4-(Phenylsulfonyl)-4-lithiocyclopentene as a nucleophilic 2-pentene-1,5-dial synthetic equivalent. An aziridine-based synthetic approach to (-)-alstonerine

Article abstract of DOI:10.1016/j.tetlet.2005.04.033

Reaction of 4-lithio-4-(phenylsulfonyl)cyclopentene with an l-tryptophan-derived N-tosylaziridine provides an adduct. Oxidative cleavage of the cyclopentene double bond provides a dialdehyde, which enters into acid-catalysed Pictet-Spengler-type bicyclisation to give a tetracyclic aldehyde. Completely regioselective silyl dienol ether formation followed by completely stereoselective hetero-Diels-Alder reaction with monomeric formaldehyde gives a late-stage intermediate in a planned total synthesis of the macroline-related alkaloid (-)-alstonerine.

Full text of DOI:10.1016/j.tetlet.2005.04.033

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4687–4690
4-(Phenylsulfonyl)-4-lithiocyclopentene as a nucleophilic
2-pentene-1,5-dial synthetic equivalent. An aziridine-based
synthetic approach to (ꢀ)-alstonerine
Paul Cox,a Donald Craig,b,* Stephanos Ioannidisb and Volker S. Rahnb
aAventis Pharmaceuticals, Route 202–206, PO Box 6800, Bridgewater, NJ 08807-0800, USA
bDepartment of Chemistry, Imperial College London, South Kensington Campus, London SW7 2AZ, UK
Received 10 March 2005; accepted 7 April 2005
Available online 24 May 2005
Abstract—Reaction of 4-lithio-4-(phenylsulfonyl)cyclopentene with an L-tryptophan-derived N-tosylaziridine provides an adduct.
Oxidative cleavage of the cyclopentene double bond provides a dialdehyde, which enters into acid-catalysed Pictet–Spengler-type
bicyclisation to give a tetracyclic aldehyde. Completely regioselective silyl dienol ether formation followed by completely stereo-
selective hetero-Diels–Alder reaction with monomeric formaldehyde gives a late-stage intermediate in a planned total synthesis
of the macroline-related alkaloid (ꢀ)-alstonerine.
Ó 2005 Elsevier Ltd. All rights reserved.
Previous work in this laboratory has been concerned
with the use of N-substituted aziridines1 derived from
a-aminoacids as building blocks for the assembly of
pyrrolidines2 and piperidines.3 In the latter context, we
demonstrated that aziridine-derived 1,4-bis(tolylsulfon-
yl)tetrahydropyridines are substrates for highly stereo-
selective, acid-catalysed reduction and cyclisation
processes. We showed further that in some cases the acy-
clic precursors of bis(tolylsulfonyl)tetrahydropyridines
undergo acid-catalysed bicyclisation to give more com-
plex structures directly. Specifically, we found that sub-
strate 2 could readily be made by combining the lithio-
anion of 1-phenylsulfonyl-3,3-dimethoxypropane with
the L-tryptophan-derived aziridine 1.4 Subsequent treat-
ment with iodotrimethylsilane (TMSI) provided the in-
dole-containing tetracycle
3
in moderate yield,3b
avoiding the need to isolate the intermediate tetrahydro-
pyridine (Scheme 1). We became interested in applying
this chemistry in a total synthesis of the macroline-
related alkaloid (ꢀ)-alstonerine 4,5 since it was antici-
pated that a Pictet–Spengler-type6 acid-mediated cycli-
sation related to that depicted in Scheme 1 would
O
Ts
Ts
Ts
O
H
H
TsN
Li
THF
TMEDA
98%
TMSI
MeCN
49%
MeO
MeO
MeO
HN
Ts
N
N
MeO
Ts
Me
TBDMSN
MeN
TBDMSN
TBDMSN
ref. 4
ref 3(b)
1
2
3
4
Scheme 1.
Keywords: Alstonerine; Aziridine; Cyclisation; Pictet–Spengler; Sulfone.
*
Corresponding author. Tel.: +44 20 7594 5771; fax: +44 20 7594 5868; e-mail: d.craig@imperial.ac.uk
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.04.033

