Cyclopropane-Aldehyde annulations at quaternary donor sites: Stereoselective access to highly substituted tetrahydrofurans

Article abstract of DOI:10.1021/ol200395e

A diastereoselective synthesis of pentasubstituted tetrahydrofurans via a Lewis acid catalyzed (3p2)-annulation of quaternary donor site cyclopropanes and aldehydes is described. The reaction is catalyzed by Sn(OTf)_2, SnCl₄, or Hf(OT

Full text of DOI:10.1021/ol200395e

ORGANIC
LETTERS
2011
Vol. 13, No. 8
1996–1999
Cyclopropane-Aldehyde Annulations at
Quaternary Donor Sites: Stereoselective
Access to Highly Substituted
Tetrahydrofurans
Austin G. Smith, Michael C. Slade, and Jeffrey S. Johnson*
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill,
North Carolina 27599-3290, United States
jsj@unc.edu
Received February 11, 2011
ABSTRACT
A diastereoselective synthesis of pentasubstituted tetrahydrofurans via a Lewis acid catalyzed (3 þ 2)-annulation of quaternary donor site cyclopropanes
and aldehydes is described. The reaction is catalyzed by Sn(OTf)2, SnCl4, or Hf(OTf)4 in yields up to 95% and diastereomeric ratios as high as 99:1.
Donor-acceptor (D-A) cyclopropanes are versatile
building blocks for the construction of carbocycles and
heterocycles via (3þn)-annulation reactions.1 Their inher-
ent strain energy (27.5 kcal/mol) allows them to react as
1,3-dipolar synthons in the presence of a Lewis acid.2 We
have reported stereoselective (3 þ 2)-annulations of D-A
cyclopropanes of type 1 (R0 = alkyl) and electronically
diverse aldehydes 2 (X = O) that provide access to (2,
5-dialkyl) tetrahydrofurans with high cis-diastereoselectivity
(3, Figure 1).3 Enantioenriched 1 (R0 = Ph, er >99:1) gave
(R,R)-THF 3 with complete chirality transfer (R = Ph,
99:1 er). Carbon-oxygen bond formation occurred at the
donor-substituted carbon of 1, with the reaction proceeding
with inversion of configuration. The accumulated experimen-
tal data were consistent with an unusual substitution mecha-
nism in which 2 acts as a nucleophile toward a configura-
tionally stable intimate ion pair.3b Since reaction rates
correlated with the stability of the nascent carbenium ion,
we questioned whether cyclopropane-1,1-diesters with full
substitution at the donor site could also serve as effective
building blocks in (3 þ 2)-annulations with aldehydes. Where
2-substituted-cyclopropane-1,1-diesters have been extensively
studied in (3 þ n) annulations, analogous reactions with
quaternary donxor site cyclopropanes (4, R0, R00 ¼ H) have
not been explored to the same degree.4
Annulations with cyclopropanes of this type and aldehyde
dipolarophiles would yield (2,2,5-trialkyl) tetrahydrofurans
(5, Figure 1), structural motifs present in a number of biologi-
cally active natural products.5 Herein we report a diastereo-
selective synthesis of pentasubstituted tetrahydrofurans via a
Lewis acid catalyzed (3 þ 2)-annulation of quaternary donor
site cyclopropanes and aldehydes. Results collected from
(1) For selected examples, see: (a) Sugita, Y.; Kawai, K.; Yokoe, I.
Heterocycles 2000, 53, 657–664. (b) Lautens, M.; Han, W. J. Am. Chem.
Soc. 2002, 124, 6312–6316. (c) Young, I. S.; Kerr, M. A. Angew. Chem.,
Int. Ed. 2003, 42, 3023–3026. (d) Pohlhaus, P. D.; Johnson, J. S. J. Org.
Chem. 2005, 70, 1057–1059. (e) Carson, C. A.; Kerr, M. A. J. Org. Chem.
2005, 70, 8242–8244. (f) Korotkov, V. S.; Larionov, O. V.; Hofmeister, A.;
Magull, J.; de Meijere, A. J. Org. Chem. 2007, 72, 7504–7510. (g) Bajtos, B.;
Yu, M.; Zhao, H.; Pagenkopf, B. L. J. Am. Chem. Soc. 2007, 129, 9631–
9634. (h) Perreault, C.; Goudreau, S. R.; Zimmer, L. E.; Charette, A. B.
Org. Lett. 2008, 10, 689–692. (i) Parsons, A. T.; Smith, A. G.; Neel, A. N.;
Johnson, J. S. J. Am. Chem. Soc. 2010, 132, 9688–9692.
(2) For D-A cyclopropane reviews, see: (a) Reissig, H-U; Zimmer, R.
Chem. Rev. 2003, 103, 1151–1196. (b) Yu, M.; Pagenkopf, B. L. Tetra-
hedron 2005, 61, 321–347. (c) Carson, C. A.; Kerr, M. A. Chem. Soc. Rev.
2009, 38, 3051–3060. (d) Campbell, M. J.; Johnson, J. S.; Parsons, A. T.;
Pohlhaus, P. D.; Sanders, S. D. J. Org. Chem. 2010, 75, 6317.
(4) (a) Sibi, M. P.; Ma, Z.; Jasperse, C. P. J. Am. Chem. 2005, 127,
5764–5765. (b) Carson, C. A.; Kerr, M. A. Org. Lett. 2009, 11, 777–779.
(c) Xing, Z.; Pan, W.; Liu, C.; Ren, J.; Wang, Z. Angew. Chem. Int. Ed.
2010, 49, 3215–3218.
(5) Dutton, C. J.; Banks, B. J.; Cooper, C. B. Nat. Prod. Rep. 1995,
12, 165–181.
(3) (a) Pohlhaus, P. D.; Johnson, J. S. J. Am. Chem. Soc. 2005, 127,
16014–16015. (b) Pohlhaus, P. D.; Sanders, S. D.; Parsons, A. T.; Li, W.;
Johnson, J. S. J. Am. Chem. Soc. 2008, 130, 8642–8650. (c) Parsons,
A. T.; Johnson, J. S. J. Am. Chem. Soc. 2009, 131, 3122–3123.
r
10.1021/ol200395e
Published on Web 03/11/2011
2011 American Chemical Society

