Catalytic enantiospecific [3+2] annulation of aminocyclopropanes with ketones

Article abstract of DOI:10.1002/chem.201103971

An almost familiar ring: The first enantiospecific [3+2] annulation of donor-acceptor aminocyclopropanes with ketones is reported (see scheme; Phth=phthaloyl). The reaction is catalysed by tin(IV) chloride (5 mol%) at -78°C and gives aminotetrahydrofurans bearing a quaternary C5 atom in high yield, diastereoselectivity and enantiospecificity (see scheme). Copyright

Full text of DOI:10.1002/chem.201103971

DOI: 10.1002/chem.201103971
Catalytic Enantiospecific [3+2] Annulation of Aminocyclopropanes with
Ketones
[
a]
Fides Benfatti, Florian de Nanteuil, and Jꢀrꢁme Waser*
[
7]
The exploitation of strain release in small rings as a driving
force to trigger synthetic transformations has received in-
creased attention over the last decade. In this context, cyclo-
propanes have predominantly been investigated, due to the
abundance of efficient methods for their preparation, com-
bined with their exceptional reactivity. A strategy to further
enhance the inherent strain energy of cyclopropanes consists
of the introduction of vicinal donor and acceptor groups (D
and A, Scheme 1) able to stabilise the incipient positive and
panes in hand, we sought to develop a catalytic and stereo-
selective protocol for the [3+2] annulation of D–A aminocy-
clopropanes and ketones. There are only a few reports of
the annulation and cyclisation reactions of D–A aminocyclo-
[8]
propanes, despite their high synthetic potential for the
preparation of N-containing hetero- and carbocycles. Imple-
menting the [3+2] annulation of D–A cyclopropanes with
ketones would indeed allow expedient access to a variety of
2-aminotetrahydrofurans bearing a rare quaternary carbon
in position 5 (Scheme 2). Furthermore, the 2-aminotetrahy-
Scheme 1. Donor–Acceptor cyclopropanes as 1,3-zwitterionic synthons.
D=donor. A=acceptor. X=Y=generic double bond.
negative charges derived from the cleavage of the activated
s bond. The so-called D–A cyclopropanes can therefore be
considered to be synthetically equivalent to 1,3-zwitterionic
[1]
synthons. As such, they have been extensively used in
[
2]
[
3+2] annulations. These reactions allow the efficient as-
Scheme 2. The [3+2] annulation of D–A aminocyclopropanes with car-
bonyl compounds. Phth=phthaloyl.
sembly of a variety of 5-membered hetero- and carbocycles.
In particular, the [3+2] reaction with carbonyl com-
[
3,4]
pounds
represents a valuable tool for the synthesis of tet-
[5]
rahydrofurans (THFs).
drofuran scaffold can be considered to be a privileged struc-
ture, due to its occurrence in nucleosides and in nucleoside-
The annulation of D–A cyclopropanes with aldehydes is
well established, and efficient catalytic, as well as enantiose-
[9]
derived synthetic drugs. It is noteworthy that current
methods mainly yield analogues bearing a tertiary centre at
C5 (Scheme 2), with little deviation from the natural mole-
[3f,h–n]
lective, protocols have been reported.
In contrast, only
a few catalytic methods have been described for annulation
reactions involving the less reactive ketones as the reaction
[10]
cules.
The methodology described, herein, however,
[4]
partners. Furthermore, the scarcity of highly diastereose-
lective protocols indicates an intrinsic difficulty in achieving
face discrimination in the addition of D–A cyclopropanes to
allows access to the less explored chemical space populated
by structures bearing a quaternary C5 atom. Herein, we
report the first catalytic [3+2] annulation of D–A aminocy-
clopropanes with ketones, allowing the preparation of rare
C5-disubstituted aminotetrahydrofurans. In contrast to our
previous work with aldehydes by using an iron catalyst that
[6]
non-symmetrical ketones.
In this context, and with our recent advancements involv-
ing cyclisation and annulation reactions of D–A cyclopro-
[7f]
induced racemisation, the tin-catalysed annulation of ke-
tones is enantiospecific, giving access to enantioenriched
aminotetrahydrofurans.
