A stereoselective and short total synthesis of the polyhydroxylated γ-amino acid (-)-detoxinine, based on stereoselective preparation of dihydropyrrole derivatives from lithiated alkoxyallenes

Article abstract of DOI:10.1002/chem.200390160

Based on our earlier results employing lithiated methoxyallene 2 as C₃ building block and imines 3 for the synthesis of dihydropyrrole derivatives 5, we have investigated chiral imines 6, 10, and 15 as electrophilic components. Combined with lithiated alkoxyallenes, these imines provide the corresponding primary adducts and finally the dihydropyrrole derivatives 8, 12, 17, 20, and 22 in good yields and with high to excellent syn selectivities. This stereochemical outcome is interpreted as a result of achelate control. Treatment with hydrochloric acid converted syn-8 and syn-12 into bicyclic compounds 9 and 13, whereas under more mildly acidic conditions adduct syn-17 was transformed into diol syn-18. The total synthesis of the uncommon γ-amino acid (-)-detoxinine could be achieved by starting from (S)-malic acid, which was converted into imine 15 in four steps. Lithiated benzyloxyallene added to imine 15 and efficiently furnished the crucial dihydropyrrole derivative syn-22. The hydrogenolysis of this compound did not directly provide the protected triol 29 as anticipated, but a stepwise protocol made the triol available in a fairly satisfactory manner. A second crucial step of the synthesis was the selective oxidation of 29, which could be achieved by employing platinum dioxide and oxygen. The resulting bicyclic lactone 30 was smoothly transformed into enantiopure (-)-detoxinine. Thus, a fairly short synthesis of this natural product based on a lithiated alkoxyallene could be performed, demonstrating the potential of these intermediates for syntheses of interesting functionalized heterocyclic compounds.

Full text of DOI:10.1002/chem.200390160

FULL PAPER
A Stereoselective and Short Total Synthesis of the Polyhydroxylated
g-Amino Acid (À)-Detoxinine, Based on Stereoselective Preparation of
Dihydropyrrole Derivatives from Lithiated Alkoxyallenes
Oliver Flˆgel,[a] Marlyse Ghislaine Okala Amombo,[a] Hans-Ulrich Rei˚ig,*[a]
Gernot Zahn,[b] Irene Br¸dgam,[c] and Hans Hartl[c]
Abstract: Based on our earlier results
employing lithiated methoxyallene 2 as
C3 building block and imines 3 for the
synthesis of dihydropyrrole derivatives
5, we have investigated chiral imines 6,
10, and 15 as electrophilic components.
Combined with lithiated alkoxyallenes,
these imines provide the corresponding
primary adducts and finally the dihydro-
pyrrole derivatives 8, 12, 17, 20, and 22 in
good yields and with high to excellent
syn selectivities. This stereochemical
outcome is interpreted as a result of a-
chelate control. Treatment with hydro-
chloric acid converted syn-8 and syn-12
into bicyclic compounds 9 and 13, where-
as under more mildly acidic conditions
adduct syn-17 was transformed into diol
syn-18. The total synthesis of the un-
common g-amino acid (À)-detoxinine
could be achieved by starting from (S)-
malic acid, which was converted into
imine 15 in four steps. Lithiated benzyl-
oxyallene added to imine 15 and effi-
ciently furnished the crucial dihydropyr-
role derivative syn-22. The hydrogenol-
ysis of this compound did not directly
provide the protected triol 29 as antici-
pated, but a stepwise protocol made the
triol available in a fairly satisfactory
manner. A second crucial step of the
synthesis was the selective oxidation of
29, which could be achieved by employ-
ing platinum dioxide and oxygen. The
resulting bicyclic lactone 30 was smooth-
ly transformed into enantiopure (À)-
detoxinine. Thus, a fairly short synthesis
of this natural product based on a
lithiated alkoxyallene could be per-
formed, demonstrating the potential of
these intermediates for syntheses of
interesting functionalized heterocyclic
compounds.
Keywords: allenes ¥ amino acids ¥
imines ¥ pyrroles ¥ total synthesis
cyclized to the dihydropyrrole derivatives 5 either under basic
conditions (potassium tert-butoxide in DMSO)or alterna-
tively by use of silver nitrate in acetone. Depending on the
substituents at the nitrogen center, the cyclization may also
occur at the stage of N-lithiated 4, leading directly to
dihydropyrroles 5. Thus, the combination of 2 with 3
established a new and highly flexible synthesis of functional-
ized pyrrole derivatives by means of an efficient [3‡2]
cyclization (Scheme 1).[2, 3]
Herein we present our investigations on the diastereose-
lective additions of 2 and related lithiated alkoxyallenes to
chiral imines,[4] which allow syntheses of enantiopure dihy-
dropyrrole derivatives. As a first application we also present
the straightforward synthesis of the unusual g-amino acid (À)-
detoxinine.
Introduction
In a preliminary communication we reported an expedient
synthesis of pyrrole derivatives with lithiated methoxyallene
and imines as crucial building blocks.[1] Addition of the
nucleophilic C3 unit 2–easily generated by lithiation of
methoxyallene 1 with n-butyllithium–to the imines 3 and
aqueous workup generally provided primary adducts 4 in
excellent yields. Since methoxyallene 1 is easily available on
large scale it is often used in excess to improve the conversion
and yields of this reaction. The allenyl amines 4 can be
[a] Prof. Dr. H.-U. Rei˚ig, O. Flˆgel, Dr. M. G. Okala Amombo
Institut f¸r Chemie Organische Chemie
Freie Universit‰t Berlin
Takustrasse 3, 14195 Berlin (Germany)
Fax (‡49)30-838-55367
E-mail: hans.reissig@chemie.fu-berlin.de
[b] Dr. G. Zahn
Results and Discussion
Institut f¸r Kristallographie und Festkˆrperphysik
Technische Universit‰t Dresden, 01062 Dresden (Germany)
Model reactions: Initial examples with chiral imines were
already presented in our preliminary publication.[1] Treatment
of lithiated methoxyallene 2 with the (R)-glyceraldehyde-
derived N-phenyl imine 6 in tetrahydrofuran furnished an
[c] I. Br¸dgam, Prof. Dr. H. Hartl
Institut f¸r Chemie Anorganische Chemie
Freie Universit‰t Berlin
Fabeckstrasse 34 36, 14195 Berlin (Germany)
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Scheme 1. Synthesis of dihydropyrrole derivatives 5 from methoxyallene 1
and imines 3.
89:11 mixture of the two diastereomeric adducts syn-7 and
anti-7 in excellent yield (Scheme 2). Treatment of this mixture
with silver nitrate afforded a moderate yield of the two
expected cyclization products syn-8 and anti-8 in a similar
ratio of isomers. Chromatography allowed isolation and
characterization of the major diastereomer syn-8, and an
X-ray analysis of a crystal unequivocally confirmed the
anticipated syn configuration (Figure 1).[5] Treatment of syn-
8 with hydrochloric acid (generated by methanolysis of p-
toluenesulfonyl chloride (p-TsCl)) provided bicyclic acetal 9
in good yield, a transformation which demonstrates the
potential of enantiopure dihydropyrroles of type 8 for further
synthetic elaboration. Compound 9 was also used to establish
the configuration by NMR spectroscopy (NOE).
Figure 1. Structure of dihydropyrrole syn-8 (Schakal representation,
hydrogen atoms are shown only at the stereogenic centers).
Scheme 3. Diastereoselective addition of lithiated methoxyallene 2 to
chiral imine 10.
in excellent yield. This mixture was converted into pure syn-12
by silver nitrate catalysis in 57% yield. A more efficient
preparation of this compound was achieved when imine 10
and lithiated methoxyallene 2 were combined at À408C and
the reaction mixture was allowed to warm up to room
temperature over 24 h. This reaction protocol furnished pure
syn-12 in 63% yield. Generally, lithiated primary adducts
bearing an N-alkyl substituent are prone to cyclization under
conditions considerably milder than those required for sub-
strates with electron-withdrawing groups such as phenyl,
tosyl, or tert-butoxycarbonyl substituents.[2, 6, 7] Dihydropyr-
role 12 was converted into bicyclic acetal 13 by treatment with
6n hydrochloric acid in methanol. The moderate yield of only
44% may be due to loss of material by formation of the highly
polar hemiacetal related to 13.
Scheme 2. Diastereoselective addition of lithiated methoxyallene 2 to
chiral imine 6.
Similar results were obtained with the (R)-glyceraldehyde-
derived N-benzyl imine 10 (Scheme 3). Addition of lithiated
methoxyallene 2 to this imine in tetrahydrofuran gave syn-
configured products exclusively. Under standard conditions
with aqueous quenching at À208C, a 1:1 mixture of primary
adduct syn-11 and its cyclization product syn-12 was isolated
Whereas only syn-configured products were observed in
tetrahydrofuran as solvent, treatment of 2 with imine 10 was
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Stereoselective Synthesis of Dihydropyrroles
1405 1415
considerably less diastereoselective in diethyl ether (syn-11/
anti-11 63:37, 83% yield of crude product)or in toluene ( syn-
11/anti-11 57:43, conversion ca. 90%, 72% yield of crude
product).[2] Interestingly, only primary adducts 11 and no
cyclized dihydropyrroles 12 were isolated when these less
polar solvents were employed.[8] It is evident that the excellent
syn selectivity requires polar solvents such as tetrahydrofuran,
which also enhance the cyclization rate, due to the increased
nucleophilicity of the intermediate N-lithiated addition pro-
duct. The syn selectivity may be explained in terms of a chelate-
controlled addition of lithiated methoxyallene 2 to imine 10
involving the a-oxygen of the dioxolane ring in complex
formation (Figure 2).[9] Chelation of the lithium ion by the
tection of this triol furnished 1,3-dioxane derivative 14 in
excellent overall yield (Scheme 4).[11] Swern oxidation of this
alcohol and condensation of the resulting aldehyde with
benzylamine in the presence of magnesium sulfate provided
crude imine 15, which was not purified but directly treated
with lithiated methoxyallene 2. Standard conditions (aqueous
quenching at À208C)furnished the desired primary adduct 16
exclusively as the required syn diastereomer in 45% overall
yield (with respect to alcohol 14). Silver nitrate treatment
converted syn-16 into dihydropyrrole syn-17 in good yield.
This compound was available even more efficiently by direct
cyclization of the lithiated primary adduct derived from 15
and 2, when the reaction mixture was allowed to warm up to
room temperature. The overall yield for syn-17 of 51%, based
on alcohol 14, is very satisfactory since four reaction steps are
involved (oxidation, condensation, addition, cyclization).
Again, the syn diastereomer of 17 was isolated exclusively.
The assignment as the syn isomer was first assumed by
analogy to the outcome with the related imines 6 and 10, but
later confirmed by conversion of derivative syn-22 into (À)-
detoxinine and the X-ray analysis of intermediate 30 (see
below).
Interestingly, compound syn-17 could be hydrolyzed in
good yield just to the stage of diol syn-18–and not to the
expected cyclic acetal related to compounds 9 or 13–by
application of p-toluenesulfonic acid. Apparently, the weaker
sulfonic acid attacks the enol ether unit of syn-17 and syn-18
only slowly, although this behavior was not studied system-
atically.[7] A second model reaction with imine 15 involved
lithiated 2-(trimethylsilyl)ethoxyallene (19)which was gen-
erated under standard conditions from the corresponding
alkoxyallene derivative (Scheme 5).[12] The cyclized product
syn-20 was isolated exclusively, and the overall yield of 44%
(based on alcohol 14)was again fair.
Figure 2. a-Chelate model for the addition of 2 to imines 6 and 10.
imine nitrogen atom and the b-oxygen atom should lead to the
anti products, which would also predominate if stereoelec-
tronic Felkin Anh control were operative in these additions
to 10. Among the solvents examined, tetrahydrofuran is
apparently the most suitable solvent to steer the reaction
pathway via the a-chelate. This interpretation is in accordance
with other reported nucleophilic addition reactions involving
chiral imine 10.[5]
Another model reaction involved imine 15, since alkoxy-
allene adducts derived thereof might be highly suitable for the
planned (À)-detoxinine synthesis (see below). The ultimate
precursor of 15 was (S)-malic acid, which was smoothly
reduced to a chiral 1,2,4-butanetriol.[10] Regioselective pro-
Total synthesis of (À)-detoxinine: (À)-Detoxinine is an
uncommon polyhydroxylated g-amino acid and the parent
component of several depsipeptide metabolites produced by
Streptomyces caespitosus var. detoxicus 7072 GC1 and known
as detoxin complex.[13] Glasshouse tests have shown that
Scheme 4. Synthesis of chiral imine 15 and its diastereoselective reaction with lithiated methoxyallene 2.
