Asymmetric Synthesis of 2,3-Dihydrofurans and of Unsaturated Bicyclic Tetrahydrofurans through α-Elimination and Migratory Cyclization of Silyloxy Alkenyl Aminosulfoxonium Salts. Generation and Intramolecular O, Si-Bond Insertion of Chiral Disubstituted β-Silyloxy AlkyHdene Carbenes

Article abstract of DOI:10.1021/ja030501v

Treatment of the bis(allylsulfoximine)titanium complexes derived from the β-methyl-substituted acyclic allylic sulfoximines 13a and 13b with aldehydes gave with high selectivities the corresponding sulfoximine-substituted homoallylic alcohols which were isolated as the silyl ethers 15a-h. Methylation of sulfoximines 15a-h afforded the aminosulfoxonium salts 5a-h which upon treatment with LiN(H)tBu gave in high yields the enantio- and diastereomerically pure silyl-substituted 2,3-dihydrofurans 4a-h. Treatment of the titanium complexes derived from the cyclic allylic sulfoximines 17a, 17b, and ent-17c with p-MeOC₆H₄-CHO delivered with high selectivities the corresponding sulfoximine-substituted cyclic homoallylic alcohols which were isolated as the silyl ethers 18a, 18b, and ent-18c, respectively. Methylation of sulfoximines 18a, 18b, and ent-18c furnished the aminosulfoxonium salts 8a, 8b, and ent-8c, respectively, whose treatment with LiN(H)t-Bu gave the enantio- and diastereomerically pure fused bicyclic 2,3-dihydrofurans 6a, 6b, and ent-6c, respectively, in good yields. It is proposed that the 1-alkenyl aminosulfoxonium salts 5a-h, 8a, 8b, and ent-8c react with the base under α-elimination and formation of the acyclic and cyclic β-silyloxy alkylidene carbenes 2a-h, 7a, 7b, and ent-7c, respectively, which then undergo a 1,5-O,Si-bond insertion and 1,2-silyl migration. The cyclic aminosulfoxonium salts 8a, 8b, and ent-8c upon treatment with 1,8-diazabicyclo[5.4.0]-7-undecene did not undergo an α-elimination but suffered a novel migratory cyclization with formation of the enantio- and diastereomerically pure bicyclic tetrahydrofurans 9a, 9b, and ent-9c, respectively. It is proposed that the 1-alkenyl sulfoxonium salts 8a, 8b, and ent-8c are isomerized to the allylic aminosulfoxonium salts 10a, 10b, and ent-10c, respectively, which then suffer an intramolecular substitution of the (dimethylamino)sulfoxonium group by the silyloxy group followed by a desilylation. The syntheses of the 2,3-dihydrofurans 4a-h, 6a, and 6b and of the tetrahydrofurans 9a and 9b are accompanied by the formation of sulfinamide 16 of ≥98% ee, which can be converted via sulfoxide 28 of ≥98% to the starting sulfoximine 11 of ≥98% ee.

Full text of DOI:10.1021/ja030501v

Published on Web 03/25/2004
Asymmetric Synthesis of 2,3-Dihydrofurans and of
Unsaturated Bicyclic Tetrahydrofurans through r-Elimination
and Migratory Cyclization of Silyloxy Alkenyl
Aminosulfoxonium Salts. Generation and Intramolecular
O,Si-Bond Insertion of Chiral Disubstituted â-Silyloxy
Alkylidene Carbenes
Hans-Joachim Gais,* Leleti R. Reddy, Gadamsetti S. Babu, and Gerhard Raabe
Contribution from the Institut fu¨r Organische Chemie der Rheinisch-Westfa¨lischen Technischen
Hochschule (RWTH) Aachen, Prof.-Pirlet-Strasse 1, D-52056 Aachen, Germany
Received August 18, 2003; E-mail: Gais@RWTH-Aachen.de
Abstract: Treatment of the bis(allylsulfoximine)titanium complexes derived from the â-methyl-substituted
acyclic allylic sulfoximines 13a and 13b with aldehydes gave with high selectivities the corresponding
sulfoximine-substituted homoallylic alcohols which were isolated as the silyl ethers 15a-h. Methylation of
sulfoximines 15a-h afforded the aminosulfoxonium salts 5a-h which upon treatment with LiN(H)tBu gave
in high yields the enantio- and diastereomerically pure silyl-substituted 2,3-dihydrofurans 4a-h. Treatment
of the titanium complexes derived from the cyclic allylic sulfoximines 17a, 17b, and ent-17c with p-MeOC6H4-
