The synthesis of (+)-preussin and related pyrrolidinols by diastereoselective Paterno-Buechi reactions of chiral 2-substituted 2,3-dihydropyrroles

Article abstract of DOI:10.1002/1521-3765(20001016)6:20<3838::AID-CHEM3838>3.0.CO;2-1

The N-alkoxycarbonyl substituted 2,3-dihydropyrroles 3 and 8 are converted to 2-benzyl-3-pyrrolidinols by the Paterno - Buechi reaction followed by hydrogenolysis. Since the addition of the photoexcited benzaldehyde at the unsaturated heterocycle proceeds in a syn fashion, the benzyl group at C-2 and the hydroxy group at C-3 of the product are cis oriented. The simple and facial diastereoselectivities of the Paterno -Buechi reaction were studied more closely and the relative configuration of the products was elucidated. The thermodynamically less stable endo product is formed as a result of simple diastereo-selection. The face differentiation in 2-substituted 2,3-dihydropyrroles is presumably due to the nonplanarity of these heterocycles, which forces attack of the carbonyl group on the face with the existing substituent. All-cis-pyrrolidinols are consequently formed after hydrogenolysis. Following this route, a total synthesis of the pyrrolidinol alkaloid (+)-preussin (1) was conducted, which yielded the target compound in a total yield of 11% over nine steps starting from L-pyroglutaminol (11).

Full text of DOI:10.1002/1521-3765(20001016)6:20<3838::AID-CHEM3838>3.0.CO;2-1

FULL PAPER
The Synthesis of (‡)-Preussin and Related Pyrrolidinols by Diastereoselective
PaternoÁ ± Büchi Reactions of Chiral 2-Substituted 2,3-Dihydropyrroles
Thorsten Bach,*[a,b] Harm Brummerhop,[a] and Klaus Harms[a,c]
Dedicated to Professor Bernd Giese on the occasion of his 60th birthday
Abstract: The N-alkoxycarbonyl substi-
tuted 2,3-dihydropyrroles 3 and 8 are
converted to 2-benzyl-3-pyrrolidinols by
ly and the relative configuration of the
products was elucidated. The thermody-
namically less stable endo product is
formed as a result of simple diastereo-
selection. The face differentiation in
2-substituted 2,3-dihydropyrroles is pre-
sumably due to the nonplanarity of these
heterocycles, which forces attack of the
carbonyl group on the face with the
existing substituent. All-cis-pyrrolidi-
nols are consequently formed after hy-
drogenolysis. Following this route, a
total synthesis of the pyrrolidinol alka-
loid (‡)-preussin (1) was conducted,
which yielded the target compound in a
total yield of 11% over nine steps
starting from l-pyroglutaminol (11).
Á
the Paterno ± Büchi reaction followed by
hydrogenolysis. Since the addition of the
photoexcited benzaldehyde at the unsa-
turated heterocycle proceeds in a syn
fashion, the benzyl group at C-2 and the
hydroxy group at C-3 of the product are
cis oriented. The simple and facial
Keywords: asymmetric synthesis
´
Á
oxetanes ´ Paterno ± Büchi reactions
Á
diastereoselectivities of the Paterno ±
´ photochemistry ´ pyrrolidines
Büchi reaction were studied more close-
The general route for unsaturated nitrogen heterocycles is
outlined in Scheme 1 (PG ˆ protecting group).
Introduction
The regio- and stereoselective functionalization of double
bonds is a key strategy in organic synthesis.[1] In this respect,
the [2‡2] photocycloaddition of carbonyl compounds and
[2, 3]
Á
alkenes, commonly called the Paterno ± Büchi reaction,
allows an efficient carbohydroxylation reaction to occur at
the olefinic precursor. In particular, heteroatom-substituted
alkenes, which undergo the reaction readily and with high
regioselectivity,[4] can be converted effectively to oxetanes by
Scheme 1. The carbohydroxylation of unsaturated nitrogen heterocycles.
À
this means. Subsequent O C bond cleavage generates the
From our previous experience with N-acylated enamines in
carbohydroxylation products.[5, 6] We have used this strategy
for the synthesis of various 1,2-diols and 1,2,3-triols from
acyclic silyl enol ethers.[7] If cyclic unsaturated olefins are
employed as substrates, cis-substituted heterocycles with
vicinal arylmethyl and hydroxy groups should be obtained.
[8]
Á
the Paterno ± Büchi reaction, we expected the photocy-
cloaddition ± hydrogenolysis sequence to proceed with ease
and we planned to use this sequence for the construction of
biologically active five- and six-membered nitrogen hetero-
cycles. Prominent examples for potentially accessible pyrro-
lidinols and piperidinols include (‡)-preussin (1),[9, 10] an
[a] Prof. Dr. T. Bach, Dipl.-Chem. H. Brummerhop, Dr. K. Harms
Fachbereich Chemie der Philipps-Universität
Hans-Meerwein-Strasse, 35032 Marburg (Germany)
HO
[b] Prof. Dr. T. Bach
5
2
(+)-Preussin (1)
Ph
Newaddress:
N
Lehrstuhl für Organische Chemie I
Technische Universität München, Lichtenbergstr. 4
85747 Garching (Germany)
Fax : (‡49)89-2891-3315
Me
antifungal agent isolated from Aspergillus ochraceus and from
Preussia sp., and FR901483,[11, 12] an immunosuppressant
isolated from Cladobotryum sp. No. 11231.
E-mail: thorsten.bach@ch.tum.de
[c] Dr. K. Harms
Crystal structure determination
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Chem. Eur. J. 2000, 6, No. 20

3838±3848
Table 1. Preparation and photocycloaddition/hydrogenolysis of 2,3-dihy-
dropyrroles 3 according to Scheme 2.
Our initial efforts, which we would like to report in this
account, were directed towards the synthesis of pyrrolidinols.
The general propensity of N-protected 2,3-dihydropyrroles to
Substrate
PG
3 [%][a]
4 [%][b]
5 [%][c]
Á
the Paterno ± Büchi reaction was studied, the regio- and
1
2
3
4
2a
2b
2c
2d
COOMe
COOEt
Boc[d]
42
43
53
65
57
52
41
96
53
56
stereoselectivity of the reaction was investigated for chiral
2-substituted substrates and attempts to induce the hydro-
genolytic ring opening were undertaken. The work culmi-
nated in the synthesis of enantiomerically pure (‡)-preus-
sin[13] and related pyrrolidinols.
[f]
[g]
Ts[e]
±
±
[a] Yield of isolated product over three steps (reduction, acetalization,
elimination). [b] Yield of the isolated major oxetane diastereoisomer.
[c] Yield of isolated pyrrolidinol 5 according to Scheme 2. [d] Boc ˆ tert-
butyloxycarbonyl. [e] Ts ˆ p-toluenesulfonyl. [f] The desired product was
not isolated. [g] The hydrogenolysis experiment was not conducted.
Results and Discussion
readily accessible.[14±16] Reduction with diisobutylaluminum
hydride (DIBAL-H) or superhydride (LiBEt3H) yields the
corresponding lactamols, which can be converted into the
N,O-acetals by treatment with 2,2-dimethoxypropane. The
final elimination step was advantageously carried out with
trimethylsilyl trifluoromethanesulfonate (TMSOTf) and N,N-
diisopropylethylamine as the base.[15, 17] The photocycloaddi-
tion was conducted in acetonitrile as the solvent and with
benzaldehyde as the carbonyl substrate. Rayonet lamps (RPR
3000 Š) were employed as the irradiation source (l ˆ
300 nm). In general, a 1:2 aldehyde/dihydropyrrole ratio was
required to suppress intermolecular side reaction of the
aldehyde (photopinacolization). Unreacted dihydropyrrole
could be recovered by flash chromatography. The three
alkoxycarbonyl-substituted substrates 3a ± c all reacted rea-
sonably well and yielded the desired oxetanes 4 (Table 1,
entries 1 ± 3). Substrate 3d, however, failed to undergo the
Choice of protecting group and simple diastereoselectivity:
Various N-protected 2,3-dihydropyrroles can be considered as
Á
substrates for the Paterno ± Büchi reaction. An acceptor
substituent appeared to be the best choice, as it decreases
the oxidation potential of the enamines and avoids side
reactions arising from single electron transfer. Four substrates
3a ± d were prepared which bear an electron-withdrawing
group (Scheme 2, Table 1). Starting from the corresponding
N-substituted pyrrolidinone 2 these dihydropyrroles are
Á
Paterno ± Büchi reaction and decomposed under the irradi-
ation conditions (Table 1, entry 4). No defined decomposition
products could be isolated.
The relative configuration of the oxetanes 4a ± c was
established by NOE and NOESY studies (Figure 1). All
hydrogen atoms within the oxetane ring are evidently
Scheme 2. The photochemical synthesis of simple 2-benzyl-3-hydroxypyr-
rolidines 5 from dihydropyrroles 3 (cf. Table 1).
