Stereospecific ring expansion of chiral vinyl aziridines

Article abstract of DOI:10.1021/ol200263g

In this report, it is demonstrated that chiral vinyl aziridines can be stereospecifically ring expanded. This synthetic approach allows controlled access to chiral 2,5-cis-or 2,5-trans-3-pyrroline products from starting materials with the appropriate aziridine geometry. Twenty three ring expansion examples, most of which feature a stereospecific cyclization, are presented.(Figure Presented)

Full text of DOI:10.1021/ol200263g

ORGANIC
LETTERS
2011
Vol. 13, No. 5
1110–1113
Stereospecific Ring Expansion of Chiral
Vinyl Aziridines
Matthew Brichacek,† Mauricio Navarro Villalobos,† Alexandra Plichta,† and
Jon T. Njardarson*,†,‡
Department of Chemistry and Chemical Biology, Baker Laboratory, Cornell University,
Ithaca, New York 14853, United States, and Department of Chemistry and
Biochemistry, University of Arizona, 1306 East University Blvd., Tucson,
Arizona 85721, United States
njardars@email.arizona.edu
Received December 26, 2010
ABSTRACT
In this report, it is demonstrated that chiral vinyl aziridines can be stereospecifically ring expanded. This synthetic approach allows controlled
access to chiral 2,5-cis- or 2,5-trans-3-pyrroline products from starting materials with the appropriate aziridine geometry. Twenty three ring
expansion examples, most of which feature a stereospecific cyclization, are presented.
A cursory review of the structural motifs of the top 200
top selling drugs1 reveals that around 90% contain at least
one nitrogen atom and approximately 65% are decorated
with a heterocycle. Not surprisingly, the majority of these
heterocycles are nitrogenous, with pyrrolidines a com-
monly occurring heterocyclic scaffold. Given the success
of chiral pyrrolidines as important pharmaceutical build-
ing blocks it follows that a range of practical synthetic
methods are needed2 to provide access to any targeted struc-
tural and stereochemical pyrrolidine pattern.
We have chosen to tackle the challenge of developing
useful pyrrolidine forming methods by revisiting the ring
expansion of vinyl aziridines, first reported by Atkinson.3
Surprisingly, despite the potential usefulness of converting a
vinylaziridine into a 3-pyrroline, there had only been a single
study focused on using metal catalysts to aid the
rearrangement prior to our contribution to this field.4
Oshima and co-workers found that tosylated diene-aziri-
dines could be ring expanded in the presence of a palladium
catalyst to the 3-pyrrolines. Both the N-tosyl group and the
diene moiety were reported to be essential for the success of
this rearrangement. Simple nondienic vinyl aziridines did
not ring expand, furnishing instead a complex mixture of
products. In our recent report, we demonstrated that this
significant substrate limitation could be solved by using
Cu(hfacac)2 as a catalyst.5 The substrate scope of this new
transformation, which we demonstrated for a range of tosyl
(Ts) and N-phthalimide (NPhth) protected vinyl aziridines,
was shown to be quite broad. In this report we expand these
investigations further and focus our attention on stereospe-
cific vinyl aziridine ring expansions and application of this
new methods toward accessing chiral pyrroline products.
To maximize the synthetic potential of our method for
preparing chiral pyrroline products, it is essential that
reliable, asymmetric, convergent, and scalable routes
be availabletoaccesstherequisite startingmaterials (chiral
† Cornell University.
‡ University of Arizona.
(1) The structures of the top 200 selling drugs can be downloaded
from http://cbc.arizona.edu/njardarson/group. McGrath, N. A.;
Brichacek, M.; Njardarson, J. T. J. Chem. Educ. 2010, 87, 1348–1349.
(2) Asymmetric Synthesis of Nitrogen Heterocycles; Royer, J., Ed.;
Wiley-VCH: Weinheim, Germany, 2009.
(3) (a) Atkinson, R. S.; Rees, C. W. Chem. Commun. 1967, 1232–
1232. (b) Hudlicky, T.; Frazier, J. O.; Kwart, L. D. Tetrahedron Lett.
1985, 26, 3523–3526. (c) Pearson, W. H. Tetrahedron Lett. 1985, 26,
3527–3530. (d) Hudlicky, T.; Reed, J. W. Angew. Chem., Int. Ed. 2010,
49, 4864–4876. (e) Scheiner, P. J. Org. Chem. 1967, 32, 2628–2630.
(f) Hirner, S.; Somfai, P. Synlett 2005, 3099–3102.
(4) (a) Fugami, K.; Morizawa, Y.; Oshima, K.; Nozaki, H. Tetra-
hedron Lett. 1985, 26, 857–860. (b) Fugami, K.; Miura, K.; Morizawa,
Y.; Oshima, K.; Utimoto, K.; Nozaki, H. Tetrahedron 1989, 45, 3089–
3098.
(5) (a) Brichacek, M.; Lee, D.; Njardarson, J. T. Org. Lett. 2008, 10,
5023–5026. (b) For a review of 3-pyrroline synthetic approaches:
Brichacek, M.; Njardarson, J. T. Org. Biomol. Chem. 2009, 7, 1761–
1770.
r
10.1021/ol200263g
Published on Web 02/10/2011
2011 American Chemical Society

