5-endo-trig Cyclisations in heterocycle synthesis: Enantiospecific synthesis of (+)-monomorine I

Article abstract of DOI:10.1039/a706333d

The indolizidine alkaloid monomorine I is synthesised from D-norleucinol using 5-endo-trig cyclisation and intramolecular reductive amination as the key ring-forming steps.

Full text of DOI:10.1039/a706333d

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5-endo-trig Cyclisations in heterocycle synthesis: enantiospecific synthesis of
(+)-monomorine I
Malcolm B. Berry,a Donald Craig,*a Philip S. Jonesb and Gareth J. Rowlandsa
a Department of Chemistry, Imperial College of Science, Technology and Medicine, London, UK SW7 2AY
bRoche Discovery Welwyn, Broadwater Road, Welwyn Garden City, Hertfordshire, UK AL7 3AY
The indolizidine alkaloid monomorine I is synthesised from
D-norleucinol using 5-endo-trig cyclisation and intramo-
lecular reductive amination as the key ring-forming steps.
converted directly into 6 by treatment with diphenylphosphinic
chloride and triethylamine in THF followed by excess sodium
hydride according to the method of Sweeney (Scheme 2).8
Addition of 6 to a THF–N,N,NA,NA-tetramethylethylenediamine
solution of lithio(phenylsulfonyl)methane followed by proton
quench gave the expected product of aziridine ring-opening at
the less substituted carbon atom. This was dephosphinylated
and reprotected as the benzamide 8 in good overall yield for the
three steps from 6.9 Exposure of 8 to 2 equiv. of base followed
by hex-5-enal, and in situ trapping of the intermediate
alkoxides, gave ester 9, mostly as one diastereoisomer.‡
Pyrrolidine formation was effected in a single step by treating a
dilute THF solution of 9 with 2 equiv. of potassium tert-
butoxide in the presence of tert-butyl alcohol, which effected
one-pot elimination to give 3 followed by cyclisation. Pyrroli-
dine 2 formed in this way was a single, 2,5-syn diastereoisomer
as evidenced by single-crystal X-ray diffraction analysis.§
Interestingly, treatment of 9 with 1 equiv. of base followed by
immediate proton quench gave in 89% isolated yield a 4:1 E:Z
mixture of geometric isomers of 3, which could be converted
into 2 in a separate operation by treatment with a further 1 equiv.
of base. Compound 2 prepared in this way was identical in all
respects to material made in the one-pot reaction.
Pyrrolidines occur widely in nature as pheromones, venoms and
toxins, and as structural motifs in more complex molecules such
as pyrrolizidines and indolizidines.1 As part of our programme
investigating 5-endo-trig cyclisation reactions2 for heterocycle
construction3 we have been looking at sulfone-mediated