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which should first reduce the enol ether double bond to
deliver the required configuration at the missing stereogenic
center, and then transform the benzyl ether and N-benzyl-
amine moieties into free hydroxyl groups and the secondary
amine function under mild conditions. The second, crucial,
reaction would involve the selective oxidation of the primary
alcohol of 21 or its equivalent to the carboxylic acid of
(À)-detoxinine, a problem which could be solved in a
satisfactory manner.
Scheme 5. Diastereoselective addition of lithiated alkoxyallene 19 to
chiral imine 15.
Benzyloxyallene 23 was prepared and lithiated under
standard conditions.[16] Addition of freshly generated imine
15 to the solution of lithiated 23 at À408C followed by slow
warming up to room temperature led to the formation of syn-
22 in 50% overall yield (based on the precursor of 15, alcohol
14, Scheme 7). When this reaction was performed on a larger
scale it was possible to isolate the second diastereomer anti-22
in small amounts by HPLC separation.[17] On the basis of this
experiment, the diastereoselectivity of the addition of lithi-
ated 23 to 15 was calculated to be higher than 97:3 in favor of
the syn isomer. To explore the reactivity of compounds of type
syn-22 we treated it with diisobutylaluminum hydride
(DIBALH), which induced a reductive cleavage of the 1,3-
dioxane ring. Surprisingly, the secondary hydroxy group in the
resulting product syn-24 was unprotected, but not the
expected primary hydroxyl group as expected according to a
literature report.[18] The additional functional groups of syn-22
may undergo complexation with the reducing agent and thus
lead to altered ring-opening behavior. Our hope of selectively
deprotecting the primary alcohol function incorporated in
syn-22, which should facilitate its smooth conversion into a
carboxylic group as required in (À)-detoxinine, was thus
frustrated by this unexpected regioselectivity.
detoxins decrease the phytotoxicity of the rice blast fungicide
Blasticidin S–a nucleoside antibiotic–without interfering
with its desired properties. Total syntheses of racemic[14] and
enantiopure detoxinine[15] have been reported. In general,
these involve many steps with complex reagents, since the
dense sequence of functional groups and the three stereogenic
centers of the natural product are rather challenging.
Our retrosynthetic analysis of (À)-detoxinine first goes
back to (protected)trihydroxylated pyrrolidine derivative 21,
which should be available from the appropriately functional-
ized dihydropyrrole syn-22 (Scheme 6). This compound dis-
connects into C3 building block benzyloxyallene 23 and chiral
We therefore followed our initial plan (Scheme 6)and
examined the reductive conversion of syn-22 into triol 21.
Although we employed several catalysts and a variety of
different reaction conditions, we disappointingly did not
succeed in performing this transformation directly.[7, 19] Hydro-
genolysis of syn-22 in the presence of Pearlman×s catalyst
Pd(OH)2 and Boc anhydride gave dihydropyrrole 25 as major
product, together with smaller amounts of pyrrolidinone 26
(Scheme 8). This experiment reveals to our surprise that the
reductive N-debenzylation of syn-22 is apparently the fastest
step in the anticipated sequence of hydrogenolysis leading to
N-Boc-protected compounds 25 and 26. It also demonstrates
that debenzylation of the enol ether unit of the dihydropyr-
role core is probably faster than debenzylation of the 1,3-
dioxane ring and, most importantly, faster than hydrogenation
of the enol ether double bond. O-Debenzylation leads to an
enol intermediate, which is evidently the precursor of the
Scheme 6. Retrosynthetic analysis of (À)-detoxinine.
imine 15. Since our model studies suggested that syn-22
should be readily available–see the synthesis of compounds
syn-17 and syn-20–the first crucial step of our approach
should be the conversion of syn-22 into triol 21 or its
equivalents. For this purpose we initially planned a one-step
transformation with hydrogen and an appropriate catalyst,
Scheme 7. Stereoselective synthesis of enantiopure dihydropyrrole derivative syn-22.
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Stereoselective Synthesis of Dihydropyrroles
1405 1415
Scheme 8. Hydrogenolyses of syn-22 to provide pyrrolidinone derivative
26.
carbonyl group in compound 26. The moderate mass balance
(50% yield)of this experiment indicates that further products
are generated during this reduction, but these could not be
isolated, due to their higher polarity. We believe that free
secondary amines are formed and that these poison the
palladium catalyst, which is then not able to catalyze the
subsequent desired steps. Experiments performed in the
absence of Boc anhydride or with longer reaction times
provided rather complex product mixtures that could not be
characterized. This is interpreted as further evidence that free
secondary amines generated during the hydrogenolysis com-
plicate this reductive transformation. The 1,3-dioxane ring
with benzylic bonds can be smoothly cleaved under similar
conditions as shown by transformation of 28 into 29 (see
below).
Scheme 9. Completion of the total synthesis of (À)-detoxinine.
methods–including variants which first provide an inter-
mediate aldehyde[20, 7] to be further oxidized into the carbox-
ylic acid–but finally found that direct oxidation of 29 with
platinum dioxide and oxygen provided the most satisfactory
result.[21, 15c] The generated carboxylic acid immediately cy-
clized to d-lactone 30, isolated in 66% yield. The constitution
and configuration of this bicyclic lactone was verified by an
X-ray structure analysis (Figure 3), which clearly demon-
strates that the anticipated syn configuration of all precursors
We came closer to our goal when performing the reduction
with palladium on carbon in the presence of Boc anhydride.
Pyrrolidinone 26 was now the major component, isolated in
50% yield together with saturated pyrrolidine derivative 27.
Formation of 26 is explained by consecutive N- and O-
debenzylation followed by enol ketone tautomerism and N-
Boc protection. The isolation of the benzyl ether 27 demon-
strates that the reduction of the enol ether double bond of
syn-22 is apparently only slightly slower than the O-debenzy-
lation under these conditions. The configuration of 27 was not
rigorously established, but we assume that the double bond
was reduced from the less shielded back side, forming the
stereogenic center as depicted. Again, the catalyst was
probably poisoned by produced amines, since the 1,3-dioxane
ring of 26 and 27 survived under the reductive conditions.
Although syn-22 could be transformed into pyrrolidinone
26 in 50% yield only, this compound is a very good precursor
for the remaining steps of our (À)-detoxinine synthesis.
Reduction of the carbonyl group of 26 proceeded with
excellent diastereoselectivity and efficiency, furnishing pyrro-
lidinol derivative 28 in 84% yield (Scheme 9). Reductive
cleavage of the 1,3-dioxane ring of 28 now occurred without
any problems, leading to an almost quantitative yield of N-
Boc-protected triol 29, which is equivalent to the desired triol
21 as introduced in our plan (see Scheme 6). We mentioned
above that the next hurdle in our route might be the selective
oxidation of the primary hydroxy group. We tried several
Figure 3. Structure of lactone 30 (ORTEP representation, hydrogen atoms
are shown only at the stereogenic centers).
of this compound was correct. This crystal structure makes it
very likely that the assignments for model compounds syn-17
and syn-20 as discussed are also correct. Finally, lactone 30
was treated with trifluoroacetic acid, which induced Boc-
deprotection and opening of the lactone ring to provide (À)-
detoxinine in 89% yield as colorless crystals. The optical
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interpreted as first-order spectra if possible. 13C chemical shifts are
reported relative to CDCl3 (d ˆ 77.0 ppm). Neutral aluminium oxide
(activity III, Fluka/Merck)or silica gel (0.040 0.063 mm, Fluka)were
used for column chromatography. Nucleosil 50 5 (Macherey & Nagel)was
used for HPLC. Melting points are uncorrected. Optical rotations were
determined with Perkin Elmer 141 or Perkin Elmer 241 polarimeters.
Starting materials 1,[24] 6,[25] 10,[26] and 23[16] were prepared by literature
procedures. All other chemicals were commercially available and were
used as received.
rotation of our sample (À5.0 in water), the melting point, and
the spectroscopic data agree well with values reported in
literature for the enantiopure natural product.[15] Most
importantly, these results establish that no racemization
occurred during our multistep synthesis.
A new and short synthesis of (À)-detoxinine, based on a
compound derived from the pool of chiral compounds (malic
acid), was thus established. Our route to this natural product
also opens the way to analogues by exploitation of the enol
ether functionality of syn-22 or the carbonyl group of
pyrrolidinone 26 for the introduction of other or additional
substituents. In addition, epimers of this g-amino acid may be
prepared by selective inversion of configuration at one of the
stereogenic centers.
(1R,4'S)- and (1S,4'S)-[1-(2,2-Dimethyl-1,3-dioxolan-4-yl)-2-methoxybuta-
2,3-dienyl]phenylamine (syn-7, anti-7): nBuLi (2.1m in n-hexane, 6.60 mL,
13.8 mmol)was added at À408C to a solution of methoxyallene 1 (1.08 g,
15.4 mmol)in absolute THF (30 mL). After the mixture had been stirred at
À408C for 5 min, 6 (1.44 g, 7.03 mmol)in absolute THF (7 mL)was added,
and the reaction mixture was allowed to warm up to À208C over 2 h and
then quenched with water (20 mL). The aqueous phase was separated and
extracted with Et2O (3 Â 40 mL). The organic extracts were combined and
dried (Na2SO4). After removal of the solvents, a brown oil (1.76 g, 91%,
purity >90%)was isolated as a mixture of two diastereomers ( syn-7/anti-7
1
89:11, calculated from H NMR spectroscopy).
Conclusion
1
Major diastereomer syn-7: H NMR (CDCl3, 300 MHz): d ˆ 7.16 (dd, J ˆ
7.3, 7.8 Hz, 2H; Ph), 6.72 (t, J ˆ 7.3 Hz, 1H; Ph), 6.65 (d, J ˆ 7.8 Hz, 2H;
Ph), 5.58 5.51, 5.47 5.42 (2  m, 2H; 4-H), 4.42 (q, J ˆ 6.3 Hz, 1H; 4'-H),
In this report we have demonstrated that lithiated alkoxyal-
lenes add with high to outstanding syn diastereoselectivities to
chiral N-phenyl and N-benzyl imines derived from (R)-
glyceraldehyde or an aldehyde prepared from (S)-malic acid.
The resulting primary adducts were either cyclized under
appropriate conditions, or they underwent direct ring-forma-
tion, leading to enantiopure syn-dihydropyrrole derivatives
syn-8, syn-12, syn-17, syn-20, and syn-22. With compound syn-
22 as crucial intermediate we were able to complete a fairly
short and efficient synthesis of the uncommon g-amino acid
(À)-detoxinine. From (S)-malic acid, as a chiral pool com-
pound, we required ten steps (with eight isolated intermedi-
ates)to arrive at this natural product, with an overall yield of
10%. Several of these steps have not been optimized. The
most intriguing feature of our synthetic plan–the reductive
transformation of dihydropyrrole derivative syn-22 into triol
29–could not be achieved directly, but the problem could be
solved by the introduction of two additional steps.
Our results again demonstrate the versatility and high
synthetic value of lithiated alkoxyallenes for serving as C3
building blocks, allowing the stereoselective preparation of
highly functionalized enantiopure heterocycles such as furans,
pyrroles, and 1,2-oxazines, suitable for many further trans-
formations, including syntheses of natural products and their
analogues.[22] Our (À)-detoxinine synthesis emphasizes that
the combination of lithiated alkoxyallenes with chiral imines
allows smooth, flexible, and stereoselective synthesis of
substituted pyrrolidin-3-ol derivatives, a structural motif quite
frequently found in many biologically active natural prod-
ucts.[23]
À
4.17 (dbr, J ˆ 8.0 Hz, 1H; N H), 4.10 4.05 (m, 1H; 1-H), 3.93 3.88 (m,
2H; 5'-H), 3.41 (s, 3H; OMe), 1.45, 1.39 ppm (2 Â s, each 3H, 2 Â Me); 13C
NMR (CDCl3, 75.5 MHz): d ˆ 198.5 (s; C-3), 147.3, 129.1, 117.9, 114.1 (s,
3 Â d; Ph), 132.9 (s; C-2), 109.8 (s; C-2'), 92.5 (t; C-4), 76.6 (d; C-4'), 66.9 (t;
C-5'), 57.3 (d; C-1), 56.5 (q; OMe), 26.6, 25.4 ppm (2 Â q; 2 Â Me).