CHO delivered with high selectivities the corresponding sulfoximine-substituted cyclic homoallylic alcohols
which were isolated as the silyl ethers 18a, 18b, and ent-18c, respectively. Methylation of sulfoximines
18a, 18b, and ent-18c furnished the aminosulfoxonium salts 8a, 8b, and ent-8c, respectively, whose
treatment with LiN(H)t-Bu gave the enantio- and diastereomerically pure fused bicyclic 2,3-dihydrofurans
6a, 6b, and ent-6c, respectively, in good yields. It is proposed that the 1-alkenyl aminosulfoxonium salts
5a-h, 8a, 8b, and ent-8c react with the base under R-elimination and formation of the acyclic and cyclic
â-silyloxy alkylidene carbenes 2a-h, 7a, 7b, and ent-7c, respectively, which then undergo a 1,5-O,Si-
bond insertion and 1,2-silyl migration. The cyclic aminosulfoxonium salts 8a, 8b, and ent-8c upon treatment
with 1,8-diazabicyclo[5.4.0]-7-undecene did not undergo an R-elimination but suffered a novel migratory
cyclization with formation of the enantio- and diastereomerically pure bicyclic tetrahydrofurans 9a, 9b, and
ent-9c, respectively. It is proposed that the 1-alkenyl sulfoxonium salts 8a, 8b, and ent-8c are isomerized
to the allylic aminosulfoxonium salts 10a, 10b, and ent-10c, respectively, which then suffer an intramolecular
substitution of the (dimethylamino)sulfoxonium group by the silyloxy group followed by a desilylation. The
syntheses of the 2,3-dihydrofurans 4a-h, 6a, and 6b and of the tetrahydrofurans 9a and 9b are accompanied
by the formation of sulfinamide 16 of g98% ee, which can be converted via sulfoxide 28 of g98% to the
starting sulfoximine 11 of g98% ee.
Introduction
However, the few studies of silyloxy alkylidene carbenes
reported thus far dealt only with achiral or racemic carbenes,
We recently described an asymmetric synthesis of the
disubstituted homopropargylic alcohols 3, a key step of which
is an elimination of the alkylidene carbene aminosulfoxonium
ylides 1, R3 ) H, with formation of the alkylidene carbenes 2,
R3 ) H (Figure 1).1 During the course of these investigations
we observed that the â-Me-substituted alkenyl sulfoxonium salt
1, R1 ) Ph, R2 ) i-Pr, R3 ) Me, rather than giving the
corresponding methyl-substituted alkyne afforded the 2,3-
dihydrofuran 4a in good yield. Apparently the intermediate
methyl-substituted alkylidene carbene 2a, R1 ) Ph, R2 ) i-Pr,
R3 ) Me, had suffered an intramolecular 1,5-O,Si-bond insertion
rather than a 1,2-Me shift. This type of O,Si-bond insertion of
â-silyloxy alkylidene carbenes had been observed previously.2-4
and it has not yet been demonstrated whether the methods
applied to their generation are suitable for the enantio- and
diastereoselective synthesis of disubstituted alkylidene carbenes
of type 2.
Highly substituted 2,3-dihydrofurans of type 4 would make
particularly interesting starting materials for the asymmetric
synthesis of tetrahydrofurans, structural motifs which can be
found in many important natural products including polyether
antibiotics, lignans, and nucleosides.5 Not only the activated
double bond but also the vinylic silyl group of 4 should allow
useful synthetic transformations,6 including a replacement by a
(2) Miwa, K.; Aoyama, T.; Shioiri, T. Synlett 1994, 461.
(3) Kim, S.; Cho, C. M. Tetrahedron Lett. 1995, 36, 4845.
(4) Feldman, K. S.; Wrobleski, M. L. J. Org. Chem. 2000, 65, 8659.
(1) Reddy, L. R.; Gais, H.-J.; Woo, C.-W.; Raabe, G. J. Am. Chem. Soc. 2002,
124, 10427.
9
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J. AM. CHEM. SOC. 2004, 126, 4859-4864
4859

A R T I C L E S
Gais et al.
Figure 1. Generation and reactivity of silyloxy alkylidene carbenes.
Figure 2. Retrosynthetic analysis of mono- and bicyclic 2,3-dihydrofurans
and bicyclic tetrahydrofurans.
