Scope and mechanism for Lewis acid-catalyzed cycloadditions of aldehydes and donor-acceptor cyclopropanes: Evidence for a stereospecific intimate ion pair pathway

Article abstract of DOI:10.1021/ja8015928

In this work, the one-step diastereoselective synthesis of cis-2,5-disubstituted tetrahydrofurans via Lewis acid catalyzed [3 + 2] cycloadditions of donor-acceptor (D-A) cyclopropanes and aldehydes is described. The scope and limitations with respect to both reaction partners are provided. A detailed examination of the mechanism has been performed, including stereochemical analysis and electronic profiling of both reactants. Experimental evidence supports an unusual stereospecific intimate ion pair mechanism wherein the aldehyde functions as a nucleophile and malonate acts as the nucleofuge. The reaction proceeds with inversion at the cyclopropane donor site and allows absolute stereochemical information to be transferred to the products with high fidelity. The mechanism facilitates the stereospecific synthesis of a range of optically active tetrahydrofuran derivatives from enantioenriched D-A cyclopropanes.

Full text of DOI:10.1021/ja8015928

Published on Web 06/11/2008
Scope and Mechanism for Lewis Acid-Catalyzed
Cycloadditions of Aldehydes and Donor-Acceptor
Cyclopropanes: Evidence for a Stereospecific Intimate Ion
Pair Pathway
Patrick D. Pohlhaus, Shanina D. Sanders, Andrew T. Parsons, Wei Li, and
Jeffrey S. Johnson*
Department of Chemistry, UniVersity of North Carolina at Chapel Hill,
Chapel Hill, North Carolina 27599-3290
Received March 3, 2008; E-mail: jsj@unc.edu
Abstract: In this work, the one-step diastereoselective synthesis of cis-2,5-disubstituted tetrahydrofurans
via Lewis acid catalyzed [3 + 2] cycloadditions of donor-acceptor (D-A) cyclopropanes and aldehydes is
described. The scope and limitations with respect to both reaction partners are provided. A detailed
examination of the mechanism has been performed, including stereochemical analysis and electronic profiling
of both reactants. Experimental evidence supports an unusual stereospecific intimate ion pair mechanism
wherein the aldehyde functions as a nucleophile and malonate acts as the nucleofuge. The reaction proceeds
with inversion at the cyclopropane donor site and allows absolute stereochemical information to be
transferred to the products with high fidelity. The mechanism facilitates the stereospecific synthesis of a
range of optically active tetrahydrofuran derivatives from enantioenriched D-A cyclopropanes.
Scheme 1. General Strategy for THF Synthesis
Introduction
Substituted tetrahydrofurans are important small molecules
due to their appearance in a variety of biologically important
compounds.1 Among the myriad methods for the preparation
of tetrahydrofurans, cycloadditions are particularly attractive
with regard to convergency and atom economy. To this end,
several research groups have achieved the synthesis of substi-
tuted tetrahydrofurans through the application of donor-acceptor
(D-A) cyclopropanes.2 These versatile three carbon building
blocks are useful in organic synthesis due to both their reactivity
and ease of preparation.3 Reissig has demonstrated the use of
siloxycyclopropanecarboxylates and TiCl4 in the synthesis of
γ-lactols and homoaldol products.4–6 The tautomeric γ-lactols
can be taken on to substituted tetrahydrofuran derivatives after
cleavage of the anomeric hydroxyl group.7 Oshima has syn-
thesized substituted tetrahydrofurans via the TiCl4/nBu4NI-
promoted reaction of cyclopropyl ketones and aldehydes.8 The
proposed mechanism invokes an aldol intermediate that either
cyclizes spontaneously or upon treatment with activated alumina.
This sequence does not allow for the preparation of tetrahy-
drofurans substituted at the 5-position. Related work by Sugita
has shown that methanochromanones react with aldehydes and
ketones under Lewis acid catalysis to give trans-fused tetrahy-
drofurobenzopyranone derivatives in good yields and good
diastereoselectivity.9,10 This paper describes the highly diaste-
reoselective, stereospecific synthesis of cis-2,5-disubstituted
tetrahydrofurans via the Lewis acid-catalyzed cycloaddition of
D-A cyclopropanes and aldehydes (Scheme 1).11,12 The scope
and mechanism are discussed in detail.
(1) (a) Wolfe, J. P.; Hay, M. B. Tetrahedron 2007, 63, 261–290. (b)
Harmange, J.-C.; Figade´re, B. Tetrahedron: Asymmetry 1993, 4, 1711–
1754.
Results and Discussion
(2) D-A cyclopropane reviews: (a) Reissig, H.-U.; Zimmer, R Chem.
ReV. 2003, 103, 1151–1196. (b) Yu, M.; Pagenkopf, B. L. Tetrahedron
2005, 61, 321–347. (c) Wong, H. N. C.; Hon, M. Y.; Tse, C. W.;
Yip, Y. C.; Tanko, J.; Hudlicky, T. Chem. ReV. 1989, 89, 165–198.
(d) Reissig, H. U. Top. Curr. Chem. 1988, 144, 73–135.
(3) (a) Xie, H.; Xu, L.; Li, H.; Wang, J.; Wang, W. J. Am. Chem. Soc.
2007, 129, 10886–10894. (b) Jiang, H.; Deng, X. M.; Sun, X. L.; Tang,
Y.; Dai, L. X. J. Org. Chem. 2005, 70, 10202–10205.
Reaction Design. D-A cyclopropanes are the key building
blocks in the cycloaddition strategy we pursued. A central goal
in our design plan was to develop reactions that could employ
a carbon-based donor as the activating group as opposed to the
more common heteroatom donor groups that must be cleaved
subsequent to cycloaddition.2 The omission of the anomeric
hydroxyl group would allow for the direct synthesis of the 2,5-
dialkyl substitution pattern commonly found in naturally oc-
(4) Reissig, H. -U. Tetrahedron Lett. 1981, 22, 2981–2984.