Á
Abstract in German: Durch eine Sequenz aus Paterno ± Büchi-
Reaktion und /Hydrogenolyse lassen sich die N-Alkoxycarbo-
nyl-substituierten 2,3-Dihydropyrrole 3 und 8 in 2-Benzyl-3-
pyrrolidonole überführen. Da die Addition des photoange-
regten Benzaldehyds an den ungesättigten Heterocyclus als syn
Addition verläuft, stehen im Produkt die Benzylgruppe an C-2
und die Hydroxylgruppe an C-3 cis zueinander. Die einfache
Ph
Ph
O
5
O
5
7
7
N
H
N
H
1
1
COOEt
Boc
2.1%
H
9.8%
H
H
H
3.8%
5.3%
2.7%
7.9%
4b
1
4c
Á
und faciale Diastereoselektivität der Paterno ± Büchi-Reaktion
Figure 1. Principal H NOE data recorded for compounds 4b and 4c.
wurden genauer untersucht und die Relativkonfiguration der
Produkte einwandfrei aufgeklärt. Als Resultat der einfachen
Diastereoselektivität entsteht bevorzugt das thermodynamisch
ungünstigere endo-Produkt. Die Seitendifferenzierung in chi-
ralen 2-substituierten 2,3-Dihydropyrrolen basiert vermutlich
auf der Nichtplanarität dieser Heterocyclen, die einen Angriff
der Carbonylkomponente auf die Seite bedingen, auf der auch
der Substituent steht. Nach Hydrogenolyse entstehen deshalb
all-cis-Pyrrolidinole. Auf diesem Weg wurde eine Totalsyn-
these des Pyrrolidinol-Alkaloids (‡)-Preussin (1) durchge-
führt, die ausgehend von l-Pyroglutaminol (11) in einer
Gesamtausbeute von 11% über neun Stufen die Zielverbin-
dung liefert.
oriented cis to each other. The relative configuration of the
oxetanes 4 is in accord with earlier findings we made in our
work on acyclic enamides.[8] According to a proposal by
Griesbeck et al., the major diastereoisomer arises from a
favored intersystem crossing (ISC) transition[18] of the inter-
mediate biradical. This phenomenon is common to hetero-
atom-substituted alkenes which bear no additional a-sub-
stituent, whereas a-substituted alkenes showa preference for
the thermodynamically more stable product.[19] Possible
reasons for this behavior have been discussed in detail
elsewhere[4b, 19] although further data are required if a unified
Chem. Eur. J. 2000, 6, No. 20
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3839

T. Bach et al.
FULL PAPER
picture is to be obtained. Figure 1 shows typical NOE data
recorded at 233 K (500 MHz) for the major rotamers of
oxetanes 4b and 4c. Additional data for these compounds and
for oxetane 4a can be found in the Experimental Section. The
subsequent hydrogenolysis of oxetanes 4a ± c turned out to be
more dependent on the protecting group than we had
anticipated. Under the standard conditions which we had
previously employed for the hydrogenolysis of acid-sensititive
oxetanes,[6] the N-methoxycarbonyl-substituted oxetane 4a
clearly outperfomed the other two hydrogenolysis substrates
4b and 4c. We ascribe the lower yields for pyrrolidinols 5b
and 5c to the higher lability of the protecting group. Even in
the case of the most stable oxetane 4a, we found it better to
use a high catalyst/substrate ratio instead of prolonged
reaction times to facilitate a complete hydrogenolysis. The
expected relative configuration of the pyrrolidinol 5a was
again confirmed by NOE studies. Product 5c delivered
crystals suitable for single-crystal X-ray analysis. The crystal
structure is depicted in Figure 2.[20]
the stereogenic center and is prepared either from l-proline[22]
or from l-pyroglutamic acid.[16] Correia et al. showed that
ketene additions to this substrate occur with good facial
diastereoselectivity.[23] The ketene adds to the dihydropyrrole
from the face opposite the methoxycarbonyl group, the
cyclobutanone 7 being the major product. Heck reactions of
2-alkoxymethyl-2,3-dihydropyrroles occur at the C-5 carbon
atom and exhibit similar diastereoselectivies.[24]
In photocycloaddition reactions to N-acylated pyrroles the
mono adduct, which still contains a 2,3-dihydropyrrole sub-
structure, was reported to react further to a tricyclic product
with two oxetane rings attached to the central pyrrolidine.[25]
The second photocycloaddition occured from the more
accessible face of the concave bicyclic 2-aza-7-oxabicyclohep-
tene.
In the present study, we concentrated on 2-alkyl- and 2-aryl-
substituted 2,3-dihydropyrroles as olefin components. This
selection was based on our interest in the synthesis of
pyrrolidinols related to (‡)-preussin and possible epimers
thereof. The dihydropyrroles 8 were prepared in enantiomeri-
cally pure form starting from the corresponding enantiomeri-
cally pure N-methoxycarbonylpyrrolidinones, which were in
turn obtained from l-pyroglutamic acid according to known
procedures.[15, 26±30] The procedure will be detailed briefly for
the 2-nonylderivative 8d in a later section. The 2-phenyl-2,3-
dihydropyrrole rac-8e was prepared by Heck reaction of
phenyl iodide and dihydropyrrole 3a employing Pd(OAc)2/
P(o-Tol3)3 as the catalyst.[31]
The photocycloaddition reactions of the dihydropyrroles 8
were conducted with benzaldehyde as the carbonyl com-
pound. Disappointingly, the initial irradiation experiments
a
b
c
d
R = CH3
2
2
5
5
Ph
R = C2H5
R = CH2Ph
R = C9H19
R
N
N
COOMe
COOMe
Figure 2. A molecule of compound 5c in the crystal.
rac-8e
8
As a major consequence of these preliminary studies, we
selected N-methoxycarbonyl-substituted dihydropyrroles for
our further experiments. The facial diastereoselectivity of
failed although they were carried out under conditions fully
identical to those successfully employed for the conversion of
dihydropyrrole 3a (room temperature, acetonitrile as the
solvent, RPR 3000 Š). Rapid decomposition of the starting
materials 8 was observed and the yield of oxetane products
remained low. As we suspected that the long-wavelength
absorption of the dihydropyrroles (lmax ˆ ca. 240 nm), which
partially intersects the emission band of the RPR 3000 Š
lamps, was responsible for the decomposition, an irradiation
source which emits at longer wavelenghts (RPR 3500 Š, l ˆ
350 nm) was used. Indeed, we observed only minor dihydro-
pyrrole decomposition under these conditions and the ox-
etane yields were satisfactory. As expected, the reaction
yielded two major products 9 and 10 which could be separated
by flash chromatography. Diastereoisomer 9 prevailed in all
cases to a significant extent. The results of the study are
summarized in Scheme 4 and Table 2.
Á
their Paterno ± Büchi reaction was examined for substrates
which bear a stereogenic center at the C-2 carbon atom.
Benzaldehyde remained the standard aldehyde although
there are ample precedents for the employment of other
Á
aromatic aldehydes and ketones in the Paterno ± Büchi
reaction.[3, 21]
Facial diastereoselectivity: The 2-substituted 2,3-dihydropyr-
role 6 was employed as a substrate in thermal addition
reactions (Scheme 3). It carries the methoxycarbonyl group at
O
H
CHCl2COCl, NEt3
(hexane)
2
5
Cl
Cl
COOMe
COOMe
COOMe
N
N
63%
H
COOMe
The structure elucidation of compounds 9 and 10 was, to a
great extent, performed by NMR studies. Products derived
from single diastereoisomeric products 9 confirmed the
7
6
Scheme 3. Stereoselective ketene addition to dihydropyrrole 6.
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Asymmetric Synthesis
3838±3848
H4α
H4α
H5
H
H5
H
H4β
H3
H4β
H3
O
O
C4H9
C4H9
N
N
Ph
Ph
COOMe
COOMe
10f
9f
Scheme 4. Photochemical oxetane formation from 2-substituted 2,3-dihy-
dropyrroles 8 (cf. Table 2).
J
4β,5 = 2.6 Hz
4α,5 = 6.8 Hz
J4β,3
J4α,3
=
=
J
4β,5 = 5.2 Hz
4α,5 = < 1 Hz
J4β,3
=
7.3 Hz
8.3 Hz
2.1 Hz
J
J
J
4α,3 = 7.5 Hz
Á
Table 2. Yields and facial diastereoselectivities obtained in the Paterno ±
Büchi reaction of 2,3-dihydropyrroles 8 as shown in Scheme 4.
Figure 4. Calculated[32] 1H NMR coupling constants in the bicyclic com-
Substrate
R
Time [h][a]
dr (9/10)[b]
Yield [%][c]
pounds 9 f and 10 f.
1
2
3
4
5
8a
8b
8c
8d
CH3
6
5
6
6
7
76/24
71/29
57
±
57
65
63[e]
[d]
C2H5
CH2Ph
C9H19
Ph
constants for compounds 9 and 10, which are given in the
experimental section.
