Hydride-promoted ring expansion of 2-azaspiropyrrolinium salts: An approach towards the synthesis of (-)-nitramine

Article abstract of DOI:10.1055/s-2005-871555

An enantioselective approach toward the synthesis of the spiroalkaloid (-)-nitramine was achieved by electrophile-induced cyclization of a suitably substituted and protected chiral α-allylcyclohexanecarboxaldimine. Its hydride-promoted ring expansion after spirocyclization gave rise to the competitive formation of isomeric spiropyrrolidines and a spiropiperidine, the latter being further transformed into (-)-nitramine. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-871555

1726
LETTER
Hydride-Promoted Ring Expansion of 2-Azaspiropyrrolinium Salts:
An Approach Towards the Synthesis of (–)-Nitramine
H
ydride-Promo
r
ted Ring
i
E
xpan
c
sion of 2-A
k
z
aspiropyrrolinium
R
Salts osas Alonso, Kourosch Abbaspour Tehrani,1 Mark Boelens, Norbert De Kimpe*
Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium
Fax +32(9)2646243; E-mail: norbert.dekimpe@UGent.be
Received 17 March 2005
These 1-azaspiro alkaloids, isolated from the neotropical
Abstract: An enantioselective approach toward the synthesis of the
poisonous frog Dendrobates histrionicus, disturb the
spiroalkaloid (–)-nitramine was achieved by electrophile-induced
cyclization of a suitably substituted and protected chiral a-allylcy-
clohexanecarboxaldimine. Its hydride-promoted ring expansion af-
transfer of neuromuscular impulses at the level of the syn-
apses.11
ter spirocyclization gave rise to the competitive formation of
isomeric spiropyrrolidines and a spiropiperidine, the latter being
kaloids have been published in the literature, only a few of
further transformed into (–)-nitramine.
Despite the fact that a number of syntheses of Nitraria al-
them were enantioselective.12a–k
Key words: alkaloids, cyclizations, ring expansion, spiro com-
In most of the syntheses of Nitraria alkaloids, the majority
of reports establish the creation of the heterocyclic ring by
either formation of the C(1)–N bond or formation of the
C–C bonds of the spiro carbon, i.e. C(1)–C(6) or C(5)–
C(6) (Scheme 1).
pounds
2-Azaspiro compounds witnessed a great attention in re-
cent years due to their physiological activities. Polyzon-
imine 1 is a 2-azaspiro[4.4]non-1-ene alkaloid, produced
by the millipede Polyzonium rosalbum, which utilizes this
compound as an insect repellent against its natural preda-
tors such as ants.2–4
Ref. 10g,e,f; 12k
Ref. 9h
Ref. 10b,d,j,l,m; 12a,d,e,f,i
Ref. 12h,
this report
NR
1
11
10
8
2
3
6
9
4
7
5
10c
Similar 2-azaspiro[4.5]decanes and 2-azaspiro[4.5]dec-2-
enes have been shown to exhibit insect repellent proper-
ties.5 A variety of 2-azaspiro compounds have been isolat-
ed from Nitraria plants. These alkaloids, e.g. 2 (sibirine),
3 (nitramine) and 4 (isonitramine) often occur as optically
pure substances but also sometimes as racemates
(Figure 1).6–8 This phenomenon was recently discussed in
detail in an excellent review.9
Ref. 10g,i,k,o; 12c,g
Ref. 10n
OH
Scheme 1
In this communication, the electrophile-induced cycliza-
tion of a suitable chiral a-allylaldimine was evaluated in
the construction of (–)-nitramine via a C(3)–N bond
formation.
Ever since their isolation and structural elucidation, sever-
al reports on the synthesis of Nitraria alkaloids have been
published.10a–o The interest in these natural compounds
stems from the structural similarity with the neurotoxic
(–)-histrionicotoxin 5 and (–)-perhydrohistrionicotoxin 6
which have a 1-azaspiro[5.5]undecane-8-ol structure.