4688
P. Cox et al. / Tetrahedron Letters 46 (2005) 4687–4690
O
H
O
OSiR3
CHO
CHO
O
H
O
H
O
+
H
LG
OHC
H
H
N
N
P
N
P
N
P
PHN
Me
MeN
MeN
MeN
MeN
MeN
4
5
6
7
8
TsN
P = protecting group; LG = leaving group
CHO
LG
+
Li
OHC
9
10
11
MeN
SO2Ph
SO2Ph
Scheme 2.
allow rapid access to an advanced, tetracyclic intermedi-
ate from relatively simple starting materials. This letter
reports the results of these investigations.
group. It was felt also that the cyclic nature of the highly
substituted anion would maximise its nucleophilicity
through minimisation of steric crowding, and this indi-
cated its selection in preference to acyclic congeners such
as the 1,6-diene-containing species 9.
Our retrosynthetic analysis is shown in Scheme 2. We
reasoned that the vinylogous ester moiety embedded in
the oxygen heterocyclic ring of 4 could be elaborated
at a late stage from a d-lactone 5. This would be
accessed by an unusual hetero-Diels–Alder reaction7
involving combination of formaldehyde with the silyl
dienol ether 6, which in turn would be generated from
the enal 7. In light of the conversion 2 ! 3 depicted in
Scheme 1, the identification of enal 7 as a key intermedi-
ate target indicated dialdehyde 8 or a derivative as a cyc-
lisation substrate. Pictet–Spengler-type cyclisation and
E1cB elimination would provide the enal. Intermediate
8 would be accessed by reaction of the L-tryptophan-
derived aziridine 11 with a synthetic equivalent of the
3-pentane-1,5-dial synthon possessing anionic character
and a leaving group at C3, followed by unmasking of
the aldehyde groups. Our previous success2,3 in combin-
ing sulfone-stabilised carbanions with aziridines in
nucleophilic ring-opening reactions led us to focus on
sulfone-containing intermediates. It occurred to us that
4-(phenylsulfonyl)-4-lithiocyclopentene 108 possessed
both the necessary latent 1,5-dialdehyde in the form of
a cyclopentene and the masked double bond inherent
in the presence of the sulfone as a potential leaving
Prior to our work, the studies by Mioskowski had in-
volved the generation of 10 by reductive desulfonyl-
ation of 4,4-bis(phenylsulfonyl)cyclopentene 12 using
dissolving metal conditions.8 Thus, treatment of 129
with lithium naphthalenide and addition of aziridine
1110 gave the adduct 13 in a maximum yield of 72%,
though typically yields were in the range 55–64%. After
extensive experimentation, it was found that dihydrox-
ylation of the cyclopentene double bond was best car-
ried out using a modified permanganate reagent system,
which provided the cis-diols 14 as a 4:1 diastereomeric
mixture in ca. 60% yield.11 Subsequent Pb(OAc)4-
mediated oxidative cleavage gave a dialdehyde, which
without purification was subjected directly to trifluoro-
acetic acid-catalysed cyclisation in the presence of rigor-
ously dried MgSO4, providing the tetracycle 15 as a 1:1
epimeric mixture in excellent yield from 14. The synthe-
sis of key aldehyde 15 is depicted in Scheme 3.
With a short sequence to 15 established, a key issue
remained concerning the regiochemistry of dienol ether
formation. It was postulated that on exposure to base
HO
OH
CHO
PhSO2
MeN
1. Pb(OAc)4,
NaHCO3,
PhSO2
PhSO2
LiC10H8,THF
-78 ºC
KMnO4,
Bu4NBr
ClCH2CH2Cl
0 ºC to r.t.
N
TsHN
MeN
TsHN
MeN
Ts
SO2Ph
add 11, DMPU
-78 ºC to r.t.
CH2Cl2
0 ºC to r.t.
2. TFA, MgSO4
SO2Ph
12
CH2Cl2
r.t.
94%
61%
55-64%
13
14
15
Scheme 3.