Minor diastereomer anti-7: 1H NMR signals are hidden by those of the
major diastereomer; 13C NMR (CDCl3, 75.5 MHz): d ˆ 198.9 (s; C-3),
147.1, 129.2, 118.1, 114.2 (s, 3 Â d; Ph), 131.5 (s; C-2), 110.5 (s; C-2') , 91.4 (t;
C-4), 77.2 (d; C-4'), 66.4 (t; C-5'), 58.0 (d; C-1), 56.5 (q; OMe), 26.6,
25.4 ppm (2 Â q; 2 Â Me).
(2R,4'S)- and (2S,4'S)-2-(2,2-Dimethyl-1,3-dioxolan-4-yl)-3-methoxy-1-
phenyl-2,5-dihydro-1H-pyrrole (syn-8, anti-8): Silver nitrate (618 mg,
3.60 mmol)was added to a mixture of crude 7 (3.64 g, syn/anti 89:11)
dissolved in acetone (106 mL), and the resulting mixture was stirred under
argon with exclusion of light at room temperature for 3 h. The mixture was
filtered through Celite with ethyl acetate (84 mL)and the filtrate was
evaporated. After column chromatography on aluminium oxide (n-hexane/
ethyl acetate 9:1), dihydropyrrole 8 was isolated as a yellow oil (1.97 g,
54%, two diastereomers). The mixture was treated with n-hexane and the
major diastereomer syn-8 was isolated as a yellow solid (916 mg, 25%).
After removal of n-hexane from the remaining solution, a yellow oil was
isolated as a mixture of both diastereomers (syn-8/anti-8 43:57, 1.05 g,
29%).
Major diastereomer syn-8: M.p. 83 848C; [a]3D2 ˆ ‡165.7 (c ˆ 1.0, CHCl3);
1H NMR (CDCl3, 500 MHz): d ˆ 7.25 7.22 (m, 2H; Ph), 6.74 6.68 (m,
3H; Ph), 4.78 (sbr, 1H; 4-H), 4.65 (mc, 1H; 2-H), 4.43 (dt, J ˆ 4.0, 6.6 Hz,
1H; 4'-H), 4.21 (ddd, J ˆ 1.6, 5.4, 12.0 Hz, 1H; 5-HA), 3.97 3.93 (m, 2H;
5-HB, 5'-HA), 3.82 (dd, J ˆ 6.6, 8.3 Hz, 1H; 5'-HB), 3.68 (s, 3H; OMe), 1.45,
1.32 ppm (2  s, each 3H; 2  Me); 13C NMR (CDCl3, 125.8 MHz): d ˆ
155.6 (s; C-3), 147.4, 129.1, 116.7, 111.8 (s, 3 Â d; Ph), 109.1 (s; C-2') , 91.4 (d;
C-4), 75.9 (d; C-4'), 65.4 (t; C-5'), 63.0 (d; C-2), 56.8 (q; OMe), 53.9 (t; C-5),
ˆ À
25.8, 24.9 ppm (2  q; 2  Me); IR (KBr): nÄ ˆ 3100 3000 ( C H), 2990
À1
À
ˆ
À
À
2800 (C H), 1660 (C C), 1240 (C O), 1060 cm (C N); elemental
analysis calcd (%)for C 16H21NO3 (275.3): C 69.79, H 7.69, N 5.09; found: C
70.05, H 8.05, N 5.06.
Crystals of syn-8 suitable for X-ray analysis were obtained by recrystalli-
zation from n-hexane/ethyl acetate. C16H21NO3, Mr ˆ 275.3; Tˆ 302(2)K;
crystal size: 1.20  0.60  0.50 mm; orthorhombic, space group P212121, a ˆ
Experimental Section
7.9028(8), b ˆ 8.6153(7), c ˆ 21.862(2)ä; Vˆ 1488.5(2)ä 3; Z ˆ 4; 1calcd
ˆ
1.229 MgmÀ3
;
F(000) ˆ 592; m(MoKa) ˆ 0.084mmÀ1
. F range for data
General methods: Unless otherwise stated, all reactions were performed
under argon atmosphere in flame-dried flasks by addition of the
components by syringe. All solvents were dried by standard procedures.
IR spectra were measured with Perkin Elmer Nicolet 5 SXC or Nico-
let 205 FT-IR spectrometers. 1H and 13C NMR spectra were recorded on
Bruker instruments (AC 300, WH 270, AC 250, AC 200, AC 500). Proton
chemical shifts are reported in ppm relative to TMS (d ˆ 0.00 ppm)or to
CHCl3 (d ˆ 7.26 ppm). Higher order NMR spectra were approximately
collection: 1.86 27.988; index ranges: À8 ꢀ h ꢀ 8, À13 ꢀ k ꢀ 13, À42 ꢀ
l ꢀ 42; reflections collected/unique: 4062/3592 (Rint ˆ 0.0085); final R [I >
2s(I)]: R1 ˆ 0.0358, wR2 ˆ 0.0931; R (all data): R1 ˆ 0.0439, wR2 ˆ 0.1012.
The programs SHELXS97 and SHELXL97 were used for structure
solution and refinement.[27]
Minor diastereomer anti-8: 13C NMR (CDCl3, 75.5 MHz): d ˆ 155.4 (s;
C-3), 148.1 (s; i-Ph), 128.7, 116.5, 112.6 (3 Â d; Ph), 109.7 (s; C-2') , 91.0 (d;
1410
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/03/0906-1410 $ 20.00+.50/0
Chem. Eur. J. 2003, 9, No. 6

Stereoselective Synthesis of Dihydropyrroles
1405 1415
C-4), 77.4 (d; C-4'), 64.9 (t; C-5'), 62.6 (d; C-2), 56.9 (q; OMe), 54.6 (t; C-5),
25.9, 25.5 ppm (2 Â q; 2 Â Me).
(3S,3aS,6aS)-4-Benzyl-6a-methoxy-3,3a,4,5,6,6a-hexahydrofuro[3,2-b]-
2H-pyrrol-3-ol (13): Compound syn-12 (168 mg, 0.58 mmol)in absolute
methanol (10 mL)was added to 6 n HCl (10 mL). After stirring for 18 h at
room temperature the solution was neutralized by addition of 2n NaOH
solution. After addition of Et2O (10 mL)the aqueous phase was separated
and extracted with ethyl acetate (5 Â 15 mL). The organic extracts were
combined and dried (Na2SO4), and the solvents were removed. After
column chromatography on aluminium oxide (100% n-hexane to 100%
ethyl acetate), 13 (63 mg, 44%)was isolated as a colorless oil. 1H NMR
(CDCl3, 300 MHz): d ˆ 7.33 7.23 (m, 5H; Ph), 4.24 (dd, J ˆ 4.4, 9.0 Hz,
1H; 3-H), 3.96 3.92 (m, 2H; 2-H), 3.84, 3.61 (2  d, J ˆ 13.0 Hz, each 1H;
CH2-Ph), 3.35 (s, 3H; OMe), 2.99 (ddd, J ˆ 2.0, 7.5, 9.0 Hz, 1H; 5-H), 2.91
(s, 1H; 3a-H), 2.51 (td, J ˆ 7.5, 9.0 Hz, 1H; 5H), 2.12 2.04 (m, 1H; 6-H),
2.00 1.90 (m, 1H; 6-H), 1.88 ppm (sbr, 1H; OH); 13C NMR (CDCl3,
75.5 MHz): d ˆ 138.4, 128.9, 128.4, 127.3 (s, 3  d; Ph), 118.7 (s; C-6a), 79.4
(d; C-3), 75.7 (t; C-2), 74.7 (d; C-3a), 59.0 (t; C-5), 53.4 (t; CH2Ph), 50.5 (q;
(3S,3aS,6aS)-6a-Methoxy-4-phenyl-3,3a,4,5,6,6a-hexahydrofuro[3,2-b]-
2H-pyrrol-3-ol (9): Compound syn-8 (100 mg, 0.36 mmol)in absolute
methanol (2 mL)was added to p-TsCl (35 mg, 0.18 mmol)in absolute
methanol (2 mL). After the mixture had been stirred at room temperature
for one day, NaHCO3 solution (10 mL)was added. The aqueous phase was
extracted with dichloromethane (3 Â 10 mL), the combined organic phases
were washed with water and dried (Na2SO4), and the solvents were
removed. After column chromatography on aluminum oxide (n-hexane/
ethyl acetate 6:4), 9 (61 mg, 71%)was isolated as a colorless oil. [ a]D31
ˆ
‡93 (c ˆ 0.55, CHCl3); 1H NMR (CDCl3, 300 MHz): d ˆ 7.28 7.23 (m, 2H;
Ph), 6.74 (t, J ˆ 7.3 Hz, 1H; Ph), 6.66 6.63 (m, 2H; Ph), 4.30 4.27 (m, 1H;
3-H), 4.17 4.10 (m, 1H; 2-H), 4.08 3.97 (m, 2H; 2-H, 3a-H), 3.52 3.32
(m, 2H; 5-H), 3.42 (s, 3H; OMe), 2.49 (sbr, 1H; OH), 2.39 2.32, 2.10
2.05 ppm (2  m, each 1H; 6-H); 13C NMR (CDCl3, 75.5 MHz): d ˆ 146.1,
129.3, 116.8, 112.4 (s, 3 Â d; Ph), 117.2 (s; C-6a), 76.3, 47.3, 32.1 (3 Â t; C-2,
C-5, C-6), 74.1 (d; C-3), 73.4 (d; C-3a), 51.1 ppm (q; OMe); IR (neat): nÄ ˆ
À
ˆ À
OMe), 33.4 ppm (t; C-6); IR (neat): nĈ 3440 (O H), 3090 3030 ( C H),
À1
À
À
À
2940 2800 (C H), 1100 (C N), 1130 cm (C O); elemental analysis calcd
(%)for C 13H17NO3 (235.3): C 67.45, H 7.68, N 5.62; found: C 66.96, H 7.25,
N 5.62.
À
ˆ À
À
À
3600 3400 (O H), 3100 3000 ( C H), 2940 2800 (C H), 1200 (C N),
1130 cmÀ1 (C O); elemental analysis calcd (%) for C 13H17NO3 (235.3): C
À
(S)-1,2,4-Butanetriol:[10] (S)-Malic acid (2.00 g, 14.9 mmol) in dry THF
(10 mL)was added dropwise at 0 8C to a stirred solution of borane di-
methylsulfide complex (24.0 mL, 48.0 mmol, 2m in THF)and trimethylbo-
rate (5.00 mL, 4.55 g, 43.8 mmol). After the mixture had been stirred for
15 min at 08C, the cooling bath was removed. After the mixture had been
stirred for 16 h, methanol (12 mL)was carefully added and the resulting
solution was evaporated to dryness. A further three co-evaporations with
methanol (3 Â 20 mL)and subsequent flash chromatography (dichloro-
methane/methanol 85:15)afforded the triol as a colorless oil (1.58 g,
quant.). 1H NMR (250 MHz, [D6]DMSO): d ˆ 4.46 (t, J ˆ 5.7 Hz, 1H),
3.97 3.90 (m, 2H), 3.17 3.02 (m, 3H; OH), 2.91 2.76 (m, 2H), 1.58 (dtd,
J ˆ 3.9, 7.1, 13.9 Hz, 1H), 1.03 0.89 ppm (m, 1H).
66.36, H 7.28, N 5.95; found: C 66.44, H 7.56, N 6.23.
(1S,4'S)-Benzyl[1-(2,2-dimethyl-1,3-dioxolan-4-yl)-2-methoxybuta-2,3-di-
enyl]amine (syn-11): nBuLi (2.3m in n-hexane, 9.00 mL, 20.7 mmol)was
added at À408C to a solution of methoxyallene 1 (1.61 g, 23.0 mmol)in
absolute THF (46 mL). After the mixture had been stirred at À408C for
5 min, 10 (2.45 g, 11.2 mmol)in absolute THF (12 mL)was added, and the
reaction mixture was allowed to warm up to À208C over 2 h and then
quenched with water (20 mL). The aqueous phase was separated and
extracted with Et2O (3 Â 40 mL). The organic extracts were combined and
dried (Na2SO4). After removal of the solvents, 3.04 g (94%) of an orange
oil was isolated as a mixture of allene syn-11 and dihydropyrrole syn-12
(ratio 52:48). The cyclization of the mixture was completed in the next step.
