Syntheses of 2,5-disubstituted dihydrofurans from γ-substituted chiral allenamides

Article abstract of DOI:10.1021/jo0503411

Details of a synthesis of dihydrofurans using γ-substituted chiral allenamides are described here. Some transformations of these dihydrofurans are also examined including a highly stereoselective dihydroxylation and a rare account of a Lewis acid-mediated

Full text of DOI:10.1021/jo0503411

Syntheses of 2,5-Disubstituted Dihydrofurans from γ-Substituted
Chiral Allenamides
Craig R. Berry, Richard P. Hsung,* Jennifer E. Antoline, Matthew E. Petersen,
Rameshkumar Challeppan, and Jessica A. Nielson
Department of Chemistry, University of Minnesota, Minneapolis, Minnesota 55455
hsung@chem.umn.edu
Received February 22, 2005
Details of a synthesis of dihydrofurans using γ-substituted chiral allenamides are described here.
Some transformations of these dihydrofurans are also examined including a highly stereoselective
dihydroxylation and a rare account of a Lewis acid-mediated removal of an N-acyl substituent at
the anomeric carbon of a tetrahydrofuran ring system. These studies provide further support for
the synthetic utility of allenamides.
Introduction
mides that can be used in stereoselective intramolecular
[4 + 3] cycloaddition reactions.5 However, our past work
had only allowed for selective deprotonation at the
R-position of allenamide 1 followed by addition of elec-
trophiles such as MeI to produce R-substituted allena-
mide 2 (Scheme 1).8 With only the R-position being
blocked, subsequent deprotonation of 2 at the γ-position
was successful, but after a D2O quench only provided a
modest diastereomeric ratio (2:1) for 3 in 60% yield. A
more practical, efficient, and selective access to these
compounds was desired.
Allenamides have emerged as a useful functional group
in organic synthesis.1-9 In our own work,4-8 we encoun-
tered the need for accessing γ-substituted chiral allena-
(1) For a review on allenamides, see: Hsung, R. P.; Wei, L.-L.; Xiong,
H. Acc. Chem. Res. 2003, 36, 773.
(2) For reviews on allenes, see: (a) Saalfrank, R. W.; Lurz, C. J.
Heterosubstituierte Allene and Polyallene. In Methoden Der Organis-
chen Chemie (Houben-Weyl); Kropf, H., Schaumann, E., Eds.; Georg
Thieme Verlag: Stuttgart, 1993; pp 3093-3102. (b) Schuster, H. E.;
Coppola, G. M. Allenes in Organic Synthesis; John Wiley and Sons:
New York, 1984.
In 2002, Seebach9 reported a very elegant method to
synthesize γ-substituted allenamides (Scheme 1). Treat-
ment of TMS-protected N-propargyloxazolidinone 4 with
(3) For recent allenamide chemistry, see: (a) An˜orbe, L.; Poblador,
A.; Dom´ınguez, G.; Pe´rez-Castells, J. Tetrahedron Lett. 2004, 45, 4441.
(b) Achmatowicz, M.; Hegedus, L. S. J. Org. Chem. 2004, 69, 2229. (c)
Ranslow, P. D. B.; Hegedus, L. S.; de los Rios, C., J. Org. Chem. 2004,
69, 105. (d) Bacci, J. P.; Greenman, K. L.; Van Vranken, D. L. J. Org.
Chem. 2003, 68, 4955. (e) Armstrong, A.; Cooke, R. S.; Shanahan, S.
E. Org. Biomol. Chem. 2003, 1, 3142. (f) Kozawa, Y.; Mori, M.
Tetrahedron Lett. 2002, 43, 1499. (g) Nair, V.; Sethumadhavan, D.;
Nair, S. M.; Shanmugam, P.; Treesa, P. M.; Eigendorf, G. K. Synthesis
2002, 1655. (h) Kozawa, Y.; Mori, M. Tetrahedron Lett. 2001, 42, 4869.
