allylation of
in situ formed bicyclic
N-acyl iminium ion
HO
X
HO
N
NHCbz
O
O
H
HO
O
3 X = H, H, (+)-deoxoprosophylline
4 X = O, (+)-prosophylline
N+
O
Cbz
A
Figure 1 Prosopis alkaloids
10
OH
TBDPSO
O
Previously, we reported the synthesis of some piperidine-
based alkaloids.3 In continuation of our interest in the syn-
thesis of piperidine alkaloids, we undertook the synthesis
of 1 and the results are described herein. Although several
syntheses have been reported for 1,4 we envisioned a stra-
tegically different route. Our strategy involves Miyashita
endoselective epoxide ring opening and, more important-
6
Scheme 1 Retrosynthetic analysis of (+)-deoxoprosopinine
We describe a short and efficient synthesis of 1 in eight
steps from known chiral epoxy alcohol 67 in 27% overall
yield (Scheme 2). The chiral epoxy alcohol 6, upon highly
regioselective ring-opening reaction from the C-2 posi-
tion by the azide nucleophile, afforded 7 (78%) as the ma-
jor isomer (C2/C3, 9:1); the minor 1,2-diol, formed from
C3 ring opening, was removed by NaIO4-mediated oxida-
SYNLETT 2012, 23, 2814–2816
Advanced online publication: 09.11.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317514; Art ID: ST-2012-D0727-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Total Synthesis of (+)-Deoxoprosopinine
2815
tive cleavage. The ring-opening reaction was carried out The structure and stereochemistry of allyl piperidine 11
by utilizing the Miyashita8 endoselective epoxide-open- were thoroughly characterized by extensive NMR experi-
ing protocol [NaN3, B(OMe)3, DMF, 60 °C, 3 h]. Diol 7, ments, including 2-D double quantum filtered correlation
thus obtained, was protected as its acetonide derivative 8 spectroscopy (DQF-COSY), nuclear Overhauser effect
(92%) by using 2,2-dimethoxypropane and catalytic spectroscopy (NOESY) and HSQC. The strong NOE
PTSA in anhydrous CH2Cl2. Subsequently, the azide cross peaks observed between H2/H1′′, H3/H1′, H3/CH3
functionality in 8 was converted into its benzyl carbamate (acetonide methyl), and H6/H2′′ protons are indicative of
by catalytic hydrogenation (H2, Pd/C, EtOAc, r.t., 6 h), their relative spatial orientation, their relationship with
followed by treatment of the resulting amine with benzyl one another, and their respective planar arrangement.
chloroformate and sodium bicarbonate in a EtOAc–H2O Thus, the relative and absolute stereochemistry of C2 and
(1:1) solvent system, which gave the corresponding carba- C6 was unequivocally proved. Additionally, the coupling
mate 9 (83% over two steps). The TBDPS group was then constant between H2 and H3 (JH2–H3 = 10.2 Hz) confirms
deprotected (TBAF, anhydrous THF, 0 °C→r.t., 1 h) to that these protons are trans to each other. Furthermore, the
afford the primary alcohol 10 (90%), which was oxidized exclusive formation of the trans-isomer may be rational-
under Dess–Martin conditions to afford an aldehyde that, ized on the basis of stereoeletronically controlled addition
without further purification, on exposure to trifluoroacetic of a π-type nucleophile (from allyltrimethylsilane) axially
acid (TFA) at –40 °C for 20 min, was converted into the on the thermodynamically more stable conformation of
bicyclic N-acyl iminium ion5c–e in situ. The iminium ion bicyclic N-acyliminium ion,5d,e leading to 11. The charac-
thus formed was diastereoselectively trapped by a π-type teristic 1H NMR signal of H2 appeared at δ = 3.21 ppm as
nucleophile (allyltrimethylsilane) to afford allyl piperi- a double-triplet (J = 6.1, 10.2 Hz) and the H6 proton ap-
dine 11 (70%) as an exclusive trans adduct.
peared at δ = 4.52–4.40 ppm as a multiplet. Further sup-
port for the structure was provided by HRMS analysis
(m/z [M + Na]+ calcd for C20H27NO4Na: 368.1837; found:
368.1834). The presence of terminal olefinic protons sub-
stantiated the assigned structure. Ally piperidine 11 con-
stitutes the key building block in the synthesis of 1.
ref. 7
OH
OH
a
TBDPSO
HO
O
6
N3
N3
c
OH
b
TBDPSO
TBDPSO
O
O
OH
7
8
The terminal olefin in 11 was utilized in olefin cross-me-
tathesis, as a means of achieving C–C bond formation,
with 1-undecene under standard conditions [G-II catalyst
(10 mol%), anhydrous CH2Cl2, reflux, 12 h] to afford 5.