(2S,4S)-4-(Hydroxymethyl)-2-phenyl-1,3-dioxane (14):[11] (S)-1,2,4-Butane-
triol (1.58 g, 14.9 mmol)and benzaldehyde dimethylacetal (2.64 g,
15.9 mmol)in dry dichloromethane (50 mL)were stirred at room temper-
ature in the presence of camphorsulfonic acid (174 mg, 0.75 mmol). After
the mixture had been stirred for 16 h, triethylamine (144 mg, 1.57 mmol)
was added and the solvents were removed under reduced pressure. The
product 14 (2.45 g, 84%, purity 90 95%, ca. 5 10% stereoisomers and
constitutional isomers)was obtained after column chromatography on
silica gel (n-hexane/ethyl acetate 2:1 to 1:1)as a colorless oil. 1H NMR
(500 MHz, CDCl3): d ˆ 7.51 7.30 (m, 5H; Ph), 5.49 (s, 1H; 2-H), 4.24 (dd,
J ˆ 5.2, 11.4 Hz, 1H; 4-HA), 3.94 3.87 (m, 2H; 4-HB, 2-H), 3.60 3.55 (m,
2H; CH2OH), 2.69 2.56 (sbr, 1H; OH), 1.88 1.77 (m, 1H; 5-HA), 1.36 ppm
(dbr, J ˆ 13.4 Hz, 1H; 5-HB); 13C NMR (125.8 MHz, CDCl3): d ˆ 138.2,
128.8, 128.1, 126.0 (s, 3 Â d; Ph), 101.1 (d; C-2), 77.4 (d; C-4), 66.4 (t; C-6),
Allene syn-11: 13C NMR (CDCl3, 75.5 MHz): d ˆ 198.9 (s; C-3), 140.2,
128.3, 128.2, 127.9 (s, 3 Â d; Ph), 130.7 (s; C-2), 109.5 (s; C-2'), 91.1 (t; C-4),
77.2 (d; C-4'), 67.0 (t; C-5'), 62.2 (d; C-1), 56.3 (q; OMe), 51.1 (t; CH2Ph),
27.7, 26.7 ppm (2 Â q; 2 Â Me).
(2S,4'S)-1-Benzyl-2-(2,2-dimethyl-1,3-dioxan-4-yl)-3-methoxy-2,5-dihydro-
1H-pyrrole (syn-12): The mixture of syn-11 and syn-12 (2.98 g)was
dissolved in acetone (42 mL)under argon atmosphere, silver nitrate
(245 mg, 1.44 mmol)was then added, and the resulting mixture was stirred
at room temperature with exclusion of light for 3 h. The mixture was
filtered through Celite with ethyl acetate (84 mL)and the filtrate was
evaporated. After column chromatography on aluminium oxide (n-hexane/
ethyl acetate 19:1), syn-12 was isolated as a yellow oil (1.69 g, 57%), which
crystallized during storage. M.p. 58 608C; [a]2D0 ˆ ‡50.7 (c ˆ 1.0, CHCl3);
1H NMR (500 MHz, CDCl3): d ˆ 7.40 7.19 (m, 5H; Ph), 4.56 (dd, J ˆ 1.5,
1.9 Hz, 1H; 4-H), 4.30 (d, J ˆ 13.2 Hz, 1H; NCH2Ph), 4.14 (ddd, J ˆ 6.7, 7.8,
8.3 Hz, 1H; 4'-H), 4.07 (dd, J ˆ 6.7, 8.3 Hz, 1H; 5'-HA), 3.80 (dd, J ˆ 7.8,
8.3 Hz, 1H; 5'-HB), 3.70 3.65 (m, 1H; 2-H), 3.64 (d, J ˆ 13.2 Hz, 1H;
NCH2Ph), 3.61 3.57 (m, 1H; 5-HA), 3.58 (s, 3H; OMe), 3.17 (ddd, J ˆ 1.9,
3.5, 12.0 Hz, 1H; 5-HB), 1.41, 1.36 ppm (2 Â s, each 3H; 2 Â Me); 13C NMR
(125.8 MHz, CDCl3): d ˆ 155.9 (s; C-3), 139.7, 128.8, 128.2, 126.8 (s, 3  d;
Ph), 108.5 (s; C-2'), 92.4 (d; C-4), 79.7 (d; C-4'), 69.4 (d; C-2), 66.8 (t; C-5'),
À
65.3 (t; CH2OH), 26.7 ppm (t; C-5); IR (neat): nÄ ˆ 3430 (O H), 3070 3035
À1
‡
ˆ À
À
( C H), 2955–2860 cm (C H); MS (80 eV, EI): m/z (%): 194 (85) [M] ,
‡
‡
‡
163 (96)[ M À CH2OH] , 105 (100)[ M À C7H5] , 91 (36)[Bn] ; elemental
analysis calcd (%)for C 11H14O3 (194.2): C 68.02, H 7.27; found: C 67.93, H
7.21.
(2S,4S)-4-Formyl-2-phenyl-1,3-dioxane:[11]
A solution of dry DMSO
(0.70 mL, 771 mg, 9.86 mmol)in dichloromethane (5 mL)was added
dropwise, at À608C under argon, to a solution of oxalyl chloride (0.40 mL,
582 mg, 4.59 mmol)in dichloromethane (10 mL.) After the mixture had
been stirred for 12 min, a solution of alcohol 14 (826 mg, 4.25 mmol)in
dichloromethane (5 mL)was added dropwise. The mixture was stirred at
À608C for 30 min and was then treated with triethylamine (2.80 mL, 2.03 g,
20.1 mmol). After a further 5 min the cooling bath was removed, water
(20 mL)was added, and the mixture was allowed to warm up to room
temperature. The phases were separated, the aqueous phase was extracted
with dichloromethane (3 Â 20 mL), and the combined organic extracts were
washed with saturated ammonium chloride solution (60 mL)and water
(60 mL)and dried (Na 2SO4). Evaporation of the solvents afforded crude
aldehyde (800 mg, 98%). The product was used in the next step without
purification. 1H NMR (250 MHz, CDCl3): d ˆ 9.73 (s, 1H; CHO), 7.56 7.35
(m, 5H; Ph), 5.61 (s, 1H; 2-H), 4.41 4.33 (m, 2H; 4-H, 6-HA), 4.03 (td, J ˆ
2.8, 11.9 Hz, 1H; 6-HB), 2.06 1.76 ppm (m, 2H; 5-H); 13C NMR
(62.9 MHz, CDCl3): d ˆ 200.1 (s; CHO), 137.6, 129.0, 128.1, 126.0 (s, 3 Â
d; Ph), 100.9 (d; C-2), 80.1 (d; C-4), 66.2 (t; C-6), 25.7 ppm (t; C-5).
60.3 (t; NCH2Ph), 56.8 (q; OMe), 56.7 (t; C-5), 26.5, 25.5 ppm (2 Â q; 2 Â
À1
ˆ À
À
ˆ
Me); IR (KBr): nÄ ˆ 3130 2780 ( C H, C H), 1660 cm (C C); elemental
analysis calcd (%)for C 17H23NO3 (289.4): C 70.56, H 8.01, N 4.84; found: C
70.84, H 8.18, N 4.65.
One-pot synthesis of syn-12 from 10: nBuLi (2.3m in n-hexane, 2.90 mL,
6.54 mmol)was added at À408C to a solution of methoxyallene 1 (509 mg,
7.26 mmol)in absolute THF (15 mL). After the mixture had been stirred
for 5 min at À408C, 10 (717 mg, 11.2 mmol)in absolute THF (12 mL)was
added, the reaction mixture was allowed to warm up to À208C over 2 h, the
cooling bath was removed, and the reaction mixture was stirred for 22 h at
room temperature. After addition of water (20 mL)the aqueous phase was
separated and extracted with Et2O (3 Â 20 mL). The organic extracts were
combined and dried (Na2SO4), and the solvents were removed. After
column chromatography on aluminium oxide (n-hexane/ethyl acetate 19:1)
syn-12 was isolated as a yellow oil (614 mg, 63%), which crystallized during
storage.
Chem. Eur. J. 2003, 9, No. 6
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/03/0906-1411 $ 20.00+.50/0
1411

H.-U. Rei˚ig et al.
FULL PAPER
(2S,4S)-Benzyl[2-phenyl-(1,3-dioxan-4-yl)methylen]amine (15): Magnesi-
um sulfate (501 mg, 4.16 mmol)and benzylamine (446 mg, 4.16 mmol)in
dichloromethane (5 mL)were added to a solution of freshly prepared
(2S,4S)-4-formyl-2-phenyl-1,3-dioxane (800 mg, 4.16 mmol) in dichloro-
methane (15 mL). The mixture was stirred for 3 h at room temperature and
then filtered, and the filtrate was evaporated to produce a yellowish oil
(1.03 g, 88%). Product 15 was used in the next step without purification.
[a]2D0 ˆ À13.8 (c ˆ 0.96, CHCl3); 1H NMR (250 MHz, CDCl3): d ˆ 7.76 (d,
tography on aluminium oxide (n-hexane/ethyl acetate 8:1), syn-17 was
isolated as a yellowish oil (736 mg, 51% with respect to 14).
(2R,4'S)-1-(1-Benzyl-3-methoxy-2,5-dihydro-1H-pyrrol-2-yl)propane-1,3-
diol (syn-18): p-Toluenesulfonic acid monohydrate (571 mg, 3.00 mmol)
was added at room temperature to a solution of syn-17 (702 mg, 2.00 mmol)
in absolute methanol (40 mL). After stirring for 44 h at room temperature,
the reaction mixture was quenched with potassium carbonate solution
(10% in water, 40 mL). The aqueous phase was extracted with dichloro-
methane (3 Â 40 mL), the combined organic phases were dried (Na2SO4),
and the solvents were removed under reduced pressure. After purification
by column chromatography on silica gel (dichloromethane/methanol 20:1),
18 was isolated as a yellowish oil (402 mg, 76%). [a]2D0 ˆ À49.2 (c ˆ 0.25,
CHCl3); 1H NMR (500 MHz, CDCl3): d ˆ 7.36 7.25 (m, 5H; Ph), 4.59
4.56 (mc, 1H; 4'-H), 4.05 (d, J ˆ 13.1 Hz, 1H; NCH2Ph), 3.86 3.60 (m, 6H;
1-H, 3-HA, 3-HB, 2'-H, 5'-HA, OH), 3.72 (d, J ˆ 13.1 Hz, 1H; NCH2Ph), 3.66
(s, 3H; OMe), 3.50 (sbr, 1H; OH), 3.23 (ddd, J ˆ 2.1, 3.2, 12.4 Hz, 1H; 5'-
HB), 1.84 1.78 ppm (m, 2H; 2-H); 13C NMR (125.8 MHz, CDCl3): d ˆ
155.7 (s; C-3), 138.0, 128.6, 128.5, 127.4 (s, 3 Â d; Ph), 91.6 (d; C-4'), 71.8,
71.6 (2 Â d; C-1, C-2'), 61.6, 61.1 (2 Â t; NCH2Ph, C-3), 57.0 (t, q; C-5',
ˆ
J ˆ 3.7 Hz, 1H; N CH), 7.53 7.15 (m, 10H; Ph), 5.52 (s, 1H; 2-H), 4.55 (s,
2H; PhCH2), 4.47 (dbr, J ˆ 11.5 Hz, 1H; 4-H), 4.23 (ddd, J ˆ 1.3, 5.0,
11.6 Hz, 1H; 6-HA), 3.91 (ddd, J ˆ 2.6, 11.6, 12.3 Hz, 1H; 6-HB), 2.02 (dddd,
J ˆ 5.0, 11.5, 12.3, 13.3 Hz, 1H; 5-HA), 1.68 ppm (dtd, J ˆ 1.3, 2.6, 13.3 Hz,
1H; 5-HB); 13C NMR (62.9 MHz, CDCl3): d ˆ 164.3 (s; C N), 138.3, 138.0,
ˆ
128.6, 128.2, 128.0, 127.7, 126.8, 125.9 (2 Â s, 6 Â d; Ph), 100.9 (d; C-2), 77.8
(d; C-4), 66.3 (t; C-6), 64.3 (t; CH2Ph), 28.3 ppm (t; C-5).