(5) Brueckner, C.; Reissig, H.-U. J. Org. Chem. 1988, 53, 2440–2450.
(6) Reissig, H.-U.; Holzinger, H.; Glomsda, G. Tetrahedron 1989, 45,
3139–3150.
(7) (a) Brueckner, C.; Holzinger, H.; Reissig, H.-U. J. Org. Chem. 1988,
53, 2450–2456. (b) Schmitt, A.; Reiꢀig, H.-U. Eur. J. Org. Chem.
2000, 3893–3901. (c) Larsen, C. H.; Ridgway, B. H.; Shaw, J. T.;
Woerpel, K. A. J. Am. Chem. Soc. 1999, 121, 12208–12209.
(8) Han, Z.; Uehira, S.; Tsuritani, T.; Shinokubo, H.; Oshima, K.
Tetrahedron 2001, 57, 987–995.
(9) Sugita, Y.; Kawai, K.; Yokoe, I. Heterocycles 2000, 53, 657–664.
(10) Sugita, Y.; Kawai, K.; Yokoe, I. Heterocycles 2001, 55, 135–144.
9
8642 J. AM. CHEM. SOC. 2008, 130, 8642–8650
10.1021/ja8015928 CCC: $40.75
2008 American Chemical Society

Lewis Acid-Catalyzed Cycloadditions of Aldehydes
A R T I C L E S
Table 1. Lewis Acids in [3 + 2] Cycloaddition of Benzaldehyde
and D-A Cyclopropane 6a
curring tetrahydrofurans 3 (eq 1). The donor group serves to
stabilize the partial positive charge on intermediate 2 that is
created as the C1-C2 bond of 1 is cleaved. At the outset it
was assumed (erroneously, vide infra) that the achiral zwitterion
2 would be a key intermediate. The donor group can also serve
as an additional functional handle on the cycloadducts for further
elaboration. Aryl, vinyl, and alkyl groups were targeted to serve
in this capacity. The acceptor group is composed of a malonyl
dimethyl ester group in most cases. The Lewis acid activates
the cyclopropane by association with the acceptor group.2 Led
by the seminal work of Kerr, similiarly activated cyclopropanes
have been used extensively in recent years.13a–q
entry
Lewis acid
% yielda
d.r.b
1
2
3
4
5
6
7
8
AgOTf
AgNTf2
AlCl3
<5
73
81
75
94
28
20
30
23
96
84
97
98
90
32
44
74
54
70
n.d.
>100:1
2:1
>100:1
>69:1
>80:1
n.d.
2:1
>71:1
2:1
>100:1
>100:1
>100:1
>40:1
>100:1
>100:1
>100:1
>63:1
>61:1
Ce(OTf)3
Cu(OTf)2
Dy(OTf)3
Er(OTf)3
Hf(OTf)4
Ho(OTf)3
Sc(OTf)3
SnCl2
Sn(OTf)2
Sn(OTf)2
SnCl4
Tb(OTf)3
Tm(OTf)3
Yb(OTf)3
ZnCl2
9
10
11
12
13
14
15
16
17
18
19
c
Zn(OTf)2
Cyclopropane Preparation and Cycloaddition Reaction
Conditions. The preparation of racemic 2-aryl-cyclopropane-
1,1-dicarboxylic acid dimethyl esters 6 was accomplished
through the direct cyclopropanation of benzylidene malonates
4 with dimethyloxosulfonium methylide derived from 5 (eq
2).14,15 Benzylidene malonates were synthesized from the
corresponding aldehydes and dimethyl malonate under Knoev-
enagel condensation conditions.14,16,17
a Determined by 1H NMR spectroscopy using a mesitylene standard.
b Determined by 1H NMR spectroscopy. n.d.
) not determined.
c Catalyst ) 5 mol %.
Several Lewis acids were found to promote the [3 + 2]
cycloaddition of D-A cyclopropane 6a and benzaldehyde, albeit
in a range of conversions and diastereoselectivities (Table 1).
Optimal reaction conditions for the cycloaddition of cyclopro-
pane 6a are 5 mol % of Sn(OTf)2 in dichloromethane and 3
equiv of aldehyde.
(11) (a) Pohlhaus, P. D.; Johnson, J. S. J. Org. Chem. 2005, 70, 1057–
1059. A related reaction was subsequently published: (b) Gupta, A.;
Yadav, V. K Tetrahedron Lett. 2006, 47, 8043–8047.
Substrate Scope and Limitations. Under the optimized
reaction conditions, a variety of electronically and sterically
diverse tetrahydrofurans were synthesized in excellent yields
and cis-diastereoselectivities as determined by NOESY analysis
(Table 2). Electron-poor p-nitrobenzaldehyde (Table 2, entry
4) required an increased catalyst loading and reaction time but
gave similar results under the optimized conditions. The
heterocyclic aldehydes furfural and 2-thiophenecarboxaldehyde
(Table 2, entries 11 and 12) were also suitable substrates;
however, 2-pyridinecarboxaldehyde was completely unreactive,
presumably due to coordination of Sn(OTf)2 with the Lewis
basic nitrogen. We previously reported difficulty employing
aliphatic aldehydes in this cycloaddition reaction.11 The use of
SnCl4 solved this problem and allowed for the synthesis of
2-alkyl-substituted tetrahydrofurans in high yields and diaste-
reoselectivities (Table 2, entries 13 and 14).
More synthetically useful cis-2,5-disubstituted tetrahydro-
furans can be prepared from cyclopropanes where the donor
group can be easily manipulated after the cycloaddition.
Employing an alkenyl group as the donor substituent supplies
an additional functional handle on the cycloadducts. The
2-butenyl cyclopropane 8a was synthesized via Corey-Chayk-
ovsky cyclopropanation analogous to equation 2. Reactions with
these substituted-vinyl species proceed with good yield and
excellent diastereoselectivities (Table 3, entries 1 and 2). 2-Vinyl
cyclopropanes 8b and 8c were prepared from the double
(12) Pohlhaus, P. D.; Johnson, J. S. J. Am. Chem. Soc. 2005, 127, 16014–
16015.