The electrophile-induced cyclization of w-alkenylimines
has been found to be a good method for the synthesis of
piperidines. This process proceeds via the intermediacy of
cyclic iminium salts and ring expansion of transient 2-
(bromomethyl)pyrrolidines.13,14
OH
OH
OH
Me
N
HN
HN
H
N
N
N
H
HO
OH
1
2
3
4
5
6
Figure 1
SYNLETT 2005, No. 11, pp 1726–1730
0
7
.0
7
.2
0
0
5
Advanced online publication: 27.06.2005
DOI: 10.1055/s-2005-871555; Art ID: G06405ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Hydride-Promoted Ring Expansion of 2-Azaspiropyrrolinium Salts
1727
In order to utilize this synthetic strategy, the synthesis of The conversion of 9 to 12 was performed by a chelate con-
a suitable g,d-unsaturated aldimine 8 was required. This trolled reaction of the bis-anion derived from 9. Treatment
target substrate holds the R- and S-stereochemistry at C(1) of hydroxyester 9 with 2.1 equivalents of LDA in THF
and C(2), respectively, while it carries a protective group gives a deprotonation of the hydroxyl function and the a-
at oxygen. The allyl substituent is at the right place in or- position with respect to the ester. The lithium enolate is
der to allow cyclization to a spiropyrrolinium salt, which chelated by the lithium alkoxide of the 2-position. The
is capable to be rearranged to a 2-azaspiropiperidine. The chelate-controlled reaction of the double deprotonated
N-benzyl substituent was initially chosen in order to arrive substrate 9 underwent stereoselective alkylation with allyl
at a N-benzyl spiroalkaloid, which requires a final hydro- bromide in THF to afford b-hydroxy-a-allylester 12 (90%
genolysis.
yield, 97.5:2.5), resulting from a front-side attack of the
enolate structure.18 The protection of the hydroxyl
function in the chiral b-hydroxyester 12 was at this point
pictured by three different protective groups, namely
tetrahydropyranyl, tert-butyldimethylsilyl and benzyl, in
order to evaluate a possible directing influence on the
final ring expansion step (Scheme 3).
The retrosynthetic analysis of (–)-nitramine 7 and the
target aldimine 8 requires the synthesis of the chiral b-hy-
droxyester 9, which constitutes the building block for this
chiral synthesis (Scheme 2).
R
O
N
OH O
OH
In this way, b-hydroxy-a-allylester 12 was protected with
DHP in CH2Cl2 in the presence of a catalytic amount of
p-TsOH, affording THP ether 13a in 95% yield.19,20
H
S
S
R
N
H
O
R
Reduction of the carboxylic ester 13a with LiAlH4 in re-
fluxing ether for 90 minutes gave rise to (1R,2S)-alcohol
14a in 88% yield. The oxidation of hydroxymethyl deriv-
ative 14a to the aldehyde 15a was performed with PCC in
CH2Cl2 in the presence of NaOAc, yielding 76% of 15a
after purification. The imination of ethyl-(+)-(1S,2S)-al-
dehyde 15a with BnNH2 in CH2Cl2 in the presence of
MgSO4 and K2CO3 at room temperature for 25 hours pro-
duced N-benzyl-(+)-(1R,2S)-aldimine 16a in 89% yield.
This aldimine was reacted with an equimolar amount of
7 (–)-nitramine
(6R,7S)-2-azaspiro [5.5]undecan-7-ol
8
9
R = protective group
Scheme 2
b-Ketoester 11 was prepared from cyclohexanone by
ethoxycarbonylation,15 which was enantioselectively
reduced with Saccharomyces cerevisiae in aqueous
sucrose.16 b-Hydroxyester 9 was obtained in 76% yield
from 11, with an enantiomeric excess superior to 95%.17
O
O
O
OH O
O
baker's yeast
Sacc. cerevisiae
2.5 equiv
O
O
S
R
O
O
3 equiv NaH/PhH
∆, 1.5 h
10
11 (62%)
9 (76%)
1) 2.1 equiv LDA, THF
–60 °C
–15 °C, 30 min
Br
2) 1.3 equiv
THF, –15 °C, 2 h
r.t. 2.5 h
PG
O
PG
O
OH
O
O
OH
O
S
S
O-protection
reduction
S
S
O
R
S
14a PG = THP (88%)
14b PG = TBDMS (82%)
14c PG = Bn (81%)
13a PG = THP (95%)
13b PG = TBDMS (88%)
13c PG = Bn (78%)
12 (90%)
oxidation
PG
PG
O
PG
O
Br
1 equiv BnNH2
CH2Cl2, 0.7 equiv MgSO4,
1 equiv Br2
O
O
N
S
R
N
CH2Cl2
0 °C, 10 min
S
S
H
H
S
R
0.5 equiv K2CO3, r.t. 25 h
S and R
Br
15a PG = THP (76%)
15b PG = TBDMS (57%)
15c PG = Bn (79%)
16a PG = THP (89%)
16b PG = TBDMS (93%)
16c PG = Bn (95%)
17a PG = THP
17b PG = TBDMS
17c PG = Bn
Scheme 3
Synlett 2005, No. 11, 1726–1730 © Thieme Stuttgart · New York