(1R,2'S,4'S)-Benzyl[2-methoxy-1-(2-phenyl-1,3-dioxan-4-yl)buta-2,3-dienyl]-
amine (syn-16): nBuLi (2.5m in n-hexane, 4.00 mL, 10.0 mmol)was added
at À408C to a solution of methoxyallene 1 (1.00 mL, 840 mg, 12.0 mmol)in
absolute THF (20 mL). After the mixture had been stirred at À408C for
15 min, crude 15 (1.00 g, from 4.25 mmol 14)in absolute THF (10 mL)was
added, and the reaction mixture was allowed to warm up to À208C over 2 h
and then quenched with water (20 mL). The aqueous phase was separated
and extracted with Et2O (3 Â 20 mL). The organic extracts were combined
and dried (Na2SO4), and the solvents were removed. After column
chromatography on aluminium oxide (20% ethyl acetate/n-hexane) syn-
À
ˆ À
OMe), 36.9 ppm (t; C-2); IR (neat): nÄ ˆ 3405 (O H), 3085 3005 ( C H),
À1
À
ˆ
2935 2835 (C H), 1665 cm (C C); MS (80 eV, EI): m/z (%): 263 (2)
‡
‡
‡
[M] , 220 (6)[ M À C2H3O] , 188 (100)[ M À C3H7O2] , 172 (3)[ M À
‡
‡
C7H7] , 91 (75)[C H7] ; HRMS (80 eV): calcd for C15H21NO3: 263.15214;
7
found 263.15365.
(2R,2'S,4'S)-1-Benzyl-(2-phenyl-1,3-dioxan-4-yl)-3-[2-(trimethylsilyl)ethoxy]-
2,5-dihydro-1H-pyrrole (syn-20): nBuLi (2.5m in n-hexane, 5.00 mL,
12.5 mmol)was added at À508C to a solution of 1-[2-(trimethylsilyl)-
ethoxy]allene[12] (2.24 g, 14.4 mmol)in absolute THF (30 mL.) After the
mixture had been stirred for 30 min at À40 to À508C, crude 15 (1.51 g,
from 6.00 mmol 14)in absolute THF (10 mL)was added, and the reaction
mixture was allowed to warm up to room temperature over 16 h and then
quenched with water (20 mL). The aqueous phase was extracted with Et2O
(3 Â 20 mL), the combined organic phases were dried (MgSO4), and the
solvents were removed under reduced pressure. After purification by
column chromatography on aluminium oxide (n-hexane/ethyl acetate 10:1)
and drying in vacuo (0.02 mbar, 508C), syn-20 was isolated as a yellowish oil
(1.15 g, 44% with respect to 14) . [a]2D0 ˆ À13.6 (c ˆ 1.38, CHCl3); 1H NMR
(500 MHz, CDCl3): d ˆ 7.57 7.24 (m, 10H; Ph), 5.58 (s, 1H; 2'-H), 4.69
4.58 (mc, 1H; 4-H), 4.32 (ddd, J ˆ 1.1, 4.7, 11.3 Hz, 1H; 6'-HA), 4.24 (d, J ˆ
13.4 Hz, 1H; NCH2Ph), 4.04 3.96 (m, 2H; 4'-H, 6'-HB), 3.93 3.88 [m, 2H;
OCH2CH2Si(CH3)3], 3.80 3.76 (m, 1H; 2-H), 3.72 (d, J ˆ 13.4 Hz, 1H;
NCH2Ph), 3.71 (ddd, J ˆ 2.0, 4.9, 12.3 Hz, 1H; 5-HA), 3.18 (ddd, J ˆ 2.0, 3.0,
12.3 Hz, 1H; 5-HB), 2.11 2.01 (m, 1H; 5'-HA), 1.83 1.78 (m, 1H; 5'-HB),
1.17 1.12 (mc, 2H; CH2Si(CH3)3), 0.10 ppm (s, 9H; Si(CH3)3); 13C NMR
(125.8 MHz, CDCl3): d ˆ 155.0 (s; C-3), 139.8, 139.0, 128.5, 128.3, 128.0,
127.9, 126.6, 126.1 (2 Â s, 6 Â d, Ph), 101.2 (d; C-2'), 92.3 (d; C-4), 80.1 (d;
C-4'), 70.9 (d; C-2), 67.0, 67.0 (2 Â t; C-6', OCH2CH2Si(CH3)3) , 61.2 (t;
NCH2Ph), 57.1 (t; C-5), 27.5 (t; C-5'), 17.4 (t; CH2Si(CH3)3), À1.5 ppm (q;
16 was isolated as a yellowish oil (672 mg, 45% with respect to 14) . [a]D20
ˆ
‡10.3 (c ˆ 0.6, CHCl3); 1H NMR (500 MHz, CDCl3): d ˆ 7.60 7.25 (m,
10H; Ph), 5.60 (s, 1H; 2'-H), 5.56 (s, 2H; 4-H), 4.32 (dd, J ˆ 4.3, 11.1 Hz,
1H; 6'-HA), 4.14 (mc, 1H; 4'-H), 4.03 3.97 (m, 1H; 6'-HB), 4.00, 3.82 (2 Â d,
J ˆ 13.9 Hz, each 1H; PhCH2), 3.50 (s, 3H; OMe), 3.39 (d, J ˆ 8.3 Hz, 1H;
1-H), 2.43 (sbr, 1H; NH), 1.97 (ddt, J ˆ 4.3, 11.7, 12.6 Hz, 1H; 5'-HA),
1.62 ppm (dbr, J ˆ 12.6 Hz, 1H; 5'-HB); 13C NMR (125.8 MHz; CDCl3): d ˆ
199.4 (s; C-3), 139.9, 138.2, 128.3, 127.8*, 127.7, 126.3, 125.6 (2 Â s, 5 Â d; Ph),
130.8 (s; C-2), 100.6 (d; C-2'), 90.2 (t; C-4), 77.6 (d; C-4'), 66.3 (t; C-6'), 63.8
(d; C-1), 55.8 (q; OMe), 50.8 (t; PhCH2), 27.7 ppm (t; C-5'),* higher
intensity; IR (neat): nÄ ˆ 3340 (N H), 3085 2850 (C H), 1955 cmÀ1
À
À
‡
‡
ˆ ˆ
(C C C); MS (80 eV, EI): m/z (%): 351 (6) [M] , 336 (1)[ M À CH3] ,
‡
188 (100)[ M À C10H11O2] ; elemental analysis calcd (%)for C 22H25NO3
(351.5): C 75.19, H 7.17, N 3.99; found: C 74.82, H 7.19, N 3.76.
(2R,2'S,4'S)-1-Benzyl-3-methoxy-2-(2-phenyl-1,3-dioxan-4-yl)-2,5-dihy-
dro-1H-pyrrole (syn-17): Compound syn-16 (657 mg, 1.87 mmol)was
dissolved in acetone (20 mL), silver nitrate (63 mg, 0.37 mmol) was added,
and the resulting mixture was stirred under argon with exclusion of light at
room temperature for 16 h. The mixture was filtered through Celite with
ethyl acetate (3 Â 20 mL)and the filtrate was evaporated. After column
chromatography on aluminium oxide (n-hexane/ethyl acetate 8:1), syn-17
was isolated as a colorless oil (579 mg, 88%). [a]2D0 ˆ À27.6 (c ˆ 1.25,
CHCl3); 1H NMR (500 MHz, CDCl3): d ˆ 7.57 7.53 (m, 2H; Ph), 7.41 7.22
(m, 8H; Ph), 5.56 (s, 1H; 2'-H), 4.54 (sbr, 1H; 4-H), 4.24 (dd, J ˆ 4.7,
11.3 Hz, 1H; 6'-HA), 4.17 (d, J ˆ 13.3 Hz, 1H; NCH2Ph), 3.95 3.87 (m, 2H;
6'-HB, 4'-H), 3.74 (dbr, J ˆ 4.8 Hz, 1H; 2-H), 3.64 (d, J ˆ 13.3 Hz, 1H;
NCH2Ph), 3.62 (ddd, J ˆ 2.1, 4.8, 12.4 Hz, 1H; 5-HA), 3.56 (s, 3H; OMe),
3.13 (ddd, J ˆ 2.1, 3.2, 12.4 Hz, 1H; 5-HB), 1.94 (ddt, J ˆ 4.7, 12.0, 12.9 Hz,
1H; 5'-HA), 1.78 ppm (dbr, J ˆ 12.9 Hz, 1H; 5'-HA); 13C NMR (125.8 MHz,
CDCl3): d ˆ 156.0 (s; C-3), 139.5, 138.7, 128.4, 128.3, 128.0, 127.9, 126.6,
125.9 (2 Â s, 6 Â d; Ph), 101.2 (d; C-2'), 92.2 (d; C-4), 79.8 (d; C-4'), 70.5 (d;
ˆ À
À
Si(CH3)3); IR (neat): nÄ ˆ 3085 3000 ( C H), 2960 2850 (C H),
‡
1655 cmÀ1 (C C); MS (80 eV, EI): m/z (%): 437 (6) [M] , 274 (100)
ˆ
‡
‡
‡
[M À C10H11O2] , 91 (48)[Bn] , 73 (55)[Si(CH 3)3] ; elemental analysis
calcd (%)for C 26H35NO3Si (437.7): C 71.35, H 8.06, N 3.20; found: C 71.15,
H 8.18, N 2.99.
(2R,2'S,4'S)-1-Benzyl-3-benzyloxy-2-(2-phenyl-1,3-dioxan-4-yl)-2,5-dihy-
dro-1H-pyrrole (syn-22): nBuLi (2.5m in n-hexane, 10.0 mL, 25.0 mmol)
was added at À508C to a solution of benzyloxyallene 23 (3.98 g, 27.2 mmol)
in absolute THF (50 mL). After the mixture had been stirred for 20 min at
À40 to À508C, crude 15 (2.65 g, from 10.0 mmol 14)in absolute THF
(20 mL)was added, and the reaction mixture was allowed to warm up to
room temperature over 16 h and then quenched with water (50 mL). The
aqueous phase was extracted with Et2O (3 Â 50 mL), the combined organic
phases were dried (MgSO4), and the solvents were removed under reduced
pressure. After purification by column chromatography on aluminium
oxide (n-hexane/ethyl acetate 10:1), syn-22 was isolated as a yellowish oil
(2.15 g, 50% with respect to 14) . [a]2D0 ˆ À32.9 (c ˆ 0.49, CHCl3); 1H NMR
(250 MHz, CDCl3): d ˆ 7.51 7.16 (m, 15H; Ph), 5.51 (s, 1H; 2'-H), 4.83 (s,
2H; OCH2Ph), 4.66 (mc, 1H; 4-H), 4.26 (ddd, J ˆ 1.2, 4.9, 11.3 Hz, 1H; 6'-
HA), 4.16 (d, J ˆ 13.5 Hz, 1H; NCH2Ph), 4.00 3.88 (m, 2H; 4'-H, 6'-HB),
3.84 (ddt, J ˆ 1.4, 3.3, 4.7 Hz, 1H; 2-H), 3.69 (d, J ˆ 13.5 Hz, 1H; NCH2Ph),
3.67 (ddd, J ˆ 2.0, 4.7, 12.4 Hz, 1H; 5-HA), 3.18 (ddd, J ˆ 2.0, 3.3, 12.4 Hz,
1H; 5-HB), 2.10 1.91 (m, 1H; 5'-HA), 1.80 1.69 ppm (m, 1H; 5'-HB);
C-2), 66.9 (t; C-6'), 60.7 (t; NCH2Ph), 56.6 (q; OMe), 56.6 (t; C-5), 27.0 ppm
À1
ˆ À
À
(t; C-5'); IR (neat): nÄ ˆ 3090 3000 ( C H), 2960 2850 (C H), 1660 cm
‡
‡
ˆ
(C C); MS (80 eV, EI): m/z (%): 351 (1) [M] , 246 (3)[ M À NCH2Ph] , 188
‡
‡
(45)[ M À C10H11O2] , 91 (100)[Bn] ; HRMS (80 eV): calcd for C22H25NO3:
351.18344; found 351.18731; elemental analysis calcd (%)for C 22H25NO3
(351.5): C 75.19, H 7.17, N 3.99; found: C 74.92, H 7.16, N 3.64.
