Total synthesis of (-)-indolizidine 167B via an unusual Wolff rearrangement from an α,β-unsaturated diazoketone

Article abstract of DOI:10.1016/j.tetlet.2011.12.029

A concise synthesis of the (-)-indolizidine alkaloid 167B and two formal syntheses of (-)-indolizidine 209D and (-)-coniceine are described in just three steps from an α,β-unsaturated diazoketone, via an unusual photochemical Wolff rearrangement. Preparat

Full text of DOI:10.1016/j.tetlet.2011.12.029

Tetrahedron Letters 53 (2012) 876–878
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Total synthesis of (ꢀ)-indolizidine 167B via an unusual Wolff rearrangement
from an
a
,b-unsaturated diazoketone
⇑
Vagner D. Pinho, Antonio C. B. Burtoloso
Instituto de Química de São Carlos, Universidade de São Paulo, CEP 13560-970, São Carlos, SP, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise synthesis of the (ꢀ)-indolizidine alkaloid 167B and two formal syntheses of (ꢀ)-indolizidine
Received 19 November 2011
Revised 6 December 2011
Accepted 8 December 2011
Available online 14 December 2011
209D and (ꢀ)-coniceine are described in just three steps from an
a,b-unsaturated diazoketone, via an unu-
sual photochemical Wolff rearrangement. Preparation of the unsaturated diazoketone is straightforward
from N-Cbz-prolinal and a 3-diazo-2-oxopropylphosphonate, employing a Horner–Wadsworth–Emmons
reaction. The strategy should be feasible and easily adaptable to the synthesis of other indolizidine alka-
loids and analogues.
Keywords:
Ó 2011 Elsevier Ltd. All rights reserved.
Indolizidine alkaloids
Unsaturated diazoketones
Wolff rearrangement
Arndt–Eistert homologation
Photochemical
Indolizidine alkaloids are among the most important classes of
nitrogen heterocycles. Possessing an azabicyclic unit, these com-
pounds have become common targets in synthesis due to their
unique structure and interesting pharmacological activities.1 For
example, non-natural2 indolizidines 167B and 209D and the natu-
ral pumiliotoxins (Scheme 1), isolated from the skin secretions of
certain neotropical amphibians, are noncompetitive blockers of
neuromuscular transmission3 and promising cardiotonics,4 respec-
tively. Despite many interesting total syntheses of these com-
pounds, more general, short and diversity-oriented approaches
are still desirable.
As depicted in Scheme 1, we envisaged that the synthesis of
indolizidines 167B and 209D, as well as other indolizidine alkaloids
such as pumiliotoxins, coniceine, and castanospermine analogues,
could be easily and concisely reached from b,
1. In turn, key intermediate 1 could be prepared in a single step
by an unusual Wolff rearrangement from an ,b-unsaturated
c-unsaturated ester
a
diazoketone such as 2. In contrast to the enormous number of
applications from common saturated diazoketones, few reports
of applications of the rarer
a,b-unsaturated diazoketones are found
in the literature. Despite that, we believe that
a
,b-unsaturated
Recently, we described a new method5 to prepare
a,b-unsatu-
rated diazoketones from aldehydes, employing a new Horner–
Wadsworth–Emmons (HWE) reagent, and its application in a short
synthesis of pyrrolidines. Herein, in continuation with this chemis-
try, we would like to describe an expedient synthesis of (ꢀ)-
indolizidine 167B in four steps from commercially available and
easily prepared (S)-N-Cbz-prolinal.6 It is worth of mentioning that
the majority of examples in the literature1,7,8 describes the asym-
metric total synthesis of these indolizidines in lengthy paths
(8–14 steps) from commercially available reagents, only a few being
shorter than that. Shibasaki9 and Rovis10 reported the shortest
syntheses known to date of (ꢀ)-indolizidine 209D (five steps from
glutarimide and 5-hexenoic acid, respectively), whereas O’Brien11
and Settambolo12 reported the syntheses of (ꢀ)-indolizidine 167B
O
O
H
N
OH
H
R
H
N
N
R
pumiliotoxines
indolizidine 167B (R = Pr)
indolizidine 209D (R = hex)
coniceine (R=H)
OH
H
HO
N
2 steps
castanospermine analogues
O
H
H
MeO2C
Wolff
N2
N
in six steps from N-Boc-Pyrrolidine and D-norvaline, respective.
rearrangement
2
N
Cbz
1
Cbz
α,β-unsaturated
diazoketone
⇑
Corresponding author. Tel.: +55 16 3373 8641; fax: +55 16 3373 9952.