[
a] Dr. F. Benfatti, F. de Nanteuil, Prof. Dr. J. Waser
Laboratory of Catalysis and Organic Synthesis
Ecole Polytechnique Fꢀdꢀrale de Lausanne, EPFL SB ISIC LCSO
BCH 4306, 1015 Lausanne (Switzerland)
Fax : (+41)21-693-9700
We commenced our investigation by screening Lewis
acids for the model reaction of phthaloyl cyclopropane 1a
with acetophenone (2a). At first, we tested iron
ACHTUNGTRENNUNG( III) chlo-
E-mail: jerome.waser@epfl.ch
ride on alumina, which successfully promoted the [3+2] an-
nulation with aldehydes (Table 1, entry 1). Unfortunately,
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201103971.
[7f]
4844
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Chem. Eur. J. 2012, 18, 4844 – 4849

COMMUNICATION
[
a]
Table 1. Screening of Lewis acids in the reaction with acetophenone.
isomer epi-3aa became detectable in the crude if the reac-
[13]
tion was run at À108C (Table 2, entry 4). In the presence
of 20 mol% of SnCl , epi-3aa was formed at even lower
4
temperatures (À208C), although the increased amount of
catalyst induced significant decomposition (Table 2, entry 3).
[
b]
[c]
[b]
[c]
At À108C and with 20 mol% of SnCl , it was the only dia-
Entry Lewis acid
Yield [%]
Entry Lewis acid
Yield [%]
4
stereoisomer observed in the crude reaction mixture
(Table 2, entry 4). Unfortunately, the isolated yield under
these conditions was poor (19%), hampering the develop-
ment of a temperature-dependent synthesis of both diaste-
reoisomers of aminoTHFs.
1
2
3
4
FeCl
SnCl
AuCl
3
-Al
2
O
3
20
100
50
5
6
7
8
In
Sc
Sn
Hf
A
H
U
G
R
N
U
G
3
33
25
13
decomp.
[
d]
4
3
3
2
Cu
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(OTf)
2
10
4
[
(
a] Reaction conditions: 1a (1.0 equiv), 2a (1.5 equiv), Lewis acid
20 mol%), in dichloromethane (0.1m). Phth=phthaloyl; d.r.=diastereo-
meric ratio; OTf=trifluoromethanesulfonate. [b] No reaction with: Zn-
(OTf) , TiCl , AuCl, EtAlCl , Me AlCl or CeCl . [c] Yield was deter-
mined by H NMR spectroscopy using hexamethyldisiloxane as the inter-
nal standard. [d] Performed at À788C; at RT, only traces of 3aa were de-
tected.
To determine if epi-3aa could be derived from 3aa
through a tin(IV)-catalysed isomerisation, aminotetrahydro-
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
2
4
2
2
3
1
furan 3aa was treated with SnCl (20 mol%) at À108C. In
4
this case, its partial conversion to starting material 1a, likely
through a retro-[3+2] annulation, was mainly observed. To
explain this result, we assume that 3aa might isomerise to
epi-3aa through a sequence of retro-[3+2] annulation fol-
a poor yield was obtained, due to extensive degradation of
the cyclopropane partner in the presence of the catalyst. We
then examined tin(IV) chloride, which we have employed
previously to promote the [3+2] annulation of phthaloyl cy-
[14]
lowed by [3+2] annulation (Scheme 3). As intermediates,
[7e]
clopropane with silyl enol ethers (Table 1, entry 2).
At
À788C, complete conversion was observed after 90 min, and
the desired aminotetrahydrofuran 3aa was formed quantita-
tively, as a single diastereoisomer. The relative configuration
of 3aa was unambiguously assigned to be 2,5-cis on the
[
11]
basis of X-ray diffraction analysis.
salts failed to catalyse the process, with the surprising excep-
tion of gold(III) chloride, which gave 3aa in modest yield
Table 1, entry 3). Owing to decomposition of 1a, the
screening of metal triflates (Table 1, entries 4–8) as potential
Other metal chloride
ACHTUNGTRENNUNG
(
Scheme 3. The formation of tetrahydrofurans 3aa and epi-3aa through
[3+2] annulation. L.A.=Lewis acid.
