Diastereoselective zwitterionic aza-Claisen rearrangement: The synthesis of bicyclic tetrahydrofurans and a total synthesis of (+)-dihydrocanadensolide

Article abstract of DOI:10.1021/jo9600464

The zwitterionic Claisen rearrangement of optically-active N-allyl pyrrolidines and various acid chlorides proceeds with high simple diastereoselection (internal asymmetric induction) and high 1,2-asymmetric induction, generating a new C-C bond adjacent to a chiral C-O function. The resulting γ,δ-unsaturated amides were cyclized to the corresponding optically active γ-butyrolactones, which are useful intermediates in natural product synthesis. On one hand, a diastereoselective iodocyclization of several lactones led to tetrahydrofurans with a substitution pattern representing a key intermediate of an oxa-prostaglandin synthesis. On the other, a one-pot procedure of a Swern oxidation and consecutive Grignard reaction of one γ-lactone allowed a diastereoselective chain elongation. The final oxidation/cyclization sequence completed a highly efficient synthesis of the (+)-dihydrocanadensolide or its C-3 epimer, respectively.

Full text of DOI:10.1021/jo9600464

J . Org. Chem. 1996, 61, 3677-3686
3677
Dia ster eoselective Zw itter ion ic Aza -Cla isen Rea r r a n gem en t: Th e
Syn th esis of Bicyclic Tetr a h yd r ofu r a n s a n d a Tota l Syn th esis of
(+)-Dih yd r oca n a d en solid e
Udo Nubbemeyer
Institut fu¨r Organische Chemie, Freie Universita¨t Berlin, Takustrasse 3, D-14195 Berlin, Germany
Received J anuary 4, 1996X
The zwitterionic Claisen rearrangement of optically-active N-allyl pyrrolidines and various acid
chlorides proceeds with high simple diastereoselection (internal asymmetric induction) and high
1,2-asymmetric induction, generating a new C-C bond adjacent to a chiral C-O function. The
resulting γ,δ-unsaturated amides were cyclized to the corresponding optically active γ-butyrolac-
tones, which are useful intermediates in natural product synthesis. On one hand, a diastereose-
lective iodocyclization of several lactones led to tetrahydrofurans with a substitution pattern
representing a key intermediate of an oxa-prostaglandin synthesis. On the other, a one-pot
procedure of a Swern oxidation and consecutive Grignard reaction of one γ-lactone allowed a
diastereoselective chain elongation. The final oxidation/cyclization sequence completed a highly
efficient synthesis of the (+)-dihydrocanadensolide or its C-3 epimer, respectively.
Sch em e 1
In tr od u ction
The influence of a chiral center outside the pericyclic
system on the stereochemical result of the Claisen
rearrangement has been widely investigated. In most
cases the degree of 1,2-asymmetric induction (relative
asymmetric induction) is low for the formation of a new
C-C bond in R-position to a chiral C-O bond.1 Espe-
cially in acyclic substrates bearing glyceraldehyde or
related fragments,2 high diastereoselectivities are more
of an exception.3
Diastereoselective ketene Claisen rearrangements of
allyl thioethers are well known,4 but the scope of the
reaction is restricted to activated ketenes like chloro-,
chloroalkyl-, and dichloroketene.5 Aza-ketene Claisen
reactions involving in situ generated ketenes (especially
dichloroketene) suffer from the same disadvantages.6 All
rearrangements are accompanied by varying amounts of
tarry side products.6a In contrast, treatment of N-
allylpyrrolidines with acid chlorides in presence of tri-
methylaluminum in a two-phase system led to the
corresponding γ,δ-unsaturated amides in high yields
(zwitterionic variant, for a postulated reaction path see
Scheme 1).7,8 Low 1,2-asymmetric induction (generation
of a new C-C bond adjacent to a chiral C-O function)
was observed when reacting acetyl chloride with the
allylamines, but the rearrangement with propionyl chlo-
ride allowed the generation of two new chiral centers in
one step with a high diastereomeric excess.8
The major competing reaction observed is a von Braun
type dealkylation process6b,9 involving a nucleophilic
attack of a chloride ion on an intermediate acyl am-
monium salt.8 The von Braun type reaction path pre-
dominated whenever R,R-disubstituted acid chlorides
(e.g., dichloracetyl chloride) were used.
X Abstract published in Advance ACS Abstracts, May 1, 1996.
(1) (a) Ziegler, F. E. Chem. Rev. 1988, 88, 1429. (b) Frauenrath, H.
In Houben Weil, Vol. E21d: Stereoselective Synthesis; Helmchen, G.,
Hoffmann, R. W., Mulzer, J ., Schaumann, E., Eds.; Thieme: Stuttgart,
New York, 1995; p 3301. (b) Wipf, P. In Comprehensive Organic
Synthesis; Trost, B. M., Flemming, I., Paquette, L. A., Eds.; Pergamon
Press: New York, 1991; Vol. 5, p 827. (d) Hill, R. K. In Asymmetric
Synthesis; Morrison, J . D., Ed.; Academic Press: New York, 1984; Vol.
3, p 503.
(2) (a) Suzuki, T.; Sato, E.; Kamada, S.; Tada, H.; Unno, K.;
Kametami, T. J . Chem. Soc., Perkin Trans. 1 1986, 387. (b) Hatakeya-
ma, S.; Saijo, K.; Takano, K. Tetrahedron Lett. 1985, 26, 865. (c) Cha,
J . K.; Lewis, S. C. Tetrahedron Lett. 1984, 25, 5263. (d) Kametami, T.
Heterocycles 1982, 19, 205.
(6) Two types of zwitterionic aza Claisen Rearrangements are
known: (a) Ketene Claisen rearrangement to generate γ,δ unsaturated
amides: Cid, M. M.; Eggnauer, U.; Weber, H. P.; Pombo-Villar, E.
Tetrahedron Lett. 1991, 32, 7233. Cid, M. M.; Pombo-Villar, E. Helv.
Chim. Acta 1993, 76, 1591. Edstrom, E. D. J . Am. Chem. Soc. 1991,
113, 6690. Ishida, M.; Muramaru, H.; Kato, S. Synthesis 1989, 562.
Roberts, S. M.; Smith, C., Thomas, R. J . J . Chem. Soc. Perkin Trans.
1
1990, 1493. (b) Alkinester Claisen rearrangement to generate
stabilized conjugated enamines: Vedejs, E.; Gingras, M. J . Am. Chem.
Soc. 1994, 116, 579. Baxter, E. W.; Labaree, D.; Ammon, H. L.;
Mariano, P. S. J . Am. Chem. Soc. 1990, 112, 7682-7692. Baxter, E.
W.; Labaree, D.; Chao, S.; Mariano, P. S. J . Org. Chem. 1989, 54, 2839-
2904. Chao, S.; Kunng, F.-A.; Gu, J .-M.; Ammon, H. L.; Mariano, P. S.
J . Org. Chem. 1984, 49, 2708-2711. Kunng, F.-A.; Gu, J .-M.; Chao,
S.; Chen, Y.; Mariano, P. S. J . Org. Chem. 1983, 48, 4262-4266.
Schwan, A. L.; Warkentin, J . Can. J . Chem. 1988, 66, 1686. Kandeel,
K. A.; Vernon, J . M. J . Chem. Soc., Perkin Trans. 1 1987, 2023.
Bamatraf, M. M. M.; Vernon, J . M.; Wilson, G. D. J . Chem. Soc., Perkin
Trans. 1 1995, 1647.
(3) (a) Tadano, K.; Shimada, K.; Ishihara, J .; Ogawa, S. J . Carbo-
hydr. Chem. 1991, 10, 1. (b) Mulzer, J .; Shanyoor, M. Tetrahedron Lett.
1993, 34, 6545.
(4) Nubbemeyer, U.; O¨ hrlein, R.; Gonda, J .; Ernst, B.; Bellus, D.
Angew. Chem., Int. Ed. Engl. 1991, 30, 1465.
(5) (a) Malherbe, R.; Bellus, D. Helv. Chim. Acta 1978, 61, 3096. (b)
Malherbe, R.; Rist, G.; Bellus, D. J . Org. Chem. 1983, 48, 860. (c)
O¨ hrlein, R.; J eschke, R.; Ernst, B.; Bellus, D. Tetrahedron Lett. 1989,
30, 3517.
(7) Diederich, M.; Nubbemeyer, U. Angew. Chem., Int. Ed. Engl.
1995, 34, 1026.
(8) Nubbemeyer, U. J . Org. Chem. 1995, 60, 3773.
(9) Hagemann, H. A. Org. React. 1953, 7, 198.
S0022-3263(96)00046-1 CCC: $12.00 © 1996 American Chemical Society

3678 J . Org. Chem., Vol. 61, No. 11, 1996
Nubbemeyer
Ta ble 1. Resu lts of th e Zw itter ion ic Aza -Cla isen Rea r r a n gem en t
ratio
yield [%]
entry
R1
yield [%]
4
5
6
7
8
9
10
11
ref
a
b
c
d
e
f
H
CH3
82
77
74
45
62
60
52
82
60
90
70
>97
>97
<1
<1
96
40
10
<1
<1
<1
<1
<1
2
-
-
<1
<1
<1
<1
<1
<1
<1
92b
85a
92b
91b
84a
-
90b
89b
-
-
-
-
-
-
-
-
-
-
-
5
5
<1
30
CH2CH2Cl
CH(CH3)2
CHdCH2
CHdCHCHdCH2
C6H5
90b
-
<1
<1
>97
>97
<1
-
-
-
-
85a
92b
-
g
h
-
-
Cl
95a
88b
92a
-
i
OCH2C6H5
83
87
8.7
<1
4.3
59b
-
29b
R2 ) H. R2 ) TBDMS.
a
b
Sch em e 2
Resu lts a n d Discu ssion
(entries a-d). The corresponding γ,δ-unsaturated amides
could be isolated in high yields in the case of linear chains
(entries a-c). While the adduct with acetyl chloride
(entry a) rearranged with modest 1,2 asymmetric induc-
tion, propionyl chloride (entry b) gave a mixture of amides
4b and 5b in a 9:1 ratio.8 The reaction of the 4-chlo-
robutyric acid chloride (entry c) did not produce the anti
amide 5c or 7c (100% 1,2-asymmetric induction), but the
simple diastereoselection was found to be nonuniform.
Presumably, the product 4c had partially epimerized
during the extended reaction time. Furthermore, 3-me-
thylbutyric acid chloride (branched side chain, entry d)
could be used to generate the amide 4d exclusively, but
only a modest yield (45%) was obtained, despite a very
long reaction time (about 3-4 weeks), and a significant
amount of von Braun type side products was formed.
2-Methylpropionic acid chloride did not give any rear-
rangement product.
In the first part of this paper, the scope and the
limitations of the zwitterionic aza-Claisen rearrangement
of the acyclic allylamine 1 is reported. The allylamine 1
was generated in six steps starting from D-mannitol, or
in three steps from (S)-E-4,5-(isopropylidenedioxy)-2-
pentenoic acid ethyl ester.8
Dia ster eoselective Aza -Cla isen Rea r r a n gem en t.
The N-allylpyrrolidine 1 was treated with several types
of acid chlorides, as described in Table 1 and Scheme 2.
All isolated amides 4-7 were cyclized to the correspond-
ing γ-butyrolactones 8-11 in MeOH/TFA.10 In several
attempts, the remaining hydroxyl function was protected
as the tert-butyldimethylsilyl ether.11 The relative ster-
eochemistry of each compound from 8 to 11 was un-
equivocally proved via NOEDS (nuclear Overhouser
effect difference spectroscopy) analysis.
In the first series, allylamine 1 was acylated with a
range of alkanoyl chlorides to give rearranged products
In the second series, rearrangements with unsaturated
acid chlorides were investigated (entries e-g). In all
attempts, only a single diastereomer could be detected.
The reaction of allylamine 1 with 2-butenoic- or 2,4-
hexadienoic acid chloride formed the corresponding un-
(10) Leblanc, Y.; Fitzsimmons, B. J .; Adams, J .; Perez, F.; Rokach,
J . J . Org. Chem. 1986, 51, 789.
(11) Corey, E. J .; Venkateswarlu, A. J . Am. Chem. Soc. 1972, 94,
6190.