(13) (a) Ivanona, O. A.; Budynina, E. M.; Grishin, Y. K.; Trushkov, I. V.;
Verteletskii, P. V. Angew. Chem., Int. Ed. 2008, 47, 1107–1110. (b)
Perreault, C.; Goudreau, S.; Zimmer, L.; Charette, A. Org. Lett. 2008,
10, 689–692. (c) Bajtos, B.; Yu, M.; Zhao, H. D.; Pagenkopf, B. L.
J. Am. Chem. Soc. 2007, 129, 9631–9634. (d) Kang, Y. B.; Sun, X. L.;
Tang, Y. Angew. Chem., Int. Ed. 2007, 46, 3918–3921. (e) Korotkov,
V. S.; Larionov, O. V.; Hoftneister, A.; Magull, J.; de Meijere, A. J.
Org. Chem. 2007, 72, 7504–7510. (f) Karadeolian, A.; Kerr, M. A. J.
Org. Chem. 2007, 72, 10251–10253. (g) Korotkov, V. S.; Larionov,
O. V.; de Meijere, A. Synthesis 2006, 3542–3546. (h) Bowman, R. K.;
Johnson, J. S. Org. Lett. 2006, 8, 573–576. (i) Venkatesh, C.; Singh,
P. P.; Ila, H.; Junjappa, H. Eur. J. Org. Chem. 2006, 5378–5386. (j)
Morra, N. A.; Morales, C. L.; Bajtos, B.; Wang, X.; Jang, H.; Wang,
J.; Yu, M.; Pagenkopf, B. L. AdV. Synth. Catal. 2006, 348, 2385–
2390. (k) Kang, Y.-B.; Tang, Y.; Sun, X.-L. Org. Biomol. Chem. 2006,
4, 299–301. (l) Jiang, H.; Deng, X. M.; Sun, X. L.; Tang, Y.; Dai,
L. X. Angew. Chem., Int. Ed. 2005, 44, 7832–7835. (m) Young, I. S.;
Williams, J. L.; Kerr, M. A. Org. Lett. 2005, 7, 953–955. (n) Carson,
C. A.; Kerr, M. A. J. Org. Chem. 2005, 70, 8242–8244. (o) Young,
I. S.; Kerr, M. A. Org. Lett. 2004, 6, 139–141. (p) Young, I. S.; Kerr,
M. A. Angew. Chem., Int. Ed. 2003, 42, 3023–3026. (q) England,
D. B.; Woo, T. K.; Kerr, M. A. Can. J. Chem. 2002, 80, 992–998. (r)
England, D. B.; Kuss, T. D. O.; Keddy, R. G.; Kerr, M. A. J. Org.
Chem. 2001, 66, 4704–4709.
(14) Fraser, W.; Suckling, C. J.; Wood, H. C. S. J. Chem. Soc., Perkin
Trans. 1990, 1, 3137–3144.
(15) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353–
1364.
(16) Beyler, R. E.; Sarett, L. H. J. Am. Chem. Soc. 1952, 74, 1397–1401.
(17) Sepac, D.; Marinic, Z.; Portada, T.; Zinic, M.; Sunjic, V. Tetrahedron
2003, 59, 1159–1167.
9
J. AM. CHEM. SOC. VOL. 130, NO. 27, 2008 8643

A R T I C L E S
Pohlhaus et al.
Table 2. Aryl Cyclopropane Scope in the [3 + 2] Cycloaddition
with Aldehydes
Figure 1. Unsuccessful dipolarophiles.
Scheme 2. Site Selectivity in 2,3-Disubstituted Malonyl
Cyclopropanes and NOESY Analysis of the Derived Cyclohexane
entry
R′ (product)
t (h)
yield (%)a
d.r.
1
2
3
4
5
6
7
8
Ph (7a)
2.5
4.75
3.5
15
3.5
6
>98
96
98
89
96
92
95
93
90
87
82
98
>98
98
>100:1
>80:1
>86:1
>19:1
17:1
4-ClPh (7b)
4-MeOPh (7c)
4-NO2Phb (7d)
(E)-CH)CHPh (7e)
C≡CPh (7f)
4-MePh (7g)
4-BrPh (7h)
4-AcOPh (7i)
4-MeO2CPh (7j)
2-furyl (7k)
1.6:1
2.25
3
>100:1
>100:1
>100:1
>100:1
23:1
>83:1
>36:1
>56:1
9
3.75
5.5
3.25
3.25
1.75
2.5
10
11
12
13
14
2-thienyl (7l)
Et (7m)
iPr (7n)
a Isolated yield. b Sn(OTf)2 (10 mol %) used.
3-position could activate this center resulting in reduced
regioselectivity in the cycloaddition. To probe this issue, 2,3-
disubstituted malonyl cyclopropane 13 was prepared from the
Rh2(OAc)4 catalyzed decomposition of dimethyl diazomalonate
in the presence of 1,3-cyclohexadiene.19 Reaction with benzal-
dehyde occurs exclusively at the more activated allylic position
to form the bicyclic tetrahydrofuran 14 (Scheme 2). In this
experiment, complete allylic site selectivity demonstrates the
ability to distinguish between C2 and C3 of the cyclopropane
based on its electronic character. The trans ring junction in the
product was supported by NOESY analysis and characteristic
coupling constant values for the ring junction protons in the
derived cyclohexane 15. This reaction was also performed with
isobutyraldehyde in the presence of SnCl4. In this case, product
formation was observed but undesired products were present
in significant quantities.