[12]
catalysts did not lead to improved results.
Consequently, we selected SnCl as the catalyst to further
4
screen for the effects of temperature (T) and catalyst load-
ing on the diastereoselectivity of the [3+2] annulation be-
tween 1a and acetophenone (2a; Table 2). By using 5 mol%
of the catalyst, the reaction showed a classic inverse d.r. de-
pendence with respect to temperature, with the diastereose-
lectivity being decreased with an increase in T. The 2,5-trans
both an intimate ion pair Ia or a completely dissociated
zwitterion Ib could be considered. In the presence of one
equiv ACHUTNGRENNUGa lent of 2a, full conversion of 3aa was achieved and
epi-3aa was obtained in 45% yield. Although this result
would be in good agreement with a process having either Ia
or Ib as the intermediate because a higher concentration of
2
a would be particularly important for allowing efficient iso-
merisation in this case, the interconversion of the open zwit-
terions II and III or the reaction of Ia or Ib with acetophe-
none (2a) to give 3aa directly are also possible reaction
pathways.
Table 2. Diastereomeric ratios observed in the reaction of 1a with 2a,
with 5 or 20 mol% SnCl , at different temperatures.
4
[
a]
Next, the scope of the reaction was evaluated by applying
the optimised conditions to a variety of aromatic, heteroaro-
matic and aliphatic ketones (Table 3). D–A cyclopropanes
[
b]
Entry
T [8C]
d.r. with SnCl
4
1
a and 1b displayed similar reactivity towards acetophe-
5
mol%
20 mol%
none (2a), providing aminoTHFs 3aa and 3ba in excellent
yields and diastereoselectivities (Table 3, entries 1 and 2).
A lower yield (79%, Table 3, entry 3) was obtained in the
case of 1’-acetonaphthone (2b), most likely due to the un-
favourable ortho substitution. Electron-rich aromatic ketone
1
2
3
4
5
À78
À40
À20
À10
0
>20:1
>20:1
>20:1
5:1
>20:1
>20:1
9:1
<1:20
<1:20
[15]
[c]
[d]
3:1
[
a] Reaction conditions: 1a (1.0 equiv), 2a (1.5 equiv), SnCl
4
(5 or
2
c and heteroaromatic ketone 2d showed lower diastereose-
2
0 mol%), in dichloromethane (0.1m) at the indicated temperature.
1
lectivities for the [3+2] annulation (Table 3, entries 4 and 5).
Nevertheless, the d.r. could be improved through a single re-
crystallisation.
[
b] Determined by H NMR spectroscopy of the crude reaction mixture
and expressed as cis/trans (3aa/epi-3aa). [c] 80% combined isolated
yield. [d] 19% isolated yield.
Chem. Eur. J. 2012, 18, 4844 – 4849
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www.chemeurj.org
4845

J. Waser et al.
[
a]
Table 3. Scope of the [3+2] annulation with ketones.
Electron-poor aromatic ketones 2e and 2 f
were also tested, giving the corresponding ami-
noTHFs 3be and 3bf in high yields, as single
diastereoisomers (Table 3, entries 6 and 7). Ex-
cellent stereochemical discrimination between
the phenyl and the ethyl substituent was also ob-
served with propiophenone (2g), demonstrating
the versatility of our methodology (Table 3,
entry 8). 1-Tetralone (2h) displayed excellent re-
Entry Substrate Ketone
Product
Yield
[
%]
[b,c]
d.r.
9
9
>
>
>
20:1 activity and selectivity, delivering 3ah in high
1
2
1a
1b
2a
2a
3aa
3ba
yield and diastereoselectivity, but favouring the
2
,5-trans isomer for this cyclic system (Table 3,
9
20:1
6
[16]
entry 9).