assembly of pyrrolidines, and have discovered that 2,5-di-
substituted pyrrolidines may efficiently and stereoselectively be
prepared from amino acid-derived precursors.4 Here we report
the application of this methodology to the total synthesis of the
indolizidine alkaloid monomorine I 1, the trail pheromone of the
Pharaoh worker ant Monomorium pharaonis.5,6
Our synthetic plan for 1 involved initial assembly of the
pyrrolidine ring in 2 by 5-endo-trig cyclisation reaction of a
substrate such as 3. Closure of the remaining, six-membered
cycle would be effected either by electrophile-induced addition
of the pyrrolidine nitrogen atom to the distal double bond, as in
4, or by intramolecular reductive amination of a derived side-
chain ketone moiety, as in 5 (Scheme 1).
Retrosynthetic analysis of the cyclisation substrate 3 indi-
cated N-protected aziridine 6 as the starting material. This was
synthesised in two steps from commercially available
d-norleucine;† reduction using the NaBH4–iodine reagent
system described by Meyers7 gave d-norleucinol 7, which was
Initial attempts to complete the assembly of the indoliz-
idine nucleus by closure of the six-membered ring involved
mercury(ii)-assisted cyclisation. Thus, debenzoylation of 2
using Super-Hydride®,10 and treatment of the resulting free
amine with Hg(OAc)2 followed by in situ reduction with
NaBH4,11 gave in 90% yield a 9:4 mixture of 10 and the desired
H
N
i
HO
Ph2P(O)N
1 (+)-monomorine I
electrophile-mediated
reductive amination;
cyclisation, reduction;
desulfonylation
NH2
7
6
desulfonylation
ii–iv 58%
PhSO2
PhSO2
PhSO2
PhSO2
O
v
NHBz
OAc
75%
NHBz
N
H
N
Bn
8
4
5
9
vi
vii 89%
73%
PhSO2
viii
2
3
E:Z = 4:1
79%
Scheme 2 Reagents and conditions: i, Ph2P(O)Cl, (2.1 equiv.), Et3N (3
equiv.), THF (0.3 m), 0 °C?room temp., 12 h, then excess NaH, room
temp., 1–2 weeks; ii, PhSO2Me (1 equiv.), BuLi (1 equiv.), 3:1 THF–
Me2N(CH2)2NMe2 (0.4 m), 278 °C, add 6, 278 °C?room temp., 12 h; iii,
BF3·OEt2 (10 equiv.), 1:1 CH2Cl2–MeOH (0.1 m), room temp., 12 h; iv,
BzCl (1.2 equiv.), pyridine (1.1 equiv.), CH2Cl2 (0.2 m), room temp., 12 h,
work-up with Me2N(CH2)3NH2; v, BuLi (2.1 equiv.), 3:1 THF–
Me2N(CH2)2NMe2, 278 °C, add hex-5-enal (1.3 equiv.), 278 °C, 40 min,
then add Ac2O (5 equiv.), 278 °C?room temp., 12 h; vi, ButOK (2.1 equiv.
of a 1 m solution in THF), ButOH (10 equiv.) in THF (0.033 m), room temp.,
12 h; vii, ButOK (1.05 equiv. of a 1 m solution in THF), ButOH (5 equiv.)
in THF (0.1 m), room temp., < 1 min; viii, ButOK (1.05 equiv. of a 1 m
solution in THF), ButOH (10 equiv.) in THF (0.033 m), room temp., 12 h
N
Bz
2
PhSO2
NHBz
3
Scheme 1
Chem. Commun., 1997
2141

