Highly efficient asymmetric access to 1-azaspiro[4.4]nonane skeleton

Article abstract of DOI:10.1055/s-2002-34232

Vinylogous Mukaiyama aldol type reaction of chiral non-racemic silyloxypyrroles followed by acidic treatment affords an efficient asymmetric access to 1-azaspiro[4.4]nonanes in high diastereoisomeric excess (up to 79%).

Full text of DOI:10.1055/s-2002-34232

LETTER
1629
Highly Efficient Asymmetric Access to 1-Azaspiro[4.4]nonane Skeleton
H
ighly Efficien
o
A
symmetri
ï
c
A
cce
s
c
s
to 1-Azaspiro[4
P
.4]nonane Ske
l
leton anas,a Joëlle Pérard-Viret,a Jacques Royer,*a Mohamed Selkti,b Alain Thomasb
a
Laboratoire de Chimie Thérapeutique, UMR 8638, CNRS-Université Paris 5, 4 avenue de l’Observatoire, 75270 Paris cedex 06, France
Fax +33(1)43291403; E-mail: royer@pharmacie.univ-paris5.fr
b
Laboratoire de Cristallographie, UMR 8015, CNRS-Université Paris 5, 4 avenue de l’Observatoire, 75270 Paris cedex 06, France
Received 31 July 2002
Abstract: Vinylogous Mukaiyama aldol type reaction of chiral
non-racemic silyloxypyrroles followed by acidic treatment affords
an efficient asymmetric access to 1-azaspiro[4.4]nonanes in high
diastereoisomeric excess (up to 79%).
Keys words: spiro compounds, asymmetric synthesis, ring expan-
sion, rearrangement, pyrroles
1-Azaspiro[4.4]nonanes are building blocks difficult to
access since the formation of quaternary spiro centers has
always been a tricky exercise in organic synthesis. Never-
theless, methods to form a spiro center to the nitrogen of
a pyrrolidine have been developed, and they are based
upon a wide variety of different methodologies.1 Among
them, the use of radicals,1a cycloadditions,1b ring closure
reaction,1c palladium,1d N-acyliminiums,1e phenol
oxidation1f and more recently the use of aluminium amide
in domino reactions,1g have been described. It is notewor-
thy that only few of these methods are stereoselective1b,e
and can be used for asymmetric synthesis of natural prod-
ucts containing this moiety.
Scheme 2
The ring expansion of cyclobutanol derivatives giving rise
to spiro compound via a semi-pinacol type reaction is
known for a decade. It was well described by Paquette
with dihydrofuran and tetrahydropyran derivatives,3 and
recently, an example with piperidine compounds has been
published.4 The key step for this reaction is the formation
of a carbocation to the carbinol of cyclobutanol, may it
be an oxonium or a N-acyliminium.
This method appeared very attractive for us, since we an-
ticipated that the cyclobutanol derivative required for the
semi-pinacolic rearrangement should be the , -unsatur-
ated -lactam 6 (Scheme 3). It could be quite readily ac-
cessible by a vinylogous Mukaiyama aldol condensation
of the silyloxypyrrole 5 with cyclobutanone.
We planned to develop a new asymmetric entry to 1-aza-
spiro[4.4]nonane, like the lactam 1, as a key intermediate
in the synthesis of (–)-cephalotaxine 2 (Scheme 1).
Scheme 1
We anticipated that this could be possible by the use of
chiral non racemic , -unsaturated -lactams 3 that we
have been developing for some years.2 The possibility to
diastereoselectively substitute -lactams 3 at the C-5 po-
sition with either an electrophile [via the silyloxypyrrole,
path (a)] or a nucleophile [via a N-acyliminium, path (b),
Scheme 2], permits to construct a quaternary spiro center
at this carbon. As a matter of fact, the application of path
(a) maintains the , -unsaturation, allowing further use of
path (b).
Scheme 3 Reagents and conditions: (a) 2,5-Dihydro-2,5-dime-
thoxyfuran, HCl, H2O, r.t.; (b) TBSOTf, Et3N, CH2Cl2, r.t.; (c) cyclo-
butanone, BF3 OEt2, CH2Cl2, –78 °C; (d) aq conc. HCl, CH2Cl2, r.t.