During this reaction, although no homodimerization of 11
was observed, 1-undecene did undergo dimerization.
Consequently, to achieve complete conversion of 11 and
obtain an optimum yield of the desired cross-product 5
(90%), it was found necessary to use 3.0 equivalents of 1-
undecene. The 1H NMR spectrum of 5 revealed the olefin-
ic protons (δ = 5.58–5.42 and 5.32–5.21 ppm) as multi-
plets, in addition to other characteristic peaks pertaining
to the aliphatic carbon chain.
NHCbz
NHCbz
O
d
e
HO
TBDPSO
O
O
O
10
9
Me
4'
O
4
Me
O
5
3
H
3'
O
2'
O
2''
1
N+
Cbz
6
N
2
1''
1'
3''
H
H
Cbz
11
A
H
(more stable conformer of bicyclic N-acyliminium ion)
O
g
f
O
N
7
(+)-1
With compound 5 having been obtained, its extrapolation
to the target molecule 1 was all that remained. According-
ly, deprotection of the Cbz group and saturation of the
double bond took place in one pot through catalytic hy-
drogenation of 5 (H2, Pd/C, EtOAc, r.t., 7 h) to furnish
acetonide-protected (+)-deoxoprosopinine, which was pu-
rified by column chromatography and characterized.
Upon treatment of the latter with a catalytic amount of
PTSA in methanol, (+)-1 was obtained in 89% yield. The
physical and spectroscopic data of synthetic 1 was consis-
tent with the reported values.4,9 The HRMS spectrum was
also in agreement with the expected structure (m/z [M +
H]+ calcd for C18H38NO2: 300.2902; found: 300.2911).
Cbz
5
CH3
H
H
3
H
4
H
5
3'
4'
CH3
O
1
1'
H
6
N
H
O
2
2'
H
Cbz
1''
H
H
H
H
2''
H
H
3''
H
observed NOE correlations in 11
Scheme 2 Reagents and conditions: (a) i. NaN3, B(OMe)3, DMF,
60 °C, 3 h, 78%; ii. NaIO4, aq sat. NaHCO3, THF–H2O (4:1), 1 h;
(b) 2,2-DMP, PTSA, anhydrous CH2Cl2, 0 °C→r.t., 2 h, 92%;
(c) i. H2, Pd/C, EtOAc, 6 h; ii. Cbz-Cl, NaHCO3, EtOAc–H2O (1:1),
r.t., 2 h, 83%; (d) TBAF, anhydrous THF, 0 °C→r.t., 1 h, 90%;
(e) i. Dess–Martin periodinane, anhydrous CH2Cl2, r.t., 1 h; ii. TFA,
–40 °C, 20 min; iii. allyltrimethylsilane, –40 °C, 1.5 h, 70%; (f) G-II,
1-undecene, anhydrous CH2Cl2, reflux, 12 h, 90%; (g) i. H2, Pd/C,
EtOAc, 7 h, 90%; ii. cat. PTSA, MeOH, 0.5 h, 89%.
In conclusion, we report a short and efficient total synthe-
sis of (+)-deoxoprosopinine through the Miyashita en-
doselective epoxide ring-opening reaction and
diastereoselective allylation of the bicyclic N-acyl imini-
um ion formed in situ to furnish the allyl piperidine ring
skeleton initially, which, on Grubbs olefin cross-metathe-
sis reaction and deprotection, led to the final compound.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2814–2816

2816
P. R. Krishna et al.
LETTER
(8) Sasaki, M.; Tanino, K.; Hirai, A.; Miyashita, M. Org. Lett.
2003, 5, 1789.
This strategy could be adapted for the synthesis of related
natural products.
(9) Compound 7: Yellow oily liquid; [α]D25 –13.1 (c 1.11,
CHCl3). 1H NMR (500 MHz, CDCl3): δ = 7.68–7.58 (m, 4 H,
Ar-H), 7.45–7.33 (m, 6 H, Ar-H), 3.85 (dd, J = 5.2, 1.3 Hz,
2 H, OCH2), 3.76–3.72 (m, 1 H, OCH), 3.70 (t, J = 4.9 Hz,
2 H, OCH2), 3.33 (q, J = 5.1 Hz, 1 H, -N3CH), 1.92–1.78 (m,
1 H), 1.72 (quint, J = 6.4 Hz, 2 H), 1.65–1.53 (m, 1 H), 1.05
(s, 9 H, t-Bu). 13C NMR (75 MHz, CDCl3): δ = 135.5, 132.9,
129.8, 127.7, 72.7, 66.5, 64.3, 63.1, 31.6, 28.6, 26.7, 19.0.