In addition to probing the regioselectivity of the reaction, the
requirements of the donor group were explored using n-butyl
cyclopropane 16. The alkyl cyclopropane was synthesized
through the Rh2(OAc)4-catalyzed decomposition of dimethyl
diazomalonate in the presence of 1-hexene.20 Reaction with
isobutyraldehyde yielded 70% of the cycloadduct 17 in a 4.7:1
diastereomeric ratio. The catalyst loading for this reaction was
increased to 30 mol % and the temperature to 45 °C (eq 3).
The success of this reaction demonstrates not only that a simple
alkyl group can function as an electron-donating group in these
reactions, but that alkyl aldehydes can serve as viable dipo-
larophiles. While the diastereoselectivity is modest, this reaction
nonetheless indicates a process where postcycloaddition func-
tionalization of the donor group in target-directed synthesis
might not be necessary. ꢀ-Keto esters may be employed as the
activating group as demonstrated by the cycloaddition of
bicyclo[4.1.0]heptanone 18 to give hydroisobenzofuran 19 in
73% yield and good diastereocontrol (eq 4).
alkylation of the malonate ester with (E)-1,4-dibromo-but-2-
ene.18 Reaction of the vinyl cyclopropane 8b with benzaldehyde
and isobutyraldehyde produced the corresponding tetrahydro-
furans in yields of 94% and 96% with diastereoselectivities of
8.9:1 and 5.7:1 respectively. The reduced steric demand of the
vinyl cyclopropane 8b in comparison to 8a may explain the
decreased diastereoselectivity of these reactions. Efforts were
made to increase the diastereoselectivities of the unsubstituted
vinyl cyclopropanes as the cis and trans isomers were insepa-
rable by flash chromatography. A screen of Lewis acids,
solvents, dicarboxyester groups, and temperature led to an
increase in the diastereoselectivity for both of these cycloadducts
(Table 3, entries 3 and 4). Entry 3 was improved upon by
switching the acceptor group to dicarboxybenzyl esters leading
to an increase in the diastereomeric ratio (to 24:1). Entry 4 was
optimized by changing the solvent from dichloromethane to
toluene leading to an increased diastereostereomer ratio of 24:
1. The final two entries of Table 3 demonstrate the use of ketone
dipolarophiles. Acetone was used successfully in the cycload-
dition with vinylcyclopropanes 8b and 8c with both SnCl4 and
Sn(OTf)2 to produce the cycloadducts in excellent yields.
Aldehydes containing a heteroatom were also subjected to
the [3 + 2] cycloaddition with vinyl cyclopropane 8b. Aldehyde
11a (Figure 1) gave only trace amounts of product with SnCl4
and was not reactive with Sn(OTf)2 under normal reaction
conditions. Aldehyde 11b was also unreactive with Sn(OTf)2
under normal reaction conditions. Some product formation could
be seen with this dipolarophile in the presence of SnCl4 but
byproduct formation and other inconsistencies hindered opti-
mization of this reaction. Although acetone worked well in the
[3 + 2] cycloaddition with vinyl cyclopropane, acetophenone
(12) displayed variable results. This reaction was plagued by
incomplete conversions and byproduct formation. A major
byproduct in these reactions is possibly derived from chloride
addition to the cyclopropane C2 position.
The utility of this cycloaddition strategy hinges in part on
the ability to manipulate the tetrahydrofuran products. Upon
treatment with NaCN in wet DMSO, tetrahydrofuran 7a
underwent decarboxylation in a stereoselective fashion to afford
In this work, C3 of the cyclopropane is usually unsubstituted
and reactions occur exclusively at C2. Substitution at the
(18) Vardapetyan, A. A.; Khachatryan, D. S.; Panosyan, G. A.; Morlyan,
(19) Yang, M.; Webb Livant, T. R. J. Org. Chem. 2001, 66, 4945.
(20) Davies, H. M. L.; Panaro, S. A. Tetrahedron 2000, 56, 4871–4880.
N. M. Zh. Org. Khim. 1986, 22, 2266–2270.
9
8644 J. AM. CHEM. SOC. VOL. 130, NO. 27, 2008

Lewis Acid-Catalyzed Cycloadditions of Aldehydes
A R T I C L E S
Table 3. Vinyl Cyclopropane Scope in Lewis Acid Catalyzed Cycloadditions of D-A Cyclopropanes with Aldehydes and Ketones
a Isolated yield. b Sn(OTf)2 (10 mol %) was used. c Sn(OTf)2 (20 mol %) was used. d Sn(OTf)2 (5 mol %) was used. e SnCl4 (20 mol %) was used.
aldehydes the next step was development of an asymmetric
variant. Assuming participation of a ring-opened species such
as 2, it would have been necessary to employ ligand control to
effect absolute stereochemical induction. Sibi employed this
strategy in the asymmetric cycloaddition of nitrones with D-A
cyclopropanes;22 however, an initial control experiment with
(S)-6a revealed that chirality transfer from the cyclopropane
occurred with high fidelity in the cycloaddition. This fortuitous
discovery allowed the synthesis of a variety of optically active
tetrahydrofurans without the need for ligand control in the
the monoester 20 in good yield (eq 5).21 This facile process
should allow simple functionalization of the ring 3-position. The
vinyl tetrahydrofurans can be easily functionalized via ozo-
nolysis as demonstrated in a reaction revealing the aldehyde
21 in 93% yield (eq 6).
Reaction Stereochemistry. After successfully performing the
[3 + 2] cycloaddition with a range of cyclopropanes and
(22) Sibi, M. P.; Ma, Z.; Jasperse, C. P. J. Am. Chem. Soc. 2005, 127,
(21) Krapcho, A. P. Synthesis 1982, 805–822.
5764–5765.
9
J. AM. CHEM. SOC. VOL. 130, NO. 27, 2008 8645

A R T I C L E S
Pohlhaus et al.
Table 4. Aldehyde Scope in the Lewis Acid-Catalyzed
Stereospecific [3 + 2] Cycloaddition of Cyclopropane (S)-6a
Chart 1. Sn(II)-Catalyzed Cyclopropane Racemization as a
Function of Time
entry
R (product)
t (h)
yield (%)a
d.r.
e.r.