In order to check this two step sequence we prepared silyl-
oxypyrrole 5a derived from -methylbenzylamine 4a us-
ing the methodology already reported, namely
condensation of 4a with dimethoxydihydrofuran to give
3a followed by TBDMSOTf treatment in presence of
base. The expected compound (6a) was obtained in 85%
yield and 83% diastereoisomeric excess when silyloxy-
pyrrole 5a was reacted with cyclobutanone (Scheme 3).5
Synlett 2002, No. 10, Print: 01 10 2002.
Art Id.1437-2096,E;2002,0,10,1629,1632,ftx,en;D14502ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

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L. Planas et al.
LETTER
The major isomer could be crystallized and allowed us to
determine the absolute configuration of the new chiral
center by X-ray analysis to be S (Figure 1).
Scheme 4
In all cases, this two steps sequence occurred in very high
yield. Using phenylglycinol derivatives allowed us to im-
prove the diastereoisomeric excess of the ring expansion
reaction, but a real hit was obtained with (S)-1-(1-naphth-
yl)ethylamine. This chiral amine has already been used in
asymmetric syntheses with good stereochemical results7
and is a suitable source of nitrogen and chirality for our
target alkaloid. The diastereoisomeric excess could be fur-
ther enhance from 74% to 79%, operating at 0 °C instead
of 20 °C, while time to reaction completion was raised
from 2 hours to 9 hours. Nevertheless, at –20 °C, no reac-
tion occurred after 24 hours.
Figure 1 Crystal structure of 6a, determined by X-ray.6
Then, 6a was placed under acidic conditions to achieve
the ring expansion. Depending on the reaction conditions
(Table 1), we observed either degradation or the elimina-
tion product or the expected product as a mixture of two
diastereoisomers. The reaction could be carried out under
different conditions but the best result was obtained by the
use of concentrated hydrochloric acid in dichloromethane
(Table 1, entry 7), as described for N-tosyliminiums by
Dake’s group.4
Table 2 Diastereoselectivity in the Rearrangement Reaction to 1-
We can suggest that water was needed for this reaction, to
ensure the spiro center formation instead of elimination
(Scheme 4).
Azaspiro[4.4]nonane Skeleton8
Entry Starting Amine
1
6,a,b Yield (de) % 7,b Yield (de) %
85 (83)
84 (18)
75 (48)
77 (4)
99 (20)
Table 1 Semi-pinacolic Rearrangement of Cyclobutanol Derivative
6a Under Various Acidic Conditions
Entry Acid
Solvent Temp 7aa
CH2Cl2 r.t.
8a
degradation
degradation
degradation
2
3
4
99 (40)
1
2
3
4
5
6
7
CSA
99 (63)
PTSA
toluene reflux
CH2Cl2 r.t.
TfOH
99 (74-79)c
Amberlyst 15
Amberlyst 15
CH2Cl2 r.t.
toluene r.t.
70%
30%
75%
25%
10%
<1%
5d
62 (30)
99 (68)
Dowex 50X8-100 CH2Cl2 r.t.
concd HCl CH2Cl2 r.t.
90%
>99%
a Yield of isolated product.
a Product ratios are determined by integration of 1H NMR spectra.
b De determined by integration of corresponding signal in the 1H NMR
spectra of the crude reaction product.
c Reaction at 0 °C.
Unfortunately, despite the excellent chemical yield, the
diastereoisomeric excess was modest (20%), and we then
decided to investigate other chiral auxiliaries in order to
improve this result.
d Using racemic material.
Because of the improved de observed with O-substituted
phenylglycinols, we envisioned the use of O-methyl-
naphthylglycinol (Table 2, entry 5). Different asymmetric
syntheses of naphthylglycinol exist,9 but we preferred to
prepare the more accessible racemic one. Thus, 4e was
prepared in four steps from 1-napthaldehyde as shown in
Scheme 5.