(i) Kinderman, S. S.; van Maarseveen, J. H.; Schoemaker, H. E.;
Hiemstra, H.; Rutjes, F. P. T. Org. Lett. 2001, 3, 2045. (j) van Boxtel,
L. J.; Korbe, S.; Noltemeyer, M.; de Meijere, A. Eur. J. Org. Chem.
2001, 2283. (k) Grigg, R.; Ko¨ppen, I.; Rasparini, M.; Sridharan, V.
Chem. Commun. 2001, 964 and key references therein. (l) For other
papers during or before 2001, see ref 1.
(5) For our efforts in [4 + 3] cycloadditions using allenamides, see:
(a) Huang, J.; Hsung. R. P. J. Am. Chem. Soc. 2005, 125, 50. (b)
Rameshkumar, C.; Hsung, R. P. Angew Chem., Int. Ed. 2004, 43, 615.
(c) Xiong, H.; Huang, J.; Ghosh, S.; Hsung, R. P. J. Am. Chem. Soc.
2003, 125, 12694. (d) Xiong, H.; Hsung. R. P.; Berry, C. R.; Ramesh-
kumar, C. J. Am. Chem. Soc. 2001, 123, 7174. (e) Rameshkumar, C.;
Xiong, H.; Tracey, M. R.; Berry, C. R.; Yao, L. J.; Hsung, R. P. J. Org.
Chem. 2002, 67, 1339.
(6) For radical cyclization using allenamides, see: Shen, L.; Hsung,
R. P. Org. Lett. 2005, 7, 775.
(7) For Diels-Alder cycloadditions using allenamides, see: (a) Berry,
C. R.; Hsung, R. P. Tetrahedron 2004, 60, 7629. (b) Rameshkumar,
C.; Hsung, R. P. Synlett 2003, 1241. (c) Berry, C. R.; Rameshkumar,
C.; Tracey, M. R.; Wei, L.-L.; Hsung, R. P. Synlett 2003, 791. (d) Wei,
L.-L.; Hsung, R. P.; Xiong, H.; Mulder, J. A.; Nkansah, N. T. Org. Lett.
1999, 1, 2145. (e) Wei, L.-L.; Xiong, H.; Douglas, C. J.; Hsung, R. P.
Tetrahedron Lett. 1999, 40, 6903.
(4) For syntheses of allenamides, see: (a) Xiong, H.; Tracey, M. R.;
Grebe, T. P.; Mulder, J. A.; Hsung, R. P.; Wipf, P.; Smotryski, J. Org.
Synth. 2004, 81, 147. (b) Tracey, M. R.; Grebe, T. P.; Brennessel, W.
W.; Hsung, R. P. Acta Crystallogr. 2004, C60, o830. (c) Wei, L.-L.;
Mulder, J. A.; Xiong, H.; Zificsak, C. A.; Douglas, C. J.; Hsung, R. P.
Tetrahedron 2001, 57, 459.
10.1021/jo0503411 CCC: $30.25 © 2005 American Chemical Society
Published on Web 04/14/2005
4038
J. Org. Chem. 2005, 70, 4038-4042

Syntheses of 2,5-Disubstituted Dihydrofurans
SCHEME 1
prepared in our work or those reported in Seebach’s
paper,9 is oxazolidinone based. When we prepared γ-sub-
stituted allenamides containing an imidazolidinone based
auxiliary, such as the Close auxiliary,11 we encountered
facile dihydrofuran formation under both basic and acidic
conditions. Dihydrofurans have been shown to be versa-
tile intermediates in methodological studies and key
components of many natural products.12,13 We report here
syntheses of 2,5-disubstituted dihydrofurans via a ste-
reodivergent intramolecular cyclizations of γ-substituted
chiral allenamides.
Results and Discussion
Our initial encounter in the dihydrofuran formation
was with allenyl alcohol 14 that was prepared in com-
parable yields and diastereoselectivity from TMS-pro-
tected N-propargylimidazolidinone 13 utilizing conditions
described by Seebach.9 However, we were unable to
achieve a successful [4 + 3] cycloaddition using 14
because we never got beyond the desilylation step. Upon
exposure to TBAF to remove the TMS group, dihydro-
furan 16 was obtained in 38% yield as a mixture of two
diastereomers, 2,5-syn and 2,5-anti, with a ratio of 1:1
(Scheme 3). We then proceeded to synthesize a series of
allenyl alcohol 17a-j employing N-propargylimidazoli-
dinone derivative 13 (Table 1).