metal atom.6c,d,f Up to now the application of chiral 2,3-
dihyrofurans in natural product synthesis has been hampered
by the lack of general methods for their asymmetric synthesis.7,8
The only more general route giving access to 2,3-dihydrofurans
carrying, however, no substituent at the 2-position involves the
reductive elimination of γ-butyrolactones,9 several asymmetric
syntheses of which have been described.10 Since a number of
tetrahydrofuranoide natural products contain a fused bicyclic
ring skeleton,5 the attainment of bicyclic 2,3-dihydrofurans of
type 4 in which R1 and R2 are part of a ring system would also
be highly desirable. These considerations led us to probe the
generation of the silyloxy-substituted alkylidene and cyclo-
alkylidene carbenes 2 and 7, respectively, from the 1-alkenyl
aminosulfoxonium salts 5 and 8, respectively (Figure 2) and to
study their propensity for 1,5-O,Si-bond insertion. We have
already described an asymmetric synthesis of sulfoximine-
substituted homoallylic alcohols of type 5 and 8 starting from
the corresponding bis(allylsulfoximine)titanium complexes and
aldehydes.11,12 The methyl-substituted salts 5 were selected in
anticipation of a O,Si-bond insertion of 2 being faster than a
1,2-methyl migration (vide supra). Very little was known,
however, at the beginning of our investigations about the
reactivity of alkylidene carbenes of type 2 with regard to the
competition between O,Si-bond insertion, methyl migration, and
1,5-C,H-bond insertion13 in dependence of the substituents R1
and R2. Since silyloxy-substituted cycloalkylidene carbenes of
type 7 were unknown at the beginning of our investigations, it
was particularly interesting to see whether 1,5-O,Si-bond
insertion or ring enlargement with formation of the correspond-
ing alkynes would predominate.13,14
(5) (a) Gottlieb, O. R. New Natural Products and Plant Drugs with Pharma-
cological, Biological, or Therapeutical ActiVity; Springer-Verlag: Berlin-
Heidelberg, Germany, 1987; p 227. (b) Ward, R. S. Tetrahedron 1990, 46,
5029. (c) Fraga, B. M. Nat. Prod. Rep. 1992, 9, 217. (d) Merrit, A. T.;
Ley, S. V. Nat. Prod. Rep. 1992, 9, 243. (e) Moody, C. J.; Davies, M.
Stud. Nat. Prod. Chem. 1992, 10, 201. (f) Koert, U. Synthesis 1995, 115.
(g) Benassi, R. In ComprehensiVe Heterocyclic Chemistry II; Katritzky,
A. R., Rees, C. W., Scrivan, E. F. V., Bird, C. W., Eds.; Elsevier: Oxford,
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75.
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Andersson, P. G. J. Org. Chem. 1998, 63, 6007. (c) Jarowicki, K.;
Kocie´nski, P. J.; O’Shea, M.; Stocks, M. Synthesis 1995, 195. (d) Fargeas,
V.; Le Me´nez, P.; Berque, I.; Ardisson, J.; Pancrazi, A. Tetrahedron 1996,
52, 6613. (e) Denmark, S. E.; Neuville, L. Org. Lett. 2000, 2, 3221. (f)
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L.; Lanter, J. C.; Corral, M. A. J. Org. Chem. 2001, 66, 2828.
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J. C. J. Org. Chem. 1998, 63, 9406. (d) Garzino, F.; Me´ou, A.; Brun, P.
Tetrahedron Lett. 2000, 41, 9803. (e) Evans, D. A.; Sweeney, Z. K.; Rovis,
T.; Tedrow, J. S. J. Am. Chem. Soc. 2001, 123, 12095.
Although the primary goal of our investigations was the
development of an asymmetric synthesis of 2,3-dihydrofurans
of types 4 and 6, the prospect of 1-alkenyl aminosulfoxonium
salts serving as a new source for chiral alkylidene carbenes was
also of particular interest. Alkylidene carbenes have already
received much attention in mechanistic and synthetic terms.13
However, the development of a new entry to these reactive
intermediates could open new possibilities for their application
in organic synthesis.15 The starting materials which have been
used most frequently for their generation are diazo-
alkenes,2,3,15a,d-i,16 alkenyl halides,17 and alkenyliodonium
(11) (a) Gais, H.-J.; Hainz, R.; Mu¨ller, H.; Bruns, P. R.; Giesen, N.; Raabe, G.;
Runsink, J.; Nienstedt, S.; Decker, J.; Schleusner, M.; Hachtel, J.; Loo,
R.; Woo, C.-W.; Das, P. Eur. J. Org. Chem. 2000, 3973. (b) Gais, H.-J.;
Loo, R.; Roder, D.; Das, P.; Raabe, G. Eur. J. Org. Chem. 2003, 1500.
(12) For the asymmetric synthesis of compounds of this type carrying an
additional chiral substituent at the N-atom, see: (a) Reggelin, M.;
Weinberger, H.; Gerlach, M.; Welcker, R. J. Am. Chem. Soc. 1996, 118,
4765. (b) Reggelin, M.; Gerlach, M.; Vogt, M. Eur. J. Org. Chem. 1999,
1011.
(13) For reviews of alkylidene carbenes and alkylidene carbenoids, see: (a)
Stang, P. J. Chem. ReV. 1978, 78, 383. (b) Stang, P. J. Acc. Chem. Res.
1982, 15, 348. (c) Stang, P. J. In Methoden der Organischen Chemie
(Houben-Weyl); Regitz, M., Ed.; Thieme: Stuttgart, Germany, 1989; Vol.
