Microwave-assisted rearrangement of vinylaziridines to 3-pyrrolines: Formal synthesis of (-)-anisomycin

Article abstract of DOI:10.1055/s-2005-921934

An efficient microwave-assisted rearrangement of activated vinylaziridines to 3-pyrrolines is described. The rearrangement proceeds in good to excellent yields and is mediated by NaI or LiI in MeCN at elevated temperatures. The synthetic utility of this r

Full text of DOI:10.1055/s-2005-921934

LETTER
3099
Microwave-Assisted Rearrangement of Vinylaziridines to 3-Pyrrolines:
Formal Synthesis of (–)-Anisomycin
Synthesis of
3e
KTH Chemical Science and Engineering, Organic Chemistry, 100 44 Stockholm, Sweden
Fax +46(8)7912333; E-mail: somfai@kth.se
Received 14 October 2005
dynamically less favored endo-trans-1 conformation8 will
give the Z-configurated intermediate B. Only the latter in-
termediate can ring-close to the desired pyrroline 2. Alter-
natively, A and B can reform the aziridine moiety, leading
Abstract: An efficient microwave-assisted rearrangement of acti-
vated vinylaziridines to 3-pyrrolines is described. The rearrange-
ment proceeds in good to excellent yields and is mediated by NaI or
LiI in MeCN at elevated temperatures. The synthetic utility of this
reaction is shown in an efficient formal total synthesis of the antibi- to the corresponding cis-isomer. However, without fur-
otic (–)-anisomycin.
ther mechanistical studies, an SN2 mechanism for the
formation of 2a cannot be excluded.
Key words: vinylaziridines, pyrrolines, rearrangement, ring expan-
sion, total synthesis
R
N
3-Pyrrolines are valuable intermediates in organic chem-
istry and have frequently been used in natural product
synthesis.1a–c They also show diverse biological
activities1d–g and a number of routes towards this impor-
tant compound class have been developed.2 A straightfor-
ward approach to the preparation of 3-pyrrolines involves
the rearrangement of 2-vinylaziridines, a reaction that has
been known for more than 35 years and successfully used
in the synthesis of pyrrolizidin alkaloids.3 However, most
examples that have been published are limited in substrate
scope and to date no general methodology has been devel-
oped. We thus decided to investigate this rearrangement
in detail, and herein report our initial results.
Activated4 N-Ts-2-vinylaziridines 1 were chosen as suit-
able starting materials, as the tosyl group was expected to
facilitate the rearrangement (Scheme 1). Surprisingly,
treatment of trans-1a5 afforded less than 10% of the de-
sired product 2a and the main product was instead cis-1a.6
This results from an equilibration of trans-1a to give the
thermodynamically more stable cis-isomer.7
Ts
2
I
H
H
I
H
H
H
H
R
H
H
Ts
H
R
R
H
N
N
N
Ts
I
Ts
endo-trans-1
B
endo-cis-1
I
I
H
H
H
H
H
H
H
R
H
H
I
H
R
R
N
N
N
Ts
Ts
Ts
exo-trans-1
A
exo-cis-1
Scheme 2 Proposed mechanism for the iodide-mediated equilibra-
tion of vinylaziridines trans-1 and cis-1 and the formation of pyrrol-
ines 2
R
R
The rearrangement conditions were subsequently opti-
mized by variation of the solvent, additive and tempera-
ture, and the results are summarized in Table 1.