SCHEME 2
The overall yields of allenyl alcohols 17a-j were less
as compared with Seebach’s report, but diastereoselec-
tivities were all comparable (g95:5). Allenyl alcohols
17a-h (entries 1-8) derived from aromatic aldehydes
appeared to be less prone to decomposition than their
nonaromatic counterparts 17i and 17j (entries 9 and 10)
during purification using silica gel column chromatog-
raphy. Notably, allenyl alcohol 17j (entry 10) was found
to partially cyclize to its respective dihydrofuran during
the purification. In addition, it is noteworthy that a TBS
protected N-propargylimidazolidinone (entry 2) gave the
expected allenyl alcohol (17b) in comparable yields and
diastereoselectivity.
n-BuLi and TiCl(i-PrO)3 followed by the addition of a
range of different aldehydes led to the isolation of allenyl
alcohols 6 with excellent diastereoselectivities (g95:5)
and good yields. The proposed mechanistic model (see 5)
involves coordination by the Ti metal to form a six-
membered chairlike transition state where the aldehyde
adds at the π-facial away from the i-Pr group on the
auxiliary.
The initial cyclization experiment was repeated, and
allenyl alcohol 17a was subjected to 1.2 equiv of TBAF
Utilizing Seebach’s protocol,9 N-propargyloxazolidinone
7 was used to give allenyl alcohol 8 in slightly lower
yields (40-50%) but the same high degree of stereochem-
ical integrity (g95:5) (Scheme 2).5b While this γ-substi-
tuted chiral allenamide 8 itself did not undergo the
desired intramolecular [4 + 3] cycloaddition, allenamide
9, after desilylation using TBAF followed by protection
of the hydroxyl group, did undergo a highly stereoselec-
tive [4 + 3] cycloaddition involving a rare example of a
nitrogen-stabilized oxyallyl cation to form cycloadduct 12
in 61% yield and a 9:1 ratio of diastereomers favoring
the one shown.5b However, this was where we became
intrigued because it is well documented that 2,3-allenyl
alcohols such as 10 can readily undergo cyclization to
form dihydrofurans 1110 under acidic or basic conditions.
Since neither 8 nor 9, two more reactive allenyl alcohols,
cyclized under TBAF conditions, we further investigated
this unusual stability.
(10) (a) For a review on cyclizations of allenyl alcohols, see: (a)
Olseon, L.; Claesson, A. Synthesis 1979, 743. For some examples, see:
(b) Takano, S.; Iwabuchi, Y.; Ogasawara, K. J. Chem. Soc., Chem.
Commun. 1989, 1371. (c) Marshall, J. A.; Pinney, K. G. J. Org. Chem.
1993, 58, 7180. (c) Marshall, J. A.; Wang, X.-J. J. Org. Chem. 1991,
56, 4913. (d) Pravia, K.; White, R.; Fodda, R. Maynard, D. F. J. Org.
Chem. 1996, 61, 6031. (e) Ma, S.; Li, L. Org. Lett. 2000, 2, 941 and
references therein
(11) Close, W. J. J. Org. Chem. 1950, 15, 1131.
(12) For some recent examples of syntheses of substituted dihydro-
furan derivatives, see: (a) Antonioletti, R.; Malancona, S.; Bovicelli,
P. Tetrahedron 2002, 58, 8825. (b) Jiang, Y.; Ma, D. Tetrahedron:
Asymmetry 2002, 13, 1033. (c) Ma, S.; Gao, W. Synlett 2002, 65 and
references therein. (d) Hagiwara, H.; Sato, K.; Nishino, D.; Hoshi, T.;
Suzuki, T.; Ando, M. J. Chem. Soc., Perkin Trans. 1 2001, 2946. (e)
Wang, Y. L.; Zhu, S. Z. Tetrahedron 2001, 57, 3383. (f) Carrido, J. L.;
Alonso, I.; Carretero, J. C. J. Org. Chem. 1998, 63, 9406. (g) Melikyan,
G. G.; Vostrowsky, O.; Bauer, W.; Bestmann, H. J.; Khan, M.; Nicholas,
K. M. J. Org. Chem. 1994, 59, 222.
(13) (a) Fraga, B. M. Nat. Prod. Rep. 1992, 9, 217. (b) Merrit, A. T.;
Ley, S. V. Nat. Prod. Rep. 1992, 9, 243. (c) Lipshutz, B. H. Chem. Rev.