E19b, p 84. (d) Kirmse, W. Angew. Chem. 1997, 109, 1213; Angew. Chem.,
Int. Ed. Engl. 1997, 36, 1164. (e) Braun, M. Angew. Chem. 1998, 110,
444; Angew. Chem., Int. Ed. 1998, 37, 430. (f) Kunishima, M. ReV.
Heteroat. Chem. 1999, 21, 117.
(8) For recent syntheses and applications of racemic 2,3-dihydrofurans, see:
(a) Bottex, M.; Caviccholi, M.; Hartmann, B.; Monteiro, N.; Balme, G. J.
Org. Chem. 2001, 66, 175. (b) Ma, S.; Gao, W. Synlett 2002, 65. (c) Calo,
V.; Scordari, F.; Nacci, A.; Schingaro, E.; D’Accolti, L.; Monopoli, A. J.
Org. Chem. 2003, 68, 4406.
(9) (a) Fuentes, L. M.; Larson, G. L. Tetrahedron Lett. 1982, 23, 271. (b)
Ziegler, F. E.; Cain, W. T.; Kneisley, A.; Stirchak, E. P.; Wester, R. T. J.
Am. Chem. Soc. 1988, 110, 5442. (c) Jarowicki, K.; Kocienski, P.; Norris,
S.; O’Shea, M.; Stocks, M. Synthesis 1995, 195. (d) Walker, J. A., II; Chen,
J. J.; Wise, D. S.; Townsend, L. B. J. Org. Chem. 1996, 61, 2219. (e)
Fargeas, V.; Le Me´nez, P.; Berque, I.; Ardisson, J.; Pancrazi, A. Tetrahedron
1996, 52, 6613. (f) Wang, Z.-X.; Wiebe, L. I.; De Clercq, E.; Balzarini, J.;
Knaus, E. E. Can. J. Chem. 2000, 78, 1081.
(14) (a) Baxter, G. J.; Brown, R. F. C. Aust. J. Chem. 1978, 31, 327. (b) Meier,
H. AdV. Strain Org. Chem. 1991, 1, 215. (c) Johnson, R. P.; Daoust, K. J.
J. Am. Chem. Soc. 1995, 117, 362. (d) Harad, T.; Iwazaki, K.; Otani, T.;
Oku, A. J. Org. Chem. 1998, 63, 9007, and references therein.
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Eur. J. 2003, 9, 260, and references therein.
9
4860 J. AM. CHEM. SOC. VOL. 126, NO. 15, 2004

Asymmetric Synthesis of Di- and Tetrahydrofurans
A R T I C L E S
Scheme 1. Asymmetric Synthesis of Sulfoximine-Substituted
ylides,4,15b,c,f,18 all containing, however, an achiral leaving
group.13 The interesting aspect of 1-alkenyl aminosulfoxonium
salts as a potential alkylidene carbene source is the chiral leaving
group which is readily generated through methylation of the
corresponding sulfonimidoyl group. The latter has already found
many applications as a chiral auxiliary in asymmetric synthesis.19
Because of this the synthesis of a number of 1-alkenyl
sulfoximine groups containing chiral compounds can be envi-
sioned, which could perhaps serve for the generation of
enantiopure alkylidene carbens including analogues of 2 and 7
which carry a sulfonylamino instead of a silyloxy group20 and
axially chiral cycloalkylidene carbenoids.21,22
Acyclic Homoallylic Alcohols
In this paper we report about the generation of chiral
alkylidene and cycloalkylidene carbenes of type 2 and 7 from
5 and 8, respectively, and their utilization in the asymmetric
synthesis of highly substituted mono- and bicyclic 2,3-di-
hydrofurans of types 4 and 6, respectively. Furthermore we
describe that by the suitable choice of a base a novel migratory
cyclization of 8 can be induced, which also provides with the
putative intermediate formation of the allylic aminosulfoxonium
salts 10 an asymmetric synthesis of the unsaturated fused
bicyclic tetrahydrofurans 9.