Table 1. Ring Expansion: Nitrogen Substituent Toleranceh
Scheme 1. Retrosynthetic Analysis for Chiral Pyrrolines
entry
P =
time (h)
yield of 11 (%)
a
b
c
d
e
f
Ts
5
2
2
2
5
1
5
5
2
5
92
97
0c
0d
60
0e
NPhtha,b
Pha
Bna
Boc
vinyl aziridines).6 The union of an imine and suitably acti-
vated nucleophile quickly emerged as the optimal approach
(Scheme 1). The imine-based retrosynthetic analysis is
highlighted for chiral pyrroline 3, which we envisioned
would originate from the copper-catalyzed ring expansion
of a trans- or cis-vinyl aziridine (4 and 5). These isomeric
vinyl aziridinescould beaccessedbytreating imines7 and 8
with nucleophiles 6 and 9, respectively. An attractive fea-
ture of this disconnection approach is that either the imine
or the nucleophile could serve the role of chiral auxiliary.
Prior to assembling the requisite chiral aziridines it was
of critical importance to learn what other nitrogen protect-
ing groups (P) besides Ts and Phth might also be suitable
for this reaction (Table 1). We realized that aryl- and acyl-
substituted aziridines would be particularly challenging
substrates, given their known tendency to undergo com-
peting Claisen rearrangements or intramolecular displace-
ment reactions.7 This prediction turned out to be true as in
the case of N-benzyl (entry d) a known hydride shift oc-
curred instead,8 while for N-phenyl (entry c) the expected
Claisen rearrangement was observed.9 Boc-protected azir-
idine 10 (entry e) did ring expand to the desired 3-pyrroline,10
while in contrast when a benzoyl group (entry j) was pre-
sent, the ring expansion failed and instead a mixture of
five- and seven-membered heterocycles was formed.11
When vinyl aziridine 10 was not protected (NH, entry i)
it rapidly oligomerized when subjected to the reaction con-
ditions. Curiously, the tert-butyl sulfinamide-substituted
vinyl aziridine (entry f) formed 1-phenylbutadiene in high
yield rather than the expected 3-pyrroline product (11).12
We were delighted to find that 4-nitrobenzylsulfonamide
(Ns) and Bus tert-butylsulfonamide (Bus) groups, in
S(O)tBu
Bus
g
h
i
86
94
0f
0g
Ns
H
j
Bz
a Racemic aziridine used. b Cis/trans mixture. c Mixture of azepine
and 2-pyrroline products. d (Z)-N-Benzylidene-1-phenylbut-2-en-1-
amine isolated in 86% yield. e (E)-Buta-1,3-dien-1-ylbenzene formed in
69% yield. f Polymer formed. g Five and seven membered ring products
observed. h Conditions: 5 mol % Cu(hfacac)2, 150 °C.
addition to p-toluenesulfonamide (entry a), were compa-
tible with the ring expansion conditions. These studies
suggest that sulfonamides are especially well suited for
our ring expansion reaction.
Armed with insights into what aziridine protecting groups
are compatible with our reaction conditions we turned our
attention to the design of a scalable asymmetric route to
vinyl aziridine substrates. The use of proline derivatives as
organocatalysts13 and as key building blocks of many
pharmaceuticals and natural products14 ensures its status
as a privileged structural motif. Chiral 2,3-dehydroproline
(3-pyrroline) products commonly originate from natural
3-hydroxy proline,15 and this neglected family of chiral
proline products emerged as an ideal target for our new
methodology. Retrosynthetic analysis for 2,5-dihydropyr-
rolidine 15 (Scheme 2) suggests that the chiral vinyl
aziridine ring expansion substrate (14) should originate
from a Darzens reaction16 between a bromo acetate (12)
and a chiral conjugated Ellman type imine17 (13). These
chiral imines are attractive substrates because they are
trivial to make, very stable, available in both enantiomeric
forms, and easy to handle. Since our nitrogen substituent
ring expansion compatibility study (Table 1) had
(6) Pellisier, H. Tetrahedron 2010, 66, 1509–1555.
(7) Pommelet, J. C.; Chuche, J. Can. J. Chem. 1976, 54, 1571–1581.
(8) Somfai, P.; Ahman, J. Tetrahedron Lett. 1995, 36, 1953–1956.
(9) Fantauzzi, S.; Gallo, E.; Caselli, A.; Piangiolino, C.; Ragaini, F.;
Re, N.; Cenini, S. Chem.;Eur. J. 2009, 15, 1241–1251.
(10) Mishra, A.; Rice, S. N.; Lwowski, W. J. Org. Chem. 1968, 33,
481–486.
(13) (a) Kotsuki, H.; Ikishima, H.; Okuyama, A. Heterocycles 2008,
75, 493–529. (b) Kotsuki, H.; Ikishima, H.; Okuyama, A. Heterocycles
2008, 75, 757–797.
(14) Mauger, A. M. J. Nat. Prod. 1996, 59, 1205–1211.
(15) (a) Meyer, S. C.; Ramanjulu, J.; Vera, M. D.; Pfizenmayer, A. J.;
Joullie, M. M. J. Org. Chem. 1994, 59, 5192–5205. (b) Greenwood, E. S.;
Hitchcock, P. B.; Parsons, P. J. Tetrahedron 2003, 59, 3307–3314.
(16) Davis, F. A.; Liu, H.; Zhou, P.; Fang, T.; Reddy, G. V.; Zhang, Y.
J. Org. Chem. 1999, 64, 7559–7567.
(17) (a) Liu, G.; Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1997,
119, 9913–9914. (b) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem.
Res. 2002, 35, 984–995. (c) Davis, F. A.; Reddy, R. T.; Reddy, R. E. J.
Org. Chem. 1992, 57, 6387–6389. (d) Davis, F. A. J. Org. Chem. 2006, 71,
8993–9003.
(11) Heine, H. W.; Fetter, M. E.; Nicholson, E. M. J. Am. Chem. Soc.
1959, 81, 2202–2204.
(12) We have not been able to find other examples of this type of
deamination reaction for sulfinamide protected aziridines. Further-
more, we have tested this on several other substrates and observed the
same deamination behavior. Aziridine deaminations are not without
precedence, see: (a) Clard, R. D.; Helmkamp, G. K. J. Org. Chem. 1964,
29, 1316–1320. (b) Muller, R. K.; Felix, D.; Schreiber, J.; Eschenmosher,
A. Helv. Chim. Acta 1970, 53, 1479–1484.
Org. Lett., Vol. 13, No. 5, 2011
1111