Various silyloxypyrroles 5a–e were prepared using our
standard methodology from amines 4a–e in 41–73% over-
all yields. These silyloxypyrroles were engaged in the vi-
nylogous Mukaiyama reaction followed by acidic
treatment to give rise to the spiro compounds (Table 2).
Synlett 2002, No. 10, 1629–1632 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Highly Efficient Asymmetric Access to 1-Azaspiro[4.4]nonane Skeleton
1631
This compound was described in the Nagasaka’s cephalo-
taxine synthesis and the comparison of its optical rotation
([ ]D –64, lit.14 –68) allowed us to assign the R-configura-
tion to the spiro center of 7d. Following identical process,
we also attributed the R-configuration to the spiro center
of 7c.
Scheme 5 Reagents and conditions: (a) NaCN, (NH4)2CO3, EtOH/
H2O 50/50, 50 °C, 24 h; (b) NaOH, H2O, reflux, 2.5 h; (c) LAH, THF
(89%); (d) KH, THF, overnight then MeI (75%).
The amino acid was first obtained from the corresponding
aldehyde through a modified Strecker synthesis as de-
scribed.10 The reduction of the carboxylic acid function by
LiAlH4 furnished the aminoalcohol which was regioselec-
tively methylated11 (KH, THF, MeI) to give 4e in 67% for
the two steps.
Unfortunenaly this new chiral auxiliary did not allow any
improvement in the diastereoselectivity of the semi-pina-
col rearrangement.
Scheme 7 Reagents and conditions: (a) Ethyleneglycol, PTSA,
toluene, reflux; (b) Li/NH3, ethanol, –78 °C; (c) HOAc/H2O 50/50,
reflux.
As suggested by the mechanism of the rearrangement and
by the discrepancy between diastereoisomeric excesses of
compounds 6 and 7, the stereochemical information of
compound 6 was lost in the semi-pinacolic rearrangement.
This was definitively proved by placing each diastereoiso-
mer of 5d, easily separable by crystallization, under the
same experimental conditions (Scheme 6). We did not no-
tice any measurable difference between the two crude
products, proving that there was no kind of survival of the
Since the ring enlargement of cyclopentanol derivatives
has been described with dihydrofuran compounds3 we en-
visaged this reaction starting with our -lactam.
The aldol product 12 was readily obtained from the silyl-
oxypyrrole 5a under the same conditions as above, in
good yield (78%) and an excellent diastereoisomeric ex-
cess (90%).
initial configuration.12 So, the chirality of the new center However, this compound did not undergo rearrangement
was only controlled by the chiral auxiliary, due to the free reaction. By varying the conditions, we obtained either the
rotation in the intermediate N-acyliminium.
elimination product or the product of hydrolysis of the N-
acyliminium moiety4 (Scheme 8).
Scheme 6
Scheme 8 Reagents and conditions: (a) Amberlyst 15, CH2Cl2, r.t.;
(b) concd HCl, THF, r.t.
Major diastereoisomer 7d could be easily separated
through crystallization by triturating the crude product in
ether (68% of the diastereopure product could be ob-
tained). We then derivatised it, on the way to determine
the absolute configuration of the newly created spiro cen-
ter (Scheme 7). First, the ketone was protected as the cy-
clic ketal 9d with ethylene glycol (77% yield), and the
latter was treated with lithium in liquid ammonia,13 to re-
move the chiral auxiliary. The ketal 10 (69% yield) could
be deprotected to obtain the simple spiro amide 11 in 86%
yield.
To summarize, we developed a highly efficient method
for the diastereoselective formation of 1-aza-
spiro[4.4]nonanes, allowing us to construct the spiro bicy-
clic system of (–)-cephalotaxine. Work is on progress to
complete a new asymmetric synthesis of (–)-cephalotax-
ine based on this methodology.
Acknowledgement
This work was supported by a grant from the M.E.N.R.T.
Synlett 2002, No. 10, 1629–1632 ISSN 0936-5214 © Thieme Stuttgart · New York

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L. Planas et al.