Table 1. Scope of Aldehyde Dipolarophilea
entry
R (product)
C6H5 (5a)
% yieldb
drc
1
2
91
95
94
93
91
82
91
87
83
82
97:3
96:4
97:3
99:1
95:5
99:1
95:5
92:8
96:4
96:4
4-MeOC6H4 (5b)
2-MeC6H4 (5c)
4-MeO2CC6H4 (5d)
4-ClC6H4 (5e)
4-CF3C6H4 (5f)
2-thienyl (5g)
(E)-(CHdCH)C6H5 (5h)
Et (5i)
3
4
5
6
7
Figure 1. Proposed annulation with quaternary donor site
cyclopropanes.
8
9
10
iPr (5j)
chirality transfer experiments with optically active quaternary
donor site cyclopropanes provide evidence for the same
stereospecific aldehyde nucleophilic attack mechanism as is
observed with type 1 D-A cyclopropanes.
a Reactions performed with 1.0 equiv of 4a, 3.0 equiv of 2, and 5 mol
% of Sn(OTf)2 in 1,2-DCE ([4a]0 = 0.30 M) in a Teflon seal-capped vial.
b Isolated yield after column chromatography, average of at least two
trials. c Determined by 1H NMR spectroscopy.
The successful application of Sn(OTf)2 in the (3 þ 2)-
annulation of type 1 D-A cyclopropanes and aldehydes
led us to employ this Lewis acid in our initial efforts.
Treatment of racemic dimethyl 2-methyl-2-phenylcyclopro-
pane-1,1-dicarboxylate 4a (available in one step via Rh-
carbenoid cyclopropanation of R-methylstyrene6) and ben-
zaldehyde with Sn(OTf)2 (5 mol %) in 1,2-dichloroethane at
23 °C provided tetrahydrofuran 5a in 91% yield and 97:3
diastereoselection; the illustrated diastereomer with the C2-
and C5-phenyl groups in a cis orientation was preferred
(entry 1, Table 1). We next investigated the reactions of
different aldehydes in (3 þ 2)-annulations with cyclopropane
4a. The reactions were tolerant of a range of electronically
diverse aromatic aldehydes, with yields from 82 to 95%
(entries 1-6, Table 1). Heteroaromatic (entry 7), R,β-un-
saturated (entry 8), aliphatic (entry 9), and branched alipha-
tic aldehydes (entry 10) also performed well under identical
reaction conditions. In addition to the high yields, we
observed high levels of cis-diastereoselection that were com-
petitive with the dr’s found in the (3 þ 2)-annulation of
aldehydes and type 1 D-A cyclopropanes, despite the steric
difference between H and Me (dr’s up to 99:1, entries 2-10).7
With the establishment of 4a as an effective substrate for
aldehyde annulation, we turned our attention to more steri-
cally demanding and functionally useful D-A cyclopro-
panes. Figure 2 summarizes the range of quaternary donor
site cyclopropanes examined with representative aldehydes.
Isopropenyl-alkyl (4b), aryl-allyl (4c), aryl-benzyl (4d), elec-
tron-withdrawing aryl-alkyl (4e), and electron-donating
aryl-alkyl (4f) cyclopropane 1,1-diesters were all competent
substrates for (3 þ 2)-annulation with aldehydes.
Annulations with 4b went with exceptionally high levels
of cis-diastereoselection, regardless of the aldehyde substitu-
ent (R). Slight modifications to the reaction conditions were
necessary for aliphatic aldehydes with 4b: 5 mol % Hf(OTf)4
at -50 °C in dichloromethane provided 5m, albeit in dimin-
ished yield. Reactions with phenyl-allyl cyclopropane 4c
proceeded in high yield and moderate dr with both benzal-
dehyde and 4-chlorobenzaldehyde (5n, 5o). Again, dimin-
ished yields were seen with propanal (5p, 32%, dr 90:10), but
more sterically hindered isobutyraldehyde provided tertiary
THF product in a promising yield (5q, 63%, dr 90:10).8 We
were pleased to observe useful diastereoselectivities in the
annulation even when R0 and R00 were similar in size.
Reactions with 4d proceeded in high yields (up to 87%)
and roughly 80:20 dr with each aldehyde (5r-5t). SnCl4 (10
mol %) in toluene provided the optimal result for the
reaction of an aliphatic aldehyde with 4d (5t, 78%, dr
81:19). Cyclopropane 4e was an excellent substrate for
annulation, despite the electron-withdrawing nature of the
para-cyano group (5u-5w, up to 90% yield, dr ∼95:5). These
results demonstrate the broad electronic tolerance of the
donor site on the quaternary cyclopropane. Electron-
donating 4-MeOC6H4-methyl cyclopropane 4f was a parti-
cularly fast reacting substrate in this study. Reaction with
benzaldehyde was complete within 20 min, providing tetra-
hydrofuran in 91% yield and 96:4 dr (5x). The product
diastereomer ratio eroded with extended reaction times
(dr 83:17 after 3.5 h, dr 1:1 after 24 h) due to product
equilibration.9
(8) Significant aldehyde decomposition was observed when isobutyr-
aldehyde was used in combination with slower-reacting cyclopropanes
(4d, 4e, and 4 g).
(9) For examples of Lewis acid catalyzed THF ring opening, see: (a)
Sanders, S. D.; Ruiz-Olalla, A.; Johnson, J. S. Chem. Commun. 2009,
5135–5137. (b) Aldous, D. J.; Dalencon, A. J.; Steel, P. G. J. Org. Chem.
2003, 68, 9159–9161.
(6) Georgakopoulou, G.; Kalogiros, C.; Hadjiarapoglou, L. P. Syn-
lett 2001, 12, 1843–1846.
(7) The reaction showed broad solvent and Lewis acid tolerance, but
the high reactivity observed with Sn(OTf)2 and 1,2-DCE led us to to use
this combination for most substrates.
Org. Lett., Vol. 13, No. 8, 2011
1997

