Synthesis of pyrrolidin-3-ones from dihydropyran precursors via spiro-N,O-acetals

Article abstract of DOI:10.1016/j.tetlet.2009.10.018

2,2-Disubstituted pyrrolidin-3-ones are prepared in three steps from simple dihydropyran derivatives; the key spiro-N,O-acetal intermediate is a useful N-sulfonylketoiminium ion precursor. This route represents a formal synthesis of the indolizidine alkal

Full text of DOI:10.1016/j.tetlet.2009.10.018

Tetrahedron Letters 50 (2009) 7141–7143
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Synthesis of pyrrolidin-3-ones from dihydropyran precursors
via spiro-N,O-acetals
a
a
b
Jeremy Robertson a, , Andrew J. Tyrrell , Praful T. Chovatia , Sarah Skerratt
*
a Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
b Pfizer Global Research and Development, Ramsgate Road, Sandwich CT13 9NJ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
2,2-Disubstituted pyrrolidin-3-ones are prepared in three steps from simple dihydropyran derivatives;
the key spiro-N,O-acetal intermediate is a useful N-sulfonylketoiminium ion precursor. This route repre-
sents a formal synthesis of the indolizidine alkaloid core, with potential application to pyrrolizidines and
quinolizidines.
Received 27 August 2009
Revised 23 September 2009
Accepted 2 October 2009
Available online 8 October 2009
Ó 2009 Elsevier Ltd. All rights reserved.
The structures of at least 400 pyrrolizidine alkaloids have been
reported and many total syntheses and innumerable synthetic ap-
proaches are now documented.1 In a previous contribution to the
area we described an unusual construction of the five-membered
widely used in C–C bond-forming processes and we expected those
proposed in Scheme 1 to behave similarly.8
During the development of routes to substrates of the form 2 we
discovered that 2-acyldihydrofurans are prone to oxidative rear-
rangement,9 therefore we focused on the more tractable deriva-
tives of dihydropyran and carried the oxygen functionality
through as the alcohol rather than the ketone. A first substrate
(10, Scheme 2) was prepared from 2-formyldihydropyran (7)10 in
three steps: addition of lithioacetonitrile,11 nitrile reduction and
sulfonylation. Spirocyclisation followed precedent well-estab-
lished in the spiroacetal literature12 and exposure of sulfonamide
10 to PPTS afforded two separable diastereomers, 11 and 12, of
the desired spirocycle (3:1 ratio, 63% isolated yield).
Unambiguous stereochemical assignment of these isomers
could not be secured by NOE experiments, but X-ray-quality crys-
tals were grown of the major isomer (11) which was then shown to
have the hydroxy group cis-to the tetrahydropyranyl oxygen, Fig-
ure 1.13 The diastereomeric ratio is assumed to represent the equi-
librium value. The calculated lowest energy conformations of both
11 and 12 are very similar to that in the crystal, and isomer 11 is
more stable under a variety of basis sets.14 In the crystal, the C–
NTs bond is situated equatorially—the steric bulk of this group
overriding any electronic axial preference15—and NOE experiments
also support this as the preferred conformation in solution [the
CH(OH) protons both correlate with just the axial CH2O proton].
We were concerned in this initial work that hydride migration
would terminate the intended iminium ion chemistry prema-
turely16 therefore, the spirocyclic alcohols were oxidised to ketone
13 which was then treated with allyltrimethylsilane in the pres-
ence of BF3ÁOEt2 (Scheme 3) according to Somfai’s procedure.8b
The reaction progressed very slowly at À78 °C, and in order to
achieve complete consumption of the spirocycle, it was necessary
to allow the mixture to reach room temperature which resulted
in a moderate yield of the allylated compound 15 along with minor
products 16 and 17 originating from secondary reactions of the
ring by C–C bond formation at the
a-amino position, exemplified
by the synthesis of heliotridane and a dihydroxylated analogue.2
More recently, we required a short route to pyrrolizidine ketone
derivatives 6 (n, m = 1), Scheme 1, bearing either H, OH, or alkyl
bridgehead substituents, which we considered might be obtained
from a common ketoiminium intermediate 4. Our overall plan
was to effect a sequence of ring-interchanges from readily-avail-
able dihydrofurans to the pyrrolizidine core via a spirocyclic N,O-
acetal as shown. An advantage of this general approach lies in its
equal applicability to indolizidines (6; n, m = 1 or 2) and quinolizi-
dines (6; n, m = 2). We now report proof-of-principle results that
establish the viability of this ring-interchange route to -izidine
alkaloids.
The spirocyclisation of an a-(x-sulfonamidoalkyl)enol ether (cf.
2?3) does not appear to have precedent; however, the intermolec-
ular N-sulfonamidation of oxonium ions derived from enol ethers
is well known.3 In addition, within their synthesis of the EFGHI-
ring system of azaspiracid-1, Oikawa et al. reported a closely
related process in which N-spirocyclisation onto an oxonium ion
derived from an acetal was achieved under carefully controlled
Lewis acidic conditions.4 The azaspiracid literature contains a
number of similar examples of spirocyclisation of carbamates,5
and the condensation of both N- and O-nucleophiles with ketones
can also be used to produce spiro-N,O-acetals.6
Precedent for the second key step (cf. 3?5) is much more lim-
ited and, to the best of our knowledge, N-tosylketoiminiums of
general structure 4 are so far not described.7 Nevertheless, N-sulfo-
nyliminium species lacking the conjugating carbonyl have been
* Corresponding author. Tel.: +44 1865 275660.
E-mail address: jeremy.robertson@chem.ox.ac.uk (J. Robertson).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.10.018