Diastereoselective Zwitterionic Aza-Claisen Rearrangement
J . Org. Chem., Vol. 61, No. 11, 1996 3679
Sch em e 3
saturated amides 4e and 6f in 62% and 60% yield,
respectively. Compared with the saturated acid chlorides
of series 1, the amount of von Braun type products
increased. It should be pointed out that the â,γ-double
bonds of the products did not isomerize, and the R,â-
unsaturated amide was not found. After the cyclization
to the γ-lactones, only the 3,4-divinyl lactone 8e con-
tained a small amount (about 5%) of the conjugated
olefinic system, which could be separated via preparative
HPLC. It is noteworthy that the γ-lactones 8e and 10f
were unstable and decomposed within one or two days.
Phenylacetyl chloride slowly reacted with the allylamine
1 to form the R-phenylpyrrolidinamide 6g exclusively in
52% yield. The very long reaction time (about 4 weeks)
led to the formation of a high amount of von Braun type
products.
The third series employed R-heteroatom-substituted
acetyl chlorides in the rearrangement reaction with the
allylamine 1 (entries h, i). Surprisingly, the reaction of
chloroacetyl chloride proceeded with excellent induction.
Simple diastereoselection generated the R-chloro amides
4h and presumably 5h (for which the relative stereo-
chemistry of the minor diastereomer has not been
determined) in a ratio of about 60:1 in 82% yield, even
though the major product could undergo a facile R-epimer-
ization. Furthermore, the cyclization and protection of
the remaining hydroxyl function in the presence of
pyridine formed the lactone 8h exclusively, and the
relative stereochemistry of all stereogenic carbon atoms
was found to be syn! In contrast, the rearrangement of
the allylamine with (benzyloxy)acetyl chloride led to the
lowest 1,2-asymmetric induction of all the tested acid
chlorides, and the amides 4i, 5i, and 7i were isolated in
a ratio of 20:2:1 and 83% yield. The minor diastereomers
5i and 7i were separated from the major product 4i via
HPLC. The separation of these components failed at this
stage, but was achieved after cyclization and silylation
to the lactones 9i and 11i. With dichloroacetyl chloride,
only von Braun type products were obtained.7,8
F igu r e 1. Chair- and boatlike intermediates of the rearrange-
ment of allylamine 1 with carboxylic acid chlorides.
chemistry14 and of Tsunoda in the rearrangement of
amide enolates,15 the deprotonation of an acyl ammonium
salt should generate the Z-enolate structure 2 (Figure
1) or 3 because of steric (and 1,3-diaxial) repulsions.
Obviously, the defined enolate geometry resulted in the
high simple diastereoselection of the zwitterionic aza-
Claisen rearrangement (Table 1, entries b-e, h, i). In
contrast, the results of entries f and g were incompatible
with these considerations.16 A speculative quantitative
epimerization under the basic reaction conditions would
not serve as a satisfactory explanation in view of the
results of entry c (R1 ) 2-chloroethyl, mixture of dias-
teromers), entry e (R1 ) vinyl), or entry h (R1 ) Cl). It
seems reasonable that either the positions of Ha and R1
are exchanged in the intermediate 2 (f 2′, E-enolate,
Figure 1) or the reaction passes through the correspond-
ing boatlike transition state 2′′ (Z-enolate, eclipsed ar-
rangement of the substituents, Figure 1). Steric argu-
ments cannot be exclusively responsible for such different
geometry (entry d: R1 ) isopropyl gave the expected
relative stereochemistry). It appears more likely that
electronic aspects of the enolate stabilization in the
extensive π-system of the phenyl and the butadienyl
substituents may be involved (“in plane arrangement”
of the π-systems of enolate and substituent R1). The
The high diastereoselection achieved with the chloro-
acetyl chloride (entry h) provided an alternative to the
unselective acetyl chloride rearrangement (entry a).8 The
dehalogenation of amide 4h with Zn/NH4Cl in reflux-
ing MeOH12 generated amide 4a in nearly quantitative
yield. The reduction with Zn in HOAc5b led to lactone
8a in 82% yield and about 8.5% of the impure corre-
sponding 5-acetoxymethyl lactone (Scheme 3).
Mech a n istic Con clu sion s. The acyclic Claisen rear-
rangement is known to pass preferentially through a
chairlike transition state1,13 arranging the substituents
in quasiequatorial positions. According to the observa-
tions of Evans, Myers, and Sonnet in their amide enolate
(13) (a) Ireland, R. E.; Wipf, P.; Xiang, J .-N. J . Org. Chem. 1991,
56, 3572. (b) Vance, R. L.; Rondan, N. G.; Houk, K. N.; J ensen, F.;
Borden, W. T.; Komornicki, A.; Wimmer, E. J . Am. Chem. Soc. 1988,
110, 2314. (c) J ohnson, W. S.; Bauer, V. J .; Margrave, J . L.; Frisch, M.
A.; Dreger, L. H.; Hubbard, W. N. J . Am. Chem. Soc. 1961, 83, 606.
(d) Vittorelli, P.; Hansen, H.-J .; Schmid, H. Helv. Chim. Acta 1975,
58, 1293.
(14) (a) Evans, D. A.; Takacs, J . M. Tetrahedron Lett. 1980, 21, 4233.
(b) Larcheveque, M.; Ignatova, E.; Cuvigny, T. Tetrahedron Lett. 1978,
3961. (c) Sonnet, P. E.; Heath, J . R. J . Org. Chem. 1980, 45, 3139.
(15) (a) Ito, S.; Tsunoda, T. Pure Appl. Chem. 1990, 62, 1405. (b)
Tsunoda, T.; Sakai, M.; Sasaki, O.; Sako, Y.; Hondo, Y.; Ito, S.
Tetrahedron Lett. 1992, 33, 1651. (c) Ito, S.; Tsunoda, T. Pure Appl.
Chem. 1994, 66, 2071.
(16) All attempts to trap an intermediate (with TBDMSOTf, etc.)
failed. Additional rearrangements with some sterically hindered acid
chlorides gave unsatisfying results (very low yields).
(12) Ramesh, U.; Ward, D.; Reusch, W. J . Org. Chem. 1988, 53, 3469.

3680 J . Org. Chem., Vol. 61, No. 11, 1996
Nubbemeyer
Sch em e 4
mostly high simple diastereoselectivity (internal asym-
metric induction) is comparable to those achieved with
the well known Eschenmoser type rearrangements.17
In view of the model for the steric and electronic course
of [3,3]-sigmatropic processes proposed by Kahn,18 Houk,19
and Felkin,20 the reaction should preferentially pass
through intermediate 2, 2′ or 2′′ leading to the observed
1,2-asymmetric induction (formation of the amides 8 or
10). The generally high asymmetric induction with a
range of acid chlorides represents the major advantage
of this variant of the Claisen rearrangement.
In the second part of this paper, the γ,δ-unsaturated
amides and the corresponding γ-lactones were investi-
gated in further synthetic applications.
Iod ocycliza tion s. In analogy to the high 1,2-asym-
metric induction achieved during the Claisen rearrange-
ment, the defined functionalization of the remaining
double bond was investigated using iodocyclizations.
Yoshida et al.21 showed that acyclic 2-substituted and 2,3-
disubstituted γ,δ-unsaturated N,N-dimethylamides of
defined configuration underwent diastereoselective io-
dolactonization. The de values observed were g90% in
accordance with high remote stereocontrol in a postulated
five-membered transition state. In contrast, initial ex-
periments starting from the 2,3-disubstituted pyrrolidine
amide 4h resulted in disappointing diastereoselectivity,
despite the similar substitution pattern to that described
by Yoshida (leading to high stereoselectivity). Presum-
ably in this case, the favored transition state 13 generat-
ing the syn-lactone 15 was counteracted by the relative
stereochemistry of the stereogenic dioxolane center. The
mismatched configuration of 4h resulted in unselective
iodolactonization, with formation of a 54:46 mixture of
the lactones 14 and 15. The relative stereochemistry was
determined via NOEDS analysis (Scheme 4).
Significantly higher stereoselectivity could be achieved
by cyclization of the hydroxy lactones 8a to 8i. While
after the cyclization of lactone 8a two diastereomers 18a
and 19a could be detected in a 5:1 ratio, the cyclizations
of the lactones 8b to 8i generated single diastereomers
18b to 18i in high yields (Scheme 4). The relative
stereochemistry was confirmed by NOEDS analysis.
Obviously, the 3,4,5-syn substitution pattern of the
lactones of type 8 favored a defined arrangement of the
double bond in the iodonium intermediate 16 that
resulted in a diastereoselective formation of the 2,3,4-
trisubstituted tetrahydrofuran system. The substitution
pattern is known from a synthesis of oxa-prostaglan-
dins.22 The lack of the syn-substituent at C-3 proved
crucial and resulted in decreased stereoselection, as
shown in the reaction of lactone 8a .
Ta ble 2. Resu lts of th e Iod ocycliza tion of La cton e 8
ratio
entry
R1
yield [%]
18
84
>98
>98
>98
19
a
b
h
i
H
CH3
Cl
87
88
85
94
16
<2
<2
<2
OCH2C6H5
total synthesis was described by Mulzer.25 The highly
efficient diastereoselective generation of the γ-butyro-
lactone 8b was used in a short synthesis of (+)-dihydro-
canadensolide (24) and its C-3 epimer 22 (Scheme 5). The
n-butyl side chain was introduced via a one-pot procedure
of a Swern oxidation and Grignard addition following a
procedure developed previously.26 The fourth stereo-
center was introduced according to the cyclic Cram
model27 generating predominantly the desired syn prod-
uct 21 (ratio: 21:20 ) 10:1) in 88% yield. The diaster-
eomers could be separated via preparative HPLC or via
flash column chromatography. The annulation of the
second γ-lactone ring was achieved by a sequence of two
oxidation steps:26 After ozonolysis of the syn-lactone 21
Syn th esis of th e Dih yd r oca n a d en solid es 22 a n d
24. Dihydrocanadensolide 24 is a mold metabolite of
Penicillum canadense with unknown biological activity,
isolated by McCorkindale.23 The correct relative stere-
ochemistry was determined by Yoshikoshi24 and a first
(17) Felix, D.; Gschwend-Steen, K.; Wick, A. E.; Eschenmoser, A.
Helv. Chim. Acta 1969, 52, 741.
(18) Kahn, S. D.; Hehre, W. J . J . Org. Chem. 1988, 53, 301.
(19) Houk, K. N.; Moses, S. R.; Wu, Y.-D.; Rondan, N. D.; J a¨ger, V.;
Schohe, R.; Fronczek, F. R. J . Am. Chem. Soc. 1984, 106, 3880.
(20) Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968,
2199.
(24) Kato, M.; Kageyama, M.; Tanaka, R.; Kuwahara, K.; Yoshiko-
shi, A. J . Org. Chem. 1975, 40, 423.
(21) Tamaru, Y.; Mizutani, M.; Furukawa, Y.; Kawamura, S.;
Yoshida, Z.; Yanagi, K.; Minobe, M. J . Am. Chem. Soc. 1984, 106, 1079.
(22) Lourens, G. J .; Koekemoer, J . M. Tetrahedron Lett. 1975, 3715
and 3719.
(23) McCorkindale, N. J .; Wright, J . L. C.; Brian, P. W.; Chlarke,
S. M.; Hutchinson, S. A. Tetrahedron Lett. 1968, 727.
(25) Mulzer, J .; Kattner, L. Angew. Chem., Int. Ed. Engl. 1990, 29,
679.
(26) Nubbemeyer, U. Synthesis 1993, 1120.
(27) (a) Cram, D. J .; Abd El Hafez, F. A. J . Am. Chem. Soc. 1952,
74, 5828. (b) Still, W. C.; McDonald, J . H., III. Tetrahedron Lett. 1980,
21, 1031.

Diastereoselective Zwitterionic Aza-Claisen Rearrangement
J . Org. Chem., Vol. 61, No. 11, 1996 3681
Sch em e 5
torial position of the substituent of the acid chloride in a
chairlike conformation. An interpretation of the different
behavior of 2,4-hexadienoic acid chloride and phenyl-
acetyl chloride is still speculative. Further experiments
concerning this problem are in progress.