+
R
N
N
N
Ts
Ts
Ts
The use of DABCO and PPh3, which are typical catalysts
in the mechanistically related Baylis–Hillman reaction9
proved to be less efficient than NaI in the rearrangement
(entries 3, 4). In nucleophilic solvents such as MeOH and
DMSO, the vinylaziridine underwent ring-opening or ox-
idation (entries 5, 6). The use of DMF led to the best con-
version but also gave considerable amounts of
unidentified by-products (entry 7). The best solvent
proved to be MeCN since no by-product formation was
observed (entry 8), but the results were still far away from
satisfactory. We thus decided to perform the reaction un-
der microwave irradiation, which often leads to strongly
enhanced reaction rates and less by-products.10 Pleasing-
R = C6H13
2a
trans-1a
cis-1a
Scheme 1 Reagents and conditions: 8 equiv NaI, acetone, reflux,
48 h
The proposed mechanism for the rearrangement is depict-
ed in Scheme 2, and starts with an SN2¢ ring-opening of
trans-1. Opening in the exo-trans-1 conformation leads to
intermediate A with E-configuration, whereas the thermo-
SYNLETT 2005, No. 20, pp 3099–3102
Advanced online publication: 28.11.2005
DOI: 10.1055/s-2005-921934; Art ID: G33705ST
© Georg Thieme Verlag Stuttgart · New York
1
9
.1
2
.2
0
0
5

3100
S. Hirner, P. Somfai
LETTER
Table 1 Optimization of the Rearrangement of Trans-1a
Entry
Additive (equiv)
NaI (8)
Solvent
Acetone
Acetone
Toluene
Acetone
MeOH
DMSO
DMF
Temp. (°C)
Reflux
100b
Time (h)
48
Ratio of trans-1a:cis-1a:2aa
1
2
4:88:8
8:82:10
3:95:2
96:4:0
NaI (8)
4
3
DABCO (1)
PPh3 (1)
NaI (8)
180b
1
4
Reflux
100b
20
d
5
15
–
d
6
NaI (8)
100b
15
–
7
NaI (8)
100b
15
11:65:24
8:83:9
8
NaI (8)
MeCN
MeCN
MeCN
MeCN
100b
15
9
NaI (2)
160c
0.17
0.33
0.33
17:71:12
0:0:100
0:0:100
10
11
NaI (2)
200c
LiI (2)
200c
a Determined by 1H NMR of the crude reaction product.6
b The reaction was performed in a sealed tube.
c The reaction was performed under microwave irradiation.
d By-products were formed.
ly, when 1a was treated with NaI or LiI in acetonitrile un- To verify the generality of the optimized reaction condi-
der microwave irradiation (20 min, 200 °C),11 full tions, several variously substituted vinylaziridines 1b–g
conversion was achieved (entries 10, 11) and 2a could be were synthesized and successfully transformed into pyr-
obtained in 90% yield (Table 2, entry 1). Without a metal rolines 2b–g as summarized in Table 2.12 Substrates 1c–
iodide, no reaction could be observed under the same con- e,g were prepared as cis:trans mixtures from the corre-
ditions, demonstrating the high thermal stability of the sponding aldehydes in two steps.13
substrate.
Table 2 Microwave-Assisted Rearrangement of Vinylaziridines to 3-Pyrrolinesa
R
MI
R
(41–95%)
N
N
200 °C
Ts
Ts
1a–g
2a–g
Entry
1
a
a
b
c
c
d
e
f
R
Cis:transb
0:100
100:0
0:100
31:69
31:69
28:72
18:82
0:100
30:70
MI
NaI
NaI
NaI
NaI
LiI
LiI
LiI
LiI
LiI
Time (min)
Yield (%)c
1
2
3
4
5
6
7
8
9
n-Hexyl
n-Hexyl
BnOCH2
Cy
20
20
10
30
30
15
30
10
1
90
86
94
54
82
92
95
92
41
Cy
Ph(CH2)2
t-Bu
PMB
g
Ph
a Conditions: 2 equiv MI, MeCN, microwave, 200 °C.
b Isomeric ratio of the vinylaziridines determined by 1H NMR.
c Isolated yields.
Synlett 2005, No. 20, 3099–3102 © Thieme Stuttgart · New York

LETTER
Synthesis of 3-Pyrrolines
3101
MeO
MeO
Gratifyingly, the reactions were found to proceed smooth-
ly in good to excellent yields. Compound 1c gave moder-
ate yields with NaI, whereas LiI afforded 2c in good
yields (entries 4, 5). Vinylaziridine 1g was the only excep-
tion, both in reaction time and yield (entry 9). The phenyl
moiety in 1g seems to increase the reactivity and decrease
the selectivity of the substrate, affording several by-prod-
ucts.
OH
a
O
NH2
6
7
b
MeO
c
MeO
NTs
The next aim was to study the reaction of vinylaziridines
with an additional methyl substituent on the double bond.
Applying the same reaction conditions as above it was
hoped to obtain 2,5-disubstituted 3-pyrrolines. Disap-
pointingly, both the E- and Z-substituted vinylaziridines 3
and 413a exclusively afforded the diene 5 (Scheme 3).