LETTER
2976, 2937, 1660 cm–1. MS (CI, NH3): m/z = 308 (MH+),
238 (MH+ – C4H6O). 1H NMR (300 MHz, CDCl3): = 0.35–
0.5 (m, 1 H), 1.01 (s, 1 H, D2O exch.), 1.35–1.55 (m, 2 H),
1.55–1.70 (m, 2 H), 1.78 (d, J = 7.1 Hz, 3 H), 1.85–2.00 (m,
1 H), 4.25 (t, J = 1.6 Hz, 1 H), 6.30 (m, 2 H), 6.94 (dd,
J = 7.0, 6.0 Hz, 1 H), 7.40–7.60 (m, 4 H), 7.83 (d, J = 8.1 Hz,
References
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1 H), 7.90 (d, J = 8.3 Hz, 1 H), 8.23 (d, J = 8.4 Hz, 1 H). 13
C
NMR (75 MHz, DMSO): = 17.7, 24.4, 36.2, 40.6, 55.1,
74.8, 81.3, 128.5, 130.3, 130.8, 131.7, 132.9, 134.3, 134.5,
136.1, 139.0, 143.5, 151.3, 177.6. Major diastereoisomer:
[ ]D25 –13.8 (c 0.97, CHCl3). Mp = 196–198 °C (Et2O). IR
(KBr): = 3382, 2977, 2934, 1658, 1394 cm–1. MS (CI,
NH3): m/z = 308 (MH+), 238 (MH+ – C4H6O). 1H NMR (300
MHz, CDCl3): = 1.36 (m, 1 H), 1.80–2.10 (m, 5 H), 1.75
(s, 1 H), 1.86 (d, J = 7.0 Hz, 3 H), 3.51 (t, J = 1.5 Hz, 1 H),
6.07 (q, J = 7.0 Hz, 1 H), 6.28 (dd, J = 1.6, 6.0 Hz, 1 H), 6.81
(dd, J = 1.8, 6.0 Hz, 1 H), 7.47 (m, 3 H), 7.63 (m, 2 H), 7.84
(m, 2 H). 13C NMR (75 MHz, CDCl3): = 13.6, 19.1, 31.9,
36.2, 49.0, 69.6, 75.9, 123.2, 125.2, 125.8, 126.1, 127.3,
128.5, 129.1, 129.2, 132.0, 134.0, 136.2, 145.7, 173.3. Anal.
Calcd for C20H21NO2: C, 78.15; H, 6.89; N, 4.56. Found: C,
78.03; H, 7.06; N, 4.60.
(2) (a) Baussanne, I.; Chiaroni, A.; Husson, H.-P.; Riche, C.;
Royer, J. Tetrahedron Lett. 1994, 35, 3931. (b) Baussanne,
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180815.
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(5) Typical Procedure for Silyloxypyrroles 5.
To a solution of 2,5-dimethoxy-2,5-dihydrofuran (1 equiv)
and chiral amine 4a,c–e (1 equiv) in water (0.25 M) was
added a concd solution of HCl (1.5 equiv). The mixture was
stirred at r.t. for 3 h then neutralized with solid NaHCO3 and
extract with CH2Cl2. The combined organic layers were
dried over MgSO4 and the solvent distilled off. A red oil,
mixture of the , and , unsaturated lactams was then
obtained. tert-Butyldimethylsilyl triflate (1 equiv) was
slowly added to a solution of either the crude product or the
purified lactams (1 equiv) and NEt3 (2 equiv) in CH2Cl2 (0.1
M) and the mixture was stirred at r.t. for 1 h. The solvent was
evaporated under vacuum and the residue purified by
filtration on a pad of alumina with a mixture of heptane and
EtOAc. (Nota: silyloxypyrroles are used to be kept under
argon at –20 °C). Analyses for 5d: [ ]D25 +11.7 (c 0.69,
CH2Cl2). Mp = 97 °C (heptane–EtOAc). IR (KBr):
= 2929, 2858, 1560, 1492, 1438 cm–1. 1H NMR (300 MHz,