7142
J. Robertson et al. / Tetrahedron Letters 50 (2009) 7141–7143
O
O
O
R
n N
6
O
R
N
(
)
n
O
(
)
n
O
O
( )n
O
( )n
Ts
( )n
Ts
N
(
)
( )m
N
(
)
m
Ts
N
H
( )m
( )m
HO
HO
( )m
Ts
1
2
3
4
5
Scheme 1. General route to pyrrolizidine, indolizidine and quinolizidine ketones from cyclic enol ethers via spiro-N,O-acetals (n, m = 1, 2; R = H, OH, Me).
O
O
O
(i)
(ii)
H
NHR
85%
quant.
crude
O
CHO
O
CN
O
O
HO
N
Ts
N
Ts
N
Ts
OH
OH
7
8
9, R = H
10, R = Ts
HO
(iii) 63%
18 (57%)
19 (16%)
20 (31% brsm)
HO
HO
O
Figure 2. Products obtained from 13 + Et3SiH/BF3ÁOEt2 (?18, 19) and 13 + 2-
(tributylstannyl)furan/BF3ÁOEt2 (?20).
(iv)
(v)
N
Ts
N
Ts
N
Ts
78%
from 10
O
O
O
11
12
13
13 was recovered) and generated a complex mixture of by-
products.
Scheme 2. Reagents: (i) LiCH2CN, THF; (ii) LiAlH4, THF; (iii) TsCl, K2CO3, aq THF; (iv)
PPTS (6%), CH2Cl2; (v) Dess–Martin periodinane, CH2Cl2.
Despite promising literature precedent,19 an attempt to trap the
iminium ion (14) with anisole returned only rearrangement prod-
ucts. Therefore, we briefly evaluated the possibility of intramolec-
ular delivery of less reactive nucleophiles via a [1,2]-shift.20
Addition of methyllithium, in up to sixfold excess, to ketone 13 re-
sulted in an incomplete reaction to produce alcohol 21 (Scheme 4)
as a 4:1 ratio of diastereomers in 25% yield (57% brsm). In contrast,
the addition of phenyllithium/CeCl3 provided alcohol 22 in excel-
lent yield and with essentially complete stereoselectivity.21 Treat-
ment of this alcohol with BF3ÁOEt2 under conditions analogous to
those used in the preparation of allyl adduct 15 was expected to
initiate C-acyliminium formation (?23) and a [1,2]-phenyl shift
to afford pyrrolidinone 24. In the event, the reaction took a differ-
ent course and tetrahydropyranyl ketone 26 was produced via oxo-
nium intermediate 25. Considering that ions 23 and 25 might be in
equilibrium, spirocycle 22 was treated with allyltributylstannane
and then BF3ÁOEt2. However, this reaction was uninformative, pro-
ducing a mixture containing starting 22, tetrahydropyran 26 and
ring-opened material corresponding to the hydrolysis of 22. Fur-
ther experiments are needed in order to shed light on the origins
of the differing outcomes in Schemes 3 and 4 but Lewis acid com-
plexation at the hydroxy group in spirocycle 22 would generate a
Brønsted acid (F3BÀ–ORH+) that may influence the course of the
reaction.
Figure 1. ORTEP view of spiro-N,O-acetal 11.13
In summary, we have demonstrated that spiro-N,O-acetals de-
rived from simple dihydropyran derivatives can be used as N-sul-
fonylketoiminium precursors. Relatively reactive nucleophiles
must then be present in order to generate 2,2-disubstituted pyrr-
O
O
(i)
13
N
Ts
N
Ts
OBF3
or (ii)
HO
14
15
olidin-3-ones effectively.
A
preliminary investigation of the
O
O
N
Ts
N
H
HO
R
HO
Ph
O
(i)
16
17
[1,2]-Ph
TsO
(iii)
13
Ph
N
Ts
N
N
H+
or (ii)
O
Scheme 3. Reagents: (i) allyl-SiMe3, BF3ÁOEt2, CH2Cl2 (15, 48%; 16, 21%; 17, 9%); (ii)
allyl-SnBu3, BF3ÁOEt2, CH2Cl2 (95%; 15 only).
Ts
Ts
OBF3
21 R = Me
22 R = Ph
OH
23
24
(iii)
iminium intermediate 14. Switching to the more reactive allyltrib-
utylstannane17 led to a much cleaner reaction that was complete
within 2 h at 0 °C with little evidence of by-products.
Similar BF3ÁOEt2-mediated reactions of ketone 13 with triethyl-
silane18 or 2-(tributylstannyl)furan provided 3-pyrrolidinone ad-
ducts 18 and 20, respectively (Fig. 2). In the former, some further
cyclisation and reduction followed to give pyrrolidino-oxepane
19. The reaction to form furyl adduct 20 was incomplete (29% of
BF3
[1,2]-Ph
H+
Ph
O
N
NHTs
O
Ts
O
Ph OH
25
26, 43%
Scheme 4. Reagents: (i) MeLi, THF (dr = 4:1, 57% brsm); (ii) PhLi, CeCl3, THF (dr
>95:5, 96%); (iii) BF3ÁOEt2, CH2Cl2.