N
R
2f R = Ts
8 R = H
1f
d
f
e
OH
AcO
O
MeO
MeO
h
Cy
Cy
Cy
Ts
81%
76%
N
H
N
R
NH
N
N
11
9
R = Ts
10 R = H
g
Ts
4
Ts
3
5
Scheme 4 Reagents and conditions: a) i) allyl chloride (2.0 equiv),
LiNCy2 (2.0 equiv), (+)-Ipc2BOMe (1.5 equiv), BF3·OEt2 (2.5 equiv),
–95 °C, 6 h, >95% ee; ii) MeOH, NH4OH (25%), 130 °C, 10 min,
52% (over 2 steps); b) TsCl (5.0 equiv), KOH (10 equiv), THF, r.t.,18
h, 93%; c) see Table 2, entry 8; d) Na, naphthalene, THF, –78 °C,
84%; e) ref. 15f; f) NIS (3.0 equiv), HClO4 (2 equiv), THF–H2O
(10:1), 1 h, then r.t., 1 h, 50%; g) MeOH, Mg, 5 h, 91%; h) ref. 15g
Scheme 3 Reagents and conditions: 2 equiv LiI, MeCN, micro-
wave, 200 °C, 1 min
To demonstrate the synthetic utility of the ring expansion
described above, it has been applied in the formal synthe-
sis of (–)-anisomycin (11), an antibiotic first isolated from
two species of Streptomyces.14a Besides its antibacterial
and fungicide activity, it also inhibits the ribosomal pep-
tide synthesis and exhibits antiviral and antitumor activi-
ties.14 Thus, much attention has been focused on the
synthesis of anisomycin within the last 40 years and to
date a vast number of routes have been published.15 The
methodology detailed in this report enables a new and
straightforward synthesis of 11 (Scheme 4).
The sequence starts with a modified Brown allylation16 of
the commercially available aldehyde 6, and successive
aminolysis of the resulting chlorohydrine afforded amino
alcohol 7 with excellent enantioselectivity.17 Tosylation
and ring-closure with KOH in THF afforded cis-vinyl-
aziridine 1f, which could be rearranged to pyrroline 2f in
excellent yield (Table 2, entry 9). Deprotection of 2f af-
forded enantiopure secondary amine 8,18 which has been
converted to ent-11.15f Alternatively, iodohydroxylation
of pyrroline 2f followed by basic work up afforded ep-
oxide 9, which was deprotected to 10,19 a known inter-
mediate in the synthesis of 11.15g,h
References
(1) For recent examples of 3-pyrrolines as intermediates in
organic synthesis, see: (a) Green, M. P.; Prodger, J. C.;
Hayes, C. J. Tetrahedron Lett. 2002, 43, 6609. (b)Huwe,C.
M.; Blechert, S. Tetrahedron Lett. 1995, 36, 1621.
(c) Burley, I.; Hewson, A. T. Tetrahedron Lett. 1994, 35,
7099. (d) As MAO inhibitors, see: Lee, Y.; Huang, H.;
Sayre, L. M. J. Am. Chem. Soc. 1996, 118, 7241. (e) As
NMDA receptor agonists, see: Rondeau, D.; Gill, P.; Chan,
M.; Curry, K.; Lubell, W. D. Bioorg. Med. Chem. Lett. 2000,
10, 771. (f) As k-agonists, see: Mou, Q.-Y.; Chen, J.; Zhu,
Y.-C.; Zhou, D.-H.; Chi, Z.-Q.; Long, Y.-Q. Bioorg. Med.
Chem. Lett. 2002, 12, 2287. (g) As tumor inhibitors, see:
Anderson, W. K.; Milowsky, A. S. J. Med. Chem. 1987, 30,
2144.
(2) For recent examples, see: (a) Dieter, R. K.; Chen, N.; Yu,
H.; Nice, L. E.; Gore, V. K. J. Org. Chem. 2005, 70, 2109.
(b) Morita, N.; Krause, N. Org. Lett. 2004, 6, 4121.
(c) Dieter, R. K.; Yu, H. Org. Lett. 2001, 3, 3855.
(d) Green, M. P.; Prodger, J. C.; Sherlock, A. E.; Hayes, C.