1
2
3
4
5
6
7
8
9
10
Ph (7a)
2.5
4.75
3.5
15
3.5
6
3.25
3.25
1.75
2.5
100
97
99
91
97
90
83
98
100
98
>100:1
>83:1
>84:1
>19:1
17:1
1.6:1
23:1
>83:1
>36:1
>56:1
98:2
98:2
99.5:0.5
67:33
99.5:0.5
94:6
99.5:0.5
99:1
98:2
4-ClPh (7b)
4-MeOPh (7c)
4-O2NPh (7d)b
(E)-CH)CHPh (7e)
C≡CPh (7f)c
2-furyl (7k)
2-thienyl (7l)
Et (7m)c
iPr (7n)d
98:2
a Isolated yields. b Sn(OTf)2 (20 mol %) was used. c Sn(OTf)2 (10
mol %) was used. d SnCl4 (5 mol %) was used.
Scheme 3. Resolution of Cyclopropane Diacid 22 with
(S)-R-Methylbenzylamine
Table 5. Aldehyde Scope in the Hf(IV)-Catalyzed Stereospecific [3
+ 2] Cycloaddition of Cyclopropane (S)-6a
cycloaddition (Table 4). The requisite enantiopure phenyl
cyclopropane (S)-6a was prepared according to the asymmetric
cyclopropanation strategy developed by Davies in 54% yield
and >99.5:0.5 e.r.23 N-Butyl cyclopropane (R)-16 (e.r. 97.5:
2.5) was prepared in an analogous fashion. We have also
developed a simple resolution of 6a13e using (S)-R-methylben-
zylamine. Two recrystallizations of the ammonium carboxylate
23 and esterification gives (S)-6a in >99.5:0.5 e.r. (Scheme 3).
Using these enantioenriched substrates, the absolute stereo-
chemical information from the cyclopropanes was regularly
transferred to the tetrahydrofuran products in high yields and
diastereoselectivities. Only extremely electron-poor aldehydes,
which require higher catalyst loadings and longer reaction times,
gave products of <96.5:3.5 e.r. To probe this observation the
reaction conditions were reproduced in the absence of p-
nitrobenzaldehyde. After quenching the reaction, complete
racemization of (S)-6a was observed. Next, the cycloaddition
reactions in entries 4 and 6 of Table 4 were reproduced but
quenched after only 45 and 30 min, respectively. In each case,
the tetrahydrofuran products were formed with an e.r. of 96.5:
3.5. With these results, it is apparent that there is noticeable
loss of stereochemical integrity of the cyclopropane throughout
the course of the reaction with these sluggish dipolarophiles.
This was confirmed in control experiments performed in the
absence of aldehyde (Chart 1).
mol
% cat.
yield
(%)a
entry
R
T (°C)
t (h)
d.r.b
e.r.c
1
2
3
4
5
6
Ph
Ph
Ph
4-ClPh
5
5
1
5
5
30
5
5
5
5
r.t.
-40
r.t.
0.05 99 >100:1
0.75 96 >100:1
96 >100:1
95 >100:1 99.5:0.5
3.75 91
90:10
99:1
98:2
6
0.5
-40
-40
-55 72
-40
-60
-40
-40
-40
-40
4-MeOPh
4-O2NPh
(E)-CH)CHPh
Ct CPh
2-furyl
>57:1 99.5:0.5
5:1 88.5:11.5
>11:1 98.5:1.5
>9:1 99.5:0.5
>30:1 98.5:1.5
54
97
87
72
7
2
9
1.5
1
8
8d
9
10
11
12
2-thienyl
Et
83 >100:1 98.5:1.5
99 >30:1 97.5:2.5
86 >100:1 98.5:1.5
5
5
iPr
5
a Isolated yields. b Determined by 1H NMR spectroscopy.
c Determined by chiral SFC analysis. d With 6.0 equiv of aldehyde.
cyclopropane decomposition and poor diastereoselectivity ham-
pered its utility. We therefore sought to alter the reaction
conditions to minimize decomposition while increasing the
diastereoselectivity of the reaction and the enantiopurity of the
product. When the standard reaction conditions were used with
benzaldehyde and Hf(OTf)4, the product was obtained in 99%
yield and 90:10 e.r. in under five minutes (Table 5, entry 1).
Cooling this reaction to -40 °C resulted in an increase of e.r.
to 99:1 with a comparable yield (entry 2) and when the reaction
was run with a catalyst loading of 1 mol % at room temperature
the product was obtained in 98% yield and 98:2 e.r. (entry 3).
Problematic aldehydes in the Sn(OTf)2 system were improved
upon in the Hf(OTf)4 system. The cycloaddition with
4-O2NPhCHO resulted in an increase in e.r. to 88.5:11.5 with a
drop in d.r. to 5:1 (entry 6), whereas cycloaddition with
3-phenylpropynal resulted in an increase in both e.r. and d.r. to
99.5:0.5 and 9:1, respectively (entry 8).
With the hope of developing a method to carry out cycload-
ditions with electron-poor aldehydes with high enantiospeci-
ficity, we investigated the use of other Lewis acids. From our
previous Lewis acid screen (Table 1), it was noted that Hf(OTf)4
is a highly active catalyst in this system, but significant
(23) Davies, H. M. L.; Bruzinski, P.; Hutcheson, D. K.; Kong, N.; Fall,
M. J. J. Am. Chem. Soc. 1996, 118, 6897–6907.
9
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Lewis Acid-Catalyzed Cycloadditions of Aldehydes
A R T I C L E S
Scheme 4. Barbituric Acid Derivative Synthesis for Absolute
Stereochemistry Determination by X-Ray Analysis
Chirality transfer also occurs in reactions of the vinyl and
alkyl D-A cyclopropanes (eq 7–9). Optically active vinyl
cyclopropanes (S)-8b and (S)-8c were prepared through resolu-
tion of the cyclopropane diacid with cinchonidine followed by
six recrystallizations.24 Subjecting the n-butyl cyclopropane (R)-
16 (e.r. 97.5:2.5) to the reaction conditions yielded the tetrahy-
drofuran with an e.r. of 96.5:3.5 (eq 9). Thus, racemization
occurs very slowly in this system compared to reaction with
the aldehyde even at elevated temperatures with a powerful
Lewis acid. A likely cause is the diminished capacity of the
alkyl group to stabilize the ring-opened zwitterion.
group of the tetrahydrofuran due to shielding ring currents. This
spectral characteristic allows facile assignment of the ester
groups.