P. Cox et al. / Tetrahedron Letters 46 (2005) 4687–4690
4689
OTBDPS
CHO
O
OTBDMS
SPh
Ts SPh
PhSO2
MeN
TBDPSCl,
DMAP,
DBU
N
N
N
N
N
N
Ts
Ts
Ts
Ts
Ts
Ts
MeN
MeN
MeN
MeN
MeN
CH2Cl2
0 ºC
95%
16
17
18
19
15
20
Scheme 4.
and silylating reagent 15 would suffer E1cB reaction to
give an enal, or enals followed by silyl dienol etherifica-
tion by proton removal from the enal or an O-silyl oxo-
nium intermediate. This deprotonation would have to
occur with complete selectivity for one of the two c-posi-
tions, irrespective of enal geometry. Our expectation that
this would be the case stemmed from an earlier phase of
the work, where it had been observed that upon
treatment with TBDMSOTf–Et3N, ketone 16 gave
the single regioisomeric enol ether 17, and that when ex-
posed to AlCl3, thioacetal 18 gave only the vinylsulfide
19.12 This striking regioselectivity pointed towards
a strong kinetic and/or thermodynamic preference in
the deprotonation reactions a- to the piperidine C4 sp2-
hybridised carbon atom in such systems, and we
reasoned that the enal vinylogues should show similar
behaviour. In the event, exposure of 15 to DBU-
TBDPSCl in the presence of sub-stoichiometric DMAP
gave in 95% yield the dienol ether 20 as the only detect-
able isomer (Scheme 4). The identity of 20 followed from
1H NMR COSY experiments,13 and from its subsequent
behaviour in the hetero-Diels–Alder reactions. The
TBDPS containing dienol ether 20 showed markedly bet-
ter stability than the TBMDS or TIPS derivatives, which
were made under analogous conditions in 79% and 47%
yields, respectively. The overall yield of 20 over five steps
from aziridine 11 and bis(sulfone) 12 was 35%.
Figure 1. X-ray crystal structure of 22.
OTBDPS
OTBDPS
OMe
O
O
HCHO
(1.6 M in THF),
Me2AlCl
N
N
N
THF
-78 ºC, 30 min,
r.t., 2.5 h
Ts
Ts
Ts
MeN
MeN
MeN
36%
20
Scheme 5.
21
22
Attention was turned finally to the hetero-Diels–Alder
reaction of dienol ether 20 with formaldehyde. After
numerous attempts failed in achieving cycloaddition
using various sources of formaldehyde (paraformalde-
hyde, 1,3,5-trioxane) in conjunction with a range of
Lewis acidic additives (BF3ÆOEt2, lanthanide triflates,
TiCl4, Me3Al, Me2AlCl), efforts were focused on use
of the monomeric reagent. Eventually, it was found that
treatment of 20 with chlorodimethylaluminium and ca.
2 M THF solutions of formaldehyde prepared using a
modification of the Schlosser method14,15 provided the
cycloadduct 21 as a single stereoisomer in 36% yield.
The structure of 21 was unambiguously established by
X-ray crystallographic analysis of the methyl ether
derivative 22 (Fig. 1).16 This demonstrated that cycload-
dition had occurred with the desired b-stereoselectivity,
and that the structure of 20 was correctly assigned. Cyc-
loadduct 21 was found during NMR studies to be unsta-
ble in CDCl3 solution, undergoing retro-cycloaddition
with regeneration of 20 and paraformaldehyde with a
half-life of ca. 2 h at room temperature (Scheme 5).
In summary, we have achieved the enantiospecific syn-
thesis of a late-stage intermediate for the synthesis of
(ꢀ)-alstonerine starting from L-tryptophan and 4,4-
bis(phenylsulfonyl)cyclopentene. This short sequence
clearly establishes the effectiveness of 4-phenylsulfonyl-
4-lithiocyclopentene as the synthetic equivalent of a
nucleophilic 2-pentene-1,5-dial synthon. In addition, in
contrast to existing approaches5 the Pictet–Spengler
reaction achieves the synthesis of both new nitrogen-
containing rings in a single transformation. Finally,
the route involves an unusual hetero-Diels–Alder reac-
tion of monomeric formaldehyde, and we have uncov-
ered remarkable regioselectivity in some derivatisation
reactions of indolo-9-azabicyclo[3.3.1] systems. Further
studies will look at the selective hydrogenation of 21
and elaboration of the oxygen heterocycle with a view
to completing the total synthesis of (ꢀ)-alstonerine.