J. Org. Lett. 2001, 3, 3377.
(3) (a) Atkinson, R. S.; Rees, C. W. J. Chem. Soc. C 1969, 778.
(b) Scheiner, P. J. Org. Chem. 1967, 32, 2628. (c) Fugami,
K.; Miura, K.; Morizawa, Y.; Oshima, K.; Utimoto, K.;
Nozaki, H. Tetrahedron 1989, 45, 3089. For reviews, see:
(d) Somfai, P.; Åhman, J. In Targets in Heterocyclic
Systems; Italian Society of Chemistry: Rome, 1999, 341.
(e) Hudlicky, T.; Reed, J. W. In Comprehensive Organic
Synthesis, Vol. 4; Trost, B. M.; Fleming, I., Eds.; Pergamon:
Oxford, 1991, 899.
In conclusion, a convenient protocol for the formation of
synthetically important 3-pyrrolines by a microwave-as-
sisted rearrangement of 2-vinylaziridines has been devel-
oped. The reaction has successfully been applied in the
formal synthesis of (–)-anisomycin.
(4) For a definition of the term-activated aziridine, see: Ham, G.
E. J. Org. Chem. 1964, 29, 3052.
Synlett 2005, No. 20, 3099–3102 © Thieme Stuttgart · New York

3102
S. Hirner, P. Somfai
LETTER
(5) Vinylaziridines 1a,b were synthesized from the
corresponding vinylepoxides.10b
(6) The cis- and trans-vinylaziridines can be distinguished by
the 3JHH coupling constant of the ring protons (cis ca. 6.8–8.4
Hz; trans ca. 4.1–4.4 Hz).
(7) A similar isomerization of vinylaziridines, catalyzed by
Pd(0), has been published: (a) Mimura, N.; Ibuka, T.; Akaji,
M.; Miwa, Y.; Taga, T.; Nakai, K.; Tamamura, H.; Fujii, N.;
Yamamoto, Y. Chem. Commun. 1996, 351. (b) Ibuka, T.;
Mimura, N.; Aoyama, H.; Akaji, M.; Ohno, H.; Miwa, Y.;
Taga, T.; Nakai, K.; Tamamura, H.; Fujii, N.; Yamamoto, Y.
J. Org. Chem. 1997, 62, 999.
(8) For ab initio calculations of the energy difference between
different conformations of vinylaziridines, see: Toda, A.;
Aoyama, H.; Mimura, N.; Ohno, H.; Fujii, N.; Ibuka, T. J.
Org. Chem. 1998, 63, 7053.
(m, 7 H), 5.62 (m, 2 H), 4.50 (m, 1 H), 4.20–4.08 (m, 2 H),
2.75 (ddd, 1 H, J = 13.8, 9.6, 6.4 Hz), 2.59 (ddd, 1 H,
J = 13.8, 9.9, 6.9 Hz), 2.41 (s, 3H), 2.17–2.03 (m, 2H). 13
C
NMR (125.8 MHz, CDCl3): d = 143.3, 141.6, 134.6, 129.6,
129.4, 128.4, 128.3, 127.4, 125.7, 125.0, 66.7, 55.7, 37.3,
30.7, 21.4. MS (ESI): m/z = 350 [M + Na]+.
The analytical data of compounds 2b and 2g were in
accordance to literature data. See: Evans, P. A.; Robinson, J.
E. Org. Lett. 1999, 1, 1929.
(13) (a) Arini, L. G.; Sinclair, A.; Szeto, P.; Stockman, R. A.
Tetrahedron Lett. 2004, 45, 1589. (b) Li, A.-H.; Dai, L.-X.;
Hou, X.-L.; Chen, M.-B. J. Org. Chem. 1996, 61, 4641.
(14) (a) Sobin, B. A.; Tanner, F. W. Jr. J. Am. Chem. Soc. 1954,
76, 4053. (b) The Merck Index, 12th ed.; Windholz, M., Ed.;
Merck: Whitehouse Station, NJ, 1996, 710. (c) Hosoya, Y.;
Kameyama, T.; Naganawa, H.; Okami, Y.; Takeuchi, T. J.
Antibiot. 1993, 46, 1300. (d) Nader, K.; Schafe, G. E.; Le
Doux, J. E. Nature (London) 2000, 406, 722.