Symmetrical aliphatic ketones (2i and 2j) are
more established substrates in [3+2] annulations
with D–A cyclopropanes. Under our conditions,
they cleanly provided the corresponding ami-
noTHFs in nearly quantitative yields (Table 3,
entries 10–12). In general, obtaining a high
degree of diastereocontrol by employing non-
symmetrical aliphatic ketones remains a chal-
[d] lenge. Gratifyingly, utilising our optimised con-
ditions on ketones 2k and 2l gave yields and
diastereoselectivities comparable to those ob-
tained with aromatic substrates (Table 3, en-
7
20:1
9
3
1b
2b
3bb
9
1
20:1
0
6:1
4
5
1a
1b
2c
2d
3ac
3bd
>
9
5
4
:1
[
d]
14:1 tries 13 and 14). Ketone substrate 2k highlights
the efficacy of the developed methodology, with
a good d.r. (10:1, Table 3, entry 13) being ob-
9
20:1
3
tained for a reaction in which two carbonyl sub-
stituents (methyl and ethyl) with only a small
difference in size were present.
>
>
>
6
7
8
1b
1b
1a
2e
2 f
2g
3be
3bf
3ag
To assess the stereospecificity of the tin(IV)-
9
9
20:1 catalysed [3+2] annulation, a selection of ke-
tones was reacted with enantioenriched phthalo-
[17]
yl cyclopropane 1a at À788C (Scheme 4).
9
20:1
5
Under these conditions, no loss of stereochemi-
cal purity was observed with acetophenone (2a)
and ketones 2h–j, although aminotetrahydrofur-
an 3ag was isolated in a slightly decreased enan-
tiomeric excess (enantiospecificity e.s.=83%).
The preservation of optical purity in [3+2] an-
nulations of D–A cyclopropanes has already
9
20:1
4
>
9
1a
2h
3ah
[3h–i,l]
been reported by Johnson et al.
and by our
nevertheless, this is the first enantio-
specific reaction between aminocyclopropanes
[7e]
group;
9
9
9
4
–
1
1
1
1
0
1
2
3
1a
1a
1b
1b
2i
3ai
3aj
3bj
3bk
[18]
and carbonyl compounds.
This result is not
only important for the application of the reac-
tion in the synthesis of enantioenriched prod-
ucts, it also demonstrates that an open zwitter-
ion (Ib in Scheme 3) is not formed during the
annulation reaction.
Based on the high enantiospecificity and dia-
stereoselectivity of the reaction, we wondered if
the reaction of racemic 1a with a chiral ketone
would allow kinetic resolution to take place. For
example, the reaction of cyclopropane 1a with
9
–
2j
2j
2k
9
–
8
1
1
9
0:1
6:1
[
d]
(
À)-menthone (2m) should in principle favour
4846
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Chem. Eur. J. 2012, 18, 4844 – 4849

ACHTUNGTRENNUNG[ 3+2] Annulation of Aminocyclopropanes
COMMUNICATION
Table 3. (Continued)
would be obtained as single enantiomers be-
cause enantiopure (À)-menthone (2m) was
used as the starting material. The opposite ab-
solute stereochemistry at the nitrogen centre
would result from the enantiospecific reaction
Entry Substrate Ketone
Product
Yield
[
%]
[b,c]
d.r.
9
6
[19]
>
20:1
of both enantiomers of 1a.
a severe steric interaction between the ester in
a and the isopropyl group in (À)-menthone
2m) is present only in 3am’; consequently, the
However,
1
4
1b
2l
3bl
1
(
[
4
a] Standard reaction conditions: 1a or 1b (0.2 mmol), 2a–l (1.5 equiv), SnCl (5 mol%), in
1
dichloromethane (0.1m) at À788C. [b] Determined by H NMR spectroscopy on the crude
reaction mixture. [c] Expressed as cis/trans. [d] Obtained after one recrystallisation (see the
Supporting Information).
formation of this diastereoisomer is expected
to be slower (mismatched case), allowing a ki-
netic resolution with re-isolation of enantioen-
riched 1a. Unfortunately, the kinetic resolution
of 1a by using sub-stoichiometric amounts of (À)-menthone
(
2m) could not be accomplished, mainly due to the sluggish
reactivity observed in this case. If the amount of 2m was in-
creased to three equivalents, the reaction was accelerated,
allowing the isolation of enantioenriched 1a after 1 h, al-
though the yield and enantiomeric excess showed a strong
batch dependency (Scheme 5b). Unexpectedly, after the
conversion was complete (2 h), the annulation product 3am
was isolated as a single diastereoisomer in 88% yield. Con-
sequently, the reaction was not enantiospecific, but stereo-
[20]
convergent.