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We thank the SERC/EPSRC (CASE Studentships to M. B. B.
and G. J. R ) and Roche Discovery Welwyn for financial support
of this research.
PhSO2
H
i, ii
2
N
80%
R2
R1
Footnotes and References
10:11 = 9:4
* E-mail: dcraig@ic.ac.uk
10 R1 = H, R2 = Me
11 R1 = Me, R2 = H
iii, iv
66%
† All yields reported herein refer to isolated, pure materials which had 1H
and 13C NMR, IR and high-resolution mass spectral characteristics in
accord with the proposed structures.
vi
v
‡ We have not been able to assign the configurations of the phenylsulfonyl-
and acetoxy-substituted stereocentres.
1
5
11
55%
89%
§ We thank Professor David J. Williams and Dr Andrew J. P. White of this
Department for this determination.
¶ Work-up after no more than 5 min was crucial to the success of this
reaction. We thank Mr Simon Ward (University of Cambridge) for
informing us of the importance of short reaction times in these trans-
formations.
Scheme 3 Reagents and conditions: i, LiBHEt3 (2.2 equiv.), THF (0.23 m),
room temp., 8 h; ii, Hg(OAc)2 (1.05 equiv.), 1:1 THF–H2O (0.25 m), then
NaBH4–NaOH (0.75 equiv.); iii, DIBAL-H (4 equiv.), CH2Cl2 (0.1 m),
278 °C?room temp., 2 h; iv, Hg(OAc)2 (1.05 equiv.), 3:1 THF–H2O (0.2
m), room temp., 1 h, then add to PdCl2 (0.6 equiv.), CuCl2 (3 equiv.), THF
(0.2 m), room temp., 1.5 h; v, 10% Pd(C), cyclohexa-1,4-diene (15 equiv.),
MeOH (0.1 m), reflux, 4 h; vi, Na+C10H82 (3.5 equiv.), THF (0.05 m), room
temp., 5 min
1 For reviews, see A. R. Pinder, Nat. Prod. Rep., 1992, 9, 17; J. P.
Michael, Nat. Prod. Rep., 1994, 11, 17.
2 J. E. Baldwin, J. Chem. Soc., Chem. Commun., 1976, 734.
3 D. Craig and A. M. Smith, Tetrahedron Lett., 1992, 33, 695; D. Craig,
N. J. Ikin, N. Mathews and A. M. Smith, Tetrahedron Lett., 1995, 36,
7531. For other pyrrolidine-forming 5-endo-trig cyclisation reactions,
see P. Knochel and J. F. Normant, Tetrahedron Lett., 1985, 26, 4455;
A. Padwa and B. H. Norman, J. Org. Chem., 1990, 55, 4801.
4 M. B. Berry, Ph.D. thesis, University of London, 1993; G. J. Rowlands,
Ph.D. thesis, University of London, 1996.
5 Isolation and characterisation: F. J. Ritter, I. E. M. Rotgans, E. Talman,
P. E. J. Verwiel and F. Stein, Experientia, 1973, 29, 530.
6 For a comprehensive collection of references to published syntheses of
both racemic and enantiomerically pure monomorine I, see
M. J. Munchhof and A. I. Meyers, J. Am. Chem. Soc., 1995, 117,
5399.
7 M. J. McKennon and A. I. Meyers, J. Org. Chem., 1993, 58, 3568.
8 H. M. I. Osborn, J. B. Sweeney and W. Howson, Synlett, 1994, 145.
9 We did not investigate reactions of lithio(phenylsulfonyl)methane with
N-benzoylaziridines, in light of an account describing their non-
chemoselective reaction with certain carbon nucleophiles: J. E.
Baldwin, R. M. Adlington and N. G. Robinson, J. Chem. Soc., Chem.
Commun., 1987, 153.
10 H. C. Brown and S. C. Kim, Synthesis, 1977, 635.
11 J. J. Perie, J. P. Laval, J. Roussel and A. Lattes, Tetrahedron, 1972, 28,
675.
C-2 epimer 11. The stereochemical assignment of 11, and
therefore that of 10 followed from the nuclear Overhauser
enhancements of the signals corresponding to the a-hydrogen
atoms at C-6 and C-9 observed on irradiation of the C-2 methyl
group. In view of this adverse selectivity, the reductive
amination route was pursued. Partial reduction of 2 to the
N-benzyl analogue using DIBAL-H, and oxidation of the side-
chain double bond in the product using a modified Wacker
procedure12 gave ketone 5. This was subjected to catalytic
transfer hydrogenation,13 which effected sequential hydro-
genolytic debenzylation and intramolecular reductive amina-
tion14 to give exclusively 11, which was identical in all respects
to material prepared via the mercury-mediated cyclisation route.
Finally, brief exposure¶ of 11 to sodium naphthalenide in THF
followed by NH4Cl work-up gave (+)-monomorine I 1 (Scheme
3), which showed 1H and 13C NMR, IR and mass spectral and
optical rotation characteristics in agreement with published
values.6
In summary, the synthesis of (+)-monomorine I has been
achieved in nine steps from aziridine 6, which is available in
two steps by known methods from d-norleucine. Both ring-
forming steps are highly stereoselective, and our synthesis
compares favourably with published approaches.6 The com-
plete selectivity of the pyrrolidine-forming reaction is partic-
ularly notable, and should be applicable to the synthesis of other
pyrrolidine-containing alkaloids, and related pyrrolizidines and
indolizidines.
12 G. T. Rodeheaver and D. T. Hunt, J. Chem. Soc., Chem. Commun.,
1971, 818.
13 A. M. Felix, E. P. Heimer, T. J. Lambros, C. Tzougraki and
J. Meienhofer, J. Org. Chem., 1978, 43, 4194.
14 R. V. Stevens and A. W. M. Lee, J. Chem. Soc., Chem. Commun., 1982,
102.
Received in Liverpool, UK, 29th August 1997; 7/06333D
2142
Chem. Commun., 1997