ꢀ 95/5
75/25
rac-8e
68/32
The data prove clearly that the attack of the photoexcited
carbonyl compound that finally leads to oxetane formation
occurs on the 2,3-dihydropyrroles 8 predominantly from the
diastereotopic face to which the side chain R points. This
facial diastereoselectivity is opposite to the selectivity ob-
served in the thermal [2‡2]-cycloaddition (Scheme 3) and in
the Heck reaction (vide supra).
[a] Irradiation time (RPR 3500 Š) after which the aldehyde had completely
disappeared according to GLC. [b] Diastereomeric ratio determined by
GLC. [c] Yield of isolated oxetane products. [d] The compound was
unstable and could not be isolated. [e] Products rac-9e and rac-10e were
racemic.
assignment (vide infra). Owing to the bent structure of
compounds 9 and 10, direct NOESY contacts between H-1
and H-3 cannot be expected. However, it is possible to
observe NOESY contacts between H-5 and H-4a or H-4b.
The protons at C-4 can in turn be related to the proton H-3. If
H-5 and H-4a are located cis to each otherÐas is the case for
diastereoisomer 10Ða strong contact is expected. For dia-
stereoisomer 9 the contact between H-5 and H-4b is strong.
This behavior is exemplified in Figure 3, which depicts the
strong (ÐÐ) and medium (- - - -) NOESY contacts observed
Discussion of the facial diastereoselectivity: Our initial
hypothesis concerning the facial diastereoselectivity was
quickly disproved. We speculated that the hydrophobic side
chain R assists the entering photoexcited aromatic aldehyde
during its attack on the carbon atom C-4 in the dihydropyr-
roles 8. The polar solvent acetonitrile should favor this
interaction. Since the diastereoselectivity of the photocy-
cloaddition remained unchanged (e.g. 9d/10d ˆ 75/25) when
the reaction was carried out in benzene as the solvent, this
idea had to be discarded. The effect of the temperature on the
facial diastereoselectivity was marginal and gave no hint of
the face-discriminating reaction step.[33] Although the kinetics
of the reaction were never followed quantitatively, there was
no apparent difference between the reaction velocity in the
reaction of the unsubstituted dihydropyrrole 3a and the
substituted dihydropyrroles 8. In addition, the simple diaste-
reoselectivity remained constant, favoring the thermodynami-
cally less stable endo products in which the five-membered
ring and the phenyl group are attached to the oxetane in a cis
fashion. Under the reasonable assumption that the oxetane
formation occurs stepwise, that is, by initial formation of the
.
for the diastereoisomers 9a and 10a ( ˆ COOMe).
Hα
CH3
3
H
Hα
CH3
Ph
5
O
H
5
3
7
N
1
Hβ
H
N
H
Hβ
H
O
1
H
H
H
7
Ph
= COOMe
9a
10a
Figure 3. 1H NOESY contacts recorded for compounds 9a and 10a.
À
À
O C bond and subsequent formation of the C C bond after
ISC, there is no evidence that the latter step influences the
facial diastereoselectivity. If it did, it could only occur by a
In addition, the coupling patterns for 9 and 10 are
completely different. Force-field calculations[32] and the
inspection of simple molecular models reveal that the
dihedral angles between H-3 and H-4a and between H-5
and H-4a in compounds 9 are roughly 908, resulting in two
À
competition between C C bond formation and ring cleavage.
As a consequence, the reaction would slow down and, even
more importantly, the simple diastereoselectivity should also
change, favoring the more stable exo product. On the basis of
3
3
À
small J coupling constants. By contrast, only one small J
coupling is recorded for compounds 10, that is, for the
coupling between H-4b and 5. The dihedral angle between
H-4a and H-3 is much larger and the dihedral angle between
H-4b and H-3 is much smaller than 908; this results in larger
coupling constants (3J ˆ ca. 7 Hz). Calculated coupling con-
stants for two model compounds 9 f and 10 f (R ˆ C4H9) are
shown in Figure 4. They compare well with the real coupling
these considerations, it seems that the C C bond-forming step
À
is unlikely to be selectivity-determining. The O C bond-
forming step appears to determine the stereoselectivity and
the question arises: Why does the photoexcited benzaldehyde
attack the carbon atom C-4 of the dihydropyrroles 8
preferentially from the Si face? The explanation we currently
favor aims at the different environment at the neighboring
carbon atom C-3. We assume the dihydropyrroles 8 to be not
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T. Bach et al.
FULL PAPER
fully planar during the approach of the photoexcited carbonyl
compound. Owing to 1,3-allylic strain[34, 35] the substituent at
C-2 prefers a pseudoaxial position; this leads to a discrim-
ination between the protons at C-3 as schematically drawn in
À
Figure 5. If this is correct, the O C bond formation should
occur preferentially antiperiplanar to the bond between C-3
and Hb, avoiding torsional strain and yielding directly a
staggered product.
O–C-bond formation
4
R
2
R
N
N
Hα
MeOOC
2
H
COOMe
Hβ
8
Figure 5. Possible explanation for the facial diastereoselection in the
Á
Paterno ± Büchi reaction of dihydropyrroles 8.
In this respect the explanation resembles a recent sugges-
tion put forward by Woerpel et al. to account for the facial
diastereoselectivity in nucleophilic displacement reactions via
five-membered oxocarbenium ions.[36] It is also in line with the
stereochemical results observed in nucleophilic addition
reactions to N-acyliminium ions.[37] The discrepancy between
the selectivities achieved in the photochemical addition to
chiral 2,3-dihydropyrroles and the selectivities recorded in
thermal reactions which occur at C-5 or simultanously at C-5
and C-4 is also readily explained. The reaction at C-5 requires
an attack from the face opposite the substituent R to avoid
steric interactions in the transition state.
It must be noted, however, that we have no evidence for the
nonplanarity of the dihydropyrroles 8 in the ground state.
Crystal structure data of these compounds are not available
but a related structure was shown by X-ray analysis to contain
a nonplanar dihydropyrrole moiety.[38] Our attempts to obtain
information about their conformation by NMR have been
unsuccessful so far. The spectra were not well resolved
because of the restricted rotation around the carbamate bond.
Therefore, the question of the possible reasons for the
observed facial diastereoselectivity cannot be conclusively
answered yet.
Scheme 5. The total synthesis of (‡)-preussin (1).
isolated in 53% yield. Its hydrogenolysis was conducted in the
presence of Pearlmanꢁs catalyst and yielded the known (‡)-
preussin precursor 17. The reduction of this compound to (‡)-
preussin (1) has already been described[10a] and was success-
fully conducted in 91% yield. The optical rotation ([a]D25
ˆ
‡22.1 in CHCl3, c ˆ 1) of synthetic preussin and its analytical
data were in accord with the literature data.[9] Moreover, we
carried out NOESY experiments which confirmed the all-cis
configuration, for example by showing a contact between H-2
and H-5, and which supported our assignment of the major
oxetane diastereoisomer 9d.
The total yield of (‡)-preussin starting from commercially
available l-pyroglutaminol was 11% over nine steps. Because
of the biological potential of (‡)-preussin[9] the synthesis of
analogs is certainly a topic of current interest. The hydro-
genolysis of further oxetane substrates could be readily
conducted and we obtained, for example, the pyrrolidinols
18 (89% yield from 9a) and 19 (88% yield from 10d) by this
means.
Synthesis of (‡)-preussin and related pyrrolidinols: We were
pleased to note that the hydrogenolyses of the photochemi-
cally prepared oxetanes 9 and 10 proceeded smoothly. This
reaction paved the way to a short synthesis of (‡)-preussin
(1), the individual steps of which are detailed in Scheme 5.
The scheme exemplifies the previously mentioned approach
to 2,3-dihydropyrroles. The reaction sequence commenced
with the tosylation of l-pyroglutaminol (11). Nucleophilic
substitution of tosylate 12 with a higher-order cuprate yielded
pyrrolidinone 13, which was N-acylated with methyl chloro-
formate. N-Methoxycarbonylpyrrolidinone 14 was reduced
with superhydride to the lactamol 15, which was converted to
the N,O-acetal 16 by treatment with 2,2-dimethoxypropane in
the presence of camphorsulfonic acid (CSA). A final elimi-
nation gave the desired dihydropyrrole 8d, the photocycload-
dition of which has already been desribed. The major
HO
HO
Ph
Ph
C9H19
N
COOMe
N
COOMe
19
18
The hydrogenolysis of compounds rac-9e and rac-10e could
not be performed selectively. Both benzylic C heteroatom
bonds were cleaved and an open-chain amino alcohol was
isolated in low yield. This was the only case, however, for
which difficulties in the hydrogenolysis step were encoun-
tered.
À
Á
diastereoisomer 9d of the Paterno ± Büchi reaction was
3842
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0620-3842 $ 17.50+.50/0
Chem. Eur. J. 2000, 6, No. 20

Asymmetric Synthesis
3838±3848
In some instances it proved advantageous to use the
hydrogenolysis product further in the LiAlH4 reduction step
without prior purification. As an example a reaction which led
to the pyrrolidinol 20 is depicted in Scheme 6.
HO
Scheme 7. Attempted carbohydroxylation of the tetrahydropyridine 21.