Table 2. Pentasubstituted D-A Cyclopropanesa,b
entry
R
% yieldc
drd
1 (5aa)
2 (5ab)
3 (5ac)
C6H5
4-ClC6H4
Et
81
75
75
99:1
99:1
77:23e
a Reactions performed with 1.0 equiv of 4g, 3.0 equiv of 2, and 5 mol
% of Sn(OTf)2 in 1,2-DCE ([4g]0 = 0.30 M) in a Teflon seal-capped vial
unless otherwise noted. b Preparation of 4g is detailed in the Supporting
Information. c Isolated yield after column chromatography, average of
at least two trials. d Determined by 1H NMR spectroscopy. e Reaction
performed with 10 mol % SnCl4 in 1,2-DCE, diastereomers separable by
column chromatography.
with slight modifications.11 R-Methylstyrene was treated
with styryldiazoacetate and the Rh2(S-DOSP)4 catalyst at
-50 °C in pentanes. The monoester was taken directly to
the desired diester via ozonolysis with NaOH/MeOH,
affording (-)-4a in 76:24 er.12 (3 þ 2)-Annulation with
anisaldehyde and (-)-4a at 23 °C with 5 mol % of Sn-
(OTf)2 provided the desired tetrahydrofuran (þ)-5b in low
enantioenrichment (58:42 er). Racemization of the starting
cyclopropane was slowed by performing the reaction at
decreased temperatures with 5 mol % Hf(OTf)4. Reaction
with anisaldehyde at -78 °C in dichloromethane gave (þ)-
5b with improved enantioselectivity (66:34 er, Figure 3).
Figure 2. (3 þ 2)-Annulations of quaternary donor site cyclo-
propanes.a,b
A more highly substituted D-A cyclopropane was ob-
tained via intramolecular cyclopropanation of a trisubstituted
alkene.10 Geraniol-derived alkyl-alkyl lactone cyclopropane
4g emerged as an effective candidate for (3 þ 2)-annulation.
High yields and diastereoselectivities were observed with
aromatic aldehydes, favoring the endo product (5aa and
5ab, Table 2). Diminished diastereocontrol was observed with
propanal using 10 mol % SnCl4 in 1,2-DCE (5ac, 75%, dr
77:23); the diastereomers in 5ac were separable by silica gel
chromatography. This (3 þ 2)-annulation can thus be ex-
tended to cyclopropanes of higher substitution and moderate
donor ability (alkyl-alkyl).
Figure 3. Chirality transfer studies.
Electron poor (-)-4e was also selected for chirality
transfer studies. (-)-4e was accessed in 95:5 er using the
Davies protocol. Annulation with anisaldehyde under stan-
dard conditions (5 mol % Sn(OTf)2, 1,2-DCE, 23 °C) gave
tetrahydrofuran (þ)-6 in 93:7 er. These results implicate a
reaction mechanism analogous to that previously proposed
Enantioenriched 2,2-substituted-1,1-cyclopropane die-
sters were accessible using a route developed by Davies,
(10) Corey, E. J.; Myers, A. G. Tetrahedron Lett. 1984, 25, 3559–3562.
(11) Davies, H. M. L.; Bruzinski, P.; Hutcheson, D. K.; Fall, M. J. J.
Am. Chem. Soc. 1996, 118, 6897–6907.
(12) Marshall, J. A.; Garofalo, A. W. J. Org. Chem. 1993, 58, 3675–
3680.
1998
Org. Lett., Vol. 13, No. 8, 2011