Different rationales could account for this result; tin(IV)
chloride is either active in the racemisation of the D–A ami-
nocyclopropane 1a or in the isomerisation of the product
3
am. To obtain additional clues, the loss of enantiomeric
purity of enantioenriched 1a (ee=94%) in the presence of
SnCl (5 mol%) was monitored at À788C. After one hour,
4
1
a was recovered with an ee of 75% and after 2.5 h almost
Scheme 4. Enantiospecific [3+2] annulation of D–A aminocyclopropanes
a with ketones. [a] Used in combination with 2a, 2g and 2i. [b] Used in
combination with 2h and 2j. [c] 99% yield based on recovered starting
material. R =Larger substituent; R =Smaller substituent; ee=enantio-
meric excess; e.s.=enantiospecificity ([ee of product/ee of starting materi-
al]ꢂ100%).
all of its stereochemical information was lost (ee=
1
[3i,21]
2
0%).
This result supports the hypothesis that the ob-
L
S
served dynamic kinetic resolution could take place through
racemisation of the aminocyclopropane 1a, probably via an
open zwitterionic intermediate Ib (Scheme 3). The apparent-
ly contradicting results obtained with (À)-menthone (2m)
could be explained by a limited lifetime for a tight ion pair
Ia; if the following annulation reaction is fast, an enantio-
specific reaction takes place, but if the desired reaction is
slow, as for the mismatched case with (À)-menthone (2m),
dissociation would have time to occur, which would lead to
racemisation even at À788C and to the stereoconvergent re-
action that was observed. In contrast, the cis/trans isomerisa-
tion described in Table 2 would require a higher tempera-
ture to proceed. We note that further experiments would be
required to confirm this interpretation.
the formation of the two diastereoisomers 3am and 3am’
because both have the phthalimide group in a cis relation-
ship to the more bulky group (Scheme 5a). Both products
In conclusion, we have reported the first enantiospecific
[
3+2] annulation of D–A cyclopropanes with ketones. Cata-
lytic amounts of tin(IV) chloride were used to catalyse the
reaction with a broad range of ketones, including non-sym-
metric ones. Yields and diastereomeric ratios were generally
excellent, demonstrating the potential of this method for the
stereoselective synthesis of aminoTHFs bearing a rare C5
quaternary centre. Furthermore, the developed transforma-
tion is enantiospecific, allowing access to enantioenriched
aminoTHFs when starting from an enantioenriched amino-
Scheme 5. Reaction of racemic 1a with (À)-menthone (2m).
Chem. Eur. J. 2012, 18, 4844 – 4849
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4847

J. Waser et al.
cyclopropane. Attempts to expand the scope of N-contain-
ing cyclopropanes, as well as further functionalisation of the
obtained products are currently underway in our laboratory.
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l (1.5 equiv) were dissolved in anhydrous dichloromethane (2 mL) at
À788C. After 5 min, SnCl
4
in dichloromethane (5 mol%, 0.01 mmol,
3 mL of a 0.43m solution) was added. The mixture was stirred under ni-
2
trogen at À788C for 90 min, then the reaction was quenched by the addi-
tion of triethylamine (0.2 mL) and subsequently flushed through a short
plug of silica gel, eluting with EtOAc (5 mL). The solvent was removed
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1
977, 99, 7360–7362; p) A. R. Daniewski, T. Kowalczyk-Przewloka,
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also be found in references [3a,b].
1
H NMR analysis to determine the d.r. before purification through flash
2
column chromatography (SiO , 8:2 to 1:1 (n-hexane/AcOEt)).
[
4] For catalytic reactions with ketones as partners, see: a) E. O. Mar-
tins, J. L. Gleason, Org. Lett. 1999, 1, 1643–1645; b) Y. Sugita, K.