E-mail address: antonio@iqsc.usp.br (Antonio C. B. Burtoloso).
Scheme 1. Indolizidines alkaloids from
a
,b-unsaturated diazoketones.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.029

V. D. Pinho, Antonio C. B. Burtoloso / Tetrahedron Letters 53 (2012) 876–878
877
Table 1
diazoketones are very promising multi-functional intermediates
Studies on the Arndt–Eistert homologation reaction
and can lead to short and diversity-oriented syntheses of many
compounds, including alkaloids.
O
We started our work by preparing a,b-unsaturated diazoketone
H
N
H
N
OMe
2 in a 70% yield as a single E isomer, employing our recently
described methodology5 (Scheme 2). No epimerization occurred at
this critical step according to careful HPLC analysis13 (>99% ee). Con-
version of diazoketone 2 into key intermediate 1 proved to be diffi-
cult, affording only low yields under usual thermal conditions for
the Wolff rearrangement (30 mol % AgOBz, Et3N, 25 °C). In view of
that, a detailed study on the Wolff rearrangement was carried out,
aiming the synthesis of the Arndt–Eistert homologated product 1
(Table 1).
O
N2
Cbz
Cbz
1
2
Entry
Catalyst (mol %)
Temp (°C)
Time (h)
Yield (%)
116,a,c
C6H5CO2Ag (30)
C6H5CO2Ag (50)
C6H5CO2Ag (40)
C6H5CO2Ag (50)
C6H5CO2Ag (50)
Ag2O (15)
CF3CO2Ag (30)
CF3SO3Ag (30)
AgNO3 (50)
CF3CO2Ag (50)
CF3SO3Ag (50)
CH3CO2Ag (50)
None
25
25
25–50
50
50
25
50
50
50
50
50
50
25
1
1
1
1
1
1
1
1
1
1
1
1
4
30
37
50
50
66
16
26
28
51
71
76
66
97
2a,b
3a,b
4a,c
5a,b
Initially, silver benzoate was selected as the model catalyst to
optimize the conditions. As described in entry 5, 50 mol % of the
catalyst is necessary to obtain a moderate yield, together with its
slow addition and a 50 °C reaction temperature. Sequential inves-
tigation employing different silver catalysts (entries 9–12) leads
to practically similar results, CF3SO3Ag being the best catalyst.
Although these conditions provided good yields for the Wollf rear-
rangement, high loadings of the expensive silver catalysts are
needed, together with tedious experimental procedures such as
the requirement of very slow addition of the catalyst for total sub-
strate conversion. Fortunately, this problem was totally circum-
vented when photochemical conditions were applied, furnishing
the desired ester 1 in almost quantitative yield with no need of
purification.14 Not withstanding the wide range of applications
known of the Arndt–Eistert homologation from saturated diazoke-
6c
7a,b
8a,b
9a,b
10a,b
11a,b
12a,b
13d
a
5 equiv of Et3N and a 0.1 M solution of 2 in dry MeOH was used, except in entry
6 where no base was used.
b
Very slow addition of the catalyst as a solution in Et3N.
Fast and direct addition of the catalyst as a solution in Et3N.
The photochemical reactions (0.3 M solution of 2 in dry MeOH) were carried out
c
d
using UV light generated by an Osram 150 Xenon lamp accommodated in an Oriel
Model 8500 Universal arc lamp source with focusing quartz lens, a water-filled
infrared filter, and a thermostated cell holder.
tones,15 the use of
a,b-unsaturated diazoketones as substrates for
this transformation is scarcely described in the literature.16 More-
over, unsaturated diazoketone 2 sets an even worse scenario due to
the existence of an epimerizable stereocenter. Fortunately, com-
parison of the optical rotation value of the N-Boc derivative of com-
3 {>99% ee from chiral HPLC;13
[
a
]D ꢀ6.7 (c 1.0, CH2Cl2); Lit18
[
a
]D ꢀ6.6 (c 1.0, CH2Cl2)} also constitutes a very concise formal
synthesis of the natural alkaloid coniceine18 and of (ꢀ)-indolizi-
dine 209D.9 Addition of propylmagnesium bromide to lactam 3,
followed by AcOH/NaBH4, concluded the total synthesis of indolizi-
dine (ꢀ)-167B as a single diastereomer19 in a 42% yield (Scheme 2),
being its spectroscopic data and optical rotation value in accor-
dance with the literature.7,8
pound 1 {[
a
]D ꢀ26.0 (c 1.0, MeOH)} with the one described in the
literature17 {[
a
]D ꢀ21.4 (c 1.0, MeOH)} demonstrated the integrity
of the chiral center after the photochemical or thermal Wolff
rearrangement.