compatible substrate (Bus-protected aziridines). This was
readily accomplished by using m-CPBA. Interestingly, we
have learned that this oxidation can also be accomplished
with ammonium molybdate tetrahydrate in excellent
yield.18
Scheme 2. Darzen Reaction Route to Chiral Proline Products
Twelvechiralaziridine substrates shown in Table2 (R =
Bus) were prepared by using the strategy detailed above.
The Darzen reaction step was in general high yielding and
the cis/trans-aziridine ratios were in the modest 2:1-4:1
range. To better understand the scope of the ring expan-
sion, the resulting cis- and trans-vinyl aziridines were sep-
arated and evaluated individually. Both cis- and trans-
vinyl aziridines readily ring expand to 3-pyrrolines in
excellent yields in the presence of catalytic amounts of
Cu(hfacac)2. Entries e-h highlight the methodologies
ability to offer two suitable retrosynthetic choices for
accessing a particular enantiomer (entries e and f give the
(S)-enantiomer and g and h the (R)-enantiomer). Entries
i-k demonstrate how control of a desired 2,5-pyrroline
substitution pattern can be achieved simply by starting
with the appropriate cis- or trans-aziridine precursor.19
Deprotection of Bus-protected cyclic dialkylamines con-
taining an adjacent electron-withdrawing group like the
3,4-dehydroproline products in Table 2 is well documented
to proceed cleanly without any epimerization.20
unfortunately revealed that the immediate products of this
union, N-sulfinamide protected vinyl aziridines, did not
ring expand we needed to resort to oxidizing the Darzen
reaction products priortoringexpansion inorder tohave a
Table 2. Ring Expansion of Bus-Protected Vinyl Aziridinesa
Scheme 3. Asymmetric Synthesis of Tosyl Protected Aziridines
A complementary convergent asymmetric approach to
chiral vinyl aziridines en route to 3-pyrroline products em-
ploys a chiral sulfide in place of a chiral imine (Scheme 3).
Although the use of chiral nucleophiles versus chiral elec-
trophiles for accessing aziridines is currently far less devel-
oped, this approach would avoid the oxidation step prior
to ring expansion. Aggarwal21 and co-workers have shown
that chiral sulfonium nucleophiles can be used to synthe-
size aziridines in a highly selective manner. We chose to
employ the limonene-based chiral auxiliary (19)22 for
(18) This cheap, practical, and simple oxidation protocol, which is
commonly employed for accessing Julia olefination substrates, has not
been reported previously for converting sulfinamides to sulfonamides:
Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002, 2563–2585.
(19) Entry l is an exception as this highly congested system scrambled
prior to ring expansion.
(20) (a) Koep, S.; Gais, H.-J.; Raabe, G. J. Am. Chem. Soc. 2003, 125,
13243–13251. (b) Gunter, M.; Gais, H.-J. . J. Org. Chem. 2003, 68, 8037–
8041. (c) Tiwari, S. K.; Gais, H.-J.; Lindenmaier, A.; Babu, G. S.; Raabe,
G.; Reddy, L. R.; Kohler, F.; Gunter, M.; Koep, S.; Iska, V. B. R. J. Am.
Chem. Soc. 2006, 128, 7360–7373.
a Conditions: 5 mol % Cu(hfacac)2, toluene, 5 h, 150 °C. Cy = cyclo-
hexyl. R=Bus (14a-l) R=S(O)tBu (16a-l).
(21) Aggarwal, V. K.; Vasse, J.-L. Org. Lett. 2003, 5, 3987–3990.
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Org. Lett., Vol. 13, No. 5, 2011