HRMS: m/z [M + Na]+ calcd for C22H31N3O3NaSi:
Acknowledgment
Three of the authors (P.S., B.K.R., and K.V.M.R) thank the CSIR,
New Delhi, for financial support in the form of fellowships.
References and Notes
436.2032; found: 436.2052.
(1) (a) Strunz, G. M.; Findlay, J. A. In The Alkaloids; Vol. 26;
Brossi, A., Ed.; Academic Press: New York, 1985, 89–183.
(b) Schneider, M. J. In Alkaloids: Chemical and Biological
Perspectives; Vol. 10; Pelletier, S. W., Ed.; Pergamon Press:
Oxford, 1996, 215–299.
(2) (a) Ratle, G.; Monseur, X.; Das, B. C.; Yassi, J.; Khuong-
Huu, Q.; Goutarel, R. Bull. Soc. Chim. Fr. 1966, 2945.
(b) Khuong-Huu, Q.; Ratle, G.; Monseur, X.; Goutarel, R.
Bull. Soc. Chim. Belg. 1972, 81, 425. (c) Khuong-Huu, Q.;
Ratle, G.; Monseur, X.; Goutarel, R. Bull. Soc. Chim. Belg.
1972, 81, 443.
(3) (a) Radha Krishna, P.; Srishailam, A. Tetrahedron Lett.
2007, 48, 6924. (b) RadhaKrishna, P.; Dayaker, G.
Tetrahedron Lett. 2007, 48, 7279. (c) Radha Krishna, P.;
Lopinti, K. Synlett 2007, 1742. (d) Radha Krishna, P.;
Reddy, P. S. J. Comb. Chem. 2008, 10, 426. (e) Radha
Krishna, P.; Reddy, B. K. Tetrahedron Lett. 2010, 51, 6262.
(f) Radha Krishna, P.; Reddy, B. K.; Srinivas, P.
Tetrahedron 2012, 68, 841.
(4) (a) Ciufolini, M. A.; Hermann, C. W.; Whitmire, K. H.;
Byrne, N. E. J. Am. Chem. Soc. 1989, 111, 3473. (b) Kadota,
I.; Kawada, M.; Muramatsu, Y.; Yamamoto, Y.
Tetrahedron: Asymmetry 1997, 8, 3887. (c) Kadota, I.;
Kawada, M.; Muramatsu, Y.; Yamamoto, Y. Tetrahedron
Lett. 1997, 38, 7469. (d) Comins, D. L.; Sandelier, M. J.;
Grillo, T. A. J. Org. Chem. 2001, 66, 6829. (e) Sasaki, N. A.;
Wang, Q. J. Org. Chem. 2004, 69, 4767. (f) Arevalo-Garcia,
E. B.; Colmenares, J. C. Tetrahedron Lett. 2008, 49, 6972.
(5) (a) Kennedy, A.; Nelson, A.; Perry, A. Beilstein J. Org.
Chem. 2005, 1, No. 2. (b) Sugiura, M.; Hagio, H.;
Hirabayashi, R.; Kobayashi, S. J. Am. Chem. Soc. 2001, 123,
12510. (c) Koviach, J. L.; Forsyth, C. J. Tetrahedron Lett.
1999, 40, 8529. (d) David, M.; Dhimane, H.; Vanucci-
Bacque, C.; Lhommet, G. Synlett 1998, 206. (e) Potts, D.;
Stevenson, P. J.; Thompson, N. Tetrahedron Lett. 2000, 41,
275. (f) Ludwig, C.; Wistrand, L. G. Acta Chem. Scand.
1992, 46, 367.
Compound 9: White solid; mp 71–72 °C; [α]D25 –43.9 (c
0.90, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.66–7.60
(m, 4 H, Ar-H), 7.40–7.32 (m, 6 H, Ar-H), 7.31–7.26 (m,
5 H, Ar-H), 5.09–5.00 (m, 2 H, OCH2), 4.49 (d, J = 8.7 Hz,
1 H, NH), 3.87 (td, J = 6.7, 3.8 Hz, 1 H, OCH), 3.66 (t, J =
4.8 Hz, 2 H, OCH2), 3.57–3.49 (m, 1 H, NCH), 3.48–3.40
(m, 2 H, OCH2), 1.84–1.64 (m, 2 H), 1.61–1.37 (m, 2 H),
1.32 (s, 6 H), 1.05 (s, 9 H, t-Bu). 13C NMR (75 MHz,
CDCl3): δ = 155.6, 136.1, 135.5, 133.9, 133.8, 129.5, 128.5,
128.1, 128.0, 127.5, 98.7, 72.0, 66.9, 63.4, 63.2, 50.1, 28.8,
28.0, 27.9, 26.9, 19.9, 19.2. HRMS: m/z [M + Na]+ calcd for
C33H43NO5NaSi: 584.2808; found: 584.2805.