First attempts at the iodolactonization of the γ,δ-
unsaturated amide 4b led to disappointing diastereose-
lection. After the cyclization of the amides to the
corresponding γ-butyrolactones, the iodocyclizations pro-
ceeded with high diastereoselections in high yields
indicating efficient remote stereocontrol via a five-
membered transition state when syn-trisubstituted re-
actants were involved. The resulting tetrahydrofurans
18 (available in nine steps from mannitol, ca. 20% yield
overall) are useful intermediates for natural product
synthesis, e.g., the generation of the well known oxa-
prostaglandins22 has been described via a bicyclic type
18a .
Furthermore, an efficient and short ex-chiral pool
synthesis of (+)-dihydrocanadensolide (24) has been
described which improves the value of the zwitterionic
aza-Claisen reaction for natural product synthesis. Two
of the four chiral centers are formed in this key step with
a high diastereoselection, one of which is built up in a
stereoselective Grignard addition. Additionally, the pri-
mary generation of the 3,4,5-syn substituted γ-lactones
allowed the efficient epimerization of the 3-position under
basic conditions, resulting in the selective synthesis of a
second substitution pattern of the γ-lactone system. The
highly diastereoselective key steps of this synthesis
recommend the method for further applications.
followed by a reductive workup, the lactol generated in
situ was transferred into a suspension of pyridinium
chlorochromate. 3-epi-Dihydrocanadensolide (22) could
be isolated in 73%. In preparation for synthesis of the
(+)-dihydrocanadensolide (24), it was imperative to
epimerize the 3-methyl group before generation of the
bislactone structure. Otherwise, the bridgehead hydro-
gen of C-3a would be abstracted under the basic condi-
tions, and the molecule would undergo a â-elimination
to form a butenolide structure.28 An epimerization of the
3-methyl substituent was successfullly carried out by
treating the lactone 21 with 0.5 mol equiv of KOtBu in
THF,29 and the diastereomeric lactone 23 was isolated
in 88% yield. The final oxidation sequence as described
for the 3-epi product allowed the generation of the (+)-
dihydrocanadensolide (24) in 80% yield over two steps.
All spectroscopic data and the melting point were identi-
cal with those published in the literature. In conclusion,
the synthesis of the dihydrocanadesolide (24) with four
asymmetric centers proceeded in 13 steps (10 isolated),
starting from D-mannitol, in 12% yield overall. All new
optically active carbon centers could be introduced with
diastereoselections g9:1.
Exp er im en ta l Section
For general experimental data see ref 26. The 1H-NMR
spectra of 6f, 8c, 8e, 10c, 14, 18a , 18b, 18i and the NOEDS
analyses of 8e, 14, 18a , 18b, 18h , 18i were recorded on a
Bruker AC 550 (500 MHz) spectrometer. Satisfactory analyti-
cal data (( 0.4% for C, H, N) are reported for all new
compounds except 5h , 5/7i, 6f, 10f (HRMS data were included
for these products).
(3S,4S) 3-Eth en yl-4,5-(isop r op ylid en d ioxy)p en ta n oic
Acid P yr r olid in a m id e (4a ). The 2-chloro amide 4h (0.3 g,
1.04 mmol) was dissolved in MeOH (30 mL), saturated with
NH4Cl. Then, Zn (powder, 0.62 g, 9.48 mmol) was added and
the mixture was heated to reflux (65 °C) with stirring. After
about 1 h, the reaction was found to be complete. After cooling
the mixture to rt, H2O (50 mL) was added and the mixture
was extracted with CH2Cl2 (5 × 25 mL). The organic layers
were dried (MgSO4), and the solvent was removed to give pure
amide 4a : 159 mg (98%). For spectral data see ref 8.
St a n d a r d P r oced u r e for t h e Zw it t er ion ic Cla isen
Rea r r a n gem en t. Under argon, dry K2CO3 (1.6 g, 11.6 mmol)
was suspended in dry CHCl3 (35 mL) and cooled to 0 °C.
N-Allylpyrrolidine (5 mmol) and acid chloride (6 mmol) were
added subsequently by means of a syringe. After about 30
min of stirring at 0 °C, a solution of Me3Al (0.25 mL, 0.51
mmol, 2 M in toluene) was added via syringe. The mixture
was stirred at 0 °C. After 24 h, a second volume of Me3Al was
injected. After 2 to 3 d, the reaction was stopped by quenching
dropwise with saturated aqueous NaHCO3 (5-10 mL) at 0 °C
until the Al2O3/K2CO3 precipitated. Then, the organic layer
was decanted, the solid residue was extracted with CH2Cl2 (5
× 20 mL), and the combined organic layers were dried
(MgSO4). The solvent was removed, and the crude mixture of
diastereomeric amides and von Braun type products was
purified by column chromatography. If necessary, diastereo-
mers were separated via HPLC or column chromatography on
silica gel.
Con clu sion
The zwitterionic Claisen rearrangement with allyl-
amine 1 is characterized by its mild reaction conditions
resulting in high diastereoselection rates with several
substituted ketene analogs. The Eschenmoser type γ,δ-
unsaturated amides were generated involving acid chlo-
rides in the process.17 A major advantage is that the
difficult synthesis of the corresponding N,N-dialkylacy-
lamide dialkylacetals and the high reaction temperatures
of the original Eschenmoser rearrangement17 can be
avoided. In contrast to the most common acyclic Claisen
rearrangements,1,2 high 1,2-asymmetric inductions were
achieved with a range of acid chlorides, and the disap-
pointing selectivity of the acetyl chloride reaction was
overcome by the chloroacetyl chloride-rearrangement/
dehalogenation sequence. The high simple diastereose-
lectivity (internal asymmetric induction) originates from
the defined enolate geometry in a hypothetical zwitteri-
onic intermediate. The majority of entries generated a
substitution pattern like in a Burke-Kallmerten30 type
rearrangement and assigned a preferentially quasiequa-
(30) (a) Burke, S. D.; Fobare, F. W.; Pacofsky, G. J . J . Org. Chem.
1983, 48, 5221. (b) Kallmerten, J .; Gould, T. J . Tetrahedron Lett. 1983,
24, 5177.
(28) Anderson, R. C.; Fraser-Reid, B. J . Org. Chem. 1985, 50, 4786.
(29) Nubbemeyer, U. Diplomarbeit, Hannover, 1986.

3682 J . Org. Chem., Vol. 61, No. 11, 1996
Nubbemeyer
If the crude product contained more than 10% allylic amine
(occurred in the majority of the experiments), the mixture was
subjected to these reaction conditions for a second cycle.
108.3 (s), 118.3 (t), 119.3 (t), 133.9 (d), 135.3 (d), 170.4 (s). Anal.
Calcd: C, 68.79; H, 9.02; N, 5.01. Found: C, 68.44; H, 8.74;
N, 4.75.
(2S,3R,4S)-2-(2-Ch lor oeth yl)-3-eth en yl-4,5-(isop r op yli-
d en d ioxy)p en t a n oic Acid P yr r olid in a m id e (4c) a n d
(2R,3R,4S)- 2-(2-Ch lor oeth yl)-3-eth en yl-4,5-(isop r op yli-
d en d ioxy)p en ta n oic Acid P yr r olid in a m id e (6c). Reaction
with allylamine 1 (2.35 g, 11.12 mmol) following the standard
procedure, reaction time: 6 d. Chromatography: EtOAc/
hexanes 1:1, Rf ) 0.17 (4c) and Rf ) 0.22 (6c). Yield: 2.77 g
(79%). Separation of the diastereomeric amides 4c and 6c
(ratio: 7:3) via preparative HPLC: Eluent: 5% 2-propanol in
hexanes. Major diastereomer amide 4c: retention time 3.33
(2S,3S,4S)-2-Ch lor o-3-e t h e n yl-4,5-(isop r op ylid e n d i-
oxy)pen tan oic Acid P yr r olidin am ide (4h ) an d (2R,3R,4S)-
2-Ch lor o-3-et h en yl-4,5-(isop r op ylid en d ioxy)p en t a n oic
Acid P yr r olid in a m id e (5h ). Reaction with allylamine 1 (3.5
g, 16.56 mmol) following the standard procedure, reaction
time: 2 d. Chromatography: EtOAc/hexanes 1:1, Rf ) 0.22
(4h ) and Rf ) 0.25 (5h ). Yield: 3.9 g (82%). Separation of
the diastereomeric amides 4h and 5h (ratio: 60:1) via pre-
parative HPLC: Eluent: 5% 2-propanol in hexanes. Major
diastereomer amide 4h : retention time 2.71 min, 3.84 g
min, 1.94 g (55.3%). [R]23 -2.1 (c ) 0.9 in CHCl3): IR (KBr,
(80.7%), mp 87 °C. [R]23 72.1 (c ) 1.3 in CHCl3). IR (KBr,
D
D
film) 3076, 1634 (CO), 1444, 1380, 1370 cm-1. MS (EI, 70 eV,
60 °C): m/ z 315 (M+), 300 (M+ - CH3), 280, 214, 175, 152,
126, 98, 83, 70. 1H-NMR δ 1.34 (s, 3 H), 1.42 (s, 3 H), 1.90
(m, 4 H), 2.08 (m, 1 H), 2.24 (m, 1 H), 2.40 (dt, J ) 2.5, 8.8 Hz,
1 H), 3.10 (dt, J ) 3.8, 8.8 Hz, 1 H), 3.46 (m, 4 H), 3.64 (m, 3
H), 3.98(t, J ) 7 Hz, 1 H), 4.36 (m, 1 H), 5.10 (d, br, J ) 17.5
Hz, 1 H), 5.16 (d, br, J ) 10 Hz, 1 H), 5.88 (td, J ) 10, 17.5
Hz, 1 H). 13C-NMR δ 24.1 (t), 24.9 (q), 25.8 (t), 25.9 (q), 32.5
(t), 42.7 (d), 43.2 (t), 45.4 (t), 46.7 (t), 48.5 (d), 66.9 (t), 73.9
(d), 108.7 (s), 118.7 (t), 134.0 (d), 171.7 (s). Anal. Calcd: C,
60.85; H, 8.3; N, 4.43. Found: C, 60.71; H, 8.15; N, 4.22.
Minor diastereomer amide 6c: retention time 2.91 min, 0.83
g (23.6%). [R]23D 31.9 (c ) 0.8 in CHCl3). IR (KBr, film) 3075,
1631 (CO), 1444, 1380, 1370 cm-1. MS (EI, 70 eV, 60 °C): m/ z
315 (M+), 300 (M+ - CH3), 280, 257, 222, 215, 175, 152, 126,
101, 98, 71. 1H-NMR δ 1.30 (s, 3 H), 1.40 (s, 3 H), 1.98 (m, 4
H), 2.40 (t, br, J ) 8 Hz, 1 H), 2.54 (q, br, J ) 7.5 Hz, 1 H),
3.08 (m, 1 H), 3.40 (dt, br, J ) 4.3, 10 Hz, 1 H), 3.52 (t, br, J
) 6.3 Hz, 2 H), 3.64 (m, 4 H), 3.92 (m, 2 H), 4.06 (t, br, J ) 6.3
Hz, 1 H), 5.12 (d, J ) 17 Hz, 1 H), 5.32 (d, J ) 10 Hz, 1 H),
5.72 (td, J ) 10, 17 Hz, 1 H). 13C-NMR δ 24.3 (t), 25.0 (q),
25.8 (t), 25.9 (q), 34.4 (t), 43.2 (d), 43.6 (t), 45.6 (t), 46.7 (t),
48.6 (d), 66.7 (t), 75.3 (d), 108.3 (s), 120.1 (t), 134.3 (d), 172.4
(s). Anal. Calcd: C, 60.85; H, 8.3; N, 4.43. Found: C, 60.61;
H, 8.17; N, 4.29.
film) 3077, 1659 (CO), 1435, 1386, 1376 cm-1. MS (EI, 70 eV,
80 °C): m/ z 287 (M+), 272 (M+ - CH3), 252, 229, 216, 194,
186, 152, 147, 101, 98, 83, 81, 70. 1H-NMR δ 1.27 (s, 3 H),
1.33 (s, 3 H), 1.82 (m, 4 H), 2.79 (dt, J ) 7, 7.5 Hz, 1 H), 3.38
(m, 4 H), 3.58 (dd, J ) 7, 7.5 Hz, 1 H), 3.94 (dd, J ) 7, 7.5 Hz,
1 H), 4.42 (d, J ) 10.8 Hz, 1 H), 4.61 (dt, J ) 2.5, 7 Hz, 1 H),
5.16 (dd, J ) 1.3, 18 Hz, 1 H), 5.20 (dd, J ) 1.3, 9.5 Hz, 1 H),
5.58 (td, J ) 9.5, 18 Hz, 1 H). 13C-NMR δ 24.0 (t), 24.7 (q),
25.8 (t), 25.9 (q), 45.9 (t), 46.5 (t), 48.4 (d), 55.9 (d), 66.5 (t),
73.3 (d), 108.9 (s), 122.5 (t), 130.8 (d), 166.0 (s). Anal. Calcd:
C, 58.43; H, 7.7; N, 4.87. Found: C, 58.16; H, 7.47; N, 4.66.