Four reasonable mechanisms for the [3 + 2] cycloaddition
can be evaluated in the context of these experimental observa-
tions (Scheme 5). First, an unusual substitution process was
considered wherein the aldehyde acts as a nucleophile, causing
inversion of the stereochemistry at the activated C-2 carbon of
the cyclopropane (mechanism A).26–28 Inversion has been
observed for the methanolysis28 and aminolysis29 of activated
cyclopropanes at elevated temperatures. Cram has proposed
carbanion-carbonium ions as transient configurationally stable
intermediates in reactions with D-A cyclopropanes of this
type.30,31 Next, an SE2-process occurring by a “corner” attack
mechanism would proceed with inversion at the cyclopropane
1-position and afford the tetrahydrofuran (mechanism B);
however, this is the minor diastereomer observed from the
labeling experiment.32–35 The cyclopropane could also undergo
“edge” attack by the aldehyde (mechanism C). This SE2 process
would occur with retention of configuration at the 1-position.6
Placing the large group of the aldehyde away from the phenyl
group on the cyclopropane would lead to the incorrect absolute
stereochemistry. If a concerted mechanism is considered, the
reaction would need to occur via a symmetry allowed [π2s +
σ2a] pathway (mechanism D).36–38 There is only one coplanar
orientation of reactants that is consistent with the observed
relative and absolute stereochemistry and would not suffer from
Reaction Mechanism. A key piece of mechanistic evidence
was gained from the control experiment employing enantioen-
riched cyclopropanes. The products were obtained without any
significant loss in the stereochemical information from the
enantioenriched cyclopropane. Racemic products would be
expected if the reaction proceeded through a ring opened
zwitterion (2). The results suggested that this zwitterion was
not significant in this cycloaddition. Therefore, it was of interest
to elucidate the mechanism and the origin of chirality transfer.
Further investigations required knowledge of the absolute
stereochemistry of the reaction products. The cycloadduct 7b
was converted to its derived barbituric acid 24, and a single-
crystal X-ray diffraction analysis determined the absolute
stereochemistry as (2R, 5R) (Scheme 4). The X-ray analysis
also revealed that inversion occurs at the cyclopropyl stereo-
center (C2) during the course of the reaction. Inversion at the
cyclopropane donor site was also confirmed in the cycloaddition
results with bicyclo[4.1.0]heptanes 13 and 18.
An additional labeling study was conducted in which one of
the diastereotopic carboxymethyl groups of the cyclopropane
was selectively labeled. It was prepared by selective hydrolysis
of the ester group trans to the phenyl substituent of 6a.23
Subsequent reesterification with perdeuterated dimethyl sulfate
yielded the labeled cyclopropane 25.25 Reaction with benzal-
dehyde gave a mixture of products in which 94% of the label
in the major product 26 was found cis to the phenyl groups (eq
(26) Danishefsky, S. Acc. Chem. Res. 1979, 12, 66–72.
(27) Meyer, C.; Blanchard, N.; Deffosseux, M.; Cossy, J. Acc. Chem. Res.
2003, 36, 766–772.
(28) Cram, D. J.; Yankee, E. W. J. Am. Chem. Soc. 1970, 92, 6329–6331.
(29) Danishefsky, S.; Rovnyak, G. J. Chem. Soc., Chem. Commun. 1972,
821–822.
1
10). A significant upfield shift in the H NMR spectrum is
(30) Cram, D. J.; Ratajczak, A. J. Am. Chem. Soc. 1968, 90, 2198–2200.
(31) Cram, D. J.; Yankee, E. W. J. Am. Chem. Soc. 1970, 92, 6328–6329.
(32) Graziano, M. L.; Iesce, M. R. J. Chem. Res. (S) 1987, 362–363.
(33) Coxon, J. M.; Steel, P. J.; Whittington, B. I.; Battiste, M. A. J. Am.
Chem. Soc. 1988, 110, 2988–2990.
regularly observed for the methyl group cis to the C2 phenyl
(24) This resolution has also been achieved with brucine: Quinkert, G.;
Schwartz, U.; Stark, H.; Weber, W-D.; Adam, F.; Baier, H.; Frank,
G.; Du¨rner, G. Lieb. Ann. Chem. 1982, 1999–2040.
(34) Graziano, M. L.; Cimminiello, G. J. Chem. Res (S) 1989, 42–43.
(35) Graziano, M. L.; Iesce, M. R.; Cermola, F.; Cimminiello, G. J. Chem.
Res. (S) 1992, 4–5.
(25) Corey, E. J.; Gant, T. G. Tetrahedron Lett. 1994, 35, 5373–5376.
9
J. AM. CHEM. SOC. VOL. 130, NO. 27, 2008 8647

A R T I C L E S
Pohlhaus et al.