Compound 11: Syrupy liquid; [α]D25 –33.1 (c 1.20, CHCl3).
1H NMR (600 MHz, CDCl3): δ = 7.40–7.30 (m, 5 H, Ar-H),
5.70–5.63 (m, 1 H, olefinic), 5.11–4.99 (m, 4 H,
2 × olefinic, -OCH2Ph), 4.52–4.40 (m, 3 H, OCH2, NCH),
3.68 (dt, J = 10.2, 3.9 Hz, 1 H, OCH), 3.21 (dt, J = 10.2,
6.1 Hz, 1 H, NCH), 2.53–2.46 (m, 1 H, allylic), 2.34–2.26
(m, 1 H, allylic), 1.80–1.53 (m, 4 H), 1.49 (s, 3 H), 1.39 (s,
3 H). 13C NMR (75 MHz, CDCl3): δ = 155.2, 136.5, 134.6,
128.4, 128.0, 127.9, 117.4, 98.2, 70.9, 67.0, 62.7, 53.4, 52.3,
34.1, 25.9, 25.6, 19.0. HRMS: m/z [M + Na]+ calcd for
C20H27NO4Na: 368.1837; found: 368.1834.
Compound 5: Oily liquid; [α]D25 –35.4 (c 0.17, CHCl3). 1H
NMR (300 MHz, CDCl3): δ = 7.42–7.32 (m, 5 H, Ar-H),
5.58–5.42 (m, 1 H, olefinic), 5.32–5.21 (m, 1 H, olefinic),
5.10–5.04 (m, 2 H, OCH2Ph), 4.53–4.34 (m, 3 H, OCH2,
OCH), 3.69 (dt, J = 8.3, 3.7 Hz, 1 H, NCH), 3.28–3.17 (m,
1 H, NCH), 2.52–2.16 (m, 4 H, allylic), 2.11–1.81 (m, 4 H),
1.52 (s, 3 H), 1.42 (s, 3 H), 1.37–1.18 (m, 14 H), 0.9 (t, J =
8.3 Hz, 3 H). 13C NMR (75 MHz, CDCl3): δ = 151.5, 133.8,
133.5, 128.4, 128.0, 127.8, 127.1, 125.6, 71.0, 67.0, 63.0,
62.6, 54.0, 53.5, 52.8, 33.0, 32.6, 32.0, 29.7, 29.5, 29.2, 29.0,
27.1, 26.6, 26.0, 25.5, 22.7, 19.1, 14.1. HRMS: m/z [M +
Na]+ calcd for C29H45NO4Na: 494.3246; found: 494.3224.
Compound 1: Colorless solid; mp 89 °C; [α]D25 +15.5 (c
0.43, CHCl3) {Lit.4b,c [α]D20 +14.6 (c 0.3, CHCl3), Lit.4d
[α]D23 +12.2 (c 0.015, CHCl3), Lit.4e [α]D25 +15.3 (c 0.3,
CHCl3)}. 1H NMR (300 MHz, CDCl3): δ = 3.69–3.60 (m,
2 H, OCH2), 3.58–3.49 (m, 1 H, OCH), 2.88 (q, J = 5.4 Hz,
1 H, NCH), 2.82–2.72 (m, 1 H, NCH), 2.33 (br s, 3 H), 1.79–
(6) (a) Chatterjee, A. K.; Grubbs, R. H. Angew. Chem. Int. Ed.
2002, 41, 3171. (b) Nolen, E. G.; Kurish, A. J.; Wong, K. A.;
Orlando, M. D. Tetrahedron Lett. 2003, 44, 2449.
(c) Grubbs, R. H. Tetrahedron 2004, 60, 7117.
(d) Vougioukalakis, G. C.; Grubbs, R. H. Chem. Rev. 2010,
110, 1746.
1.44 (m, 4 H), 1.27 (s, 22 H), 0.88 (t, J = 6.7 Hz, 3 H). 13
C
NMR (75 MHz, CDCl3): δ = 67.9, 62.2, 58.0, 49.9, 33.7,
31.9, 29.6 (6C), 29.3, 28.5, 27.2, 26.3, 22.6, 14.1. HRMS:
m/z [M + H]+ calcd for C18H38NO2: 300.2902; found:
300.2911.
(7) Baltas, M.; Narco, K.; Gorrichon, L. Tetrahedron 1999, 55,
14013.
Synlett 2012, 23, 2814–2816
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