Minor diastereomer amide 5h : retention time 2.07 min, 0.06
g (1.3%). [R]23D -21.5 (c ) 1.4 in CHCl3). IR (KBr, film) 3077,
1655 (CO), 1441, 1380, 1371 cm-1. MS (EI, 70 eV, 60 °C): m/ z
287 (M+), 272 (M+ - CH3), 252, 229, 194, 186, 152, 147, 112,
101, 98, 81, 70. HRMS (EI, 80 eV, 60 °C): calcd: 272.10535,
found: 272.10525. 1H-NMR δ 1.28 (s, 3 H), 1.40 (s, 3 H), 1.91
(m, 4 H), 2.68 (dt, br, J ) 5, 9.8 Hz, 1 H), 3.47 (m, 2 H), 3.58
(m, 2 H), 3.64 (dd, J ) 6.3, 9.4 Hz, 1 H), 3.94 (dd, J ) 6.3, 9.4
Hz, 1 H), 4.18 (td, J ) 6.3, 9.4 Hz, 1 H), 4.7 (d, J ) 5 Hz, 1 H),
5.16 (dd, J ) 1.3, 17 Hz, 1 H), 5.22 (dd, J ) 1.3, 10 Hz, 1 H),
6.16 (td, J ) 10, 17 Hz, 1 H). 13C-NMR δ 24.2 (t), 25.4 (q),
26.1 (t), 26.8 (q), 46.1 (t), 46.6 (t), 53.4 (d), 54.6 (d), 68.1 (t),
75.4 (d), 109.4 (s), 120.3 (t), 133.0 (d), 166.1 (s).
(2S,3S,4S)-2-(Ben zyloxy)-3-eth en yl-4,5-(isop r op ylid en -
d ioxy)p en ta n oic Acid P yr r olid in a m id e (4i) a n d (2R/
S,3R,4S)-2-(Ben zyloxy)-3-eth en yl-4,5-(isopr opyliden dioxy)-
p en ta n oic Acid P yr r olid in a m id e (5/7i). Reaction with
allylamine 1 (2.5 g, 11.83 mmol) following the standard
procedure, reaction time: 2 d. Chromatography: EtOAc/
hexanes 1:1, Rf ) 0.17 (4i) and Rf ) 0.21 (5/7i). Yield: 3.53 g
(83%). Separation of the diastereomeric amides 4i and 5/7i
(ratio: 20:2:1) via preparative HPLC: Eluent: 5% 2-propanol
in hexanes. Major diastereomer amide 4i: retention time 4.52
min, 3.07 g (72.2%). [R]23D -20.6 (c ) 1.3 in CHCl3). IR (KBr,
film) 3064, 3030, 1650 (CO), 1440, 1380, 1369 cm-1. MS (EI,
70 eV, 100 °C): m/ z 359 (M+), 344 (M+ - CH3), 268, 152, 128,
101, 98, 91. 1H-NMR δ 1.38 (s, 3 H), 1.40 (s, 3 H), 1.80 (m, 4
H), 2.7 (dt, J ) 3.8, 10 Hz, 1 H), 3.18 (m, 1 H), 3.42 (m, 3 H),
3.66 (t, br, J ) 7.5 Hz, 1 H), 4.02 (t, br, J ) 6.3 Hz, 1 H), 4.2
(d, J ) 10 Hz, 1 H), 4.48 (d, J ) 11.3 Hz, 1 H), 4.56 (dt, J )
3.8, 7 Hz, 1 H), 4.68 (d, J ) 11.3 Hz, 1 H), 5.12 (d, br, J ) 16.3
Hz, 1 H), 5.16 (d, br, J ) 10 Hz, 1 H), 5.76 (td, J ) 10, 16.3
Hz, 1 H), 7.36 (m, 5 H). 13C-NMR δ 23.5 (t), 25.1 (q), 25.9 (t),
26.0 (q), 45.6 (t), 45.8 (t), 49.2 (d), 67.0 (t), 71.6 (t), 73.7 (d),
77.9 (d), 108.3 (s), 120.2 (t), 127.6 (d), 127.7 (d), 128.1 (d), 131.5
(d), 137.4 (s), 169.0 (s). Anal. Calcd: C, 70.17; H, 8.13; N,
3.9. Found: C, 69.98; H, 7.9; N, 3.89. Minor diastereomer
amides 5/7i (ratio 2:1, not separable): retention time 3.48 min,
0.46 g (10.8%). Data of the major compound: IR (KBr, film)
3066, 3030, 1650 (CO), 1497, 1453 1439 cm-1. MS (EI, 70 eV,
80 °C): m/ z 359 (M+), 344 (M+ - CH3), 268, 259, 253, 152,
128, 101, 98, 91, 70. HRMS (EI, 80 eV, 90 °C): calcd:
344.18618, found: 344.18626. 1H-NMR δ 1.32 (s, 3 H), 1.40
(s, 3 H), 1.86 (m, 4 H), 2.84 (m, 1 H), 3.18 (m, 4 H), 3.48 (m, 1
H), 3.8 (t, J ) 7.5 Hz, 1 H), 3.96 (dd, J ) 6.3, 7.5 Hz, 1 H),
4.24 (d, J ) 5 Hz, 1 H), 4.32 (q, br, J ) 6.3 Hz, 1 H), 4.4 (d, J
) 11.3 Hz, 1 H), 4.68 (d, J ) 11.3 Hz, 1 H), 5.18 (d, br, J )
17.5 Hz, 1 H), 5.22 (d, br, J ) 10 Hz, 1 H), 5.88 (td, J ) 10,
17.5 Hz, 1 H), 7.34 (m, 5 H). 13C-NMR δ 23.4 (t), 25.2 (q),
26.2 (t), 26.4 (q), 45.9 (t), 46.1 (t), 49.2 (d), 66.9 (t), 71.6 (t),
(2S,3R,4S)-3-E t h en yl-2-isop r op yl-4,5-(isop r op ylid en -
d ioxy)p en ta n oic Acid P yr r olid in a m id e (4d ). Reaction
with allylamine 1 (1 g, 4.73 mmol) following the standard
procedure, reaction time: 7 d, 3-4 cycles. Chromatography:
EtOAc/hexanes 1:2, Rf ) 0.11. Yield: 0.63 g (45%). Purifica-
tion via preparative HPLC: Eluent: 5% 2-propanol in hexanes
retention time 2.51 min. [R]23 26 (c ) 1 in CHCl3). IR (KBr,
D
film) 3074, 1644 (CO), 1438, 1380, 1369, 1343 cm-1. MS (EI,
70 eV, 50 °C): m/ z 295 (M+), 280 (M+ - CH3), 237, 194, 152,
140, 138, 98, 70. 1H-NMR δ 0.84 (d, J ) 7.5 Hz, 3 H), 0.88 (d,
J ) 7.5 Hz, 3 H), 1.2 (s, 3 H), 1.28 (s, 3 H), 1.78 (m, 4 H), 2.0
(m, br, 1 H), 2.44 (m, 2 H), 3.34 (m, 4 H), 3.54 (t, br, J ) 7 Hz,
1 H), 3.84 (dd, J ) 6.3, 7.5 Hz, 1 H), 4.16 (dt, br, J ) 2.5, 6.3
Hz, 1 H), 4.92 (dd, J ) 1.1, 17.5 Hz, 1 H), 5.0 (dd, J ) 1.1, 10
Hz, 1 H), 5.84 (m, 1 H). 13C-NMR δ 18.7 (q), 20.6 (q), 24.1 (t),
25.0 (q), 25.9 (t), 26.0 (q), 28.0 (d), 45.1 (t), 46.3 (t), 47.0 (d),
50.2 (d), 67.1 (t), 75.1 (d), 108.5 (s), 118.1 (t), 134.7 (d), 171.9
(s). Anal. Calcd: C, 69.12; H, 9.89; N, 4.74. Found: C, 69.06;
H, 9.76; N, 4.5.
(2S,3R,4S)-2,3-Di-eth en yl-4,5-(isop r op ylid en d ioxy)p en -
ta n oic Acid P yr r olid in a m id e (4e). Reaction with allyl-
amine 1 (2 g, 9.47 mmol) following the standard procedure,
reaction time: 2 d. Chromatography: EtOAc/hexanes 1:1, Rf
) 0.17. Yield: 1.64 g (62%), mp 57 °C. Purification via
preparative HPLC: Eluent: 9% 2-propanol in hexanes reten-
tion time 2.89 min. [R]23 -17.9 (c ) 1.7 in CHCl3). IR (KBr,
D
film) 3077, 3014, 1633 (CO), 1435, 1381 cm-1. MS (EI, 70 eV,
60 °C): m/ z 279 (M+), 264 (M+ - CH3), 221, 208, 178, 152,
139, 124, 98, 70. 1H-NMR δ 1.24 (s, 3 H), 1.32 (s, 3 H), 1.8
(m, 4 H), 2.54 (dt, J ) 2.5, 9.5 Hz, 1 H), 3.34 (m, 4 H), 3.46 (t,
J ) 6.3 Hz, 1 H), 3.54 (t, J ) 7.5 Hz, 1 H), 3.84 (dd, J ) 6.3,
7.5 Hz, 1 H), 4.24 (m, 1 H), 5.04 (dd, J ) 1, 16.3 Hz, 1 H), 5.08
(dd, J ) 1, 9.5 Hz, 1 H), 5.14 (dd, J ) 1, 10 Hz, 1 H), 5.22 (dd,
J ) 1, 17.5 Hz, 1 H), 5.71 (td, J ) 9.5, 17.5 Hz, 1 H), 5.79 (td,
J ) 10, 16.3 Hz, 1 H). 13C-NMR δ 24.1 (t), 25.0 (q), 25.7 (t),
26.0 (q), 45.4 (t), 46.2 (t), 47.1 (d), 51.8 (d), 66.9 (t), 74.1 (d),

Diastereoselective Zwitterionic Aza-Claisen Rearrangement
J . Org. Chem., Vol. 61, No. 11, 1996 3683
74.8 (d), 78.6 (d), 108.4 (s), 118.7 (t), 127.6 (d), 127.7 (d), 128.1
(d), 133.5 (d), 137.3 (s), 168.5 (s).
Chromatography: EtOAc/hexanes 1:20, Rf ) 0.22. Yield: 279
mg (92%). [R]23 68 (c ) 2.1 in CHCl3). IR (KBr, film) 3082,
D
1780 (CO), 1472, 1361 cm-1
. MS (EI, 70 eV, 100 °C): m/ z
(1′S,1′R,2R)-2-[1-(3,3-Dim eth yl-2,4-d ioxola n yl)-2-p r op e-
n yl]-3,5-h exa d ien oic Acid P yr r olid in a m id e (6f). Reaction
with allylamine 1 (1.5 g, 7.1 mmol) following the standard
procedure, reaction time: 2 d. Chromatography: EtOAc/
hexanes 1:2, Rf ) 0.18. Yield: 1.3 g (60%). Purification via
preparative HPLC, the product should not be stored for more
than one week because of its low stability! Eluent: 5%
318 (M+), 303 (M+ - CH3), 263, 261, 243, 233, 197, 155, 117,
105, 93, 89, 81, 75. 1H-NMR δ 0.02 (s, 3 H), 0.04 (s, 3 H), 0.86
(s, 9 H),1.82 (tdd, J ) 6, 8, 13.8 Hz, 1 H), 2.17 (tdd, J ) 6, 8,
13.8 Hz, 1 H), 3.01 (td, J ) 5, 7.5 Hz, 1 H), 3.16 (ddd, J ) 6,
8, 11.3 Hz, 1 H), 3.56 (ddd, J ) 6, 8, 11.3 Hz, 1 H), 3.62 (dd,
J ) 5, 11.3 Hz, 1 H), 3.73 (m, 1 H), 3.74 (dd, J ) 5.5, 11.3 Hz,
1 H), 4.45 (q, J ) 5 Hz, 1 H), 5.22 (dd, J ) 0.5, 16.8 Hz, 1 H),
5.26 (dd, J ) 0.5, 10 Hz, 1 H), 5.52 (td, J ) 10, 16.8 Hz, 1 H).