1986, 86, 795. (d) Dean, F. M.; Sargent, M. V. In Comprehensive
Heterocyclic Chemistry; Bird, C. W., Cheeseman, G. W. H., Eds.;
Pergamon: New York, 1984: Vol. 4, Part 3, p 531. (e) Vernin, G. The
Chemistry of Heterocyclic Flavoring and Aroma Compounds; Ellis
Horwood: Chichester, 1982. (f) Dean, F. M. In Advances in Heterocyclic
Chemistry; Katritzky, A. R., Ed.; Academic: New York, 1982; Vol. 30,
p 167. (g) Nakanishi, K. Natural Products Chemistry; Kodansha Ltd.,
Academic: New York, 1974.
It turns out that this stability is auxiliary dependent.
The chiral auxiliary in γ-substituted allenamides, either
(8) Xiong, H.; Hsung, R. P.; Wei, L.-L.; Berry, C. R.; Mulder, J. A.;
Stockwell, B. Organic Lett. 2000, 2, 2869.
(9) Gaul, C.; Seebach, D. Helv. Chim. Acta 2002, 85, 963.
J. Org. Chem, Vol. 70, No. 10, 2005 4039

Berry et al.
SCHEME 3
SCHEME 4
TABLE 1
TABLE 2
entry
acid
allenamide product yield (%)a syn/anti ratiob
1
2
3
4
5
PNMSAc
CSA
p-TsOH
silica gel
PPTS
17a
17a
17a
17a
17a
19
19
19
19
19
nd
trace
nd
trace
82
ndd
nd
nd
nd
1:1
6
7
8
9
CSA
17f
17f
17f
17f
17f
20
20
20
20
20
trace
nd
nd
nd
nd
nd
1:1
p-TsOH
HNTf2
silica gel
nd
trace
80
10 PPTS
a Isolated yields. b Determined by 1NMR. c PNBSA ) p-ni-
trobenzenesulfonic acid. d nd: not determined.
transformation with the trimethylsilyl group still intact
at C-3. It is noteworthy that the vinylsilane is in itself a
viable functional group for further synthetic transforma-
tions.14
a Isolated yields, and ratios are >95:5 as determined by 1H
NMR. b TBS substituted N-propargylallenamide was used instead
of TMS.
We then examined cyclizations of remaining allenyl
alcohols 17a-j using either 1.2 equiv of TBAF or catalytic
PPTS and compared these results in Table 3. In general,
method A (TBAF) provided lower yields, while method
B (0.1 equiv PPTS) provided the desired products 21-
30 in improved yields [except those with alkyl substitu-
ents (entries 8-10)], although syn to anti diastereomeric
ratios mostly remained low. In contrast, the respective
allenyl alcohols, prepared from N-propargyloxazolidinone
7, led to no observable cyclization using either TBAF or
PPTS.