1. H2 [Pd(OH)2/C] (MeOH)
2. LiAlH4 (THF)
3
5
2
Ph
Ph
9c
N
72%
compounds are still being pursued in our laboratories. Further
results along these lines will be reported in due course.
Me
20
Scheme 6. Preparation of the preussin analogue 20.
Experimental Section
The solid pyrrolidinol 20 gave crystals suitable for single-
crystal X-ray analysis.[39] The crystal structure so obtained
(Figure 6) showed nicely the all-cis arrangement of the three
substituents at C-2, C-3, and C-5. As the configuration at these
stereogenic centers does not change in the hydrogenolysis
step, this provides conclusive evidence for the relative
configuration of oxetane 9c.
General: For general remarks, see ref.[8f]. The 2,3-dihydropyrroles 3a-d,
8a-c, and rac-8e were prepared according to reported procedures.[15, 32, 44]
NOESY contacts are reported as weak ('), medium (''), or strong (''').
General irradiation procedure: Irradiation experiments were performed in
quartz tube. The aldehyde (1.0 equiv) and the 2,3-dihydropyrrole
a
(1.5 equiv) were dissolved in acetonitrile (Merck p.a.) under Ar. This
mixture was irradiated for the indicated period of time (l ˆ 350 nm:
Rayonet RPR 3500 Š; l ˆ 350 nm: Rayonet RPR 3000 Š). The course of
the reaction was monitored by TLC and GLC. Upon complete conversion
of the aldehyde, the solvent was evaporated in vacuo. The diastereose-
lectivity (dr) was determined by GLC analysis of the crude product. The
desired oxetanes were separated in the course of the subsequent flash
chromatography and were obtained as colorless oils. The compounds
decomposed rapidly upon standing at 08C. Relative configurations were
1
determined by H NMR spectroscopy (NOE or NOESY experiments).
(1RS,5SR,7RS)-N-Methoxycarbonyl-7-phenyl-6-oxa-2-azabicyclo[3.2.0]-
heptane (4a): According to the general irradiation procedure, benzalde-
hyde (159 mg, 152 mL, 1.50 mmol) and 2,3-dihydropyrrole 3a[15, 43] (318 mg,
2.50 mmol) were irradiated in acetonitrile (15 mL) at l ˆ 300 nm for 4.5 h.
The solvent was removed in vacuo and the residue was purified by flash
chromatography (pentane/tert-butyl methyl ether (P/TBME) ˆ 80:20). A
total of 199 mg (57%) oxetane 4a was obtained as a colorless oil: Rf ˆ 0.16
(P/MTBE ˆ 40/60); 1H NMR (major rotamer, 500 MHz): d ˆ 1.81 (dddd,
Figure 6. A molecule of compound 20 in the crystal.
Additional experiments: It may seem at first sight as if the
successful photocycloaddition of dihydropyrroles such as 3
and 8 to benzaldehyde is straightforward, given the previous
experiments conducted with terminal acyclic N-acyl and N-
alkoxycarbonyl enamines.[8] Despite the apparent similarity
which was alluded to in the introduction, this conclusion is not
fully correct. It is important to note that the 2,3-dihydropyr-
roles bear a substituent at the b-position of the N-alkoxycar-
bonylenamine moiety. Hydrogen abstraction at this site
should be facile in particular since the substituent is embed-
ded in a cyclic array. Cyclopentene, for example, is a rather
3
3
3
2J(H,H) ˆ 14.3 Hz, J(H,H) ˆ 10.7 Hz, J(H,H) ˆ 9.2 Hz, J(H,H) ˆ 4.3 Hz,
1H; CHHCH2N), 2.22 (dd, 2J(H,H) ˆ 14.3 Hz, 3J(H,H) ˆ 6.8 Hz, 1H;
CHHCH2N), 3.30 (ddd, 2J(H,H) ˆ^ 3J(H,H) ˆ 10.9 Hz, 3J(H,H) ˆ 6.8 Hz,
1H; CHHN), 3.35 (s, 3H; OCH3), 3.84 (dd, 2J(H,H) ˆ^ 3J(H,H) ˆ 9.8 Hz,
3
1H; CHHN), 4.86 (dd, J(H,H) ˆ^ 3J(H,H) ˆ 4.6 Hz, 1H; CHN), 5.52 (dd,
3J(H,H) ˆ^ 3J(H,H) ˆ 4.4 Hz, 1H; OCH), 5.84 (d, 3J(H,H) ˆ 4.7 Hz, 1H;
1
CHPh), 7.19 ± 7.39 (m, 5H; Ph); H NMR (minor rotamer, 500 MHz): d ˆ
1.79 (dddd, 2J(H,H) ˆ 14.3 Hz, 3J(H,H) ˆ 10.9 Hz, 3J(H,H) ˆ 9.0 Hz,
3J(H,H) ˆ 4.5 Hz, 1H; CHHCH2N), 2.17 (dd, 2J(H,H) ˆ 14.3 Hz,
3J(H,H) ˆ 6.7 Hz, 1H; CHHCH2N), 3.44 (s, 3H; OCH3), 3.53 (ddd,
2J(H,H) ˆ^ 3J(H,H) ˆ 10.8 Hz, 3J(H,H) ˆ 6.9 Hz, 1H; CHHN), 3.73 (dd,
2J(H,H) ˆ^ 3J(H,H) ˆ 9.7 Hz, 1H; CHHN), 5.08 (dd, 3J(H,H) ˆ^ 3J(H,H) ˆ
4.9 Hz, 1H; CHN), 5.50 (dd, 3J(H,H) ˆ^ 3J(H,H) ˆ 4.7 Hz, 1H; OCH), 5.91
(d, 3J(H,H) ˆ 5.1 Hz, 1H; CHPh), 7.20 ± 7.38 (m, 5H; Ph); 13C NMR (major
rotamer, 75.5 MHz): d ˆ 31.3 (CH2CH2N), 46.9 (CH2N), 51.9 (OCH3), 61.0
(CHN), 83.9 (OCH), 84.2 (CHPh), 125.3 (Car), 127.8 (2C, Car), 128.0 (2C,
Car), 137.0 (Car), 154.8 (COOCH3); 13C NMR (minor rotamer, 75.5 MHz):
d ˆ 32.3 (CH2CH2N), 46.1 (CH2N), 52.3 (OCH3), 60.8 (CHN), 83.0 (OCH),
84.3 (CHPh), 125.1 (Car), 127.3 (2C, Car), 128.0 (2C, Car), 137.4 (Car), 154.4
(COOCH3); NOE (600 MHz): H (5.84): H (5.52) [0.6%], H (4.86) [2.9%];
H (5.52): H (5.84) [0.7%], H (4.86) [2.2%]; H (4.86): H (5.84) [3.2%], H
(5.52) [1.9%]; IR (film): nÄ ˆ 3040 cmÀ1 (w), 3010 (w), 2930 (s), 2870 (m,
Á
problematic substrate in the Paterno ± Büchi reaction and
suffers severe photoreduction.[40] In this respect, the 2,3-
dihydropyrroles are apparently more closely related to 2,3-
dihydrofurans, which undergo the photocycloaddition
smoothly and with high simple diastereoselectivity.[41, 42] If
this analogy is true, the six-membered tetrahydropyridines
should react more sluggishly than do the six-membered
dihydropyrans.[40] Indeed, the substrate 21 gave only poor
yields of photocycloadduct 22 (Scheme 7) under a variety of
conditions.
À
ˆ
C H), 1680 (vs, C O), 1440 (s), 1380 (s), 1320 (m), 1220 (m), 1190 (s), 1100
À
À
À
À
(s), 1030 (m, C H), 980 (s, C O C), 905 (m), 760 (s), 745 (m), 695 (s, C H);
‡
‡
MS (70 eV, EI), m/z (%): 216 (4) [M À Me] , 127 (100) [M À PhCHO] , 112
Although the hydrogenolysis of product 22 to piperidinols
23 was a clean process, the photocycloaddition/hydrogenolysis
approach is clearly not suited for the conversion of N-
alkoxycarbonyl-substituted tetrahydropyridines to piperidi-
nols. Because of the biological significance of 3-piperidinols
(vide infra), different photochemical approaches to these
‡
‡
‡
(54) [M À PhCHO À Me] , 105 (16) [PhCO] , 82 (28) [C5H8N] , 41 (24)
‡
[C2H3N] ; elemental analysis calcd (%) for C13H15NO3 (233.26): C 66.94, H
6.48, N 6.00; found C 66.78, H 6.68, N 5.77.
(1RS,5SR,7RS)-2-Ethoxycarbonyl-7-phenyl-6-oxa-2-azabicyclo[3.2.0]hep-
tane (4b): According to the general irradiation procedure, benzaldehyde
(212 mg, 202 mL, 2.00 mmol) and dihydropyrrole 3b[15, 43] (565 mg,
Chem. Eur. J. 2000, 6, No. 20
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0620-3843 $ 17.50+.50/0
3843

T. Bach et al.
FULL PAPER
4.00 mmol) were irradiated in acetonitrile (20 mL) at l ˆ 300 nm for 3.5 h.