CDCl3): = –0.05 (s, 3 H), 0.23 (s, 3 H), 0.80 (s, 9 H), 1.89
(d, J = 7.0 Hz, 3 H), 5.31 (dd, J = 2.0, 3.6 Hz, 1 H), 6.01 (t,
J = 3.5 Hz, 1 H), 6.16 (q, J = 7.0 Hz, 1 H), 6.35 (dd, J = 1.9,
3.4 Hz, 1 H), 7.10 (d, J = 7.2 Hz, 1 H), 7.42 (t, J = 7.9 Hz,
1 H), 7.50–7.55 (m, 2 H), 7.77 (d, J = 8.3 Hz, 1 H), 7.88 (d,
J = 7.4 Hz, 1 H), 8.08 (d, J = 8.0 Hz, 1 H). 13C NMR
(75 MHz, CDCl3): = –5.0, –4.6, 18.2, 21.4, 25.7, 49.5,
87.7, 105.2, 109.8, 123.2, 125.8, 126.5, 128.1, 129.1, 131.0,
134.1, 139.7, 142.2. HRMS (CI, NH3): m/z calcd for
C22H30NOSi (MH+): 352.2097. Found: 352.2101. Typical
Procedure for Cyclobutanols 6. To a solution of
silyloxypyrrole 5a–e (1 equiv) in anhyd CH2Cl2 (0.15 M)
with 3Å MS, under argon, was added cyclobutanone (or
cyclopentanone) (1.6 equiv). After 15 min at r.t., the solution
was cooled at –78 °C and BF3 OEt2 (1.5 equiv) was added in
the course of 15 min. The solution was stirred at –78 °C for
2 h and allowed to warm to 0 °C. The reaction was quenched
by addition of H2O, the aq phase was separated and extracted
with CH2Cl2. The organic phases were combined, dried over
Na2SO4 and the solvent was removed under vacuum. The
resulting oil was purified by flash chromatography.
Analyses for 6d: Minor diastereoisomer: [ ]D25 –264.1 (c
0.52, CHCl3). Mp = 245 °C (CH2Cl2). IR (KBr): = 3388,
(8) Typical Procedure for Spiro Compounds 7.
To a solution of cyclobutanol 6a–e (1 equiv) in CH2Cl2 (0.05
M) was added concd aq HCl (1.5 equiv). After 9 h at 0 °C,
the solvent was removed under vacuum. The crude product
was redissolved twice in CH2Cl2 and reevaporated to
eliminate trace amount of acid.
Analyses for 7d (cristallyzed from Et2O): [ ]D25 –48.4
(c 1.04, CHCl3). Mp = 140 °C (Et2O). IR (KBr): = 2968,
1750, 1679, 1380, 1347, 780 cm–1. MS (CI, NH3): m/z = 308
(MH+). 1H NMR (400 MHz, CDCl3): = 1.07–1.17 (m, 2
H), 1.34–1.55 (m, 2 H), 1.62 (ddd, J = 6.5, 8.5, 12.3 Hz,
1 H), 1.67 (d, J = 7.0 Hz, 3 H), 1.87 (ddd, J = 9.5, 11.6, 18.9
Hz, 1 H), 1.93 (ddd, J = 6.8, 8.9, 12.3 Hz, 1 H), 2.23 (dd,
J = 6.1, 18.9 Hz, 1 H), 2.43 (dd, J = 6.8, 8.5, 16.8 Hz, 1 H),
2.53 (ddd, J = 6.5, 8.9, 16.8 Hz, 1 H), 6.25 (q, J = 7.1 Hz,
1 H), 7.30–7.60 (m, 4 H), 7.83 (d, J = 9.7 Hz, 1 H), 7.79 (d,
J = 7.6 Hz, 1 H), 8.00 (d, J = 8.3 Hz, 1 H). 13C NMR (75
MHz, CDCl3): = 7.8, 18.9, 29.0, 31.7, 32.3, 35.7, 47.5,
72.3, 124.0, 125.1, 125.9, 126.3, 127.2, 129.1, 129.3, 132.7,
133.9, 136.1, 175.7, 217.0. Anal. Calcd for C20H21NO2: C,
78.15; H, 6.89; N, 4.56. Found: C, 77.96; H, 7.15; N, 4.41.
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Synlett 2002, No. 10, 1629–1632 ISSN 0936-5214 © Thieme Stuttgart · New York