One-pot synthesis of syn-17 from 15: nBuLi (2.5m in n-hexane, 4.00 mL,
10.0 mmol)was added at À408C to a solution of methoxyallene 1 (1.00 mL,
840 mg, 12.0 mmol)in absolute THF (20 mL). After the mixture had been
stirred at À408C for 15 min, crude 15 (1.00 g, from 4.12 mmol 14)in
absolute THF (10 mL)was added. The reaction mixture was allowed to
warm up to room temperature over 16 h and was then quenched with water
(20 mL). The aqueous phase was extracted with Et2O (3 Â 20 mL), the
combined organic phases were dried (Na2SO4), and the solvents were
removed under reduced pressure. After purification by column chroma-
1412
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/03/0906-1412 $ 20.00+.50/0
Chem. Eur. J. 2003, 9, No. 6

Stereoselective Synthesis of Dihydropyrroles
1405 1415
13C NMR (62.9 MHz, CDCl3): d ˆ 155.0 (s; C-3), 139.7, 138.9, 136.7, 128.5,
128.5, 128.3, 128.1, 128.0, 127.7, 127.2, 126.7, 126.2 (3 Â s, 9 Â d; Ph), 101.5 (d;
C-2'), 93.6 (d; C-4), 79.6 (d; C-4') , 71.3 (t; OCH2Ph), 70.8 (d; C-2), 67.0 (t;
10 Â d; Ph), 101.5, 101.0 (2 Â d; C-2'), 92.4, 90.0 (2 Â d; C-4), 80.0, 79.6 (2 Â
s; C(CH3)3), 76.9, 76.4 (2 Â d; C-4') , 71.4 (t; OCH2Ph), 66.9, 66.9 (2 Â t;
C-6'), 64.2, 64.1 (2 Â d; C-2), 51.5, 51.0 (2 Â t; C-5), 28.4 (q; C(CH3)3), 26.9,
ˆ À
C-6'), 60.9 (t; NCH2Ph), 57.0 (t; C-5), 27.0 ppm (t; C-5'); IR (neat): nÄ ˆ
26.6 ppm (2  t; C-5),* higher intensity; IR (neat): nÄ ˆ 3090 3035 ( C H),
À1
À1
ˆ
À
ˆ
À
ˆ
ˆ
3100 3000 ( C-H), 2975 (C H), 1655 cm (C C); MS (80 eV, EI): m/z
2975 2860 (C H), 1700 (C O), 1660 cm (C C); MS (80 eV, EI): m/z
‡
‡
‡
‡
‡
‡
(%): 427 (1) [M] , 336 (5)[ M À C7H7] , 264 (100)[ M À C10H11O2] , 91 (72)
(%): 437 (2) [M] , 436 (7)[ M À H] , 380 (2)[M À C(CH3)3] , 163 (16)
‡ ‡ ‡
‡
[Bn] ; HRMS (80 eV): calcd for (C28H29NO3 À C10H11O2; mol peak is too
[C10H11O2] , 91 (100)[Bn]
, 57 (80)[C(CH 3)3] ; HRMS (80 eV):
weak): 336.15996; found 336.15756; elemental analysis calcd (%) for
C28H29NO3 (427.6): C 78.66, H 6.84, N 3.28; found: C 78.44, H 6.80, N 2.94.
C26H31NO5 calcd 437.22022; found 437.22485.
Reduction of syn-22 with Pd/C/H2: A stirred suspension of palladium on
charcoal (498 mg, 0.47 mmol)in dry ethanol (15 mL)was saturated with
hydrogen for 30 min. A solution of syn-22 (500 mg, 1.17 mmol)in dry
ethanol (12 mL)was then added, and the mixture was stirred under
hydrogen atmosphere at normal pressure for 20 h at room temperature.
The mixture was filtered through Celite with methanol (60 mL). After
removal of the solvents under reduced pressure and column chromatog-
raphy on silica gel (n-hexane/ethyl acetate 4:1), pyrrolidinone 26 (204 mg,
50%)and pyrrolidine 27 (54 mg, 11%)were obtained as colorless oils.
(1S,2'R)-1-(1-Benzyl-3-benzyloxy-2,5-dihydro-1H-pyrrol-2-yl)-3-benzyl-
oxypropan-1-ol (syn-24): Diisobutylaluminum hydride (1.5m in toluene,
1.30 mL, 1.95 mmol)was added under argon at À788C to a solution of syn-
22 (270 mg, 0.63 mmol)in dry dichloromethane (5 mL). The mixture was
allowed to warm up to room temperature over 16 h and then cooled to 08C,
and saturated sodium potassium tartrate solution (5 mL)was added. After
1 h, water (20 mL)was added and the solution was extracted with
dichloromethane (3 Â 20 mL). The combined organic phases were dried
(MgSO4)and the solvents were removed under reduced pressure. After
column chromatography on silica gel (n-hexane/ethyl acetate 1:1), 24
(191 mg, 71%)was obtained as colorless oil. [ a]2D0 ˆ À39.6 (c ˆ 1.05,
CHCl3); 1H NMR (500 MHz, [D6]DMSO): d ˆ 7.44 7.18 (m, 15H; Ph),
4.84 (s, 2H; OCH2Ph), 4.70 (s, 1H; 4'-H), 4.44 (s, 2H; OCH2Ph), 4.22 4.00
(sbr, 1H; OH), 3.99 (d, J ˆ 13.7 Hz, 1H; NCH2Ph), 3.70 (dbr, J ˆ 9.8 Hz, 1H;
1-H), 3.73 3.61 (m, 4H; NCH2Ph, 2'-H, 3-H), 3.52 3.48 (m, 1H; 5'-HA),
3.05 (dbr, J ˆ 12.2 Hz, 1H; 5'-HB), 1.98 1.80 (m, 1H; 2-HA), 1.73 1.53 ppm
(m, 1H; 2-HB); 13C NMR (62.9 MHz, [D6]DMSO): d ˆ 155.1 (s; C-3'),
139.6, 138.7, 136.9, 128.3, 128.1, 128.1*, 127.7, 127.3, 127.2, 127.2, 126.7 (3 Â s,
8 Â d; Ph), 92.7 (d; C-4'), 72.0 (d; C-2') , 71.8 (t; OCH2Ph), 70.8 (t;
OCH2Ph), 68.2 (d; C-1), 67.4 (t; C-3), 60.7 (t; NCH2Ph), 57.0 (t; C-5'),
(2S,3R,2'S,4'S)-3-Benzyloxy-1-tert-butoxycarbonyl-2-(2-phenyl-1,3-diox-
an-4-yl)pyrrolidine (27): [a]2D0 ˆ À18.8 (c ˆ 1.17, CHCl3); 1H NMR
(500 MHz, CDCl3, 330 K): d ˆ 7.50 7.25 (m, 10H; Ph), 5.52 (s, 1H; 2'-
H), 4.58 (s, 2H; OCH2Ph), 4.25 (ddd, J ˆ 1.4, 4.9, 11.3 Hz, 1H; 6'-HA),
4.29 4.25 (m, 1H; 4'-H), 4.09 (td, J ˆ 7.5, 9.9 Hz, 1H; 3-H), 4.05 4.00 (m,
1H; 2-H), 3.93 (ddd, J ˆ 2.5, 11.3, 12.4 Hz, 1H; 6'-HB), 3.47 3.36 (m, 2H;
5-H), 2.21 (dddd, J ˆ 4.9, 12.0, 12.4, 13.4 Hz, 1H; 5'-HA), 2.20 2.06 (m, 2H;
4-H), 1.52 1.47 (m, 1H; 5'-HB), 1.45 ppm (s, 9H; C(CH)3)3); 13C NMR
ˆ
(125.8 MHz, CDCl3, 330 K): d ˆ 155.3 (s; C O), 139.3, 138.5, 128.4*, 128.0,
127.6, 127.4, 126.1 (2 Â s, 5 Â d; Ph), 101.3 (d; C-2'), 79.5 (s; C(CH3)3), 78.0
(d; C-4'), 76.4 (d; C-3), 72.2 (t, OCH2Ph), 67.4 (t; C-6'), 59.9 (d; C-2), 44.0 (t;
C-5), 29.3 (t; C-4), 29.0 (t; C-5'), 28.5 ppm (q; C(CH3)3),* higher intensity;
À
33.5 ppm (t; C-2), * signal with higher intensity; IR (neat): nÄ ˆ 3435 (O H),
À1
ˆ À
À
ˆ
IR (neat): nÄ ˆ 3090 3035 ( C H), 2975 2865 (C H), 1695 cm (C O);
À1
ˆ À
À
ˆ
3085 3030 ( C H), 2925 2860 (C H), 1665 cm (C C); MS (80 eV, EI):
‡
‡
MS (80 eV, EI): m/z (%): 439 (3) [M] , 382 (1)[ M À C(CH3)3] , 366 (9)
‡
‡
‡
m/z (%): 429 (1) [M] , 338 (3)[ M À Bn] , 264 (60)[ M À C10H11O2] , 91
‡
‡
‡
[M À OC(CH3)3] , 276 (76)[ M À C10H11O2] , 163 (20)[C 10H11O2] , 91
‡
(100)[Bn] ; HRMS (80 eV): calcd for C28H31NO3: 429.23029; found
‡
‡
(100)[Bn]
, 57 (35)[C(CH 3)3] ; HRMS (80 eV): C26H33NO5 calcd
429.23245.
439.23587; found 439.23373.
Reduction of syn-22 with Pd(OH)2/H2:
A suspension of palladium
(2S,3R,2'S,4'S)-1-tert-Butoxycarbonyl-3-hydroxy-2-(2-phenyl-1,3-dioxan-
4-yl)-pyrrolidine (28): Pyrrolidinone 26 (728 mg, 2.10 mmol)was dissolved
in dry THF (70 mL), and L-Selectride (4.20 mL, 4.20 mmol, 1m in THF)
was slowly added at À788C under argon. After the mixture had been kept
for 4 h at this temperature, water (70 mL)was added and the solution was
extracted with dichloromethane (3 Â 70 mL). The combined organic phases
were dried with MgSO4 and the solvents were removed under reduced
pressure. Product 28 was obtained as a colorless solid (612 mg, 84%)after
column chromatography on silica gel (n-hexane/ethyl acetate 2:1). M.p.
55 578C; [a]2D0 ˆ À76.1 (c ˆ 0.71, CHCl3); 1H NMR (500 MHz, CDCl3):
d ˆ 7.45 7.41 (m, 2H; Ph), 7.36 7.28 (m, 3H; Ph), 5.50 (s, 1H; 2'-H), 4.48
4.39 (m, 2H; 4'-H, 3-H), 4.27 (ddd, J ˆ 1.5, 5.1, 11.4 Hz, 1H; 6'-HA), 4.02
(dd, J ˆ 3.7, 7.1 Hz, 1H; 2-H), 3.93 (ddd, J ˆ 2.5, 11.4, 12.5 Hz, 1H; 6'-HB),
3.53 3.46 (m, 1H; 5-HA), 3.43 (ddd, J ˆ 5.2, 8.7, 10.8 Hz, 1H; 5-HB), 2.68
(dbr, J ˆ 6.3 Hz, 1H; OH), 2.21 (dddd, J ˆ 5.1, 11.9, 12.5, 13.5 Hz, 1H; 5'-
HA), 2.10 (dddd, J ˆ 5.2, 7.3, 8.3, 12.4 Hz, 1H; 4-HA), 1.94 (tdd, J ˆ 7.4, 8.7,
hydroxide on charcoal (100 mg, 0.19 mmol, pre-dried for 2 h at 608C
under reduced pressure of 10À2 mbar)in dry ethanol (8 mL)was saturated
with hydrogen for 1 h. Boc anhydride (0.22 mL, 209 mg, 0.96 mmol)and
syn-22 (200 mg, 0.47 mmol)dissolved in dry ethanol (4 mL)were then
added. After stirring at room temperature under hydrogen atmosphere for
48 h, the mixture was filtered through Celite with methanol (60 mL). After
evaporation of the solvents and purification by column chromatography on
silica gel (n-hexane/ethyl acetate 4:1), pyrrolidinone 26 (21 mg, 13%)and
dihydropyrrole 25 (73 mg, 37%)were obtained as colorless oils.