The solvent was removed in vacuo and the residue was purified by flash
chromatography (P/TBME ˆ 80:20). A total of 155 mg (52%) of oxetane
(1R,3R,5S,7R) isomer (9a) (major product): Yield: 275 mg (37%): Rf ˆ
0.11 (P/TBME ˆ 40:60); [a]2D5 ˆ À41.9 (c ˆ 1.15; CHCl3); 1H NMR
(400 MHz, [D6]DMSO, 373 K): d ˆ 1.07 (d, 3J(H,H) ˆ 6.5 Hz, 3H; CH3),
1.79 (dd, 2J(H,H) ˆ 14.7 Hz, 3J(H,H) ˆ 2.3 Hz, 1H; CHH), 2.18 (ddd,
2J(H,H) ˆ 14.7 Hz, 3J(H,H) ˆ 9.4 Hz, 3J(H,H) ˆ 5.4 Hz, 1H; CHH), 3.47 (s,
3H; OCH3), 4.04 ± 4.14 (m, 1H; CHCH3), 4.99 (dd, 3J(H,H) ˆ^ 3J(H,H) ˆ
4.6 Hz, 1H; CHN), 5.41 (dd, 3J(H,H) ˆ^ 3J(H,H) ˆ 5.1 Hz, 1H; CHO), 5.84
(d, 3J(H,H) ˆ 4,7 Hz, 1H; CHPh), 7.22 ± 7.32 (m, 5H; Ph); NOESY
(400 MHz, [D6]DMSO, 373 K): H (1.07) ± H (1.79)''; H (1.07) ± H (4.1)''';
H (1.79) ± H (2.18)'''; H (1.79) ± H (4.1)'; H (2.18) ± H (4.1)'''; H (2.18) ± H
(5.41)'''; H (4.99) ± H (5.41)''; H (4.99) ± H (5.84)'''; H (5.41) ± H (5.84)''; IR
1
4b was obtained as a colorless oil: Rf ˆ 0.37 (P/TBME ˆ 40:60); H NMR
(major rotamer, 400 MHz): d ˆ 1.09 (t, 3J(H,H) ˆ 7.1 Hz, 3H; CH2CH3),
1.82 (dddd, 2J(H,H) ˆ 15.4 Hz, 3J(H,H) ˆ 10.9 Hz, 3J(H,H) ˆ 9.2 Hz,
3J(H,H) ˆ 4.3 Hz, 1H; CHHCH2N), 2.22 (ddd, 2J(H,H) ˆ^ 3J(H,H) ˆ
15.4 Hz, 3J(H,H) ˆ 6.8 Hz, 1H; CHHCH2N), 3.56 (ddd, 2J(H,H) ˆ^
3J(H,H) ˆ 10.9 Hz, 3J(H,H) ˆ 6.8 Hz, 1H; CHHN), 3.85 ± 3.97 (m, 1H;
CHHN), 3.87 (q, 3J(H,H) ˆ 7.1 Hz, 2H; CH2CH3), 4.90 (dd, 3J(H,H) ˆ^
3J(H,H) ˆ 4.6 Hz, 1H; CHN), 5.54 (dd, 3J(H,H) ˆ^ 3J(H,H) ˆ 4.5 Hz, 1H;
CHO), 5.87 (d, 3J(H,H) ˆ 4.7 Hz, 1H; CHPh), 7.22 ± 7.36 (m, 5H; Ph);
1H NMR (minor rotamer, 400 MHz): d ˆ 1.03 (t, 3J(H,H) ˆ 7.1 Hz, 3H;
(film): nÄ ˆ 2960 cmÀ1 (m, C H), 1715 (s) 1700 (sh, C O), 1450 (s), 1385 (m);
À
ˆ
‡
‡
MS (EI, 70 eV, EI), m/z (%): 248 (0.6) [M‡H] , 247 (0.3) [M] , 141 (93)
2
‡
‡
‡
CH2CH3), 1.21 ± 1.43 (m, 2H; CH2CH2N), 3.34 (ddd, J(H,H) ˆ^ 3J(H,H) ˆ
[M À PhCHO] , 126 (100) [C6H10NO2] , 105 (37) [PhCO] ; HRMS calcd
(u) C14H17NO3 (247.29): 247.1208; found 247.1215. (1S,3R,5R,7S) isomer
(10a) (minor product): Yield 148 mg (20%): Rf ˆ 0.17 (P/TBME ˆ 40:60);
[a]2D5 ˆ À32.5 (c ˆ 1.1; CHCl3); 1H NMR (400 MHz, [D6]DMSO, 373 K):
d ˆ 1.28 (d, 3J(H,H) ˆ 6.0 Hz, 3H; CH3), 1.65 (ddd, 2J(H,H) ˆ 14.6 Hz,
3J(H,H) ˆ 8.3 Hz, 3J(H,H) ˆ 5.1 Hz, 1H; CHH), 2.48 (dd, 2J(H,H) ˆ
3
10.9 Hz, J(H,H) ˆ 6.7 Hz, 1H; CHHN), 3.68 ± 3.80 (m, 1H; CHHN), 3.78
(q, 3J(H,H) ˆ 7.1 Hz, 2H; CH2CH3), 5.09 (dd, 3J(H,H) ˆ^ 3J(H,H) ˆ 4.8 Hz,
1H; CHN), 5.52 (dd, 3J(H,H) ˆ^ 3J(H,H) ˆ 4.5 Hz, 1H; CHO), 5.93 (d,
3J(H,H) ˆ 5.0 Hz, 1H; CHPh), 7.22 ± 7.36 (m, 5H; Ph); 13C NMR (major
rotamer, 50 MHz): d ˆ 14.3 (CH2CH3), 31.1 (CH2CH2N), 46.7 (CH2CH2N),
60.7 (CH2CH3), 60.8 (CHN), 83.9 (OCH), 84.2 (CHCar), 125.3 (Car), 127.2
(2C, Car), 127.9 (2C, Car), 137.0 (Car), 153.9 (NCOO); 13C NMR (minor
rotamer, 50 MHz): d ˆ 13.9 (CH2CH3), 32.1 (CH2CH2N), 46.0 (CH2CH2N),
60.5 (CH2CH3), 60.9 (CHN), 82.9 (OCH), 84.3 (CHCar), 125.3 (Car), 126.1
(2C, Car), 127.7 (2C, Car), 137.3 (Car), 154.2 (NCOO); NOE (500 MHz): H
(5.87): H (4.90) [2.1%], H (5.54) [3.8%]; H (5.54): H (1.82) [3.4%], H
(2.22) [0.5%]; H (4.90): H (5.54) [5.3%], H (5.87) [8.4%]; IR (film): nÄ ˆ
3
14.6 Hz, J(H,H) ˆ 7.2 Hz, 1H; CHH), 3.09 (s, 3H; OCH3), 4.08 ± 4.14 (m,
1H; CHCH3), 4.88 (dd, J(H,H) ˆ^ 3J(H,H) ˆ 4.7 Hz, 1H; CHN), 5.35 (dd,
3
3J(H,H) ˆ^ 3J(H,H) ˆ 4.9 Hz, 1H; CHO), 5.74 (d, 3J(H,H) ˆ 4,7 Hz, 1H;
CHPh), 7.24 ± 7.36 (m, 5H; Ph); NOESY (400 MHz, [D6]DMSO, 373 K): H
(1.28) ± H (1.65)''; H (1.28) ± H (2.48)'; H (1.28) ± H (4.1)'''; H (1.65) ± H
(2.48)'''; H (1.65) ± H (4.88)''; H (2.48) ± H (4.1)''; H (4.88) ± H (5.35)''; H
(4.88) ± H (5.74)'''; H (5.35) ± H (5.74)''; IR (film): nÄ ˆ 3075 cmÀ1 (w), 3020
2980 cmÀ1 (m), 2895 (w, C H), 1700 (vs, C O), 1470 (s), 1385 (m), 1330 (m,
(w), 2960 (m, C H), 1700 (vs, C O), 1450 (s), 1385 (s), 1320 (m), 1200 (m,
À
ˆ
À
ˆ
À
À
À
À
À
À
À
À
C H), 1110 (m, C H), 990 (w, C O C), 970 (m), 770 (w), 750 (w), 700 (m,
C H), 990 (w, C O C), 770 (m), 735 (m), 700 (s, C H); MS (70 eV, EI),
‡
‡
‡
‡
C À H); MS (70 eV, EI), m/z (%): 247 (0.3) [M] , 202 (0.9) [M À OEt] , 174
m/z (%): 246 (4) [M À H] , 140 (100) [M À H À PhCHO] , 126 (16)
‡
‡
‡
‡ ‡ ‡
(2) [M À COOEt] , 141 (100) [M À PhCHO] , 105 (16) [PhCO] , 68 (66)
[C6H10NO2] , 105 (31) [PhCO] , 28 (76) [CO] .
‡
‡
[C4H8N] , 29 (61) [C2H5] ; HRMS calcd (u) for C14H17NO3 (247.29):
247.1208; found 247.1211.