trans-isomer (dr >20:1) while the cyclohexyl-substituted
aziridines (20f-k) were obtained with slightly lower selec-
tivity (dr = 6:1-11:1).
Table 3. Ring Expansion of Tosyl-Protected Vinyl Aziridinesa
Chiral 2-aryl-substituted pyrrolidines are important
structures and have received increased attention in recent
years.23 We were delighted tofind that all of the chiral vinyl
aziridine substrates 20a-k could be ring expanded stereo-
specifically using Cu(hfacac)2 as catalyst in uniformly ex-
cellent yields to corresponding 2-aryl-3-pyrrolines 21a-k
(Table 3). A single stereoisomer was obtained in each case.
Both electron-donating and -withdrawing substitutents
are well-tolerated, including aryl bromides, chlorides, io-
dides, and fluorides. The broad tolerance of aryl substitu-
ents should serve those researchers interested in applying
this new methodology to complex natural products, phar-
maceuticals, or organocatalytic architectures well. Impre-
ssively, the corresponding chiral cis-vinyl aziridines stereo-
specifically afford the trans-fused 3-pyrroline products as
single stereoisomeric products (entries j and k).
In summary, we have demonstrated two new practical
complementary routes to access valuable chiral 3-pyrro-
line products from readily accessible vinyl aziridine
precursors. This was accomplished by coupling an imine
with an appropriate nucleophile and then catalytically
ring expanding the resulting chiral vinyl aziridine with
Cu(hfacac)2. The substrate scope and functional group
tolerance of this new synthesis is very broad. The ex-
cellent chirality transfer demonstrated by the examples
presented also serves to underscore the mechanistic
uniqueness of this new catalytic reaction and advantage
over all other aziridine ring expansion routes aiming to
form 3-pyrrolines. It is important to note that an added
advantage to both of our asymmetric 3-pyrroline routes
is that they provide a double bond handle for further
functionalization, which can be readily converted to
more complex pyrrolidine products in a substrate-con-
trolled manner. As better asymmetric aziridine methods
are developed more opportunities will arise for applica-
tions of this new method.
Acknowledgment. We would like to thank NSF (CHE-
0848324) and the NIH (training grant, T32GM008500, to
M.B.) for financial support. Special thanks go to Dr. Emil
Lobkovsky for obtaining all X-ray crystal structures.
a Conditions: 5 mol % Cu(hfacac)2, toluene, 150 °C.
Supporting Information Available. Full experimental
details for all new compounds reported in this article
including X-ray data for compounds 15d, 15j, 15l, 21d,
and 21f. This material is available free of charge via the
Internet at http://pubs.acs.org.
additions to sulfonamide imines (18). The Aggarwal chiral
auxiliary is easily prepared in either enantiomeric form.
This route provided us with the chiral ring expansion
precursors (20) in a single step. Yields for this step were
mostly high and the cis/trans-aziridine product ratios were
in the 6:1-20:1 range. Interestingly, the bis-aryl vinyl
aziridine products (20a-e) were obtained as a single
(23) For recent approaches to chiral 2-pyrrolines consult: (a) Cam-
pos, K. R.; Klapars, A.; Waldman, J. H.; Dormer, P. G.; Chen, C. J. Am.
Chem. Soc. 2006, 128, 3538–3539. (b) Davis, F. A.; Song, M.; Augustine,
A. J. Org. Chem. 2006, 71, 2779–2786. (c) Fang, Y.-Q.; Jacobsen, E. N.
J. Am. Chem. Soc. 2008, 130, 5660–5661.
(22) Illa, O.; Arshad, M.; Ros, A.; McGarrigle, E. M.; Aggarwal,
V. K. J. Am. Chem. Soc. 2010, 132, 1828–1830.
Org. Lett., Vol. 13, No. 5, 2011
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