(Scheme 4). Dihydrofurans 18-syn and 18-anti, as indi-
1
cated by H NMR analysis, were isolated and showed a
1:1 ratio being diastereomeric at C-5. The X-ray crystal
structure (see Supporting Information for an ORTEP
drawing) of 18-anti does confirm that the chiral auxiliary
at C-5 and the naphthalene ring at C-2 are trans. Acidic
conditions for this cyclization were then examined using
allenyl alcohols 17a and 17f (Table 2). After screening a
variety of acids that either gave decomposition or a trace
amount of product, addition of a catalytic amount of
pyridinium para-toluenesulfonate (PPTS) (0.1 equiv) to
17a or 17f gave a 1:1 mixture of 19-syn/anti and 20-syn/
anti, respectively, in excellent yields. The yield for
dihydrofuran 19 is vastly improved from the TBAF
conditions that led to 18 (Scheme 4). This protocol
provides practical synthetic access to both 2,5-syn- and
2,5-anti-dihydrofurans. In addition, PPTS effected the
(14) For recent examples, see: (a) Taguchi, H.; Tsubouchi, A.;
Takeda, T. Tetrahedron Lett. 2003, 44, 5205. (b) Zhao, H.; Ming-Zhong,
C. Synth. Commun. 2003, 33, 1643. (c) Taguchi, H.; Ghoroku, K.;
Makoto, T.; Tsubouchi, A.; Takeda, T. J. Org. Chem. 2002, 67, 8450.
(d) Taguchi, H.; Miyashita, H.; Tsubouchi, A.; Takeda, T. Chem.
Commun. 2002, 19, 2218. (e) Taguchi, H.; Ghoroku, K.; Tadaki, M.;
Tsubouchi, A.; Takeda, T. Org. Lett. 2001, 3, 3811.
4040 J. Org. Chem., Vol. 70, No. 10, 2005

Syntheses of 2,5-Disubstituted Dihydrofurans
TABLE 3
SCHEME 6
a Isolated yields. b Determined by 1H NMR. c Method A: 1.2
equiv of TBAF, THF, rt, 2 h. Method B: 0.1 equiv of PPTS CH2Cl2,
rt, 2 h.
SCHEME 5
We next tested our allylation protocol to remove the
anomeric imidazolidinone substituent and elected to
employ a simpler tetrahydrofuran ring system.3c Stereo-
selective removal of an N-acyl substituent at the ano-
meric carbon was unprecedented15-17 until our recent
studies of a Lewis acid promoted allylation of related
pyranyl7b,c and piperidinyl7a heterocyclic systems. To the
best of our knowledge, stereoselective removal of an
N-acyl substituent at the anomeric carbon of a tetra-
hydrofuran ring system is not known.20
Toward this goal, simple hydrogenation of compound
18-syn with Pd/C led to tetrahydrofuran 33 in excellent
yield (Scheme 6). Allylation of 33 took place using 4.0
18,19
equiv of allyltrimethylsilane and 1.5 equiv of SnBr4
and gave the allylation product 34 in 78% yield as an
inseparable 1:1 isomeric mixture of 2,5-syn and 2,5-anti
isomers. Similarly, 18-anti was subjected to identical
allylation conditions after the hydrogenation and gave
the same allylation product 34 in 84% yield (from 35)
also in 1:1 ratio.
This result is significant because it represents the first
example of removal of an anomeric N-acyl substituent
in a tetrahydrofuran ring system in high yields, despite
the fact that it was not selective.20 Attempts using other
Lewis Acids, such as SnCl4, afforded similar results,
while BF3‚OEt2 resulted in decomposition of 18-syn.
Mechanistically, it has been suggested previously that
this reaction likely proceeds through an oxocarbenium
Because a significant amount of both 18-syn and 18-
anti could be attained, it allowed for the demonstration
of the synthetic utility of both of these 2,5-disubstituted
dihydrofurans. To this end, dihydroxylation of the en-
docyclic olefin in 18-syn was carried out using 1.1 equiv
of OsO4 in the presence of TMEDA and provided diol 31
as a single diastereomer in 58% yield (Scheme 5).
Employing identical conditions, 18-anti was dihydroxy-
lated to produce diol 32 also as one diastereomer (Scheme
5).
NOE experiments confirmed that the addition took
place from the more sterically accessible bottom face in
both cases (see A and B). These two dihydroxylation
reactions, especially the latter, support that the chiral
auxiliary, and not the large aromatic substituent, is
dictating the approach of osmium in these systems. It is
also noteworthy that dihydrofurans 18-syn and 18-anti
led to different, but complimentary, stereochemical out-
come depending upon if it is 2,5-syn or 2,5-anti in the
relative diastereomeric configuration.