(2R,2'S,4'S)-1-tert-Butoxycarbonyl-2-(2-phenyl-1,3-dioxan-4-yl)pyrrolidin-
3-one (26) (two rotamers, ratio ca. 1:1): [a]2D0 ˆ À133.9 (c ˆ 0.72, CHCl3);
1H NMR (500 MHz, CDCl3): d ˆ 7.43 7.26 (m, 5H; Ph), 5.45, 5.44 (2  s,
1H; 2'-H), 4.47 4.23 (m, 1H; 4'-H), 4.25, 4.16 (2  dt, J ˆ 2.5, 10.5 Hz, 1H;
5-HA), 4.15, 4.03 (2 Â sbr, 1H; 2-H), 4.05 3.92 (m, 1H; 6'-HB), 3.73 3.57
(m, 1H; 5-HB), 2.60 2.35 (m, 2H; 4-H), 2.21 2.02 (m, 1H; 5'-HA), 1.65
1.45 (m, 1H; 5'-HB), 1.51, 1.49 ppm (2 Â s, 9H; C(CH3)3); 13C NMR
(125.8 MHz, CDCl3): d ˆ 213.7, 213.1 (2  s; C-3), 155.0, 154.4 (2  s;
NCO), 138.2, 138.0, 128.8, 128.7, 128.1, 125.7, 125.6 (2 Â s, 5 Â d; Ph), 101.3,
101.0 (2 Â d; C-2'), 80.6, 80.3 (2 Â s; C(CH3)3), 79.8, 79.4 (2 Â d; C-4'), 66.8,
66.6 (2 Â t; C-6'), 65.4, 64.8 (2 Â d; C-2), 43.5, 42.8 (2 Â t; C-5), 37.1, 36.6
12.4 Hz, 1H; 4-HB), 1.51 (dtd, J ˆ 1.5, 2.5, 13.5 Hz, 1H; 5'-HB), 1.47 ppm (s,
13
ˆ
9H; C(CH3)3); C NMR (125.8 MHz, CDCl3): d ˆ 155.2 (s; C O), 138.3,
128.8, 128.1, 125.8 (s, 3 Â d; Ph), 101.4 (d; C-2'), 79.6 (s; C(CH3)3) , 77.3 (d;
C-4'), 72.1 (d; C-3), 67.3 (t; C-6'), 60.6 (d; C-2), 44.3 (t; C-5), 33.1 (t; C-4),
À
28.3 (q; C(CH3)3), 27.5 ppm (t; C-5'); IR (KBr): nÄ ˆ 3435 (O H), 3100
À1
ˆ À
À
ˆ
3000 ( C H), 2975 2895 (C H), 1695, 1670 cm (C O); MS (80 eV, EI):
(2  t; C-4), 28.3 (q; C(CH3)3), 27.8 ppm (t; C-5'); IR (neat): nÄ ˆ 3100 3065
‡
‡
‡
À1
ˆ À
À
ˆ
m/z (%): 349 (5) [M] , 331 (2)[ M À H2O] , 292 (10)[ M À C(CH3)3] , 276
( C H), 2975 2860 (C H), 1760, 1695 cm (C O); MS (80 eV, EI): m/z
‡
‡
‡
‡
‡
‡
(14)[ M À OC(CH3)3] , 186 (83)[ M À C10H11O2] , 163 (40)[C 10H11O2] , 91
(%): 347 (1) [M] , 290 (1)[ M À C(CH3)3] (1), 274 (4) [M À OC(CH3)3] ,
‡
‡
‡
‡
‡
(21)[Bn]
, 57 (69)[C(CH 3)3] ; HRMS (80 eV): C19H27NO5 calcd
163 (100)[C 10H11O2] , 91 (42)[Bn] , 57 (69)[C(CH )3] ; HRMS (80 eV):
3
349.18588; found 349.18892; elemental analysis calcd (%)for C 19H27NO5
(349.4): C 65.31, H 7.79, N 4.01; found: C 65.27, H 7.85, N 3.79.
found 257.12732; C12H19NO5 calcd 257.12632; elemental analysis calcd (%)
for C19H25NO5 (347.4): C 65.69, H 7.25, N 4.03; found: C 65.68, H 7.26, N
4.00.
(2S,3R,1'S)-1-tert-Butoxycarbonyl-2-(1,3-dihydroxyprop-1-yl)-3-hydroxy-
pyrrolidine (29): A stirred suspension of palladium on charcoal (174 mg,
0.17 mmol)in dry ethanol (12 mL)was saturated with hydrogen for 30 min.
A solution of 28 (555 mg, 1.59 mmol)in dry ethanol (8 mL)was then added,
and the mixture was stirred under hydrogen atmosphere at normal pressure
and at room temperature for 16 h. The mixture was filtered through Celite
with methanol (100 mL), and the filtrate was evaporated to give triol 29 as a
colorless solid (408 mg, 98%). M.p. 78 808C (with decomposition);
[a]2D0 ˆ À61.3 (c ˆ 1.02, CHCl3); 1H NMR (500 MHz, CD3OD, 330 K):
d ˆ 4.39 (td, J ˆ 7.1, 7.8 Hz, 1H; 3-H), 4.14 (td, J ˆ 3.8, 9.5 Hz, 1H; 1'-H),
(2R,2'S,4'S)-3-Benzyloxy-1-tert-butoxycarbonyl-2-(2-phenyl-1,3-dioxan-4-
yl)-2,5-dihydro-1H-pyrrole (25) (two rotamers, ratio ca. 1:1): [a]2D0 ˆ À84.6
(c ˆ 0.69, CHCl3); 1H NMR (500 MHz, CDCl3): d ˆ 7.45 7.25 (m, 10H;
Ph), 5.52, 5.48 (2 Â s, 1 H; 2'-H), 4.87 (sbr, 2H; OCH2Ph), 4.75, 4.59 (2 Â sbr
1H; 4-H), 4.68 (sbr, 1H; 2-H), 4.38 4.15 (m, 3H; 4'-H, 5-HA, 6'-HA), 4.01
,
3.92 (m, 2H; 5-HB, 6'-HB), 2.06 1.95 (m, 1H; 5'-HA), 1.55 1.42 (m, 1H; 5'-
HB), 1.49, 1.48 ppm (2 Â s, 9H; C(CH3)3); 13C NMR (125.8 MHz, CDCl3):
ˆ
d ˆ 154.8, 154.4, 153.4, 153.3 (4  s; C O, C-3), 138.8, 138.6, 136.3, 136.2,
128.6, 128.3*, 128.0, 128.0, 127.9, 127.8, 127.3, 127.2, 126.1, 126.0 (4 Â s,
Chem. Eur. J. 2003, 9, No. 6
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/03/0906-1413 $ 20.00+.50/0
1413

H.-U. Rei˚ig et al.
FULL PAPER
3.79 (dd, J ˆ 3.8, 7.1 Hz, 1H; 2-H), 3.77 3.68 (m, 2H; 3'-H), 3.50 3.38 (m,
2H; 5-H), 2.10 1.96 (m, 2H; 4-H), 1.93 1.84 (m, 1H; 2'-HA), 1.78 (dtd,
J ˆ 5.9, 9.5, 14.1 Hz, 1H; 2'-HB), 1.46 ppm (s, 9H; C(CH3)3); 13C NMR
Acknowledgement
Support of this work by the Deutsche Forschungsgemeinschaft, the Fonds
der Chemischen Industrie, and Schering AG is most gratefully appreciated.
We thank Dr. R. Zimmer for help during preparation of this manuscript.
ˆ
(125.8 MHz, CD3OD, 326 K): d ˆ 157.6 (s; C O), 81.1 (s; C(CH3)3), 72.6 (d;
C-3), 69.9 (d; C-1'), 64.2 (d; C-2), 60.7 (t; C-3'), 45.6 (t; C-5), 38.4 (t; C-2'),
À
33.1 (t; C-4), 28.8 ppm (q; C(CH3)3); IR (KBr): nÄ ˆ 3370 (O H), 3000
À1
À
ˆ
2890 (C H), 1695, 1660 cm (C O); MS (FAB, negative-mode): m/z (%):
260 (100)[ M À H]À; MS (FAB, positive-mode): m/z (%): 262 (35) [M‡H] ;
‡
elemental analysis calcd (%)for C 12H23NO5 (261.3): C 55.16, H 8.87, N 5.36;
found: C 55.21, H 8.75, N 5.24.
[1] M. Okala Amombo, A. Hausherr, H.-U. Rei˚ig, Synlett 1999, 1871
1874.
[2] M. Okala Amombo, Dissertation, Technische Universit‰t Dresden
(Germany), 2000.
(3aR,7S,7aR)-1-tert-Butoxycarbonyl-1,2,3,3a,5,6,7,7a-octahydro-7-hy-
droxypyrano-[3,2-b]pyrrol-5-one (30): A suspension of platinum dioxide
(44 mg, 0.19 mmol)in water (1 mL)was first treated with hydrogen for 1 h,
and was then saturated with argon (5 min)and then with oxygen (5 min). A
solution of triol 29 (49 mg, 0.19 mmol)in water (2 mL)was then added, and
oxygen gas was bubbled through this mixture at 408C. After 2 h the mixture
was stirred under an oxygen atmosphere at room temperature for 17 h,
water was then removed under reduced pressure, and column chromatog-
raphy on silica gel (n-hexane/ethyl acetate 1:1)furnished lactone 30 as a
colorless solid (32 mg, 66%). M.p. 140 1418C (literature value:[15c] 141
1428C); [a]2D0 ˆ À35.9 (c ˆ 0.73; CHCl3)(literature value: À6.5 (c ˆ 1.0,
CHCl3),[15b] À31.7 (CHCl3)[15c]); 1H NMR (500 MHz, C6D6, 334 K): d ˆ 5.12
(s, 1H; OH), 3.74 3.67 (m, 2H; 3a-H, 6-H), 3.38 (t, J ˆ 5.0 Hz, 1H; 7a-H),
3.08 3.03 (m, 1H; 2-HA), 2.91 (dt, J ˆ 6.1, 11.3 Hz, 1H; 2-HB), 2.72 (dd, J ˆ
4.2, 15.0 Hz, 1H; 6-HA), 2.12 (dd, J ˆ 12.7, 15.0 Hz, 1H; 6-HB), 1.51 1.45
(m, 1H; 3-HA), 1.37 (s, 9H; C(CH3)3), 0.97 ppm (dddd, J ˆ 5.1, 8.9, 11.3,
13.9 Hz, 1H; 3-HB); 13C NMR (125.8 MHz, CDCl3): d ˆ 169.6 (s; C-5),
156.0 (s; C(O)OC(CH3)3), 80.6 (s; C(CH3)3), 78.0 (d; C-3a), 70.4 (d; C-7),
[3] Reviews: a)A. Gossauer, Methoden Org. Chem. (Houben-Weyl) 4th
ed. 1994, Vol. E6a/1, pp. 556 798; b) Comprehensive Heterocyclic
Chemistry, Vol. 2 (Eds.: A. Katritzky, C. W. Rees, E. F. V. Scriven),
Pergamon Press, Oxford, 1996, pp. 1 257. For selective examples of
recent pyrrole syntheses see: c)W. von der Saal, R. Reinhardt, J.
Stawitz, H. Quast, Eur. J. Org. Chem. 1998, 1645 1652; d)A. Merz, T.
Meyer, Synthesis 1999, 94 99; e)R. K. Dieter, H. Yu, Org. Lett. 2000,
2, 2283 2286; f)R. Grigg, V. Savic, Chem. Commun. 2000, 873 874;
g)L. Ghosez, C. Franc, F. Denonne, C. Cuisinier, R. Touillaux, Can. J.
Chem. 2001, 79, 1827 1839; h)F.-A. Marcotte, W. D. Lubell, Org.
Lett. 2002, 4, 2601 2603; i)M. Friedrich, A. W‰chtler, A. de Meijere,
Synlett 2002, 619 621.
[4] For reactions of 2 with chiral hydrazones derived from SAMP or
¡
RAMP see: a)V. Breuil-Desvergnes, P. Compain, J.-M. Vate le, J.
¬
Gore, Tetrahedron Lett. 1999, 40, 5009 5012; b)V. Breuil-Des-
¡
¬
vergnes, P. Compain, J.-M. Vatele, J. Gore, Tetrahedron Lett. 1999,
¬
40, 8789 8792; c)V. Breuil-Desvergnes, J. Gore , Tetrahedron 2001, 57,
66.2 (d; C-7a), 44.6 (t; C-2), 36.3 (t; C-6), 30.5 (t; C-3), 28.3 ppm (q;
¬
1939 1950; d)V. Breuil-Desvergnes, J. Gore , Tetrahedron 2001, 57,
À1
À
À
C(CH3)3); IR (KBr): nÄ ˆ 3375 (O H), 3000 2885 (C H), 1715, 1695 cm
1951 1960.
‡
‡
ˆ
(C O); MS (80 eV, EI): m/z (%): 257 (1) [M] , 242 (1)[ M À CH3] , 57
[5] For reactions of organolithium and Grignard reagents with imines 6
and 10 see: a)J. Yoshimura, Y. Ohgo, T. Sato, J. Am. Chem. Soc. 1964,
86, 3858 3862; b)Y. Ohgo, J. Yoshimura, T. Sato, Bull. Chem. Soc.
Jpn. 1969, 42, 728 731; c)R. Badorrey, C. Cativiela, M. D. Diaz-de-
Villegas, J. A. Galves, Tetrahedron 1997, 53, 1411 1416.