13C-NMR δ -5.6 (q), 18.1 (s), 25.6 (q), 28.6 (t), 41.5 (d), 42.2
(t), 46.2 (d), 62.0 (t), 81.2 (d), 120.9 (t), 129.9 (d), 177.0 (s).
Anal. Calcd: C, 56.49; H, 8.53. Found: C, 56.35; H, 8.44.
(3S,4R,5S)-5-[(ter t-Bu t yld im et h ylsilyloxy)m et h yl]-4-
eth en yl-3-isop r op yl-2(3H)-fu r a n on e (8d ). Reaction with
amide 4d (0.1 g, 0.34 mmol) following the standard procedure.
Chromatography: EtOAc/hexanes 1:15, Rf ) 0.23. Yield: 92
mg (91%). Purification via preparative HPLC: Eluent: 5%
2-propanol in hexanes retention time 2.29 min. [R]23 -34.7
D
(c ) 1 in CHCl3). IR (KBr, film) 3077, 1639 (CO), 1432, 1369
cm-1. MS (EI, 70 eV, 60 °C): m/ z 305 (M+), 290 (M+ - CH3),
204, 165, 164, 152, 98, 83, 70. HRMS (EI, 80 eV, 60 °C):
calcd: 305.19907, found: 305.19913. 1H-NMR δ 1.3 (s, 3 H),
1.4 (s, 3 H), 1.83 (m, 2 H), 1.92 (m, 2 H), 2.65 (dt, J ) 2, 10
Hz, 1 H), 3.42 (m, 3 H), 3.49 (m, 2 H), 3.6 (t, J ) 7.5 Hz, 1 H),
3.92 (dd, J ) 6.3, 7.5 Hz, 1 H), 4.24 (dt, br, J ) 2.5, 7 Hz, 1
H), 5.07 (dd, J ) 2, 10.5 Hz, 1 H), 5.15 (dd, J ) 2, 16.3 Hz, 1
H), 5.16 (dd, J ) 2, 11 Hz, 1 H), 5.19 (dd, J ) 2, 15 Hz, 1 H),
5.74 (m, 2 H), 6.25 (dd, J ) 11, 15 Hz, 1 H), 6.34 (td, J ) 10.5,
16.3 Hz, 1 H). 13C-NMR δ 24.0 (t), 24.9 (q), 25.6 (t), 25.9 (q),
45.4 (t), 46.2 (t), 47.5 (d), 50.5 (d), 66.7 (t), 74.2 (d), 108.2 (s),
116.6 (t), 119.3 (t), 130.6 (d), 133.7 (d), 134.1 (d), 136.3 (d),
170.3 (s).
2-propanol in hexanes retention time 3.0 min. [R]23 28.7 (c
D
) 0.7 in CHCl3). IR (KBr, film) 3081, 1781 (CO), 1472, 1388
cm-1. MS (EI, 70 eV, 60 °C): m/ z 298 (M+), 283 (M+ - CH3),
263, 241, 211, 189, 155, 147, 117, 105, 95, 89, 75. 1H-NMR δ
0.04 (2 × s, 6 H), 0.86 (s, 9 H), 0.9 (d, J ) 6.5 Hz, 3 H), 1.22
(d, J ) 6.5 Hz, 3 H), 1.82 (m, 1 H), 2.3 (dd, J ) 6.3, 7.5 Hz, 1
H), 3.1 (ddd, J ) 5.5, 6.3, 10 Hz, 1 H), 3.6 (dd, J ) 5.5, 11.3
Hz, 1 H), 3.72 (dd, J ) 6.3, 11.3 Hz, 1 H), 4.32 (q, br, J ) 6
Hz, 1 H), 5.2 (dd, J ) 1.3, 16.3 Hz, 1 H), 5.24 (dd, J ) 1.3, 10
Hz, 1 H), 5.56 (td, J ) 10, 16.3 Hz, 1 H). 13C-NMR δ -5.8 (q),
-5.5 (q), 18.1 (s), 20.6 (q), 20.9 (q), 25.7 (q), 25.8 (d), 47.1 (d),
51.9 (d), 62.3 (t), 80.6 (d), 120.4 (t), 130.5 (d), 176.5 (s). Anal.
Calcd: C, 64.38; H, 10.13. Found: C, 64.3; H, 10.07.
(2S,3R,4S)-3-Eth en yl-4,5-(isop r op ylid en d ioxy)-2-p h en -
ylp en ta n oic Acid P yr r olid in a m id e (6g). Reaction with
allylamine 1 (1 g, 4.73 mmol) following the standard procedure,
reaction time: 7 d, 3-4 cycles. Chromatography: EtOAc/
hexanes 1:2, Rf ) 0.2. Yield: 0.81 g (52%), mp 113 °C.
Purification via preparative HPLC: Eluent: 2% 2-propanol
in hexanes retention time 3.99 min. [R]23 -23.3 (c ) 1.4 in
D
CHCl3). IR (KBr, film) 3075, 3040, 1632 (CO), 1602, 1491,
1456 cm-1. MS (EI, 70 eV, 90 °C): m/ z 329 (M+), 314 (M+
-
(3S,4R,5S)-3,4-Di-eth en yl-5-(h yd r oxym eth yl)-2(3H)-fu -
r a n on e (8e). Reaction with amide 4e (0.42 g, 1.5 mmol)
following the standard procedure without the silylation step.
Chromatography: EtOAc/hexanes 1:2, Rf ) 0.2. Yield: 212
mg (84%). Purification via preparative HPLC: Eluent: 7%
2-propanol in hexane retention time 3.91 min, about 30 mg of
the impure R,â-unsaturated lactone could be separated (reten-
tion time 3.37 min). The product is unstable and decomposes
CH3), 271, 258, 242, 228, 189, 160, 129, 118, 98, 91, 70. 1H-
NMR δ 1.18 (s, 3 H), 1.38 (s, 3 H), 1.78 (m, 3 H), 1.92 (m, 1 H),
2.98 (t, br, J ) 10.5 Hz, 1 H), 3.4 (m, 4 H), 3.6 (m, 3 H), 3.9 (d,
J ) 10.5 Hz, 1 H), 5.22 (d, br, J ) 10 Hz, 1 H), 5.28 (d, br, J
) 17 Hz, 1 H), 5.84 (td, J ) 10, 17 Hz, 1 H), 7.32 (m, 3 H),
7.54 (m, 2 H). 13C-NMR δ 24.0 (t), 24.9 (q), 25.8 (t), 26.1 (q),
45.6 (t), 46.2 (t), 48.4 (d), 52.4 (d), 66.7 (t), 74.1 (d), 108.2 (s),
119.6 (t), 127.1 (d), 128.3 (d), 129.0 (d), 134.5 (d), 136.9 (s),
170.2 (s). Anal. Calcd: C, 72.92; H, 8.26; N, 4.25. Found:
C, 72.9; H, 8.22; N, 4.2.
in less than two days. [R]23 28.3 (c ) 2 in CHCl3). IR (KBr,
D
film) 3438 (br, OH), 3084, 3019, 1768 (CO), 1643, 1426 cm-1
.
MS (EI, 70 eV, 60 °C): m/ z 168 (M+), 167, 137, 124, 108, 93,
91, 79, 68. 1H-NMR δ 3.3 (ddd, J ) 5, 7.5, 10 Hz, 1 H), 3.54
(t, J ) 7.5 Hz, 1 H), 3.7 (dd, J ) 4, 12.5 Hz, 1 H), 3.8 (dd, J )
7.5, 12.5 Hz, 1 H), 4.16 (s, br, 1 H, OH), 4.64 (ddd, J ) 4, 5,
7.5 Hz, 1 H), 5.2 (dd, J ) 1.2, 16.3 Hz, 1 H), 5.26 (dd, J ) 1.2,
10 Hz, 1 H), 5.32 (dd, J ) 1, 17 Hz, 1 H), 5.36 (dd, J ) 1, 10.5
Hz, 1 H), 5.64 (td, J ) 10, 16.3 Hz, 1 H), 5.72 (ddd, J ) 7.5,
10.5, 17 Hz, 1 H). 13C-NMR δ 47.6 (d), 49.0 (d), 62.1 (t), 81.9
(d), 120.4 (t), 121.2 (t), 129.5 (d), 130.5 (d), 176.3 (s). Anal.
Calcd: C, 64.27; H, 7.19. Found: C, 63.95; H, 6.88.
(4S,5S)-4-Eth en yl-5-(h yd r oxym eth yl)-2(3H)-fu r a n on e
(8a ). The 2-chloro amide 4h (0.33 g, 1.15 mmol) was dissolved
in HOAc (8 mL). Then, the mixture was heated to 105 °C,
with stirring, and Zn (powder, 0.4 g, 6.12 mmol) was added.
After about 1 h, the reaction was found to be complete. After
cooling to rt, H2O (30 mL, 0 °C) was added. The mixture was
neutralized with solid NaHCO3 and then extracted with CH2-
Cl2 (5 × 15 mL). The organic layers were dried (MgSO4), and
the solvent was removed. The crude material was purified
by chromatography on silica gel (EtOAc/hexanes 1:1) to give
lactone 8a (134 mg, 82%) and the corresponding 5-acetoxy-
methyl lactone (impure, 18 mg, 8.5%). For spectral data see
ref 21.
Sta n d a r d P r oced u r e for th e La cton iza tion a n d , If
Need Be, th e Silyla tion . The amide (1 mmol) was dissolved
in methanol (7 mL) and heated to 60 °C. TFA (2.5 mL) was
added. The mixture was stirred at 60 °C to 70 °C (about 16
h), until the reaction was found to be complete. Then, the
solvent was removed and the crude material was vacuum-
dried. The hydroxy lactone was either purified via column
chromatography on silica gel or directly used for the protection
step.
(3S,4S,5S)-3-Ch lor o-4-eth en yl-5-(h ydr oxym eth yl)-2(3H)-
fu r a n on e a n d (3S,4S,5S)-5-[(ter t-Bu tyld im eth ylsilyloxy)-
m eth yl]-3-ch lor o-4-eth en yl-2(3H)-fu r a n on e (8h ). Hydroxy
lactone 8h a : Reaction with amide 4h (0.5 g, 1.74 mmol)
following the standard procedure without the silylation step.
Chromatography: EtOAc/hexanes 1:1, Rf ) 0.14. Yield: 291
mg (95%). [R]23 33.6 (c ) 2.4 in CHCl3). IR (KBr, film) 3404
D
(br, OH), 3086, 1786 (CO), 1642, 1427 cm-1. MS (EI, 70 eV,
60 °C): m/ z 176 (M+), 145, 141, 102, 88, 81, 67, 53. 1H-NMR
δ 3.14 (s, br, 1 H, OH), 3.52 (ddd, J ) 6.2, 7.5, 10 Hz, 1 H),
3.74 (dd, J ) 3, 12.5 Hz, 1 H), 3.85 (dd, J ) 8.3, 12.5 Hz, 1 H),
4.7 (ddd, J ) 3, 6.3, 8.3 Hz, 1 H), 4.78 (d, J ) 7.5 Hz, 1 H),
5.34 (dd, J ) 1, 16.3 Hz, 1 H), 5.38 (dd, J ) 1, 10 Hz, 1 H),
5.68 (td, J ) 10, 16.3 Hz, 1 H). 13C-NMR δ 47.8 (d), 55.0 (d),
62.1 (t), 81.8 (d), 122.2 (t), 128.6 (d), 171.9 (s). Anal. Calcd:
C, 47.61; H, 5.14. Found: C, 47.49; H, 5.01. Silyloxy lactone
8h b: Reaction with amide 4h (0.3 g, 1.04 mmol) following the
standard procedure, imidazole was replaced by pyridine.