Scheme 5. Mechanistic Analysis of the [3 + 2] Lewis Acid-Catalyzed D-A Cyclopropane/Aldehyde Cycloaddition
Scheme 6
sluggish reactivity of electron-poor aldehydes, which have lower
LUMO energies and should therefore react faster if such a
mechanism were operative. It would also be predicted that Lewis
acid coordination to the malonate would lower the HOMO
(σC1-C2) and not provide rate acceleration. Computational studies
for this and related systems have identified viable stepwise
pathways.39,40
Simple variation of the donor substituents on the D-A
cyclopropane ring allows for the preparation of electronically
different tetrahydrofurans at the 5-position. Substituted tetrahy-
drofurans in entries 1-10 of Table 6 were prepared in high
yields from the corresponding substituted cyclopropanes of
varying electronic character. There was a significant drop in
the rate of the reaction as the donor substituents became more
electron withdrawing as in entries 3-5 of Table 6. This trend
is in line with the proposed mechanism since the electronics of
the cyclopropane govern the ease of formation of the ring-
opened species 28. In these highlighted cases, the electron-poor
C2 donor group destabilizes the polarized species 28. Higher
catalyst loadings as well as longer reaction times were needed
in these cases; however, under the optimized conditions these
heterocycles could be obtained in good yields and stereoselec-
tivities.
significant unfavorable steric interactions. Only mechanism A
and D predict a stereochemical outcome that matches the
experimental observation.
Further experimentation was used to distinguish mechanisms
A and D. Competition experiments were performed using
substituted benzaldehydes of varying electronic character versus
benzaldehyde (Scheme 6). When electron-rich aldehydes were
used the product ratio favors the species from the electron rich
aldehyde, product B; however, when electron poor aldehydes
are used the product ratio reverses and favors the tetrahydrofuran
A derived from benzaldehyde. In mechanism A (Scheme 5),
electron rich aldehydes should react faster if the key step is
nucleophilic attack of the oxygen lone pair on the activated
cyclopropane (mechanism A, Scheme 5), thus the competition
experiments’ ratios support this mode of action. This piece of
evidence disfavors a concerted mechanism (mechanism D,
Scheme 5). In the concerted reaction, the primary orbital
interaction would be between the HOMO of the cyclopropane
and the LUMO of the aldehyde. This is not congruent with the
Viewing the initial attack of the cyclopropane in terms of
the C1-C2 σ-bond stability allows further insight into the
mechanism. Reactions between the p-methoxyphenylcyclopro-
pane 30a (PMP-cyclopropane) and aldehydes of varying elec-
tronic character including p-nitrobenzaldehyde proceed with high
diastereoselectivities in less than 30 min with 5 mol % catalyst
(36) Wiering, P. G.; Verhoeven, J. W.; Steinberg, H. J. Am. Chem. Soc.
1981, 103, 7675–7676.
(37) Graziano, M. L.; Chiosi, S. J. Chem. Res. (S) 1989, 44–45.
(38) Graziano, M. L.; Iesce, M. R.; Cermola, F. J. Chem. Res. (S) 1996,
82–83.
(39) Wanapun, D.; Van Gorp, K. A.; Mosey, N. J.; Kerr, M. A.; Woo,
T. K. Can. J. Chem. 2005, 1752–1767.
(40) Zhang, J.; Shen, W.; Li, M. Eur. J. Org. Chem. 2007, 4855–4866.
9
8648 J. AM. CHEM. SOC. VOL. 130, NO. 27, 2008

Lewis Acid-Catalyzed Cycloadditions of Aldehydes
A R T I C L E S
Table 6. Substituted-Aryl Cyclopropane Scope in Lewis
Acid-Catalyzed [3 + 2] Cycloaddition of D-A Cyclopropanes and
Aldehydes
entry
R
R′
Time (h) % yielda (product)
d.r.
1
2
4-OMePh (30a)
4-MePh (30b)
4-BrPh (30c)
4-OAcPh (30d)
4-MeO2CPh (30e) Ph
2-thienyl (30f)
(E)-CH)CHPh
(30g)
Ph
Ph
Ph
Ph
0.1
1.25
25
24
24
85 (31a)
60 (31b)
61 (31c)
91 (31d)
83 (31e)
97 (31f)
94 (31g)
>63:1
>100:1
>100:1
>100:1
>100:1
20:1
3b
4c
5c
6
philicity of RCHO. The attack produces (E)-oxocarbenium ion
29. From the staggered conformation, a 120° rotation about the
C2-C3 σ-bond would place the zwitterion in an envelope
conformation 38. The substituents from the cyclopropane and
aldehyde occupy pseudoequatorial positions in this conforma-
tion.42 The enolate then quenches the oxocarbenium ion leading
to ring closure. It is apparently the case that little bond rotation
about the C1-C3 σ-bond occurs in oxocarbenium ion 29,
affording tetrahydrofuran 26 with the labeled carbomethoxy
group cis to the 2′- and 5′-substituents.43 This retention of
configuration is reasonable considering that scrambling of the
ester groups would require a 180° C1-C3 bond rotation to be
faster than the 120° C2-C3 bond rotation. Additionally, this
180° rotation would involve an eclipsing butane interaction
between C2 and one carboxyester group, while the 120° rotation
would not suffer similar torsional strain.
As demonstrated in the reactions with 2,3-disubstituted D-A
cyclopropanes, regioselectivity is well-controlled. All of the
cycloaddition reactions studied produce substituted tetrahydro-
furans as a single regioisomer in which the oxygen atom of the
aldehyde has become bonded to the tertiary carbon of the
cyclopropane and the carbonyl carbon atom has become bonded
to the quaternary carbon of the cyclopropane. This results from
nucleophilic attack by the aldehyde at the more electrophilic
site on the cyclopropane ring. Coordination of the Lewis acid
to the cyclopropane ester groups is expected to break the C1-C2
cyclopropane σo-bond in analogy to Cram’s thermal cleavage
reactions, providing a configurationally stable carbenium/
carbanion pair (28).28,31 The presence of an electron-releasing
group in the donor position stabilizes the positive charge, and
hence, the bond between the substituted carbon and the
quaternary carbon is preferentially broken.
Ph
Ph
0.75
1
7
2.4:1
8
9
10
4-OMePh (30a)
4-OMePh (30a)
4-OMePh (30a)
4-MeOPh
4-MeOPh
4-O2NPh
0.1
3.75
0.4
90 (31h)
90 (31h)
82 (31i)
>100:1
12:1
>83:1
a Isolated yield. b Sn(OTf)2 (10 mol %) was used. c Sn(OTf)2 (30 mol
%) was used.