(1R,3R,5S,7R)-N-Methoxycarbonyl-3-benzyl-6-oxa-7-phenyl-2-azabicyclo-
[3.2.0]heptane (9c): According to the general irradiation procedure
benzaldehyde (159 mg, 152 mL, 1.5 mmol) and 2,3-dihydropyrrole 8c[15]
(543 mg, 2.50 mmol) were irradiated in acetonitrile (15 mL) for 6 h at
l ˆ 350 nm. GLC analysis of the crude product mixture showed a single
diastereomer (drꢀ 95/5). After removal of the solvent in vacuo, flash
chromatography (P/TBME ˆ 90:10) yielded 277 mg (57%) of the oxetane
9c as a colorless oil: Rf ˆ 0.16 (P/TBME ˆ 40:60); [a]2D5 ˆ À3.60 (c ˆ 1.7 in
CHCl3); 1H NMR (400 MHz, [D6]DMSO, 373 K): d ˆ 1.93 ± 1.96 (m, 1H;
OCHCHH), 2.67 ± 2.75 (m, 3H; CHHCHCH2Ph), 3.47 (s, 3H; OCH3),
4.20 ± 4.26 (m, 1H; CHCH2Ph), 5.07 (dd, 3J(H,H) ˆ^ 3J(H,H) ˆ 4.4 Hz, 1H;
OCHCHN), 5.43 ± 5.46 (m, 1H; CHO), 5.93 (d, 3J(H,H) ˆ 4,5 Hz, 1H;
OCHPh), 7.16 ± 7.38 (m, 10H; 2 Ph); NOESY (400 MHz, [D6]DMSO,
373 K): H (1.9) ± H (2.7)'''; H (1.9) ± H (4.2)'''; H (1.9) ± H (5.4)'''; H (2.7) ± H
(4.2)''; H (2.7) ± H (7.2)'''; H (4.2) ± H (7.2)'''; H (5.07) ± H (5.4)''; H (5.07) ±
H (5.93)'''; H (5.4) ± H (5.93)'''; H (5.93) ± H (7.2)''; IR (film): nÄ ˆ 3060 cmÀ1
(1RS,5SR,7RS)-2-tert-Butoxycarbonyl-7-phenyl-6-oxa-2-azabicyclo[3.2.0]-
heptane (4c): According to the general irradiation procedure benzalde-
hyde (159 mg, 152 mL, 1.50 mmol) and dihydropyrrole 3c[15, 43] (634 mg,
3.75 mmol) were irradiated in acetonitrile (15 mL) for 4 h. The mixture was
removed in vacuo and the residue was purified by flash chromatography
(P/TBME ˆ 80:20). A total of 168 mg (41%) of oxetane 4c was obtained as
a colorless oil: Rf ˆ 0.36 (P/TBME ˆ 40:60); 1H NMR (major rotamer,
500 MHz): d ˆ 1.14 (s, 9H; C(CH3)3), 1.43 ± 1.56 (m, 1H; CHHCH2N), 2.22
(dd, 2J(H,H) ˆ 14.2 Hz, 3J(H,H) ˆ 6.1 Hz, 1H; CHHCH2N), 3.59 (ddd,
2J(H,H) ˆ^ 3J(H,H) ˆ 10.9 Hz, 3J(H,H) ˆ 7.0 Hz, 1H; CHHN), 3.86 ± 3.93
(m, 1H; CHHN), 4.79 (dd, 3J(H,H) ˆ^ 3J(H,H) ˆ 4.4 Hz, 1H; CHN), 5.52
(dd, 3J(H,H) ˆ^ 3J(H,H) ˆ 4.1 Hz, 1H; CHO), 5.83 (d, 3J(H,H) ˆ 4.3 Hz,
1H; CHPh), 7.24 ± 7.37 (m, 5H; Ph); 1H NMR (minor rotamer, 500 MHz):
d ˆ 1.16 (s, 9H; C(CH3)3), 1.73 ± 1.86 (m, 1H; CHHCH2N), 2.16 (dd,
2J(H,H) ˆ 14.2 Hz, 3J(H,H) ˆ 6.1 Hz, 1H; CHHCH2N), 3.29 ± 3.37 (m, 1H;
CHHN), 3.64 ± 3.68 (m, 1H; CHHN), 4.95 (dd, 3J(H,H) ˆ^ 3J(H,H) ˆ
4.7 Hz, 1H; CHN), 5.49 (dd, 3J(H,H) ˆ^ 3J(H,H) ˆ 4.3 Hz, 1H; CHO),
5.90 (d, 3J(H,H) ˆ 4.9 Hz, 1H; CHPh), 7.24 ± 7.37 (m, 5H; Ph); 13C NMR
(major rotamer, 125 MHz): d ˆ 27.8 (CH2CH2N), 28.2 (C(CH3)3), 30.8
(CH2CH2N), 61.0 (CHN), 79.5 (C(CH3)3), 84.0 (OCH), 84.3 (CHPh), 125.7
(Car), 126.9 (2C, Car), 128.0 (2C, Car), 136.8 (Car), 153.2 (NCOO); 13C NMR
(minor rotamer, 125 MHz): d ˆ 26.9 (CH2CH2N), 28.0 (C(CH3)3), 31.9
(CH2CH2N), 60.0 (CHN), 79.3 (C(CH3)3), 83.1 (OCH), 84.4 (CHPh),
125.10 (Car), 126.8 (2C, Car), 127.8 (2C, Car), 137.0 (Car), 13C signal for
NCOO was not obtained; NOE (500 MHz): H (5.83): H (7.31) [7.3%], H
(5.52) [2.7%], H (4.79) [9.8%]; H (5.52): H (5.83) [3.3%], H (4.79) [7.9%];
À
ˆ
(w), 3030 (m), 2970 (m), 2955 (s, C H);1700 (vs, C O), 1450 (vs), 1385 (s),
À
À À
1335 (s), 1200 (s), 1120 (m), 1080 (m, C H), 985 (m, C O C); MS (70 eV,
‡
‡
EI), m/z (%): 323 (0.9) [M] , 292 (0.8) [M À OCH3] , 217 (26) [M À
‡
‡
‡
‡
PhCHO] , 126 (100) [C6H10NO2] , 107 (48) [C7H7O] , 91 (74) [C7H7] ;
HRMS calcd (u) for C20H21NO3 (323.39): 323.1521; found 323.1511.
N-Methoxycarbonyl-3-nonyl-6-oxa-7-phenyl-2-azabicyclo[3.2.0]heptane:
According to the general irradiation procedure benzaldehyde (106 mg,
101 mL, 1.00 mmol) and 2,3-dihydropyrrole 8d (633 mg, 2.50 mmol) were
irradiated in acetonitrile (15 mL) at l ˆ 350 nm. After 4 h benzaldehyde
(53 mg, 51 mL, 0.5 mmol) was added to the reaction mixture and the
mixture was further irradiated for another 2 h. GLC analysis of the crude
product mixture showed a diastereomeric ratio dr ˆ 75/25. After removal of
the solvent in vacuo, flash chromatography (P/TBME ˆ 90:10) yielded two
separate diastereoisomers as colorless oils. (1R,3R,5S,7R) isomer (9d)
(major product): Yield: 286 mg (53%): Rf ˆ 0.10 (P/TBME ˆ 80:20);
[a]2D5 ˆ À10.7 (c ˆ 2.1; CHCl3); 1H NMR (400 MHz, [D6]DMSO, 373 K):
IR (film): nÄ ˆ 3090 cmÀ1 (w), 3065 (w), 3030 (m), 2970 (s), 2890 (s, C H),
À
ˆ
1695 (vs, C O), 1480 (s), 1455 (s), 1390 (m), 1370 (m), 1170 (s), 1115 (s,
À
À
À
À
C H), 990 (m), 970 (m, C O C), 770 (m), 750 (m), 700 (m, C H); MS
‡
‡
(70 eV, EI), m/z (%): 169 (9) [M À PhCHO] , 113 (85) [C5H7NO2] , 69 (48)
‡
‡
‡
[C4H7N] , 57 (100) [C(CH3)3] , 41 (30) [C2H3N] ; HRMS calcd (u) for
C16H21NO3 (275.34): 275.1521; found 275.1526.
3
d ˆ 0.88 (t, J(H,H) ˆ 7.0 Hz, 3H; CH2CH3), 1.08 ± 1.32 (m, 16H; (CH2)8),
1.84 (dd, 2J(H,H) ˆ 14.7 Hz, 3J(H,H) ˆ 1.9 Hz, 1H, CHH), 2.08 (ddd,
2J(H,H) ˆ 14.7 Hz, 3J(H,H) ˆ 9.1 Hz, 3J(H,H) ˆ 5.2 Hz, 1H; CHH), 3.51 (s,
3H; OCH3), 3.93 ± 3.99 (m, 1H; NCHCH2), 5.02 (dd, 3J(H,H) ˆ^ 3J(H,H) ˆ
N-Methoxycarbonyl-3-methyl-6-oxa-7-phenyl-2-azabicyclo[3.2.0]heptane:
According to the general irradiation procedure benzaldehyde (318 mg,
304 mL, 3.00 mmol) and 2,3-dihydropyrrole 8a[15, 29, 30] (635 mg, 4.5 mmol)
were irradiated in acetonitrile (30 mL) at l ˆ 350 nm for 6 h. GLC analysis
of the crude product mixture showed a diastereomeric ratio dr ˆ 76/24.