Chromatography: EtOAc/hexanes 1:20, Rf ) 0.17. Yield: 267
mg (88%). [R]23D 29.8 (c ) 1.7 in CHCl3). IR (KBr, film) 3086,
1796 (CO), 1643, 1472 cm-1. MS (EI, 70 eV, 50 °C): m/ z 290
(M+), 275 (M+ - CH3), 233, 203, 189, 123, 117, 101, 93, 75.
1H-NMR δ 0.01 (2 × s, 6 H), 0.84 (s, 9 H), 3.44 (ddd, J ) 5.5,
7.5, 10 Hz, 1 H), 3.68 (dd, J ) 5, 11.3 Hz, 1 H), 3.78 (dd, J )
Silyla tion . The hydroxy lactone was dissolved in dry CH2-
Cl2 (10 mL) and subsequently treated with imidazole (272 mg,
4 mmol) and TBDMSCl (301 mg, 2 mmol). After stirring for
12 h at rt the reaction was complete. The mixture was
quenched with H2O (25 mL), and then the aqueous layer was
extracted with CH2Cl2 (5 × 10 mL). The combined organic
layers were dried (MgSO4), and after concentration the residue
was purified via chromatography on silica gel.
(3S,4R,5S)-5-[(ter t-Bu tyld im eth ylsilyloxy)m eth yl]-3-(2-
ch lor oeth yl)-4-eth en yl-2(3H)-fu r an on e (8c). Reaction with
amide 4c (0.3 g, 0.95 mmol) following the standard procedure.

3684 J . Org. Chem., Vol. 61, No. 11, 1996
Nubbemeyer
6, 11.3 Hz, 1 H), 4.54 (q, br, J ) 5.5 Hz, 1 H), 4.66 (d, J ) 7.5
Hz, 1 H), 5.26 (d, br, J ) 16.3 Hz, 1 H), 5.32 (d, br, J ) 10 Hz,
1 H), 5.64 (td, J ) 10, 16.3 Hz, 1 H). 13C-NMR δ -5.6 (q),
-5.5 (q), 18.1 (s), 25.7 (q), 48.0 (d), 55.0 (d), 62.2 (t), 81.1 (d),
121.9 (t), 128.9 (d), 171.3 (s). Anal. Calcd: C, 53.68; H, 7.97.
Found: C, 53.59; H, 7.9.
silylation step. Chromatography: EtOAc/hexanes 1:2, Rf )
0.18. Yield: 249 mg (85%). The product is unstable and
decomposes in less than one day. [R]23D 33 (c ) 0.8 in CHCl3).
IR (KBr, film) 3439 (br, OH), 3083, 3016, 1770 (CO), 1642,
1425 cm-1. MS (EI, 70 eV, 80 °C): m/ z 194 (M+), 165, 150,
134, 119, 105, 95, 91, 85, 83, 79. HRMS (EI, 80 eV, 80 °C):
calcd: 194.09430, found: 194.09415. 1H-NMR δ 3.18 (ddd, J
) 8.4, 9.5, 11.3 Hz, 1 H), 3.5 (s, br, 1 H, OH), 3.53 (dd, J )
7.4, 11.3 Hz, 1 H), 3.76 (dd, J ) 2.7, 12.7 Hz, 1 H), 3.91 (dd, J
) 2.7, 12.7 Hz, 1 H), 4.53 (td, J ) 2.7, 8.4 Hz, 1 H), 5.09 (dd,
J ) 1.5, 9.5 Hz, 1 H), 5.22 (m, 3 H), 5.59 (dd, J ) 7.4, 14.6 Hz,
1 H), 5.94 (td, J ) 9.5, 18.1 Hz, 1 H), 6.21 (dd, J ) 10.4, 14.6
Hz, 1 H), 6.32 (td, J ) 10.3, 16.5 Hz, 1 H). 13C-NMR δ 47.7
(d), 49.1 (d), 61.5 (t), 81.0 (d), 117.6 (t), 119.8 (t), 127.3 (d),
133.4 (d), 135.0 (d), 136.0 (d), 177.3 (s).
(3S,4R,5S)-5-[(ter t-Bu t yld im et h ylsilyloxy)m et h yl]-4-
eth en yl-3-p h en yl-2(3H)-fu r a n on e (10g). Reaction with
amide 6g (0.26 g, 0.79 mmol) following the standard procedure.
Chromatography: EtOAc/hexanes 1:20, Rf ) 0.12. Yield: 241
mg (92%). [R]23D 58.5 (c ) 0.8 in CHCl3). IR (KBr, film) 3084,
3065, 3031, 1776 (CO), 1492, 1471 cm-1. MS (EI, 70 eV, 60
°C): m/ z 332 (M+), 275, 117, 89, 73. 1H-NMR δ 0.12 (2 × s,
6 H), 0.96 (s, 9 H), 3.36 (td, J ) 8.5, 11.3 Hz, 1 H), 3.86 (dd, J
) 1.2, 11.3 Hz, 1 H), 3.96 (dd, J ) 2.5, 11.3 Hz, 1 H), 4.04 (d,
J ) 11.3 Hz, 1 H), 4.54 (d, br, J ) 8.3 Hz, 1 H), 5.08 (d, br, J
) 17 Hz, 1 H), 5.18 (dd, J ) 1.2, 10 Hz, 1 H), 6.0 (ddd, J ) 8.8,
10, 17 Hz, 1 H), 7.28 (m, 5 H). 13C-NMR δ -5.9 (q), -5.8 (q),
18.0 (s), 25.7 (q), 51.8 (d), 52.2 (d), 62.6 (t), 79.9 (d), 120.2 (t),
127.3 (d), 128.4 (d), 128.6 (d), 133.5 (d), 136.4 (s), 176.7 (s).
Anal. Calcd: C, 68.63; H, 8.49. Found: C, 68.6; H, 8.44.
Sta n d a r d P r oced u r e for th e Iod ocycliza tion . The
amide (1.5 mmol) or the hydroxy lactone (1.5 mmol) was
dissolved in DME (6 mL) and H2O (6 mL). With exclusion of
light, I2 (0.76 g, 3 mmol) was added. The mixture was
vigorously stirred at rt, until the reaction was found to be
complete. Then, the excess of I2 was reduced with saturated
aqueous Na2S2O3 (5 mL), and H2O (20 mL) was added. The
mixture was extracted with Et2O (4 × 15 mL), the organic
layers were dried (MgSO4), and the solvent was removed. The
crude material was purified via column chromatography on
silica gel, and the diastereomers were separated via prepara-
tive HPLC.
(3S,4S,5S)-3-(Ben zyloxy)-4-eth en yl-5-(h yd r oxym eth yl)-
2(3H)-fu r a n on e (8i). Reaction with amide 4i (0.5 g, 1.39
mmol) following the standard procedure without the silylation
step. Chromatography: EtOAc/hexanes 1:1, Rf ) 0.17.
Yield: 318 mg (92%). [R]23 -4 (c ) 1.2 in CHCl3). IR (KBr,
D
film) 3442 (br, OH), 3087, 3065, 3032, 1788 (CO), 1642, 1497
cm-1. MS (EI, 70 eV, 100 °C): m/ z 248 (M+), 238, 189, 160,
142, 102, 99, 91, 65. 1H-NMR δ 3.32 (td, br, J ) 6.3, 10 Hz, 1
H), 3.64 (dd, J ) 4.5, 12.5 Hz, 1 H), 3.7 (s, br, 1 H, OH), 3.76
(dd, J ) 7.5, 12.5 Hz, 1 H), 4.28 (d, J ) 6.3 Hz, 1 H), 4.48 (m,
1 H), 4.72 (AB-system, J ) 11.3 Hz, 2 H), 5.28 (d, br, J ) 16.3
Hz, 1 H), 5.32 (d, br, J ) 10 Hz, 1 H), 5.74 (td, J ) 10, 16.3
Hz, 1 H), 7.32 (m, 5 H). 13C-NMR δ 46.6 (d), 62.3 (t), 72.0 (t),
75.0 (d), 80.1 (d), 121.1 (t), 127.9 (d), 128.0 (d), 128.3 (d), 128.6
(d), 136.4 (s), 173.8 (s). Anal. Calcd: C, 67.73; H, 6.5.
Found: C, 67.58; H, 6.37.
(3R,4R,5S) 3-(Ben zyloxy)-5-[(ter t-bu tyld im eth ylsilyl-
oxy)m eth yl]-4-eth en yl-2(3H)-fu r an on e (9i) an d (3S,4R,5S)-
3-(Ben zyloxy)-5-[(ter t-bu tyld im eth ylsilyloxy)m eth yl]-4-
eth en yl-2(3H)-fu r a n on e (11i). Reaction with amide 5/7i (0.2
g, 0.56 mmol) following the standard procedure. Chroma-
tography: EtOAc/hexanes 1:1, Rf ) 0.22 (9i) and Rf ) 0.11
(11i). Yield: 162 mg (82%). Separation of the diastereomeric
lactones 9i and 11i (ratio: 3:1) via preparative column
chromatography. Major diastereomer lactone 9i: 121 mg
(61.5%). [R]23 110.7 (c ) 1.7 in CHCl3). IR (KBr, film) 3084,
D
3066, 3032, 1784 (CO), 1643, 1497 cm-1. MS (EI, 70 eV, 80
°C): m/ z 362 (M+), 345, 319, 305, 301, 277, 256, 199, 171, 117,
91, 73. 1H-NMR δ 0.04 (2 × s, 6 H), 0.84 (s, 9 H), 3.16 (m, 1
H), 3.68 (dd, J ) 2.5, 11.5 Hz, 1 H), 3.9 (dd, J ) 2.5, 11.5 Hz,
1 H), 4.24 (d, J ) 6.5 Hz, 1 H), 4.4 (m, 1 H), 4.7 (d, J ) 11.3
Hz, 1 H), 4.84 (d, J ) 11.3 Hz, 1 H), 5.22 (d, br, J ) 16.5 Hz,
1 H), 5.26 (d, br, J ) 10 Hz, 1 H), 5.98 (ddd, J ) 8.8, 10, 16.5
Hz, 1 H), 7.36 (m, 5 H). 13C-NMR δ -5.8 (q), -5.7 (q), 18.0
(s), 25.6 (q), 45.7 (d), 62.3 (t), 71.9 (t), 75.1 (d), 83.0 (d), 119.1
(t), 127.8 (d), 128.3 (d), 131.9 (d), 136.9 (s), 173.9 (s). Anal.
Calcd: C, 66.26; H, 8.34. Found: C, 66.02; H, 8.11. Minor
(1′R,3S,4R,5R)-3-Ch lor o-4-(3,3-dim eth yl-2,4-dioxolan yl)-
5-(iod om eth yl)-2(3H)-fu r a n on e (14) a n d (1′R,3S,4R,5S)-
3-Ch lor o-4-(3,3-d im eth yl-2,4-d ioxola n yl)-5-(iod om eth yl)-
2(3H)-fu r a n on e (15). Reaction with amide 4h (0.63 g, 2.19
mmol) following the standard procedure, reaction time: 12 h.
Chromatography: EtOAc/hexanes 1:5, Rf ) 0.22 (12) and Rf
) 0.15 (13). Yield: 639 mg (81%). Separation of the diaster-
eomeric amides 14 and 15 (ratio: 54:46) via preparative
HPLC: Eluent: 5% 2-propanol in hexanes. Amide 15: reten-
diastereomer lactone 11i: yield 41 mg (20.5%). [R]23 4 (c )
D
1.4 in CHCl3). IR (KBr, film) 3087, 3065, 3032, 1790 (CO),
1645, 1497 cm-1. MS (EI, 70 eV, 60 °C): m/ z 362 (M+), 345,
337, 277, 256, 233, 199, 185, 171, 147, 117, 91, 75, 73. 1H-
NMR δ 0.08 (s, 6 H), 0.88 (s, 9 H), 3.2 (q, br, J ) 10 Hz, 1 H),
3.68 (dd, J ) 3.8, 11.3 Hz, 1 H), 3.9 (dd, J ) 2.5, 11.3 Hz, 1
H), 4.06 (m, 1 H), 4.12 (d, J ) 10 Hz, 1 H), 4.8 (d, J ) 12.3 Hz,
1 H), 5.0 (d, J ) 12.3 Hz, 1 H), 5.24 (d, br, J ) 10.5 Hz, 1 H),
5.28 (d, br, J ) 17.5 Hz, 1 H), 5.68 (ddd, J ) 8.8, 10.5, 17.5
Hz, 1 H), 7.36 (m, 5 H). 13C-NMR δ -5.5 (q), -5.4 (q), 18.3
(s), 25.8 (q), 47.3 (d), 61.6 (t), 72.1 (d), 77.5 (t), 80.0 (d), 120.1
(t), 128.0 (d), 128.1 (d), 128.4 (d), 133.5 (d), 137.0 (s), 173.9 (s).