tion-isomerization route11,23 depicted in Scheme 1. The inter-
mediate 1-alkenyl sulfoximines 12a and 12b were not isolated
but treated with 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) in
MeCN at elevated temperature to give mixtures of the E and Z
configured allylic sulfoximines 13a and 13b in ratios of 70:30
and 79:21, respectively. The E/Z-mixtures were readily separated
by preparative HPLC. Isomerization of the unwanted Z isomers
with DBU in MeCN again gave mixtures of the E and Z isomers,
which were separated. The N-methyl-S-phenyl sulfoximines 13a
and 13b were selected because of the ease of the preparation
of 11 (and ent-11) in enantiomerically pure form.24
Results and Discussion
Silyloxy Alkylidene Carbenes and Synthesis of 2,3-Dihy-
drofurans. (A) Monocyclic 2,3-Dihydrofurans. The acyclic
allylic sulfoximines 13a and 13b were selected for the synthesis
of the alkenyl aminosulfoxonium salts 5 in order to see whether
various 2.3-dihydrofurans 4 can be obtained carrying aryl and
sterically demanding alkyl groups at the 3-position. Sulfoximines
13a and 13b11b,23 were prepared from sulfoximine 1124 and the
corresponding methyl ketones following the addition-elimina-
The successive treatment of 13a and 13b with n-BuLi, ClTi-
(Oi-Pr)3, and 0.5 equiv of aldehydes 14a-d and the subsequent
silylation of the thus-formed homoallylic alcohols afforded the
diastereomerically pure (anti,Z)-configured silyl ethers 15a-h
in good yields (Table 1). Hydroxyalkylation of the methyl-
substituted titanium complexes derived from 13a and 13b with
the aromatic and aliphatic aldehydes 14a-d proceeded with high
regio- and diastereoselectivities similar to those of the corre-
sponding titanium complexes having only a disubstituted CC
double bond.11a Conversion of 13a and 13b was approximately
50%, and the allylic sulfoximines were recovered in 38-44%
yield. The incomplete conversion of 13a and 13b is due to the
formation of bis(allyl)titanium complexes in the reaction of the
lithiated allylic sulfoximines with equimolar amounts of ClTi-
(Oi-Pr)3, which are, however, only capable of transferring one
allylic sulfoximine unit with high selectivities to the aldehyde.11a
Methylation of the alkenyl sulfoximines 15a-h with Me3-
OBF4 in CH2Cl2 1 afforded in practically quantitative yields the
(dimethylamino)sulfoxonium salts 5a-h which were generally
not isolated (Scheme 2). Treatment of salts 5a-h with 1.1 equiv
of LiN(H)t-Bu in tetrahydrofuran (THF) first at -78 °C and
then at room temperature cleanly gave the silyl-substituted 2,3-
dihydrofurans 4a-h in high overall yields, based on 15a-h.
These results show that this 2,3-dihydrofuran synthesis works
equally well for derivatives carrying aliphatic and aromatic
(15) For recent synthetic applications of alkylidene carbenes, see: (a) Ohira,
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Gilbert, J. C.; Giamalva, D. H.; Weerasooriya, U. J. Org. Chem. 1983, 48,
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(17) (a) Ko¨brich, G.; Breckoff, W. E.; Hienemann, H.; Akhtar, A. J. Organomet.
Chem. 1965, 3, 492. (b) Walsh, R. A.; Bottini, A. T. J. Org. Chem. 1970,
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(19) For reviews, see: (a) Pyne, S. G. Sulfur Rep. 1999, 21, 281. (b) Reggelin,
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(20) Schleusner, M.; Gais, H.-J.; Koep, S.; Raabe, G. J. Am. Chem. Soc. 2002,
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A R T I C L E S
Gais et al.
Table 1. Asymmetric Synthesis of 2,3-Dihydrofurans 4a-h
1
2
3
compd
R
R
R
15 yield (%)a,b
15 dr
4 yield (%)
16 yield (%)
a
b
c
d
e
f
i-Pr
i-Pr
i-Pr
i-Pr
Ph
Ph
Ph
Ph
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
Ph
77 (96)
76 (95)
76 (92)
80 (95)
71 (94)
81 (97)
77 (95)
79 (94)
g98:2
g98:2
g98:2
g98:2
g98:2
g98:2
g98:2
g98:2
95
90
92
86
96
92
94
92
86
85
85
87
89
85
86
90
pMeOC6H4
pBrC6H4
cC6H11
Ph
pMeOC6H4
pBrC6H4
cC6H11
g
h
a Yields are based on recovered allylic sulfoximine. b Values in parentheses are yields based on aldehyde.
Scheme 2. Asymmetric Synthesis of Monocyclic
2,3-Dihydrofurans
Table 2. Asymmetric Synthesis of Bicyclic 2,3-Dihydrofurans 6a,
6b, and ent-6c
18/ent-18
compd
n
yield (%)a,b
dr
6/ent-6 yield (%)
16/ent-16 yield (%)
a
b
c
1
2
3
78 (96)
79 (95)
77 (96)
g98:2
g98:2
g98:2
89
91
90
86
90
88
a Yields are based on recovered allylic sulfoximine. b Values in paren-
theses are yields based on aldehyde.
Scheme 4. Asymmetric Synthesis of Bicyclic 2,3-Dihydrofurans
Scheme 3. Asymmetric Synthesis of Sulfoximine-Substituted
Cyclic Homoallylic Alcohols
substituents, including sterically demanding ones. Besides the
2,3-dihydrofurans the sulfinamide 16 with g98% ee was isolated
in all cases in high yields.
and the allylic sulfoximines were recovered in 38-40% yield
(vide supra). Methylation of sulfoximines 18a, 18b ,and ent-
18c with Me3OBF4 proceeded readily and gave the cyclic
(dimethylamino)sulfoxonium salts 8a, 8b, and ent-8c, respec-
tively, in practically quantitative yields (Scheme 4). Salts 8a,
8b, and ent-8c cleanly delivered upon treatment with LiN(H)-
t-Bu first at -78 °C and then at room temperature the enantio-
and diastereomerically pure bicyclic 2,3-dihydrofurans 6a, 6b,
and ent-6c, respectively, having a six-, seven-, and eight-
membered carbocyclic ring, in high overall yields, based on
18a, 18b, and ent-18c, respectively.