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for a single example of a catalytic reaction with acetone that was re-
ported by Johnson and co-workers, see reference [3i].
Acknowledgements
We thank the European Commission (Marie Curie IEF fellowship to
F.B., grant number 253274) and the Swiss National Science Foundation
(
SFN, grant number 200021_129874) for financial support. Dr. Rosario
Scopelliti (EPFL) is acknowledged for the X-ray studies. We thank Dr.
Reto Frei for proofreading the manuscript.
[
5] For a review on the stereoselective synthesis of tetrahydrofurans,
see: J. P. Wolfe, M. B. Hay, Tetrahedron 2007, 63, 261–290.
[
6] The highest d.r. values obtained previously in catalytic reactions
with prochiral ketones is 3.7:1 for intermolecular reactions (refer-
ence [4d]) and >95:5 for intramolecular ones (reference [4e]).
7] For intramolecular formal homo-Nazarov reactions, see: a) F. De
Simone, J. Andrꢃs, R. Torosantucci, J. Waser, Org. Lett. 2009, 11,
Keywords: annulation · aminotetrahydrofuran · catalysis ·
D–A aminocyclopropane · enantiospecificity · ketones
[
1
2
023–1026; b) F. De Simone, J. Gertsch, J. Waser, Angew. Chem.
010, 122, 5903–5906; Angew. Chem. Int. Ed. 2010, 49, 5767–5770;
[
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kopf, Tetrahedron 2005, 61, 321–347; c) F. De Simone, J. Waser, Syn-
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T. Saget, F. Benfatti, S. Almeida, J. Waser, Chem. Eur. J. 2011, 17,
1
4527–14538; for intermolecular [3+2] annulation with silyl enol
ethers, see: e) F. de Nanteuil, J. Waser, Angew. Chem. 2011, 123,
2281–12285; Angew. Chem. Int. Ed. 2011, 50, 12075–12079; with
aldehydes, see: f) F. Benfatti, F. de Nanteuil, J. Waser, Org. Lett.
012, 14, 386–389.
[
2] For reviews, see: a) C. A. Carson, M. A. Kerr, Chem. Soc. Rev. 2009,
1
3
8, 3051–3060; b) M. J. Campbell, J. S. Johnson, A. T. Parsons, P. D.
Pohlhaus, S. D. Sanders, J. Org. Chem. 2010, 75, 6317–6325; c) T. P.
Lebold, M. A. Kerr, Pure Appl. Chem. 2010, 82, 1797–1812;
d) V. K. Yadav, N. V. Kumar, Chem. Commun. 2008, 3774–3776;
e) O. A. Ivanova, E. M. Budynina, A. O. Chagarovskiy, I. V. Trush-
kov, M. Y. Melnikov, J. Org. Chem. 2011, 76, 8852–8868. A reviewer
proposed the use of the term [3+2] cycloaddition for this type of re-
action because it is more precise than annulation, and could be in
agreement with the IUPAC definition for cycloaddition: “A reaction
in which two or more unsaturated molecules (or parts of the same
molecule) combine with the formation of a cyclic adduct in which
there is a net reduction of the bond multiplicity.” Nevertheless,
other authors do not agree that cycloaddition is completely correct
in this case (see reference [2b]). According to a seminal publication
by Huisgen, “Cycloaddition reactions do not involve the cleavage of
sigma bonds” (rule 3): f) R. Huisgen, Angew. Chem. 1968, 80, 329–
2
[
8] For intermolecular reactions, see: a) K. Wimalasena, H. B. Wick-
man, M. P. D. Mahindaratne, Eur. J. Org. Chem. 2001, 3811–3817;
b) C. Tanguy, P. Bertus, J. Szymoniak, O. V. Larionov, A. de Meijere,
Synlett 2006, 2339–2341; for intramolecular reactions, see: c) C.