Anal. Calcd: C, 66.26; H, 8.34. Found: C, 66.0; H, 8.03.
(3R,4R,5S)-5-[(ter t-Bu tyld im eth ylsilyloxy)m eth yl]-3-(2-
ch lor oeth yl)-4-eth en yl-2(3H)-fu r a n on e (10c). Reaction
with amide 6c (0.16 g, 0.51 mmol) following the standard
procedure. Chromatography: EtOAc/hexanes 1:20, Rf ) 0.1.
tion time 1.06 min, 294 mg (37.2%), mp 110 °C. [R]23 -81.4
D
(c ) 0.9 in CHCl3). IR (KBr, film) 1793 (CO), 1454, 1430, 1381
cm-1. MS (EI, 70 eV, 80 °C): m/ z 360 (M+), 345 (M+ - CH3),
303, 285, 233, 175, 101, 72. 1H-NMR δ 1.36 (s, 3 H), 1.40 (s,
3 H), 2.92 (q, br, J ) 9.5 Hz, 1 H), 3.5 (dd, J ) 5.5, 11.3 Hz, 1
H), 3.64 (dd, J ) 3.8, 11.3 Hz, 1 H), 3.92 (dd, J ) 5.5, 8.3 Hz,
1 H), 4.16 (dd, J ) 5.5, 8.3 Hz, 1 H), 4.42 (td, J ) 5.5, 10 Hz,
1 H), 4.66 (d, J ) 10 Hz, 1 H), 4.86 (ddd, J ) 3.8, 5.5, 10 Hz,
1 H). 13C-NMR δ 3.1 (t), 25.5 (q), 26.6 (q), 51.2 (d), 51.5 (d),
67.7 (t), 73.1 (d), 77.8 (d), 109.6 (s), 170.4 (s). Anal. Calcd:
C, 33.31; H, 3.91. Found: C, 33.09; H, 3.71. Amide 14:
Yield: 145 mg (90%). [R]23 52 (c ) 2.8 in CHCl3). IR (KBr,
D
film) 3083, 1773 (CO), 1471, 1346 cm-1. MS (EI, 70 eV, 100
°C): m/ z 318 (M+), 303 (M+ - CH3), 263, 261, 233, 231, 157,
123, 155, 117, 107, 93, 89, 81, 75. 1H-NMR δ 0.04 (s, 3 H),
0.05 (s, 3 H), 0.87 (s, 9 H),1.84 (m, 1 H), 2.13 (m, 1 H), 2.93
(td, J ) 8, 10 Hz, 1 H), 3.03 (td, J ) 6.3, 11.3 Hz, 1 H), 3.68
(td, J ) 6.3, 11.3 Hz, 1 H), 3.74 (d, J ) 11.3 Hz, 1 H), 3.8 (td,
J ) 6.3, 11.3 Hz, 1 H), 3.84 (dd, J ) 2.5, 11.3 Hz, 1 H), 4.38
(d, br, J ) 8 Hz, 1 H), 5.22 (d, br, J ) 10 Hz, 1 H), 5.26 (d, br,
J ) 17.5 Hz, 1 H), 5.96 (td, J ) 10, 17.5 Hz, 1 H). 13C-NMR
δ -5.9 (q), 17.9 (s), 25.6 (q), 33.2 (t), 41.3 (d), 42.0 (t), 49.7 (d),
62.3 (t), 80.0 (d), 120.0 (t), 134.4 (d), 178.0 (s). Anal. Calcd:
C, 56.49; H, 8.53. Found: C, 56.41; H, 8.4.
retention time 1.91 min, 345 mg (43.8%), mp 84 °C. [R]23 22
D
(c ) 1.5 in CHCl3). IR (KBr, film) 1792 (CO), 1482, 1455, 1382
cm-1. MS (EI, 70 eV, 100 °C): m/ z 360 (M+), 345 (M+ - CH3),
303, 285, 169, 147, 101, 72. 1H-NMR δ 1.38 (s, 3 H), 1.47 (s,
3 H), 2.7 (q, br, J ) 7.5 Hz, 1 H), 3.54 (dd, J ) 4.5, 11.3 Hz, 1
H), 3.73 (dd, J ) 4.5, 11.3 Hz, 1 H), 3.96 (dd, J ) 5, 8.8 Hz, 1
H), 4.2 (dd, J ) 6.3, 8.8 Hz, 1 H), 4.26 (q, br, J ) 6.3 Hz, 1 H),
4.32 (m, 1 H), 4.42 (d, J ) 8.5 Hz, 1 H). 13C-NMR δ 7.5 (t),
24.9 (q), 26.3 (q), 53.2 (d), 53.6 (d), 67.1 (t), 75.3 (d), 78.4 (d),
110.0 (s), 169.9 (s). Anal. Calcd: C, 33.31; H, 3.91. Found:
C, 33.02; H, 3.62.
(E)-(3R,4R,5S)-3-Bu tadien yl-4-eth en yl-5-(h ydr oxym eth -
yl)-2(3H)-fu r a n on e (10f). Reaction with amide 6f (0.46 g,
1.51 mmol) following the standard procedure without the
(3a R ,4R ,6a S )-4-(Iod om e t h yl)fu r o[3,4-b]fu r a n -2-on e
(18a ). Reaction with lactone 8a (0.2 g, 1.41 mmol) following
the standard procedure, reaction time: 2 h. Chromatogra-

Diastereoselective Zwitterionic Aza-Claisen Rearrangement
J . Org. Chem., Vol. 61, No. 11, 1996 3685
phy: EtOAc/hexanes 1:2, Rf ) 0.21. Yield: 310 mg (82%).
Separation of the lactone 18a from a mixture of 18a and 19a
(ratio: 5:1) via preparative HPLC: Eluent: 12% 2-propanol
in hexanes. Lactone 18a : retention time 2.6 min, 207 mg
mL) was added. The aqueous layer was extracted with Et2O
(5 × 20 mL), and the combined organic layers were washed
with brine and dried (MgSO4). Evaporation of the solvent and
chromatographic purification on silica gel (EtOAc/hexanes 1:3)
gave 20 and 21: 419 mg (88%, Rf ) 1.8). Separation of the
diastereomeric lactones 20 and 21 (ratio: 1:10) via preparative
HPLC: Eluent: 5% 2-propanol in hexanes. Minor diastere-
omer lactone 20: retention time 2.21 min, 38 mg (8%), mp 107
(54.8%), mp 107 °C. [R]23 16.2 (c ) 2 in CHCl3). IR (KBr,
D
film) 1752 (CO), 1424, 1351 cm-1. MS (EI, 70 eV, 90 °C): m/ z
268 (M+), 181, 141, 127, 99, 83. 1H-NMR δ 2.56 (m, 1 H), 2.91
(m, 1 H), 2.93 (m, 1 H), 3.25 (dd, J ) 7.5, 10 Hz, 1 H), 3.3 (dd,
J ) 5, 10 Hz, 1 H), 3.91 (td, J ) 5, 7.5 Hz, 1 H), 4.09 (dd, J )
2, 11.3 Hz, 1 H), 4.21 (dd, J ) 4.5, 11.3 Hz, 1 H), 5.13 (ddd, J
) 2, 4.5, 6 Hz, 1 H). 13C-NMR δ 6.7 (t), 33.6 (t), 44.7 (d), 72.5
(t), 84.1 (d), 84.5 (d), 175.3 (s). Anal. Calcd: C, 31.37; H, 3.38.
Found: C, 31.15; H, 3.11. The complete separation of the
minor diastereomer 19a (retention time 2.7 min) from the
major compound failed, 103 mg of a 1:1 mixture of 18a and
19a remained.
°C. [R]23 43.5 (c ) 0.8 in CHCl3). IR (KBr, film) 3473 (br,
D
OH), 3081, 1777 (CO), 1456 cm-1. MS (EI, 70 eV, 60 °C): m/ z
212 (M+), 183, 170, 156, 152, 126, 111, 98, 87, 81, 70, 68. 1H-
NMR δ 0.92 (t, J ) 7 Hz, 3 H), 1.1 (d, J ) 7 Hz, 3 H), 1.33 (m,
3 H), 1.5 (m, 2 H), 1.78 (m, 1 H), 1.94, (s, br, 1 H, OH), 2.86
(qi, J ) 7 Hz, 1 H), 3.2 (ddd, J ) 4.5, 7, 10 Hz, 1 H), 3.68 (dt,
br, J ) 1.3, 8.3 Hz, 1 H), 4.11 (dd, J ) 4.5, 8.8 Hz, 1 H), 5.1
(dd, J ) 2, 16.3 Hz, 1 H), 5.14 (dd, J ) 2, 10 Hz, 1 H), 5.69 (td,
J ) 10, 16.3 Hz, 1 H). 13C-NMR δ 10.4 (q), 13.9 (q), 22.5 (t),
27.1 (t), 33.6 (t), 39.6 (d), 47.9 (d), 69.3 (d), 82.4 (d), 120.5 (t),
131.9 (d), 178.3 (s). Anal. Calcd: C, 67.89; H, 9.5. Found:
C, 67.54; H, 9.19. Major diastereomer lactone 21: retention
(3S,3a R,4R,6a S)-4-(Iod om eth yl)-3-m eth ylfu r o[3,4-b]fu -
r a n -2-on e (18b). Reaction with lactone 8b (0.15 g, 0.96 mmol)
following the standard procedure, reaction time: 3 h. Chroma-
tography: EtOAc/hexanes 1:4, Rf ) 0. 1. Yield: 238 mg (88%),
time 2.59 min, 381 mg (80%), mp 65-66 °C. [R]23 -2.2 (c )
mp 90 °C. [R]23 1.7 (c ) 1.2 in CHCl3). IR (KBr, film) 1755
D
D
(CO), 1462, 1383 cm-1. MS (EI, 70 eV, 80 °C): m/ z 282 (M+),
155, 141, 113, 99, 97, 81, 71, 69. 1H-NMR δ 1.32 (d, J ) 6.3
Hz, 3 H), 2.98 (m, 2 H), 3.25 (dd, J ) 5, 10 Hz, 1 H), 3.35 (dd,
J ) 6.2, 10 Hz, 1 H), 4.02 (q, br, J ) 5.5 Hz, 1 H), 4.12 (dd, J
) 1.3, 11.3 Hz, 1 H), 4.16 (dd, J ) 3.8, 11.3 Hz, 1 H), 5.05 (dt,
br, J ) 1.3, 3.8 Hz, 1 H). 13C-NMR δ 8.6 (t), 11.3 (q), 36.8 (d),
49.1 (d), 72.0 (t), 77.8 (d), 82.7 (d), 177.5 (s). Anal. Calcd: C,
34.06; H, 3.93. Found: C, 33.85; H, 3.7.