‡
(100)[C(CH 3)3] ; HRMS (80 eV): C12H19NO5 calcd 257.12632; found
257.12732; elemental analysis calcd (%)for C 12H19NO5 (257.1): C 55.73, H
7.25, N 5.15; found: C 56.02, H 7.44, N 5.44.
Crystals of 30 suitable for X-ray analysis were obtained by recrystallization
from n-hexane/dichloromethane. C12H19NO5, Mr ˆ 257.1; Tˆ 113(2)K;
crystal size: 0.09  0.12  0.70 mm; monoclinic, space group P21, a ˆ
6.2068(14), b ˆ 8.725(2), c ˆ 11.671(3)ä, b ˆ 96.877(5)8; Vˆ 627.5(2)ä 3;
Z ˆ 2; 1calcd ˆ 1.362 MgmÀ3; F(000) ˆ 276; m(MoKa) ˆ 0.106 mmÀ1. F range
for data collection: 1.76 30.598; index ranges: À8 ꢀ h ꢀ 8, À12 ꢀ k ꢀ 12,
À16 ꢀ l ꢀ 16; reflections collected/unique: 7864/3702 (Rint ˆ 0.0222); final
R [I > 2s(I)]: R1 ˆ 0.0317, wR2 ˆ 0.0782; R (all data): R1 ˆ 0.0340, wR2 ˆ
0.0794.
[6] A. Hausherr, Dissertation, Freie Universit‰t Berlin (Germany), 2001.
[7] O. Flˆgel, unpublished results, Freie Universit‰t Berlin (Germany).
¬
[8] For a similar solvent dependence of cyclization see the work of Gore
et al.[4]
[9] G. Frenking, K. F. Kˆhler, M. T. Reetz, Tetrahedron 1994, 50, 11197
11204.
[10] F. Sanchez-Sancho, S. Valverde, B. Herradon, Tetrahedron: Asymme-
try 1996, 7, 3209 3246.
[11] a)D. Diaz, V. Martin, Org. Lett. 2000, 2, 335 337; b)I. Shiina, J.
Shibata, R. Ibuka, Y. Imai, T. Mukaiyama, Bull. Chem. Soc. Jpn. 2001,
74, 113 122.
[12] R. W. Hoffmann, B. Kemper, R. Metternich, T. Lehmeier, Liebigs
Ann. Chem. 1985, 2246 2260.
For structure solution and refinement the programs SHELXS97 and
SHELXL97 were used.[27]
(À)-Detoxinine, (3S,2'S,3'R)-3-Hydroxy-3-(3-hydroxypyrrolidin-2-yl)pro-
pionic acid: Trifluoroacetic acid (1 mL)was added under argon at 0 8C to
lactone 30 (97 mg, 0.39 mmol). After 2 h the cooling bath was removed and
the mixture was stirred for 15 min at room temperature. After removal of
trifluoroacetic acid under reduced pressure and ion exchange chromatog-
[13] a)H. Yonehara, H. Seto, S. Aizawa, T. Hidaka, A. Shimazu, N. Otake,
J. Antibiot. 1968, 21, 369 370; b)H. Yonehara, H. Seto, A. Shimazu,
S. Aizawa, T. Hidaka, K. Kakinuma, N. Otake, Agric. Biol. Chem.
1973, 37, 2771 2776; c)T. Ogita, H. Seto, N. Otake, H. Yonehara,
Agric. Biol. Chem. 1981, 45, 2605 2611; d)comprehensive review: W.-
R. Li, S.-Y. Han, M. M. Joullie, Heterocycles 1993, 36, 359 388.
[14] J. H‰ussler, Liebigs Ann. Chem. 1983, 982 992.
[15] a)Y. Ohfune, H. Nishio, Tetrahedron Lett. 1984, 25, 4133 4136;
b)W. R. Ewing, B. D. Harris, K. L. Bhat, M. M. Joullie, Tetrahedron
1986, 42, 2421 2428; c)H. Kogen, H. Kadokawa, M. Kurabayashi, J.
Chem. Soc. Chem. Commun. 1990, 1240 1241; d)S. Denmark, A. R.
Hurd, H. J. Sacha, J. Org. Chem. 1997, 62, 1668 1674; e)G. D.
Monache, D. Misti, G. Zappia, Tetrahedron: Asymmetry 1999, 10,
2961 2973; f)( ‡)-detoxinine: J. Mulzer, A. Meier, J. Buschmann, P.
Luger, J. Org. Chem. 1996, 61, 566 572.
[16] a)F. M. Moghaddam, R. Emami, Synth. Commun. 1997, 27, 4073
4077; b)we performed the synthesis of 23 analogously to: A.
Hausherr, B. Orschel, S. Scherer, H.-U. Rei˚ig, Synthesis 2001,
1377 1385.
[17] Data for anti-22: [a]D20 ˆ À11.9 (c ˆ 1.07, CHCl3); 1H NMR (250 MHz,
CDCl3): d ˆ 7.47 7.18 (m, 15H; Ph), 5.51 (s, 1H; 2'-H), 4.84, 4.77 (AB-
system, JAB ˆ 11.7 Hz, 1H each; OCH2Ph), 4.63 (mc, 1H; 4-H), 4.44 (d,
J ˆ 13.2 Hz, 1H; NCH2Ph), 4.33 (dd, J ˆ 4.4, 11.2 Hz, 1H; 6'-HA)*,
¾
raphy (Dowex 50 Â 4 100, 1m aqueous NH3 solution as eluent), (À)-
detoxinine was isolated as a colorless solid (61 mg, 89%). M.p. 224 À 2278C
(literature value: 224 À 2278C,[15f] 225 À 2288C[15a]) ; [a]2D0 ˆ À5.0 (c ˆ 0.60,
H2O)(literature value: À4.8 (c ˆ 0.5, H2O),[15a] À4.4 (c ˆ 0.5, H2O)[15d]);
1H NMR (250 MHz, D2O): d ˆ 4.51 4.44 (m, 1H; 3'-H), 4.30 (ddd, J ˆ 4.5,
7.8, 9.2 Hz, 1H; 3-H), 3.55 3.33 (m, 3H; 2'-H, 5'-H), 2.61 (dd, J ˆ 4.5,
15.7 Hz, 1H; 2-HA), 2.40 (dd, J ˆ 7.8, 15.7 Hz, 1H; 2-HB), 2.21 (dtd, J ˆ 4.1,
10.0, 14.2 Hz, 1H; 4'-HA), 2.09 ppm (dddd, J ˆ 1.2, 3.5, 7.8, 14.2 Hz, 1H; 4'-
HB); 13C NMR (125.8 MHz, D2O): d ˆ 181.2 (s; C-1), 72.9 (d; C-3') , 71.9 (d;
C-2'), 68.4 (d; C-3), 45.2 (t; C-5'), 44.4 (t; C-2), 35.3 ppm (t; C-4'); IR (KBr):
À
À
À
ˆ
nÄ ˆ 3200 (br; N H, O H), 2915, 2720, 2505 (br; C H), 1630 (C O),
1555 cmÀ1 (N H); MS (FAB, negative-mode): m/z (%): 174 (4) [M À H];
À
‡
MS (FAB, positive-mode): m/z (%): 176 (4) [M‡H] ; elemental analysis
calcd (%)for C 7H13NO4 (175.2): C 47.99, H 7.48, N 8.00; found: C 47.66, H
7.37, N 7.73.
CCDC-195173 (syn-8)and CCDC-195174 ( 30)contain the supplementary
crystallographic data for this paper. These data can be obtained free of
charge via www.ccdc.can.ac.uk/conts/retrieving.html (or from the Cam-
bridge Crystallographic Center, 12 Union Road, Cambridge CB21EZ,
UK; Fax: (‡44)1223-336033; or deposit@ccdc.cam.ac.uk).
1414
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Chem. Eur. J. 2003, 9, No. 6

Stereoselective Synthesis of Dihydropyrroles
1405 1415
4.23 (td, J ˆ 2.4, 11.2 Hz, 1H; 4'-H), 4.10 3.94 (m, 2H; 6'-HB, 2-H),
3.58 (d, J ˆ 13.2 Hz, 1H; NCH2Ph), 3.56 (dd, J ˆ 2.2, 12.0 Hz, 1H;
5-HA)**, 3.13 (ddd, J ˆ 1.8, 4.0, 12.0 Hz, 1H; 5-HB), 2.64 2.46 (m, 1H;
Hausherr, R. Zimmer, J. Heterocyclic Chem. 2000, 37, 597 606; c)H.-
U. Rei˚ig, W. Schade, M. Okala Amombo, R. Pulz, A. Hausherr, Pure
Appl. Chem. 2002, 74, 175 180. Selected recent original publications:
d)S. Hormuth, H.-U. Rei˚ig, D. Dorsch, Angew. Chem. 1993, 105,
1513 1514; Angew. Chem. Int. Ed. Engl. 1993, 32, 1449 1450; e)S.
Hormuth, H.-U. Rei˚ig, J. Org. Chem. 1994, 59, 67 73; f)W. Schade,
H.-U. Rei˚ig, Synlett 1999, 632 634; g)R. Pulz, A. Al-Harrasi, H.-U.
Rei˚ig, Org. Lett. 2002, 4, 2353 2355.
5'-HA), 1.34 1.23 ppm (m, 1H; 5'-HB),
* further fine coupling
observed, ** further splitting was not observed due to signal over-
lapping; 13C NMR (62.9 MHz, CDCl3): d ˆ 153.9 (s; C-3), 140.3, 139.1,
136.6, 128.7, 128.6, 128.5, 128.1, 128.0, 127.4, 126.6, 126.2 (3 Â s, 8 Â d;
Ph), 102.1 (d; C-2'), 93.6 (d; C-4), 79.1 (d; C-4') , 71.4 (t; OCH2Ph), 70.1
(d; C-2), 67.2 (t; C-6'), 60.5 (t; NCH2Ph), 56.8 (t; C-5), 24.9 ppm (t;
[23] As examples: Synthesis of (À)-preussin, ref. [5]; synthesis of (‡)-
anisomycin: M. Kratzert, S. Kaden, H.-U. Rei˚ig, unpublished results,
Freie Universit‰t Berlin (Germany).
[24] a)W. Reppe, Liebigs Ann. Chem. 1955, 596, 1 158; b)F. J. Weiberth,
S. S. Hall, J. Org. Chem. 1985, 50, 5308 5314.
[25] K. B. Banik, M. S. Manhas, Z. Kaluza, K. J. Barakat, A. K. Base,
Tetrahedron Lett. 1992, 33, 3603 3606.
[26] L. Battistini, F. Zanardi, G. Rassu, P. Spanu, G. Pelosi, G. G. Fava,
M. B. Ferrari, G. Gasiraghi, Tetrahedron: Asymmetry 1997, 8, 2975
2987.
ˆ À
À
C-5'); IR (neat): nÄ ˆ 3090 3000 ( C H), 2960 2800 (C H),
‡
1660 cmÀ1 (C C); MS (80 eV, EI): m/z (%): 427 (1) [M] , 336 (5)
ˆ
‡
‡
‡
[M À C7H7] , 264 (100)[ M À C10H11O2] , 91 (92)[Bn] ; HRMS
(80 eV): C28H29NO3 calcd 427.21474; found 427.21731; NOE-data
show that syn-22 and anti-22 differ only in the configuration at C-2.
[18] T. Toshima, H. Sato, A. Ichihara, Tetrahedron 1999, 55, 2581 2590.
[19] Hydrogenolysis of syn-22 in the presence of platinum on charcoal or
Raney-nickel (in the presence of Boc anhydride)gave complex
reaction mixtures. Attempted reduction with diimine afforded only
starting material.
[27] SHELX97 (Includes SHELXS97, SHELXL97, CIFTAB)Programs for
Crystal Structure Analysis (Release 97 2), G. M. Sheldrick, Uni-
versit‰t Gˆttingen (Germany), 1998.
[20] TEMPO oxidation, for instance, see: R. Siedlecka, J. Skarzewski, J.
Michowski, Tetrahedron Lett. 1990, 31, 2177 2180.
[21] H. Paulsen, W. Kˆbernick, E. Autschbach, Chem. Ber. 1972, 105,
1524 1531.
[22] Reviews: a)R. Zimmer, Synthesis 1993, 165 178; b)H.-U. Rei˚ig, S.
Hormuth, W. Schade, M. Okala Amombo, T. Watanabe, R. Pulz, A.
Received: October 29, 2002 [F4538]
Chem. Eur. J. 2003, 9, No. 6
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0947-6539/03/0906-1415 $ 20.00+.50/0
1415