Bubert, C. Cabrele, O. Reiser, Synlett 1997, 827–829; d) H. B. Lee,
M. J. Sung, S. C. Blackstock, J. K. Cha, J. Am. Chem. Soc. 2001, 123,
11322–11324; e) L. Larquetoux, N. Ouhamou, A. Chiaroni, Y. Six,
Eur. J. Org. Chem. 2005, 4654–4662; f) S. Mangelinckx, N. De
Kimpe, Synlett 2005, 1521–1526; for applications in total synthesis,
see: g) D. Zhang, H. Song, Y. Qin, Acc. Chem. Res. 2011, 44, 447–
457; for reviews on aminocyclopropanes, see: h) F. Gnad, O. Reiser,
Chem. Rev. 2003, 103, 1603–1624; i) F. Brackmann, A. de Meijere,
Chem. Rev. 2007, 107, 4493–4537.
3
37; Angew. Chem. Int. Ed. Engl. 1968, 7, 321–328. In view of this
[9] Modified Nucleosides: in Biochemistry, Biotechnology and Medicine,
(Ed: P. Herdewijn), WILEY-VCH, Weinheim, 2008.
controversy, we kept the term annulation throughout our publica-
tion, as it is accepted as correct by all scientists in the field. We let
the reader make his own choice if he prefers to use the word cyclo-
addition.
3] For examples with aldehydes, see: a) H. U. Reissig, Tetrahedron
Lett. 1981, 22, 2981–2984; b) H. U. Reissig, H. Holzinger, G. Gloms-
da, Tetrahedron 1989, 45, 3139–3150; c) S. Shimada, Y. Hashimoto,
A. Sudo, M. Hasegawa, K. Saigo, J. Org. Chem. 1992, 57, 7126–
[10] A 2-aminoTHF substructure search on the PubChem. Compound
database gave >164000 entries for compounds with tertiary C5
atoms (3299 active in bioassays), and 3 entries for those with quater-
nary C5 atoms. For the PubChem. Compound database, see: E.
Bolton, Y. Wang, P. A. Thiessen, S. H. Bryant, in Annual Reports in
Computational Chemistry, Vol. 4, American Chemical Society, Wash-
ington, 2008.
[
7
133; d) S. Shimada, Y. Hashimoto, T. Nagashima, M. Hasegawa, K.
[11] CCDC-858768 (3aa) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
Saigo, Tetrahedron 1993, 49, 1589–1604; e) S. Shimada, Y. Hashimo-
4848
www.chemeurj.org
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 4844 – 4849

ACHTUNGTRENNUNG[ 3+2] Annulation of Aminocyclopropanes
COMMUNICATION
The Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
12] All of the Lewis acids that gave some conversion provided 3aa as
[17] Enantioenriched 1a was obtained by preparative HPLC separation
on a chiral stationary phase (see the Supporting Information for de-
tails).
[
a single diastereoisomer, except FeCl
Supporting Information for details).
3
–Al
2
O
3
and Sc
A
H
U
G
R
N
U
G
3
(see the
[18] The [3+2] annulation of aminocyclopropanes with aldehydes was
not enantiospecific (see reference [7f]).
[
13] CCDC-858769 (epi-3aa) contains the supplementary crystallograph-
ic data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
[19] The most probable stereochemical course for the enantiospecific re-
action is inversion of the stereochemistry next to nitrogen, as ob-
served by Johnson et al. (see reference [2b]). However, this still
needs to be established experimentally and will be the topic of fur-
ther investigation in our laboratory.
[20] CCDC-861951 (3am) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
[
14] According to Johnson and co-workers (reference [3i]), intermediates
II and III would provide the 2,5-cis tetrahydrofuran 3aa and the 2,5-
trans tetrahydrofuran epi-3aa, respectively. Nevertheless, pathways
leading from II to epi-3aa and from III to 3aa could also be envis-
aged.
[
15] 2,5-Relative stereochemistry was assigned on the basis of X-ray dif-
fraction analysis performed on compound 3aa and extended to the
other compounds in the series (3bb–3am) on the basis of the regu-
larity of their NMR spectra.
[21] K. Sapeta, M. A. Kerr, J. Org. Chem. 2007, 72, 8597–8599.
Received: December 19, 2011
Revised: February 4, 2012
[
16] See the Supporting Information for details.
Published online: March 15, 2012
Chem. Eur. J. 2012, 18, 4844 – 4849
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4849