Mechanistic Considerations. On the basis of the results
obtained previously with the synthesis of ylides 1 (R3 ) H),1 it
is proposed that the reaction of the aminosulfoxonium salts 5a-
h, 8a, 8b, and ent-8c with the lithium amide at low temperatures
affords the alkylidene carbene sulfoxonium ylides 19a-h, 24a,
24b, and ent-24c, respectively (Scheme 5). These alkylidene
carbenoids eliminate sulfinamides 16 and ent-16, respectively,
at higher temperatures with formation of the δ-silyloxy alky-
lidene carbenes 2a-h, 7a, 7b, and ent-7c, respectively. Sub-
sequently, the alkylidene carbenes 2a-h, 7a, 7b, and ent-7c
preferentially undergo a 1,5-O,Si-bond insertion rather than a
1,2-Me(CH2R)-shift to deliver the 2,3-dihydrofurans 4a-h, 6a,
6b, and ent-6c, respectively. Thus the 1,5-O,Si-bond insertion
(B) Bicyclic 2,3-Dihydrofurans. Having developed a high-
yield synthesis of the enantio- and diastereomerically pure
monocyclic 2,3-dihydrofurans 4a-h from the acyclic δ-silyloxy-
substituted alkenyl sulfoximines 15a-h, the synthesis of bicyclic
2,3-dihydrofurans of type 6 was investigated. The known cyclic
allylic sulfoximines 17a and 17b were prepared in one synthetic
operation without the isolation of intermediates from sulfoximine
11 and the corresponding cycloalkanones by the inverse
Peterson-olefination and isomerization sequence described
previously (Scheme 3).11a,25 Similarly the new eight-membered
cyclic allylic sulfoximine ent-17c was synthesized from sul-
foximine ent-11 and cyclooctanone in 79% yield, based on ent-
11.
The successive treatment of 17a, 17b, and ent-17c with
n-BuLi, ClTi(Oi-Pr)3 and 0.5 equiv of aldehyde 14b, and the
subsequent silylation of the intermediate homoallylic alcohols
afforded the silyl ethers 18a, 18b, and ent-18c, respectively,
each as a single diastereomer in good yields (Table 2).
Conversion of 17a, 17b, and ent-17c was approximately 50%,
(25) Gais, H.-J.; Mu¨ller, H.; Bund, J.; Scommoda, M.; Brandt, J.; Raabe, G. J.
Am. Chem. Soc. 1995, 117, 2453.
9
4862 J. AM. CHEM. SOC. VOL. 126, NO. 15, 2004

Asymmetric Synthesis of Di- and Tetrahydrofurans
A R T I C L E S
Scheme 5. Mechanistic Scheme for the Formation of Silyloxy
Alkylidene Carbenes and 2,3-Dihydrofurans
Figure 3. Migratory cyclization of (sulfonylamino)alkyl-substituted 1-alk-
enyl aminosulfoxonium salts.26
Scheme 6. Asymmetric Synthesis of Unsaturated Fused Bicyclic
Tetrahydrofurans
This observation led us to study the reaction of the cyclic
aminosulfoxonium salts 8a, 8b, and ent-8c with DBU in order
to see whether an access to unsaturated fused bicyclic tetrahy-
drofurans 9a, 9b, and ent-9c (Scheme 6) could also be opened.
Tetrahydrofurans 9 having the various ring size should be of
particular synthetic interest because of the many natural products
containing a bicyclic tetrahydrofuranoide skeleton or structural
element.5,27 The double bond should allow further synthetic
transformations. An asymmetric synthesis of 9 has to the best
of our knowledge not been described yet.28 While the chances
for a regioselective isomerization of 8 to the allylic amino-
sulfoxonium salts 10 seemed to be good, the prospects for a
cyclization of the latter with formation of 9 were considered to
be less promising because of the poor nucleophilicity of the
silyloxy group. The DBU-assisted conversion of II to III is
perhaps not representative because here the strongly nucleophilic
deprotonated sulfonylamino group attacks the C-atom in the
R-position to the aminosulfoxonium group.