4690
P. Cox et al. / Tetrahedron Letters 46 (2005) 4687–4690
natural products synthesis, see: Czerwinski, K. M.; Cook,
Acknowledgements
J. M. Adv. Het. Nat. Prod. Synth. 1996, 3, 217.
7. For examples of hetero-Diels–Alder reactions of formal-
dehyde, see: Gresham, T. L.; Steadman, T. R. J. Am.
Chem. Soc. 1949, 71, 737; Kubler, D. G. J. Org. Chem.
1962, 27, 1435; Shavrygina, O. A.; Makin, S. M. Zh. Org.
Khim. 1966, 2, 1354; Mochalin, V. B.; Varpakhovskaya, I.
S. Zh. Org. Khim. 1976, 12, 2257; Kobayashi, T.; Tsuruta,
H. Synthesis 1980, 492; Snider, B. B.; Phillips, G. B.;
Cordova, R. J. J. Org. Chem. 1983, 48, 3003; Barrish, J.
C.; Lee, H. L.; Mitt, T.; Pizzolato, G.; Baggiolini, E. G.;
Uskokovic, M. R. J. Org. Chem. 1988, 53, 4282; Myles, D.
C.; Danishefsky, S. J.; Schulte, G. J. Org. Chem. 1990, 55,
1636.
8. Yu, J.; Cho, H.-S.; Chandrasekhar, S.; Falck, J. R.;
Mioskowski, C. Tetrahedron Lett. 1994, 35, 5437.
9. Nantz, M. H.; Radisson, X.; Fuchs, P. L. Synth. Commun.
1987, 17, 55; Yu, J.; Cho, H. S.; Falck, J. R. J. Org. Chem.
1993, 58, 5892. In our hands the method reported by
Fuchs et al. resulted in more facile work-up and isolation
of product.
10. Aziridine 11 was synthesised in four steps from commer-
cially available (Aldrich Chemical Co.) 1-methyl-L-tryp-
tophan, by sequential methyl esterification, N-tosylation,
ester reduction and aziridination (70% overall). Full
details are provided in the online Supplementary infor-
mation.
11. We tentatively assign the major isomer as having the anti
relationship of the cis-diol and the phenylsulfonyl group.
12. Ioannidis, S. Ph.D. Thesis, University of London, 2000.
13. We thank Mr. R. N. Sheppard (Imperial College) for these
experiments.
We thank EPSRC (grant GR/M75181: Project Student-
ˆ
Pharmaceuticals (fully funded studentship to S.I., addi-
tional support for Project Studentship to V.S.R.) for
their support.
ship to V.S.R.) and Rhone–Poulenc Rorer/Aventis
Supplementary data
Supplementary data associated with this article can
be found, in the online version, at doi:10.1016/j.tetlet.
2005.04.033.
References and notes
1. For reviews/reports on the synthesis of aziridines and their
use in synthesis, see: McCoull, W.; Davis, F. A. Synthesis
2000, 1347; Chemla, F.; Ferreira, F. Curr. Org. Chem.
2002, 6, 539; Sweeney, J. B. Chem. Soc. Rev. 2002, 31, 247;
Dauban, P.; Dodd, R. H. Synlett 2003, 1571.
2. Craig, D.; Jones, P. S.; Rowlands, G. J. Synlett 1997, 1423;
Berry, M. B.; Craig, D.; Jones, P. S.; Rowlands, G. J.
Chem. Commun. 1997, 2141; Caldwell, J. J.; Craig, D.;
East, S. P. Synlett 2001, 1602.
3. (a) Craig, D.; McCague, R.; Potter, G. A.; Williams, M.
R. V. Synlett 1998, 55; (b) Craig, D.; McCague, R.; Potter,
G. A.; Williams, M. R. V. Synlett 1998, 58; (c) Adelbrecht,
J.-C.; Craig, D.; Dymock, B. W.; Thorimbert, S. Synlett
2000, 467; (d) Adelbrecht, J.-C.; Craig, D.; Thorimbert, S.
Tetrahedron Lett. 2001, 42, 8369.
14. Schlosser, M.; Coffinet, D. Synthesis 1971, 380.
15. Modification of the Schlosser protocol: In a flame-dried
flask a mixture of paraformaldehyde (2.0 g, 68 mmol,
1.0 equiv) and p-toluenesulfonic anhydride (328 mg,
0.1 mmol, 0.0015 equiv) in anhydrous THF (16.7 ml) was
heated and slowly distilled using a microdistillation kit at
such a rate that approximately one drop of distillate was
collected every 10 s. The distillate was collected at ꢀ78 °C
under an anhydrous N2 atmosphere to give THF solutions
of formaldehyde having concentrations of ca. 2 M,
depending on the calculation method; Rahn, V. S. Ph.D.
Thesis, University of London, 2003.
4. Williams, M. R. V. Ph.D. Thesis, University of London,
1998.
5. For recent work, and leading references on the synthesis
and biological activity of (ꢀ)-alstonerine, see: Yu, P.;
Wang, T.; Li, J.; Cook, J. M. J. Org. Chem. 2000, 65, 3173;
See also: Bailey, P. D.; McLay, N. R. J. Chem. Soc.,
Perkin Trans. 1 1993, 441; Bailey, P. D.; Hollinshead, S.
P.; Mclay, N. R. Tetrahedron Lett. 1987, 28, 5177.
6. See, for example: Alberch, L.; Bailey, P. D.; Clingan, P.
D.; Mills, T. J.; Price, R. A.; Pritchard, R. G. Eur. J. Org.
Chem. 2004, 1887; For a review covering stereochemical
aspects of the Pictet–Spengler reaction in the context of
16. We thank Dr. A. J. P. White (Imperial College) for the
X-ray structure determination. Full details will be
reported elsewhere.