1 in CHCl3). IR (KBr, film) 3327 (br, OH), 3081, 1776 (CO),
1469 cm-1. MS (EI, 70 eV, 60 °C): m/ z 212 (M+), 183, 170,
156, 139, 126, 111, 87, 81, 70. 1H-NMR δ 0.92 (t, J ) 7 Hz, 3
H), 1.13 (d, J ) 7 Hz, 3 H), 1.35 (m, 4 H), 1.5 (m, 2 H), 2.29,
(s, br, 1 H, OH), 2.91 (qi, J ) 7 Hz, 1 H), 3.06 (ddd, J ) 4.8, 7,
10 Hz, 1 H), 3.7 (t, br, J ) 7.8 Hz, 1 H), 4.21 (dd, J ) 4.8, 7.8
Hz, 1 H), 5.2 (dd, J ) 1, 17 Hz, 1 H), 5.29 (dd, J ) 1, 10 Hz,
1 H), 5.59 (td, J ) 10, 17 Hz, 1 H). 13C-NMR δ 10.4 (q), 13.8
(q), 26.3 (t), 26.9 (t), 30.1 (t), 40.1 (d), 47.7 (d), 70.3 (d), 84.6
(d), 120.4 (t), 130.6 (d), 178.0 (s). Anal. Calcd: C, 67.89; H,
9.5. Found: C, 67.8; H, 9.43.
(3S,3a R,4R,6a S)-3-Ch lor o-4-(iod om eth yl)fu r o[3,4-b]fu -
r a n -2-on e (18h ). Reaction with lactone 8h (0.16 g, 0.91 mmol)
following the standard procedure, reaction time: 4 h. Chroma-
tography: EtOAc/hexanes 1:2, Rf ) 0. 22. Yield: 233 mg
r el-(3S,3a R,6S,6a S)-6-Bu t yl-3-m et h ylt et r a h yd r ofu r o-
[3,4-b]fu r a n -2,4(3H, 3a H)-d ion e [(-)-3-epi-d ih yd r oca n a -
d en solid e (22)]:
(85%), mp 162 °C. [R]23 -2.1 (c ) 2.3 in CHCl3). IR (KBr,
D
film) 1774 (CO), 1416, 1371 cm-1
. MS (EI, 70 eV, 100 °C):
m/ z 302 (M+), 175, 161, 117, 97, 91, 88, 81, 69. 1H-NMR δ
3.24 (td, br, J ) 3.8, 8.8 Hz, 1 H), 3.4 (dd, J ) 5, 11.3 Hz, 1
H), 3.58 (dd, J ) 2.5, 11.3 Hz, 1 H), 4.12 (m, 1 H), 4.2 (d, br,
J ) 11.3 Hz, 1 H), 4.34 (dd, J ) 3.8, 11.3 Hz, 1 H), 4.9 (d, J )
8.8 Hz, 1 H), 5.16 (t, br, J ) 3.8 Hz, 1 H). 13C-NMR δ 9.1 (t),
49.8 (d), 53.2 (d), 72.9 (t), 78.5 (d), 82.6 (d), 170.1 (s). Anal.
Calcd: C, 27.79; H, 2.67. Found: C, 27.51; H, 2.44.
(3S,3a R,4R,6a S) 3-(Ben zyloxy)-4-(iod om eth yl)fu r o[3,4-
b]fu r a n -2-on e (18i). Reaction with lactone 8i (0.15 g, 0.6
mmol) following the standard procedure, reaction time: 1 h.
Chromatography: EtOAc/hexanes 1:4, Rf ) 0. 11. Yield: 212
mg (94%), mp 123 °C. [R]23D -50.6 (c ) 1 in CHCl3). IR (KBr,
film) 3062, 3035, 1783 (CO), 1455, 1427 cm-1. MS (EI, 70 eV,
120 °C): m/ z 374 (M+), 268, 141, 107, 97, 91. 1H-NMR δ 3.02
(q, br, J ) 6.3 Hz, 1 H), 3.27 (dd, J ) 4.3, 11 Hz, 1 H), 3.43
(dd, J ) 5, 11 Hz, 1 H), 4.1 (d, J ) 11.3 Hz, 1 H), 4.21 (m, 1
H), 4.45 (d, J ) 8.8 Hz, 1 H), 4.83 (d, J ) 11.5 Hz, 1 H), 4.97
(t, br, J ) 3.8 Hz, 1 H), 5.05 (d, J ) 11.5 Hz, 1 H), 7.38 (m, 5
H). 13C-NMR δ 9.7 (t), 48.6 (d), 72.7 (t), 72.9 (t), 73.4 (d), 76.9
(d), 81.3 (d), 127.9 (d), 128.2 (d), 128.6 (d), 136.5 (s), 173.5 (s).
Anal. Calcd: C, 44.94; H, 4.04. Found: C, 44.76; H, 3.9.
(1′R,3S,4R,5S)-4-Eth en yl-5-(1-h yd r oxyp en tyl)-3-m eth -
yl-2(3H)-fu r a n on e (20) a n d (1′S,3S,4R,5S)-4-Eth en yl-5-(1-
h yd r oxyp en tyl)-3-m eth yl-2(3H)-fu r a n on e (21).
Sw er n Oxid a tion . Under Ar, oxalyl chloride (0.26 mL, 391
mg, 3.08 mmol) was dissolved in dry THF (25 mL) at -60 °C.
Dry DMSO (0.24 mL, 265 mg, 3.39 mmol) in dry THF (5 mL)
was slowly injected with stirring. The reaction temperature
was maintained at -55 °C to -60 °C for 1 h, and then 8b (350
mg, 2.24 mmol) in dry THF (5 mL) was added. After stirring
for 1 h at -60 °C to -65 °C, dry Et3N (0.89 mL, 648 mg, 6.41
mmol) was injected slowly, and the white precipitate of Et3N‚
HCl occurred. After stirring for 1 h at -55 °C to -60 °C, the
mixture was allowed to warm up to rt. Careful TLC monitor-
ing indicated the completion of the oxidation after about 30
min (Rf aldehyde ) 0.17, EtOAc/hexanes, 1:1). The mixture
was then immediately cooled to -70 °C.
Ozon lysis. The hydroxy lactone 21 (150 mg, 0.71 mmol)
in MeOH (12 mL) was cooled to -78 °C. A stream of O3/O2
was bubbled through the reaction mixture until the blue color
of unreacted O3 appeared (about 5 min). Reductive workup
with PPh3 (371 mg, 1.41 mmol) led after 1 h stirring at -78
°C and 1 h stirring at rt to a solution of the corresponding
lactol (Rf ) 0.33, EtOAc/hexanes 1:1). Then, the solvent was
removed and the crude material was vacuum dried.
P CC Oxid a tion . The crude lactol in CH2Cl2 (15 mL) was
poured into a suspension of pyridinium chlorochromate (PCC,
2.41 g, 11.2 mmol) in dry CH2Cl2 (30 mL). The mixture was
stirred at rt, until the lactol disappeared after TLC control
(about 6 h, the detection of the product is quite difficult!). Then,
the solution was filtered through 10 cm silica gel (CH2Cl2) to
remove the chromium salts. Evaporation of the solvent gave
a white solid material containing 22 and PPh3O. The bislac-
tone 22 was isolated after chromatography on silica gel
(EtOAc/hexanes 1:2, Rf ) 0.1). Purification via preparative
HPLC (eluent: 10% 2-propanol in hexanes): retention time
5.77 min, yield 109 mg (73%), mp 70 °C. [R]23 -20.6 (c ) 1.3
D
in CHCl3). IR (KBr, film) 1783 and 1764 (CO), 1458 cm-1. MS
(EI, 70 eV, 100 °C): m/ z 212 (M+), 166, 155, 140, 125, 112,
98, 69. 1H-NMR δ 0.96 (t, J ) 5.5 Hz, 3 H), 1.44 (m, 4 H), 1.5
(d, J ) 7.5 Hz, 3 H), 1.88 (m, 2 H), 3.1 (dq, J ) 7.5, 10 Hz, 1
H), 3.5 (dd, J ) 5.3, 10 Hz, 1 H), 4.55 (dt, br, J ) 3.8, 7 Hz, 1
H), 5.06 (dd, J ) 3.8, 5.3 Hz, 1 H). 13C-NMR δ 10.7 (q), 13.7
(q), 22.2 (t), 27.3 (t), 28.3 (t), 36.5 (d), 44.5 (d), 78.0 (d), 81.4
(d), 172.2 (s), 176.2 (s). Anal. Calcd: C, 62.25; H, 7.6.
Found: C, 62.22; H, 7.51.
(1′S,3R,4R,5S)-4-Eth en yl-5-(1-h yd r oxyp en tyl)-3-m eth -
yl-2(3H)-fu r a n on e (23). Under Ar, 21 (160 mg, 0.75 mmol)
was dissolved in dry THF (11 mL) and KOtBu (43 mg, 0.38
mmol) was added. The mixture was stirred at rt for 1.5 h,
and then 1 N aqueous NaHSO4 (2 mL) was injected. After
neutralizing with saturated aqueous NaHCO3, the aqueous
layer was extracted with Et2O (5 × 15 mL). The combined
organic layers were dried (MgSO4), the solvent was removed,
and the crude material was purified via column chromatog-
raphy (EtOAc/hexanes 1:2, Rf ) 0.24). Purification via pre-
parative HPLC (eluent: 2% 2-propanol in hexanes): retention
Gr ign a r d Rea ction . To the in situ generated aldehyde
was injected a freshly prepared 0.5 M solution of nBuMgBr
(1.6 equiv, 7.3 mL, 3.64 mmol) in dry THF. After a reaction
time of about 4 h at -70 °C, saturated aqueous NH4Cl (40
time 2.2 min, yield 141 mg (88%). [R]23 84.1 (c ) 2.4 in
D

3686 J . Org. Chem., Vol. 61, No. 11, 1996
Nubbemeyer
CHCl3). IR (KBr, film) 3450 (br, OH), 1759 (CO), 1446 cm-1
.
1.4 (m, 4 H), 1.44 (d, J ) 7.5 Hz, 3 H), 1.84 (m, 2 H), 3.04 (q,
br, J ) 7.5 Hz, 1 H), 3.15 (d, br, J ) 6.3 Hz, 1 H), 4.53 (dt, J
) 3.8, 7 Hz, 1 H), 5.09 (dd, J ) 3.8, 6.3 Hz, 1 H). 13C-NMR δ
13.7 (q), 16.8 (q), 22.2 (t), 27.3 (t), 28.3 (t), 38.2 (d), 48.8 (d),
78.4 (d), 82.2 (d), 174.8 (s), 176.8 (s). Anal. Calcd: C, 62.25;
H, 7.6. Found: C, 62. 2; H, 7.51.
MS (EI, 70 eV, 100 °C): m/ z 212 (M+), 156, 126, 111, 97, 87,
81, 70. 1H-NMR δ 0.84 (t, J ) 6.3 Hz, 3 H), 1.07 (d, J ) 6 Hz,
3 H), 1.26 (m, 4 H), 1.58 (m, 2 H), 2.78 (m, br, 3 H), 3.65 (q,
br, J ) 6.3 Hz, 1 H), 4.26 (d, br, J ) 7.5 Hz, 1 H), 5.12 (d, J )
11.3 Hz, 1 H), 5.16 (d, J ) 16.3 Hz, 1 H), 5.92 (m, 1 H). 13C-
NMR δ 13.7 (q), 13.8 (q), 22.4 (t), 27.8 (t), 33.3 (t), 39.2 (d),
51.6 (d), 70.7 (d), 82.2 (d), 119.4 (t), 134.6 (d), 180.3 (s). Anal.
Calcd: C, 67.89; H, 9.5. Found: C, 67.81; H, 9.39.
Ack n ow led gm en t. I thank the DFG and the FNK
for support of this research.
r el-(3R,3a R,6S,6a S) 6-Bu tyl-3-m eth yltetr a h yd r ofu r o-
[3,4-b]fu r an -2,4(3H,3aH)-dion e [(+)-dih ydr ocan aden solide
(24)]. Oxidation sequence starting from hydroxy lactone 23
(120 mg, 0.56 mmol) using conditions as described for bislac-
tone 22. Chromatography: EtOAc/hexanes 1:2, Rf ) 0.14.
Purification via preparative HPLC (eluent: 12% 2-propanol
in hexanes): retention time 2.76 min, yield 96 mg (80%), mp
Su p p or tin g In for m a tion Ava ila ble: NOEDS data for the
compounds 8-11, 14, 15, 18, 22 and 13C NMR spectra for the
compounds 5h , 5/7i, 6f, 10f (7 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
93-94 °C, lit. 94 °C). [R]23 30.3 (c ) 1.9 in CHCl3), 30 (c )
D
1.7 in MeOH), (lit. 30 c ) 1.0 in MeOH). IR (KBr, film) 1767
(CO), 1468 cm-1. MS (EI, 70 eV, 100 °C): m/ z 212 (M+), 166,
155, 139, 125, 112, 98, 69. 1H-NMR δ 0.92 (t, J ) 7 Hz, 3 H),
J O9600464