differentiation. Aldehyde attack (giving 12) and 120° bond
rotation provide envelope 10 directly, where R and R00 are
pseudoequatorial. The need for lower temperatures to
promote any sort of chirality transfer in the reaction with
(-)-4a is consistent with an increasingly stabilized carbe-
nium ion at C3 and fast racemization at room temperature.
(-)-4e is sufficiently electron-withdrawing to disfavor com-
petitive racemization and, thus, reacts with a high transfer of
stereochemical information under the standard reaction
conditions.
Scheme 1. Mechanistic Rationale
In conclusion, we have developed an intermolecular
(3 þ 2)-annulation of quaternary donor site cyclopropanes
and aldehydes that provides access to highly substituted
tetrahydrofuran adducts. Aromatic and aliphatic alde-
hydes can participate, resulting in THF products in pro-
mising to high yields and moderate to excellent cis-
diastereoselectivity. The enhanced carbenium ion stability
at the donor site allows for a diverse array of nucleophi-
le-electrophile coupling partners. Experiments with en-
antionenriched cyclopropanes demonstrate that stereo-
chemical information can still be transferred from the
starting cyclopropane to the products, despite the heigh-
tened ability of the quaternary donor site cyclopropanes to
racemize when treated with a Lewis acid. This mechanistic
feature allows for access to optically active pentasubsti-
tuted tetrahydrofurans in one step from enantioenriched
cyclopropanes. Efforts in our laboratory to expand the
reactivity profile of quaternary donor site cyclopropanes
are currently underway.
for this reaction family (Scheme 1). Lewis acid coordination
to the diester facilitates intimate ion pair formation (7),
thereby enabling aldehyde nucleophilic attack that results in
inversion at the more substituted site. 120° bond rotation
about the C2-C3 bond (8), followed by diastereoselective
ring closure via an envelope transition state, in which the R
group on the aldehyde and the larger R0 group on the
cyclopropane are oriented pseudoequatorially (9), provides
the cis-THF adduct 5-(major). As R0 and R00 become similar
in size (cyclopropanes 4c and 4d), ring flip to envelope 10
potentially becomes competitive due to an increased steric
penalty in 9 (H and R00 both pseudoaxial). Ring closure at
this stage provides trans-THF 5-(minor). An alternative but
equally plausible explanation for 5-(minor) posits a 180°
reversal in aldehyde approach because of diminished steric
Acknowledgment. ThisworkwassupportedbytheNSF
(CHE-0749691) and Novartis.
Supporting Information Available. Experimental de-
tails and characterization data for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Org. Lett., Vol. 13, No. 8, 2011
1999