1728
E. Rosas Alonso et al.
LETTER
bromine in CH2Cl2 at 0 °C for 20 minutes furnishing the two equivalents of LiAlH4 towards alcohol 14b. Despite
transient pyrrolinium salt 17a21 which was directly react- many different reductive conditions, alcohol 14b could
ed with an excess of LiAlH4 in CH2Cl2–THF 1:1 at reflux not be prepared in this way, since deprotection of the silyl
for two hours, and further hydrolyzed with HCl to liberate ether along with reduction of the ester functionality was
the hydroxyl group. The reductive step produced a mix- observed. This phenomenon has also been noticed during
ture of diastereomeric pyrrolidines 18a (61%, Scheme 4), the reduction of a-hydroxynitriles and ketones.26 To over-
and the desired rearranged piperidine 19a22 (19% yield af- come this problem, 13b was then treated with 1.1 equiva-
ter purification by column chromatography). The latter lents of DIBAL-H in toluene. After three hours at –78 °C,
was then submitted to catalytic hydrogenation giving rise the target protected alcohol 14b was obtained in 82%
to (–)-nitramine 7 in 82% yield with an enantiomeric ex- yield after column chromatography on alumina. Surpris-
cess of 93%. Enantiomeric purity was calculated based on ingly, its further oxidation to aldehyde 15b was not ac-
the optical rotation values measured for 7 and that report- complished by DMSO/oxalyl chloride27 or TPAP/NMO,28
ed in the literature.23 The formation of pyrrolidines 18 and as PCC29 was not initially chosen for its slightly acidic
piperidine 19 can be rationalized in terms of a preliminary properties. Nevertheless, oxidation with PDC30 afforded
reduction of spiropyrrolinium salt 17, leading to interme- the desired aldehyde 15b in 57% of yield which could fi-
diate 20 which undergoes an intramolecular nucleophilic nally be transformed into aldimine 16b upon condensa-
substitution. The resulting tricyclic aziridinium ion 21 is tion with BnNH2 and MgSO4 in CH2Cl2. The electrophile-
then either opened at the methylene or methine position induced cyclization of the latter led, as foreseen, to the
(route b or a, respectively), to provide the aforementioned transient spiroiminium salt 17b, that was immediately re-
spiro compounds 18 and 19. The stereochemistry of inter- acted with two equivalents of LiAlH4 in THF–CH2Cl2 1:1.
mediates 17 is a mixture of isomers as a) the electrophile- Unfortunately, only spiropyrrolidines 18b were isolated
induced cyclization shows little stereoselection and b) after column chromatography of the crude mixture (ca.
mixtures of stereoisomers 18 are isolated (vide infra).
1:1,1H NMR).
In search of an increase of the yield of the rearranged These results prompted the use of a third different protect-
spiropiperidine 19 during the reductive process, TBDMS- ing group at the oxygen atom of the aldimine precursor.
protected aldimine 16b was envisaged. The tert-butyldi- Thus, 12 was protected as benzyl ether using 1.1 equiva-
methylsilyl group has been widely used in synthetic or- lents of NaH in THF followed by 1.1 equivalents of BnBr
ganic chemistry for the protection of the hydroxyl in the presence of a catalytic amount of n-Bu4NI, giving
function,24 and because of its advantageous features it was 13c.
introduced into 12 making use of a suitable procedure.25
The resulting protected ester 13b was then treated with
refluxing diethyl ether afforded 14c, which was further
Reduction of the latter with two equivalents of LiAlH4 in
OH
H
N
7 (82–88%)
H2, Pd/C
PG = Bn
PG
PG
O
1) 2 equiv LiAlH4
CH2Cl2/THF 1:1
∆, 2 h
Br
PG
O
S
+
N
O
R
S
R
N
N
S or R
2) 2 equiv HCl 2N
MeOH, r.t. 2 h
(only for 17a)
Br
S and R
Br
19
18 (1:1)
17
b
a
H
PG
PG
PG
O
O
O
N
N
N
b
a
Br
20
Br
H
21
17a PG = THP
17b PG = TBDMS
17c PG = Bn
19a (PG = H) 19%
19b 0%
19c 23%
18a (PG = H 61%)
18b (42%)
18c (51%)
Scheme 4
Synlett 2005, No. 11, 1726–1730 © Thieme Stuttgart · New York

LETTER
Hydride-Promoted Ring Expansion of 2-Azaspiropyrrolinium Salts
1729
oxidized according to the Swern procedure,27 as treatment
with PCC only resulted in a poor yield. The thus obtained
aldehyde 15c was then condensed with BnNH2 giving rise
to the expected aldimine 16c, which was reacted with one
equivalent of bromine under similar conditions as used
before.
(10) (a) Snider, B. B.; Cartaya-Marin, C. P. J. Org. Chem. 1984,
49, 1688. (b) Mieckzowski, J. B. Bull. Pol. Acad. Sci.,
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Tetrahedron Lett. 1986, 27, 3955. (e) Carruthers, W.;
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Koomen, G. J. Tetrahedron Lett. 1989, 30, 2301. (i) Kim,
D.; Kim, H. S.; Yoo, J. Y. Tetrahedron Lett. 1991, 32, 1577.