After the synthesis of 1, completion of the total synthesis of ind-
olizidine 167B was straightforward. Removal of the Cbz protecting
group in the presence of H2/Pd and TEA as base (with concomitant
reduction of the double bond and cyclization) afforded known
lactam 3 in a 92% yield and in a single step. Synthesis of lactam
In conclusion, we have shown that a,b-unsaturated diazoketones
can be powerful substrates for the short and diversity-oriented
synthesis of indolizidine alkaloids. This was demonstrated by pre-
paring indolizidine 167B in four steps from
L-Cbz-prolinal and with
an overall yield of 26%. Success in this endeavor was possible after a
O
NaH, THF
-78o C
O
P
O
Pd/C, MeOH,
OMe
MeOH, hν
25o C, 4 h
Et3N, 48 h, 25 oC
EtO
NCbz
1
O
O
EtO
N2
N
2
N2
Cbz
97%
3-diazo-2-
CbzN
(> 99% ee)
70%
oxopropylphosphonate
H
H
H
N
a) n-PrMgBr, THF, 0-25 oC
N
b) AcOH, NaBH4, 0-25 oC
42%
N
3
92%
Indolizidine 167B
H
O
(> 99% ee)
H
N
Ref. 9
Ref. 18
H
N
Indolizidine 209D
N
coniceine
Scheme 2. Synthesis of (ꢀ)-indolizidine alkaloids 167B, 209D and coniceine.

878
V. D. Pinho, Antonio C. B. Burtoloso / Tetrahedron Letters 53 (2012) 876–878
4. Daly, J. W.; McNeal, E. T.; Overman, L. E.; Ellison, D. H. J. Med. Chem. 1985, 28,
482.
5. Pinho, V. D.; Burtoloso, A. C. B. J. Org. Chem. 2011, 76, 289.
6. (S)-N-Cbz-prolinal can also be prepared in multigram quantities and in two
steps from the cheaper amino acid (S)-N-Cbz-proline. From (S)-N-Cbz-proline,
the total synthesis of indolizidine 167B is accomplished in 6 steps.
7. For the first asymmetric total synthesis of indolizidine 167B and 209D see:
Polniaszek, R. P.; Belmont, S. E. J. Org. Chem. 1990, 55, 4688.
high yielding unusual photochemical Arndt–Eistert homologation
from an unsaturated diazoketone. This strategy should be feasible
and can be easily adaptable to the concise synthesis of other indolizi-
dine alkaloids. The total syntheses of some pumiliotoxins and cast-
anospermine analogues using the present strategy will be reported
in due course.
8. For recent examples of the asymmetric synthesis of indolizidine 167B and
209D see: (a) Lazzaroni, R.; Settambolo, R. Chirality 2011, 23, 730; (b) Chou, S.-
S. P.; Chung, Y. C.; Chen, P.-A.; Chiang, S.-L.; Wu, C. J. J. Org. Chem. 2011, 76, 692;
(c) Liu, H.; Su, D.; Cheng, G.; Xu, J.; Wang, X.; Hu, Y. Org. Biomol. Chem. 2010, 8,
1899; (d) Gracia, S.; Jerpan, R.; Pellet-Rostaing, S.; Popowycz, F.; Lemaire, M.
Tetrahedron Lett. 2010, 51, 6290. and references cited therein.
9. Nukui, S.; Sodeoka, M.; Sasai, H.; Shibasaki, M. J. Org. Chem. 1995, 60, 398.
10. Yu, R. T.; Lee, E. E.; Malik, G.; Rovis, T. Angew. Chem., Int. Ed. 2009, 2379.
11. Stead, D.; O’Brien, P.; Sanderson, A. Org. Lett. 2008, 10, 1409.
Acknowledgments
We thank FAPESP (Research Supporting Foundation of the State
of Sao Paulo) for financial support and a fellowship to V.D.P. We
also thank CNPq for research fellowship to A.C.B.B. and IQSC-USP
for facilities. We also would like to thank Professor Marcio Paixão
(UFSCar), Ana M. Deobald (UFSCar), Professor André Porto (IQSC-
USP) and Lenilson Coutinho (IQSC-USP) for help with the HPLC
instrument, Professor Daniel Cardoso for help with the photochem-
ical system and DQO-UFSCar for some NMR analyses.