competes favorably with the 1,2-Me shift and the ring enlarge-
ment irrespective of the substituents and the ring size. The O,-
Si-bond insertion may occur either in a concerted or noncon-
certed fashion. In the latter case the oxonium ylides 20a-h,
25a, 25b, and ent-25c should be formed as intermediates, which
then suffer a [1,2]-silyl migration. This scheme would be in
accordance with the results of previous studies of acyclic siloxy
alkylidene carbenes2-4 and of alkylidene carbenes in general.13
Because of the different conformations the alkylidene carbenes
2 can adopt in regard to the Csp2-Csp3 bond (cf. Scheme 5)
and the high propensity alkylidene carbenes normally show for
C,H-bond insertion, not only a 1,5-O,Si-bond but also a 1,5-
C,H-bond insertion13 could in principle occur in the case of
2a-h with formation of the cyclopentene derivatives 21a-d,
22, and 23a-d, respectively. This was, however, not observed
within the limits of the yields obtained. Thus, carbenes 2 are
characterized by the following reactivity orders: 1,2-H shift >
O,Si-bond insertion, 1,5-C,H-bond insertion, and O,Si-bond
insertion > 1,2-Me(CH2R) shift, 1,5-C,H-bond insertion.
Synthesis of Unsaturated Bicyclic Tetrahydrofurans. It
was recently observed that (sulfonylamino)alkyl-substituted
1-alkenyl aminosulfoxonium salts of type I suffer upon treatment
with 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) a novel migra-
tory cyclization leading, via allylic aminosulfoxonium salts of
type II, to the formation of unsaturated fused bicyclic proline
derivatives of type III (Figure 3).26
(26) Koep, S.; Gais, H.-J.; Raabe, G. J. Am. Chem. Soc. 2003, 125, 13243.
(27) (a) McPhail, A. T. Tetrahedron Lett. 2000, 41, 4043. (b) Krause, G. A.;
Wang, X. Chem. Lett. 2000, 10, 895. (c) Marcos, I. S.; Moro, R. F.;
Carballares, S.; Urones, J. G. Synlett 2000, 4, 541. (d) Pagenkopf, B. L.;
Belanger, D. B.; O’Mahony, D. J. R.; Livinghouse, T. Synthesis 2000, 1009.
(e) Ishizaki, M.; Iwahara, K.; Niimi, Y.; Satoh, H.; Hoshino; O. Tetrahedron
2001, 57, 2729. (f) Evans, P. A.; Robinson, J. E. J. Am. Chem. Soc. 2001,
123, 4609. (g) Guo, H.; Madhushaw, R. J.; Shen, F.-M.; Liu, R.-S.
Tetrahedron 2002, 58, 5627. (h) Chai, Y.; Vicic, D. A.; McIntosh, M. C.
Org. Lett. 2003, 5, 1039. (i) Corminboeuf, O.; Overman, L. E.; Pennington,
L. D. Org. Lett. 2003, 5, 1543.
(28) Guo, H.; Madhushaw, R. J.; Shen, F.-M.; Liu, R.-S. Tetrahedron 2002,
58, 5627.
9
J. AM. CHEM. SOC. VOL. 126, NO. 15, 2004 4863

A R T I C L E S
Gais et al.
Table 3. Asymmetric Synthesis of Bicyclic Tetrahydrofurans 9a,
9b, and ent-9c
Scheme 7. Recycling of the Chiral Auxiliary
compd
n
9/ent-9 yield (%)
16/ent-16 yield (%)
a
b
c
1
2
3
69
72
74
84
87
88
was isolated with g98% ee in 93% yield (Scheme 7). Since
the conversion of 28 to sulfoximine 11 has already been
described,32 the synthesis of 28 from 16 represents a recycling
of the chiral auxiliary.
Treatment of 8a, 8b, and ent-8c with DBU in CH2Cl2 at room
temperature led to a highly regioselective migratory cyclization
and gave the enantio- and diastereomerically pure bicyclic
tetrahydrofurans 9a, 9b, and ent-9c, respectively, in 69-72%
yield after aqueous workup and chromatography. Formation of
6a, 6b, and ent-6c under these conditions was not observed.
The structures of the tetrahydrofurans 9b and ent-9c, containing
a seven- and eight-membered carbocyclic ring, were determined
by X-ray crystal structure analysis (see Supporting Information).
Besides 9a, 9b, and ent-9c the sulfinamides 16 and ent-16,
respectively, were isolated in good yields (Table 3). It is
proposed that the 1-alkenyl aminosulfoxonium salts 8a, 8b, and
ent-8c also suffer a regioselective isomerization upon treatment
with DBU with formation of the allylic aminosulfoxonium salts
10a, 10b, and ent-10c, respectively. Although the mechanism
of the isomerization of 8a, 8b, and ent-8c is, like that of I, not
known, the intermediate formation of the allylic aminosulfoxo-
nium ylides 27a, 27b, and ent-27c may play an important role.