(15) (a) Postema, M. H. D. Tetrahedron 1992, 48, 8545. (b) Levy, D.
E.; Tang, C. The Chemistry of C-Glycosides, 1st ed.; Pergamon Press:
New York, 1995; Vol. 13.
(16) Parker, K. A. Pure Appl. Chem. 1994, 66, 2135.
(17) For an example, see: Peto´, C.; Batta, G.; Gyo¨rgydea´k, Z.;
Sztaricskai, F. J. Carbohydr. Chem. 1996, 15, 465.
(18) Smith, D. M.; Woerpel, K. A. Org. Lett. 2004, 6, 2063.
(19) (a) Larsen, C. H.; Ridgeway, B. H.; Shaw, J. T.; Woerpel, K. A.
J. Am. Chem. Soc. 1999, 121, 12208. (b) Romero, J. A. C.; Tabacco, S.
A.; Woerpel, K. A. J. Am. Chem. Soc. 2000, 122, 168.
(20) For reviews on tetrahydrofuran synthesis, see: (a) Boivin, T.
L. B. Tetrahedron 1987, 43, 3309. (b) Harmange, J.-C.; Figadere, B.
Tetrahedron: Asymmetry 1993, 4, 1711 (c) Koert, U. Synthesis 1995,
115.
J. Org. Chem, Vol. 70, No. 10, 2005 4041

Berry et al.
SCHEME 7
SCHEME 8
Last, the difference between oxazolidinone-substituted
allenamides used in our previous work (and in Seebach’s
work) and these imidazolidinone-substituted allenamides
in the current work deserves some comments. This
contrast originates from the electronegativity difference
between the nitrogen and oxygen atoms. In oxazolidi-
none-substituted allenamides (see 40 in Scheme 8), the
oxygen being more electronegative allows the allenamide
nitrogen to delocalize its lone pair into the carbonyl group
in a greater extent than that in 39. This leads to a
diminished reactivity in 40, and thus, the dihydrofuran
formation occurred with imidazolidinone-substituted al-
lenamides 39 and not 40. It is noteworthy that a rather
small electronic perturbation actually plays a significant
role in dictating the overall reactivities and, thus, stabili-
ties of different allenamides.
ion intermediate where the incoming allyltrimethyl-
silane, and in this case, the nucleophilic attack occurred
indiscriminately from either face of the same oxocarbe-
nium intermediate C for both 18-syn and 18-anti.
Mechanistically, the dihydrofuran formation under
acidic conditions should proceed through vinyl iminium
ion 36 after an initial protonation of allenyl alcohols by
PPTS (Scheme 7). Cyclization would then proceed through
a 5-exo-trig mode leading to both 2,5-syn and 2,5-anti
dihydrofurans through addition at either the Re or the
Si face. It is surprising that there are no facial discrimi-
nations at all here exerted either by Close’s auxiliary or
the allylic stereocenter.
Conclusions
We have provided here details of syntheses of 2,5-
disubstituted dihydrofurans using γ-substituted allena-
mides. We have demonstrated the first example of
removal of an N-acyl substituent at the anomeric carbon
of a tetrahydrofuran ring system. Stereoselective dihy-
droxylations of these dihydrofurans are also examined
to illustrate their viability as useful organic building
blocks.
The exact pathway for the dihydrofuran formation
under the TBAF addition is not clear except perhaps that
a facile desilylation occurs to give a neutral allenamide
intermediate 37. Thus, the ensuing cyclization should be
slower, for it is likely activated only by the presence of
H2O in TBAF and perhaps in part assisted by TBAF or
hydroxide anion serving as a base (Scheme 7). A more
retarded cyclization using TBAF in part justifies a lower
yielding process than that obtained from employing PPTS
conditions.
Acknowledgment. We thank the NSF (CHE-
0094005) and NIH-NIGMS (GM066055) for support. We
also thank Mr. William W. Brennessel for solving the
X-ray structure.
Supporting Information Available: Experimental pro-
1
cedures, characterizations, and H NMR spectra for all new
compounds as well as X-ray structural data. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO0503411
4042 J. Org. Chem., Vol. 70, No. 10, 2005