(Table 6). By way of comparison, the reaction of p-nitroben-
zaldehyde with cyclopropane 6a requires 15 h and 30 mol %
catalyst loading. In contrast to the configurational stability of
25 (and thence 6a), a labeling study with the diastereomerically
pure PMP-cyclopropane 32 revealed complete scrambling of
the carboxyester groups in less than five minutes in the presence
catalytic quantities of Sn(OTf)2 (eq 11). The ability of the
p-methoxy group to stabilize any cationic charge at C2 facilitates
ring-opening of the cyclopropane. Reactions with this species
proceed swiftly regardless of the electronics of the aldehyde as
can be seen with p-nitrobenzaldehyde and probably point to a
carbenium ion electrophile that more closely resembles 2 than
28.
Conclusion
The PMP-cyclopropane 30a exhibited time-dependent dias-
tereoselectivity in the transformation to tetrahydrofurans. These
reactions proceed in high initial diastereoselectivities (Table 6,
entry 8), but epimerization occurs if the reaction is not quenched
promptly upon completion (Table 6, entry 9). A mechanism
was proposed that allows for epimerization at C5 of the
tetrahydrofuran through a postcycloaddition ring opening wherein
the cation is stabilized by the electron releasing donor group.
Lewis acid coordination to the ring oxygen would facilitate this
process (eq 12).41
The origin of the cis-diastereoselectivity in these cycloaddition
reactions can be analyzed in the context of the proposed
mechanism (Scheme 7). The more accessible trans lone pair
on the carbonyl oxygen most likely attacks the configurationally
stable carbenium-/carbanion 28 in the initial substitution reac-
tion. The rate of this capture is directly related to the nucleo-
In summary, a Lewis acid-catalyzed [3 + 2] cycloaddition
reaction of carbon-based D-A cyclopropanes and aldehydes
has been developed. This methodology achieves the facile
synthesis of cis-2,5-disubstituted tetrahydrofurans from readily
accessible starting materials. This synthesis is effective for both
alkyl and aryl aldehydes of varying electronics and typically
produces tetrahydrofurans in very high yields with excellent cis-
diastereoselectivities. Furthermore, both unsaturated and ali-
phatic substituents on the D-A cyclopropane provide the
necessary stabilization for successful reactivity, allowing access
to a diverse array of tetrahydrofuran derivatives. Mechanistic
studies have shown that this formal [3 + 2] cyclopropane/
aldehyde cycloaddition occurs via an unusual nucleophilic
(42) A transition structure with the oxygen on the flap of the envelope and
the C2′ and C5′ substituents in the equatorial positions would provide
the same product. See ref 11a.
(41) (a) Kim, H.; Wooten, C. M.; Hong, J. Org. Lett. 2007, 9, 3965–3968.
(b) Pelter, A.; Ward, R.; Collins, P.; Venkateswarlu, R.; Kay, T.
J. Chem. Soc., Perkin Trans. 1985, 1, 587–594.
(43) The numbering scheme changes from the cyclopropane starting
material going to the tetrahydrofuran product. The prime (′) denotes
an atom in the product.
9
J. AM. CHEM. SOC. VOL. 130, NO. 27, 2008 8649

A R T I C L E S
Pohlhaus et al.
Scheme 7. Origin of cis-2,5-Diastereoselectivity in [3 + 2] Cycloaddition Reactions
substitution mechanism in which the aldehyde acts as a
nucleophile toward a configurationally stable intimate ion pair.
Our original characterization of this process as an SN2 reaction12
accurately describes the stereochemical outcome, but the study
detailed herein reveals that the reaction carries all of the
hallmarks of one proceeding via an ionic electrophile: substitu-
tion at the more highly substituted carbon atom and faster
reaction rates with electron releasing groups on both the
nucleophile and electrophile.44 The stereospecificity of this
reaction mechanism mediates the efficient transfer of absolute
stereochemical information from aryl-, vinyl-, and alkyl-
substituted cyclopropanes to the products, allowing the facile
synthesis of optically active cis-2,5-disubstituted tetrahydro-
furans from enantioenriched cyclopropanes. Effective decar-
boxylation of a tetrahydrofuran derivative has demonstrated that
the products can be manipulated to allow for the synthesis of
more complex optically active heterocycles. Additional work
in our group has suggested the application of this process to
the facile synthesis of substituted tetrahydrofurans containing
an even greater degree of substitution and stereochemical
complexity is possible.
Acknowledgment. This work was supported by the NSF (CHE-
0239363 and CHE-0749691). S.D.S. acknowledges a National
Physical Science Consortium Fellowship. J.S.J. is an Alfred P. Sloan
Fellow and a Camille-Dreyfus Teacher Scholar. Additional support
from 3M, Eli Lilly, and Amgen is gratefully acknowledged. X-ray
crystallography was performed by Dr. Peter White.
(44) A reviewer suggested that our results may still be interpreted as an
SN2 mechanism. We believe that the high site selectivity in the
cycloaddition of compound 16 provides the best evidence against the
SN2 mechanism. Because the SN1/SN2 continuum contains reactions
proceeding via intimately associated ion pairs, the most complete
description consistent with the IUPAC nomenclature for such reactions
would be DN*ANint. For excellent reviews of substitution mechanisms,
see: (a) Guthrie, R. D.; Jencks, W. P. Acc. Chem. Res. 1989, 22, 343–
349. (b) Katritzky, A. R.; Brycki, B. E. Chem. Soc. ReV. 1990, 19,
83–105.
Supporting Information Available: Experimental procedures
and analytical data for all new compounds; structural and
stereochemical proofs for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
JA8015928
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8650 J. AM. CHEM. SOC. VOL. 130, NO. 27, 2008