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Lett. 1992, 1493. (k) Wanner, M. J.; Koomen, G. J.
Tetrahedron 1992, 48, 3935. (l) Keppens, M.; De Kimpe, N.
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In the same manner, the reduction of the iminium salt 17c
produced a 1:1 mixture of diastereomeric spiropyrrol-
idines 18c, which could not be separated by chromato-
graphic methods, and the spiropiperidine 19c (23%).
After catalytic hydrogenation, the latter conducted to the
2-azaspiro compound (–)-nitramine 7 in 88% yield (ca.
4% overall yield).
In summary, a new approach towards (–)-nitramine 7 has
been disclosed. This methodology makes use of an elec-
trophile-induced cyclization protocol of a suitable chiral
a-allylaldimine 8, and a hydride-promoted ring expansion
of the resulting transient spirocyclic iminium species. The
results obtained showed that chiral a-allylaldimines 16a
and 16c bearing a THP or a Bn group at oxygen, contrary
to aldimine 16b carrying a bulky TBDMS group, undergo
more efficiently such a rearrangement, probably due to
the lower steric hindrance of a Bn and THP substituent
compared to the TBDMS protective group. Stereoelec-
tronic effects might play a role, as well. In addition, a
suitable methodology was worked out for the synthesis of
spiropyrrolidines.
(11) Daly, J. W. In Progress in the Chemistry of Organic Natural
Products; Herz, W.; Griesebach, H.; Kirby, G. W., Eds.;
Springer-Verlag: Berlin, 1982, 205.
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Kurumada, T.; Maezaki, N.; Sugiyama, K.; Iwata, C. J.
Chem. Soc., Chem. Commun. 1991, 1409. (e) Westermann,
B.; Scharmann, G.; Kortmann, J. Tetrahedron: Asymmetry
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Acknowledgment
The ‘Fund for Scientific Research-Flanders (Belgium)’ (F.W.O.-
Vlaanderen), and Ghent University are greatly acknowledged for
financial support. E.R.A. is indebted to the Mexican National
Council for Science and Technology (CONACyT).
(13) De Kimpe, N.; Boelens, M. J. Chem. Soc., Chem. Commun.
1993, 916.
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(21) Experimental Conditions.
A solution of 470 mg (2.9 mmol) of bromine in 10 mL of
CH2Cl2 was slowly added to 1.0 g (2.93 mmol) of imine 16a
in 10 mL of dry CH2Cl2 at 0 °C. After 20 min of vigorous
stirring at 0 °C, the solvent was evaporated in vacuo under
gentle warming, resulting in 17a as a syrupy ocher mass
which decomposed after standing at r.t.
(22) Spectral data of (6R,7S)-2-benzyl-2-azaspiro[5.5]-undecan-
7-ol (19a): 1H NMR (270 MHz, CDCl3): d = 1.04–1.80 [12
H, m, (CH2)6], 1.93–2.03 and 2.22–2.28 (1 H each, each m,
NCH2CH2), 2.88 (1 H, br d, JAX = 11.5 Hz, CspiroHCHN),
3.24 (1 H, d, JAX = 11.5 Hz, CspiroHCHN), 3.40–3.49 (1 H,
Synlett 2005, No. 11, 1726–1730 © Thieme Stuttgart · New York

1730
E. Rosas Alonso et al.
LETTER
m, CHOH), 3.38–3.48 (1 H each, each d, JAB = 12.9 Hz,
CH2C6H5), 5.32 (1 H, br s, OH), 7.17–7.39 (5 H, m, C6H5).
13C NMR (68 MHz, C6D6): d = 21.35, 23.93, 24.60, 32.95,
37.25 and 38.40 [(CH2)4 and (CH2)2], 37.64 (Cspiro), 54.75
(NCH2CH2), 59.15 (CspiroCH2N), 63.80 (NCH2C6H5), 78.40
(CHOH), 127.56, 128.66, 129.32 and 138.40 (C6H5). MS (70
eV): m/z (%) = 259 (8) [M+], 258 (4), 231 (5), 174 (12), 168
(14), 148 (5), 146 (8), 140 (5), 134 (29), 133 (14), 132 (5),
121 (6), 120 (33), 106 (5), 92 (10), 91 (100), 67 (6), 65 (9),
55 (8), 44 (13), 43 (5), 42 (9), 41 (10). IR (NaCl): 3160–3435
(O–H) cm–1. Rf = 0.33 (CHCl3–MeOH, 95:5); [a]D22 +15
(c 1.12, CHCl3).
(23) Synthesized nitramine: [a]D23 –21.5 (c 1.51, CH2Cl2). Lit.12a
[a]D25 +23 (c 1.58, CH2Cl2). Enantiomeric excess values for
all succeeding compounds were 91–93%.
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Synlett 2005, No. 11, 1726–1730 © Thieme Stuttgart · New York