12. Settambolo, R.; Guazzelli, G.; Lazzaroni, R. Beilstein J. Org. Chem. 2005, 2, 176.
13. See Supplementary data for details.
14. Experimental procedure for the photochemical Wolff rearrangement: A solution of
diazoketone 2 (269.0 mg, 0.9 mmol) in dry methanol (3.0 mL), in a 1 cm optical
path quartz cell, was irradiated with a Osram 150 Xenon white lamp for 4 h
under magnetic stirring (nitrogen gas evolution observed). Next, the solvent
was evaporated off in a rotary evaporator to furnish 272.0 mg (97%) of ester 1
with no need of purification. 1H NMR (200 MHz, CDCl3, mixture of rotamers) d
7.30 (br s, 5H), 5.79–5.44 (m, 1H,), 5.18 (d, 1H, J = 12.0 Hz), 5.08 (d, 1H,
J = 12.0 Hz), 4.50–4.31 (m, 1H), 3.66 (s, 3H), 3.53–3.41 (m, 2H), 3.16–2.96 (m,
2H), 2.08–1.68 (m, 4H); 13C NMR (50 MHz, CDCl3, mixture of rotamers) d 172.0,
161.2, 136.9, 134.3, 133.9, 128.3, 127.7, 122.0, 66.6, 58.5, 58.2, 51.7, 46.6, 46.3,
37.31, 32.2, 31.3, 29.6, 23.5, 23.5, 22.7; FT-IR (neat, cmꢀ1): 2954, 2927, 1737,
1701, 1452, 1411, 1353, 1270, 1189, 1170; HRMS (ESI) calcd for C17H21NNaO4
Supplementary data
Supplementary data (experimental procedures and copies of
the NMR spectra of all compounds and chiral HPLC chromatograms
of diazoketone 2 and lactam 3.) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2011.12.029.
[M+Na]: 326.1368 found: 326.1360; ½a D25
ꢀ30.0 (c 4.0 CH2Cl2); Rf: 0.4 (40%
ꢁ
EtOAc/hexanes).
15. Kirmse, W. Eur. J. Org. Chem. 2002, 2193.
16. Although no example of the photochemical Wolff rearrangement applied to the
Arndt–Eistert reaction is described in the literature for an ,b-unsaturated
References and notes
a
1. (a) Michael, J. P. Nat. Prod. Rep. 2008, 25, 139; (b) Michael, J. P. Nat. Prod. Rep.
2005, 22, 603; (c) Michael, J. P. Nat. Prod. Rep. 2004, 21, 625; (d) Michael, J. P.
Nat. Prod. Rep. 2003, 20, 458; (e) Michael, J. P. Nat. Prod. Rep. 2002, 19, 719; (f)
Michael, J. P. Nat. Prod. Rep. 2001, 18, 520; (g) Michael, J. P. Nat. Prod. Rep. 2000,
17, 579.
2. Most publications describe indolizidines 167B and 209D as natural. However,
according to Daly’s recent reviews, the two isolated natural alkaloids (proposed
tentatively to be indolizidines 167B and 209D) were found to be 3,5-
disubstituted pyrrolizidines and were, therefore, tabulated as indolizidines
167F and 209K in the appendix. The code names 167B and 209D are
maintained for the synthetic indolizidines, although they have not yet been
detected in nature. Please see: (a) Daly, J. W.; Spande, T. F.; Garraffo, H. M. J.
Nat. Prod. 2005, 68, 1556; (b) Pelletier, S. W. Alkaloids: Chemical and Biological
Perspectives; Elsevier Science Ltd: Oxford, 1999.
diazoketone, a single example is described for the thermal rearrangement by
Brueckner. However, the 2 diazoketones employed in this example are simple
ones, containing no epimerizable stereocenters or heteroatoms in the chain.
For this single example, see: (a) Kapferer, T.; Brueckner, R.; Herzig, A.; Koenig,
W. A. Chem. Eur. J. 2005, 11, 2154; (b) Kapferer, T.; Brueckner, R. Eur. J. Org.
Chem. 2006, 9, 2119.
17. Miles, N. J.; Sammes, P. G.; Kennewell, P. D.; Westwood, R. J. Chem. Soc., Perkin
Trans. 1 1985, 2299.
18. Park, S. H.; Kang, H. J.; Ko, S.; Park, S.; Chang, S. Tetrahedron: Asymmetry 2001,
12, 2621.
19. The highly stereoselective reduction of the iminium ion in indolizidine
skeleton is reported by several groups. For examples see Ref.9 and references
cited therein.
3. Aronstam, R. S.; Daly, J. W.; Spande, T. F.; Narayanan, T. K.; Albuquerque, E. X.
Neurochem. Res. 1986, 11, 1227.