After removal of the solvent in vacuo, flash chromatography (P/TBME ˆ
80:20) yielded two separated diastereoisomers as colorless oils.
3
4.9 Hz, 1H; CHCHN), 5.43 (dd, J(H,H) ˆ^ 3J(H,H) ˆ 4.9 Hz, 1H; CHO),
5.85 (d, 3J(H,H) ˆ 4,8 Hz, 1H; CHPh), 7.19 ± 7.29 (m, 5H; Ph); NOESY
(400 MHz, [D6]DMSO, 373 K): H (1.84) ± H (2.08)'''; H (1.84) ± H (3.9)'; H
(1.84) ± H (5.43)''; H (2.08) ± H (3.9)'''; H (2.08) ± H (5.43)'''; H (5.02) ± H
(5.43)''; H (5.02) ± H (5.85)'''; H (5.43) ± H (5.85)'''; H (5.85) ± H (7.2)''; IR
3844
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0620-3844 $ 17.50+.50/0
Chem. Eur. J. 2000, 6, No. 20

Asymmetric Synthesis
3838±3848
(film): nÄ ˆ 2955 cmÀ1 (m), 2925 (s), 2855 (m, C H), 1725 (vs, C O), 1450
(COO); NOESY (500 MHz): H (4.8) ± H (5.3)''; H (4.8) ± H (5.9)'''; H
(5.3) ± H (5.9)'; IR (film): nÄ ˆ 3435 cmÀ1 (m), 3060 (w), 3030 (w), 2955 (m),
À
ˆ
À
À À
(s), 1385 (m), 1275 (s), 1110 (m, C H), 990 (w, C O C); MS (70 eV, EI),
‡
‡
‡
À
ˆ
À
‡
m/z (%): 359 (0.3) [M] , 253 (23) [M À PhCHO] , 126 (100) [C6H10NO2] ;
HRMS calcd (u) for C22H33NO3 (359.50): 359.2460; found 359.2458.
(1S,3R,5R,7S) isomer (10d) (minor product): Yield: 65 mg (12%): Rf ˆ
0.17 (P/TBME ˆ 80:20); [a]2D5 ˆ À18.3 (c ˆ 2.0; CHCl3); 1H NMR
(400 MHz, [D6]DMSO, 373 K): d ˆ 0.87 (t, 3J(H,H) ˆ 6.9 Hz, 3H;
CH2CH3), 1.16 ± 1.39 (m, 16H; (CH2)8), 1.78 (ddd, 2J(H,H) ˆ 14.6 Hz,
3J(H,H) ˆ 6.2 Hz, 3J(H,H) ˆ 2.2 Hz, 1H; CHH), 2.49 (ddd, 2J(H,H) ˆ
14.6 Hz, 3J(H,H) ˆ^ 3J(H,H) ˆ 7.2 Hz, 1H, CHH), 3.64 (s, 3H; OCH3),
2875 (m, C H), 1705 (s, C O), 1495 (s, C H); MS (70 eV, EI), m/z (%): 247
‡
‡
(0.2) [M] , 141 (100) [M À PhCHO] , 126 (56) [C6H10NO2] , 105 (40)
‡
‡
[PhCO] , 77 (28) [C6H5] ; HRMS calcd (u) for C14H17NO3 (247.30):
247.1208; found 247.1212.
(2SR,3SR)-N-Methoxycarbonyl-2-benzyl-3-pyrrolidinol (5a): Typical hy-
drogenolysis procedure: Pd(OH)2/C (20% [w/w], 204 mg, 0.30 mmol) was
added to a solution of oxetane 4a (233 mg, 1.00 mmol) in methanol
(30 mL), and the mixture was stirred vigorously under atmospheric
hydrogen pressure for 2 h. The course of the reaction was monitored by
TLC. Upon complete conversion, the catalyst was removed by filtration
and the solvent was evaporated in vacuo. Flash chromatography
(P/TBME ˆ 80:20) yielded 220 mg (94%) of the pyrrolidinol 5a as a
colorless oil: Rf ˆ 0.14 (P/TBME ˆ 40:60); 1H NMR (400 MHz,
[D6]DMSO, 373 K): d ˆ 1.67 (dddd, 2J(H,H) ˆ 12.3 Hz, 3J(H,H) ˆ^
3J(H,H) ˆ^ 3J(H,H) ˆ 7.5 Hz, 1H; CHHCHOH), 1.89 (dddd, 2J(H,H) ˆ
12.3 Hz, 3J(H,H) ˆ 8.0 Hz, 3J(H,H) ˆ^ 3J(H,H) ˆ 6.1 Hz, 1H; CHHCHOH),
2.86 (dd, 2J(H,H) ˆ 13.4 Hz, 3J(H,H) ˆ 4.8 Hz, 1H; CHHPh), 2.99 (dd,
2J(H,H) ˆ 13.4 Hz, 3J(H,H) ˆ 7.4 Hz, 1H; CHHPh), 3.27 (ddd, 2J(H,H) ˆ
3
4.03 ± 4.09 (m, 1H; NCHCH2), 4.83 (dd, J(H,H) ˆ^ 3J(H,H) ˆ 4.5 Hz, 1H;
CHCHN), 5.34 (dd, 3J(H,H) ˆ^ 3J(H,H) ˆ 5.0 Hz, 1H; CHO), 5.70 (d,
3J(H,H) ˆ 4.7 Hz, 1H; CHPh), 7.26 ± 7.35 (m, 5H; Ph); NOESY (400 MHz,
[D6]DMSO, 373 K): H (1.78) ± H (2.49)'''; H (1.78) ± H (5.34)'''; H (2.49) ± H
(4.0)'''; H (2.49) ± H (5.34)'; H (4.0) ± H (7.2)''; H (4.83) ± H (5.34)''; H
(4.83) ± H (5.70)'''; H (5.34) ± H (5.70)'; H (5.70) ± H (7.2)''; IR (film): nÄ ˆ
2955 cmÀ1 (m), 2925 (s), 2855 (m, C H), 1710 (vs, C O), 1445 (s), 1375 (m,
À
ˆ
‡
À
À À
C H), 990 (w, C O C); MS (70 eV, EI), m/z (%): 253 (18) [M À PhCHO] ,
‡
‡
126 (100) [C6H10NO2] , 67 (9) [C4H5N] .
N-Methoxycarbonyl-3,7-diphenyl-6-oxa-2-azabicyclo[3.2.0]heptane: Ac-
cording to the general irradiation procedure benzaldehyde (159 mg,
152 mL, 1.50 mmol) and dihydropyrrole rac-8e[31] (508 mg, 2.50 mmol)
were irradiated in acetonitrile (15 mL) at l ˆ 350 nm for 7 h. GLC analysis
of the crude product mixture showed a diastereomeric ratio dr ˆ 68/32.
After removal of the solvent in vacuo, flash chromatography (P/TBME ˆ
85:15) yielded two separated diastereoisomers as colorless oils.