(9) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. Rev.
2003, 103, 811.
(10) (a) Kappe, C. O. Angew. Chem. Int. Ed. 2004, 43, 6250.
(b) Lindström, U. M.; Olofsson, B.; Somfai, P. Tetrahedron
Lett. 1999, 40, 9273.
(11) The microwave heating was performed with a Smith Creator
single mode cavity from Personal Chemistry AB, Uppsala,
Sweden, equipped with a magnetic stirrer and automatic
temperature control..
(15) For examples, see: (a) Kaden, S.; Brockmann, M.; Reissig,
H. U. Helv. Chim. Acta 2005, 88, 1826. (b) Kim, J. H.;
Curtis-Long, M. J.; Seo, W. D.; Ryu, Y. B.; Yang, M. S.;
Park, K. H. J. Org. Chem. 2005, 70, 4082. (c) Takahata, H.;
Banba, Y.; Tajima, M.; Momose, T. J. Org. Chem. 1991, 56,
240. (d) Takano, S.; Iwabuchi, Y.; Ogasawara, K.
Heterocycles 1989, 29, 1861. (e) Jegham, S.; Das, B. C.
Tetrahedron Lett. 1988, 29, 4419. (f) Meyers, A. I.; Dupre,
B. Heterocycles 1987, 25, 113. (g) Buchanan, J. G.;
MacLean, K. A.; Wightman, R. H.; Paulsen, H. J. Chem.
Soc., Perkin Trans. 1 1985, 1463. (h) Schumacher, D. P.;
Hall, S. S. J. Am. Chem. Soc. 1982, 104, 6076.
(12) General Procedure for the Preparation of 3-Pyrrolines.
2-Tert-butyl-1-tosyl-3-pyrroline (2e).
A solution of 2-tert-butyl-1-tosyl-vinylaziridine (1e, 27.9
mg, 0.1 mmol, cis:trans = 18:82) and LiI (26.8 mg, 0.2
mmol) in dry MeCN (3 mL) was heated in the microwave
cavity for 30 min at 200 °C. After the reaction, the solvent
was removed in vacuo and the residue purified by flash
chromatography (pentane–Et2O, 10:1) to yield 2e as a white
solid (26.4 mg, 95%); mp 149–152 °C (dec). IR (neat): 2964,
1335, 1160 cm–1. 1H NMR (400.1 MHz, CDCl3): d = 7.67 (d,
2 H, J = 8.2 Hz), 7.25 (d, 2 H, J = 8.2 Hz), 5.64–5.56 (m, 2
H), 4.30 (m, 1 H), 4.12 (m, 1 H), 3.93 (m, 1 H), 2.40 (s, 3 H),
0.97 (s, 9 H). 13C NMR (100.6 MHz, CDCl3): d = 143.2,
134.8, 129.4, 128.8, 127.8, 126.5, 56.5, 36.8, 26.4, 21.5. MS
(ESI): m/z = 280 [M + H]+.
(16) (a) Hu, S.; Jayaraman, S.; Oehlschlager, A. C. J. Org. Chem.
1996, 61, 7513. (b) Hertweck, C.; Boland, W. J. Org. Chem.
1999, 64, 4462.
(17) For ee determination, the chlorohydrine was converted to the
corresponding vinylepoxide by treatment with 5 equiv DBU
in CH2Cl2 (r.t., 12 h, 96%).16b The ee was shown to be >95%
by chiral HPLC analysis (Chiracel OD, hexane–i-PrOH,
99.5:0.5, 0.5 mL/min).
(18) [a]D25 –99.9 (c 1.20, THF) {lit: [a]D25 –93.8 (c 0.485,
THF);15c [a]D25 –101.2 (c 1.44, THF);15d [a]D25 –89.3 (c 1.26,
THF)15e}.
2-Phenethyl-1-tosyl-3-pyrroline (2d).
Colorless oil. IR (neat): 2924, 2864, 1342, 1163. 1H NMR
(400.1 MHz, CDCl3): d = 7.66 (d, 2 H, J = 8.3Hz), 7.34–7.16
(19) [a]D25 –48.4 (c 0.37, CH2Cl2).
Synlett 2005, No. 20, 3099–3102 © Thieme Stuttgart · New York