Deprotonation of 8a, 8b, and ent-8c at the γ-position is expected
to be a facile process because of the stabilization of the negative
charge of 27a, 27b, and ent-27c by the aminosulfoxonium group
and the double bond. For example N,N-dimethyl-S-methylphe-
nylsulfoxonium tetrafluoroborate already has a pKa value of
15.5, and the double bond is expected to raise the acidity of
8a, 8b, and ent-8c even further.29 Cyclization of the allylic
aminosulfoxonium salts 10a, 10b, and ent-10c should primarily
lead to the silyl tetrahydrofuranium salts 26a, 26b, and ent-
26c, respectively, which are desilylated either by DBU, the
sulfonamide, or water upon aqueous workup30 with formation
of 9a, 9b, and ent-9c, respectively. In considering the low
reactivity of for example silyl ethers of 3-bromomethyl-but-3-
en-1-ol derivatives toward cyclization with formation of the
corresponding 3-methylene tetrahydrofurans,31 the facile cy-
clization of 10a, 10b, and ent-10c is noteworthy. This points to
a high nucleofugacity of the allylic (dimethylamino)sulfoxonium
group.
Conclusion
We have described an asymmetric synthesis of highly
substituted mono- and bicyclic 2-silyl-2,3-dihydrofurans from
enantio- and diastereomerically pure silyloxy alkylidene carbene
(dimethylamino)sulfoxonium ylides carrying two stereogenic
centers. Key steps are the elimination of the ylides with
formation of silyloxy alkylidene carbenes and the O,Si-bond
insertion of the latter. The advantage of this synthesis is that it
provides an access to enantio- and diasteriomerically pure 2,3-
dihydrofurans carrying various aryl and alkyl substituents
including sterically demanding ones. The results show that
1-alkenyl (dimethylamino)sulfoxonium salts can, with the
intermediacy of alkylidene carbene (dimethylamino)sulfoxonium
ylides, serve as versatile starting material for the generation of
chiral alkylidene carbenes. Interestingly 1-alkenyl (dimethy-
lamino)sulfoxonium salts show a synthetically highly useful
dichotomy in their reactivity toward bases. While with strong
bases an R-elimination of the aminosulfoxonium salts occurs,
weak bases induce an isomerization to the allylic aminosul-
foxonium salts whose (dimethylamino)sulfoxonium group shows
a high nucleofugacity in intramolecular substitution by a silyloxy
group leading to tetrahydrofurans. Thus, not only the R-(sul-
fonylamino)alkyl-substituted alkenyl aminosulfoxonium salts
obtained through aminoalkylation of cyclic allylic sulfoximines
with N-tert-butylsulfonyl iminoester are capable of undergoing
a migratory cyclization but also the R-(silyloxy)alkyl-substituted
alkenyl aminosulfoxonium salts secured through hydroxyalky-
lation of cyclic allylic sulfoximines with aldehydes.
Acknowledgment. Financial support of this work by the
Deutsche Forschungsgemeinschaft (Collaborative Research
Center “Asymmetric Synthesis with Chemical and Biological
Methods” SFB 380) is gratefully acknowledged.
Recycling of the Chiral Auxiliary. Besides the 2,3-dihy-
drofurans 4a-h, 6a, and 6b and the tetrahydrofurans 9a and
9b sulfinamide 16 with g98% ee was isolated in high yields.
Thus a conversion of 16 to the sulfoximine 11, the starting
material for the synthesis of allylic sulfoximines, was desirable.
To this end, sulfinamide 16 was treated with MeMgCl, which
gave under inversion of configuration the sulfoxide 28 which
Supporting Information Available: General comments and
materials, general experimental procedures, and analytical and
spectroscopic data and MS spectrometric data for compounds
4a-h, 5f, 6a, 6b, ent-6c, ent-8c, 9a, 9b, ent-9c, E-13a, Z-13a,
15a-h, 16, ent-17c, 18a, 18b, ent-18c, and 28, and X-ray
crystallographic data of 9b and ent-9c. This material is available
free of charge via the Internet at http://pubs.acs.org.
(29) (a) Bordwell, F. G.; Branca, J. C.; Johnson, C. R.; Vanier, N. R. J. Org.
Chem. 1980, 45, 3884. (b) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456.
(30) Hrkach, J. S.; Matyjaszewski, K. Macromolecules 1990, 23, 4042.
(31) (a) Russell, D. C.; Forsyth, C. J. J. Org. Chem. 1997, 62, 5672. (b) Paquette,
L. A.; Bennett, G. D.; Isaac M. B.; Chhatriwalla, A. J. Org. Chem. 1998,
63, 1836. (c) Loh, T.-P.; Song, H.-Y. Synlett 2002, 12, 2119.
JA030501V
(32) (a) Bach, T.; Ko¨rber, C. Eur. J. Org. Chem. 1999, 1033. (b) Johnson, C.
R.; Schroeck, C. W.; Shanklin, J. R. J. Am. Chem. Soc. 1973, 95, 7424.
9
4864 J. AM. CHEM. SOC. VOL. 126, NO. 15, 2004