J. Robertson et al. / Tetrahedron Letters 50 (2009) 7141–7143
7143
acyliminium ion chemistry; (c) Speckamp, W. N.; Moolenaar, M. J. Tetrahedron
2000, 56, 3817–3856; (d) Maryanoff, B. E.; Zhang, H. C.; Cohen, J. H.; Turchi, I. J.;
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operation of an alternative pathway via an oxonium intermediate.
9. Robertson, J.; Tyrrell, A. J.; Skerratt, S. Tetrahedron Lett. 2006, 47, 6285–6287.
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Acknowledgements
We thank Pfizer Global Research & Development and the EPSRC
for a studentship for A.J.T. We also acknowledge the Oxford Chem-
ical Crystallography Service for use of instrumentation, and Dr.
Amber Thompson for assistance.
12. Perron, F.; Albizati, K. F. Chem. Rev. 1989, 89, 1617–1661.
13. Crystal data for 11: C15H21NO4S, M = 311.40, colourless plate, monoclinic,
a = 12.5820(2), b = 8.06930(10), c = 15.2195(3) Å, V = 1527.71 Å3, T = 150 K,
space group P21/c, Z = 4, 6859 reflections measured, 3488 independent all of
which were used for refinement (Rint = 0.016), final wR = 0.116. CCDC 745600
contains the full crystallographic data for this compound; this can be obtained
free of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
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*
DH value at various levels of theory (PM3, HF/6-31G ,
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*
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