(1SR,3SR,5RS,7SR) isomer (rac-9e) (major product): Yield: 172 mg
(37%): Rf ˆ 0.14 (P/TBME ˆ 40:60); 1H NMR (500 MHz, [D6]DMSO,
373 K): d ˆ 2.29 (d, 2J(H,H) ˆ 14.9 Hz, 1H; CHH), 2.66 (ddd, 2J(H,H) ˆ
14.9 Hz, 3J(H,H) ˆ 9.6 Hz, 3J(H,H) ˆ 5.5 Hz, 1H; CHH), 3.11 (s, 3H;
OCH3), 5.13 (d, 3J(H,H) ˆ 4.0 Hz, 1H; CH2CHN), 5.16 (ddd, 3J(H,H) ˆ
5.8 Hz, 3J(H,H) ˆ^ 3J(H,H) ˆ 4.6 Hz, 1H; CHCHN), 5.47 (dd, 3J(H,H) ˆ^
3J(H,H) ˆ 5.4 Hz, 1H; CHO), 5.88 (d, 3J(H,H) ˆ 5.2 Hz, 1H; OCHPh),
7.10 ± 7.55 (m, 10H; 2 Ph); NOESY (500 MHz, [D6]DMSO, 373 K): H
(2.29) ± H (2.66)'''; H (2.29) ± H (5.13)'; H (2.29) ± H (5.47)'; H (2.66) ± H
(5.13)'''; H (2.66) ± H (5.47)'''; H (5.16) ± H (5.47)''; H (5.16) ± H (5.88)'''; H
(5.47) ± H (5.88)'; IR (film): nÄ ˆ 3080 cmÀ1 (w), 3045 (w), 2980 (m), 2975 (m,
3
3
10.7 Hz, J(H,H) ˆ 8.1 Hz, J(H,H) ˆ 5.9 Hz, 1H; CHHPh), 1H; CHHN),
3.35 (ddd, 2J(H,H) ˆ 10.7 Hz, 3J(H,H) ˆ 8.0 Hz, 3J(H,H) ˆ 6.9 Hz, 1H;
CHHN), 3.48 (s, 3H; OCH3), 3.90 (ddd, 3J(H,H) ˆ^ 3J(H,H) ˆ^ 3J(H,H) ˆ
6.2 Hz, 1H; CHCH2Ph), 4.17 (ddd, 3J(H,H) ˆ^ 3J(H,H) ˆ^ 3J(H,H) ˆ 6.4 Hz,
1H; CHOH), 7.10 ± 7.28 (m, 5H; Ph); 13C NMR (100 MHz, [D6]DMSO,
373 K): d ˆ 30.8 (CH2CHOH), 33.3 (CH2Ph), 42.9 (CH2N), 50.9 (OCH3),
61.4 (CHCH2Ph), 69.5 (CHOH), 124.9 (Car), 127.1 (2C, Car), 128.9 (2C, Car),
139.4 (Car), 154.5 (NCOO); NOE (400 MHz, [D6]DMSO, 373 K): H (4.17):
H (3.90) [7.3%], H (3.90): H (4.17) [7.1%]; IR (film): nÄ ˆ 3400 cmÀ1 (vs, b,
À
ˆ
OH), 3030 (w), 3005 (m), 2940 (s), 2860 (sh, C H), 1690 (vs, C O), 1590
À
(m), 1440 (s), 1380 (s), 1330 (s), 1260 (s), 1190 (s), 1110 (s, C H); MS (70 eV,
‡
‡
‡
EI), m/z (%): 235 (7) [M] , 234 (41) [M À H] , 144 (54) [M À C7H7] , 128
‡
‡
(100) [M À C7H7O] , 91 (35) [C7H7] ; elemental analysis calcd (%) for
C13H17NO3 (235.28): C 66.36, H 7.28, N 5.95; found C 66.21, H 7.55, N 5.93.
(2SR,3SR)-N-Ethoxycarbonyl-2-benzyl-3-pyrrolidinol (5b): According to
the typical hydrogenolysis procedure oxetane 4b (126 mg, 0.51 mmol) was
cleaved hydrogenolytically in 3 h. Flash chromatography (P/TBME ˆ
90:10) yielded 67.4 mg (53%) pyrrolidinol 5b as a colorless oil: Rf ˆ 0.11
(P/TBME ˆ 60:40); 1H NMR (200 MHz, CDCl3): d ˆ 1.25 (t, 3J(H,H) ˆ
7.0 Hz, 3H; CH2CH3), 1.38 ± 1.93 (m, 2H; CH2CHOH), 2.85 ± 2.96 (m, 2H;
CH2Ph), 3.24 ± 3.51 (m, 2H; CH2N), 3.98 ± 4.17 (m, 1H; CHCH2Ph), 4.01
(q, 3J(H,H) ˆ 7.0 Hz, 2H; CH2CH3), 4.47 ± 4.51 (m, 1H; CHOH), 7.08 ± 7.19
(m, 5H; Ph); 13C NMR (50 MHz, CDCl3): d ˆ 14.7 (CH2CH3), 26.9
(CH2CHOH), 28.6 (CH2Ph), 47.4 (CH2N), 60.0 (CHCH2Ph), 61.9
(CH2CH3), 79.1 (CHOH), 126.0 (Car), 128.3 (2C, Car), 129.5 (2C, Car),
139.4 (Car), 13C signal for NCOO was not obtained; IR (film): nÄ ˆ 3425 cmÀ1
À
ˆ
À
‡
C H), 1715 (vs), 1695 (sh, C O), 1450 (s), 1380 (m), 765 (w), 700 (m, C H);
‡
MS (EI, 70 eV, EI), m/z (%): 309 (0.6) [M] , 203 (100) [M À PhCHO] , 144
‡
‡
‡
(48) [M À PhCHO À COOCH3)] , 105 (62) [PhCO] , 77 (46) [C6H5] , 28
‡
(77) [CO] ; HRMS calcd (u) for C19H19NO3 (309.36): 309.1365; found
309.1361. (1SR,3RS,5RS,7SR) isomer (rac-10e) (minor product): Yield:
121 mg (26%): Rf ˆ 0.32; 1H NMR (400 MHz, [D6]DMSO, 373 K): d ˆ 1.92
(ddd, 2J(H,H) ˆ 14.9 Hz, 3J(H,H) ˆ 8.0 Hz, 3J(H,H) ˆ 5.5 Hz, 1H; CHH),
2.78 (dd, 2J(H,H) ˆ 14.9 Hz, 3J(H,H) ˆ 7.8 Hz, 1H, CHH), 2.93 (s, 3H;
OCH3), 5.08 ± 5.15 (m, 2H; CHNCH), 5.47 (dd, 3J(H,H) ˆ^ 3J(H,H) ˆ
4.9 Hz, 1H; CHO), 5.83 (d, 3J(H,H) ˆ 4,6 Hz, 1H; CHPh), 7.07 ± 7.40 (m,
10H; 2 Ph); NOESY (400 MHz, [D6]DMSO, 373 K): H (1.92) ± H (2.78)''';
H (1.92) ± H (5.47)''; H (2.78) ± H (5.47)''; H (2.78) ± H (5.1)''; H (5.83) ± H
À
(s, b, OH), 3065 (w), 3030 (w), 2980 (s), 2885 (sh, C H), 1700, 1675 (s,
ˆ
À
C O), 1425 (s), 1380 (s), 1335 (s), 1115 (s, C H), 775 (m), 750 (m), 705 (m,
‡
‡
(5.1)'''; IR (film): nÄ ˆ 3065 cmÀ1 (w), 3030 (m), 2955 (m), 2900 (m, C H),
À
C H); MS (70 eV, EI), m/z (%): 249 (0.2) [M] , 158 (15) [M À C7H7] , 142
À
‡
‡
‡
(100) [M À C7H7O] , 98 (19) [C6H12N] , 70 (53) [C4H8N] , 69 (11)
ˆ
1700 (s, C O), 1450 (s), 1380 (s), 1350 (m), 1325 (m), 1200 (s), 1125 (m,
‡
‡
[C4H7N] , 29 (25) [CHO] ; HRMS calcd (u) for C14H19NO3 (249.31):
249.1365; found 249.1367.
À
À
À
À
C H), 985 (m, C O C), 765 (s), 755 (s), 700 (s, C H); MS (70 eV, EI), m/z
‡
‡
(%): 309 (0.7) [M] , 203 (100) [M À PhCHO] , 144 (58) [M À PhCHO À
‡
‡
‡
‡
COOCH3] , 128 (61) [C6H12NO2] , 107 (77) [C7H7O] , 91 (23) [C7H7] , 79
(2SR,3SR)-N-tert-Butoxycarbonyl-2-benzyl-3-pyrrolidinol (5c): Accord-
ing to the typical hydrogenolysis procedure, oxetane 4c (71.0 mg,
0.26 mmol) was cleaved hydrogenolytically in 4 h. Flash chromatography
(P/TBME ˆ 90:10) yielded 40.3 mg (56%) pyrrolidinol 5c as a colorless oil.
A crystalline sample for X-ray crystal structure analysis could be obtained
by crystallization of 5c from pentane at À188C: Rf ˆ 0.29 (P/TBME ˆ
‡
(55) [C6H7] ; HRMS calcd (u) for C19H19NO3 (309.36): 309.1365; found
309.1361.
(1SR,6RS,8SR)-N-Methoxycarbonyl-8-phenyl-7-oxa-2-azabicyclo[4.2.0]-
octane (22): According to the general irradiation procedure benzaldehyde
(250 mg, 0.24 mL, 2.40 mmol) and trihydropyridine 21 (550 mg, 3.90 mmol)
were irradiated in acetonitrile (25 mL) at l ˆ 300 nm for 3.5 h. GLC
analysis of the crude product showed a mixture of simple diastereomers
(drˆ 75/25). After removal of the solvent in vacuo, flash chromatography
(P/TBME ˆ 85:15) yielded 100 mg (17%) of compound 22 as a colorless
oil: Rf ˆ 0.24 (P/TBME ˆ 40:60); 1H NMR (500 MHz): d ˆ 1.40 ± 2.25 (m,
4H; NCH2CH2CH2), 2.80 ± 3.77 (m, 2H; NCH2), 3.35 [3.55] (s, 3H; OCH3),
4.79 [5.11] (dd, 3J(H,H) ˆ^ 3J(H,H) ˆ 6.8 Hz, 1H; NCH), 5.28 [5.39] (dd,
1H; 3J(H,H) ˆ^ 3J(H,H) ˆ 3.6 Hz, CH2CHO), 5.88 [5.99] (d, 3J(H,H) ˆ
6.4 Hz, 1H; CHPh), 7.23 ± 8.08 (m, 5H; Ph); 13C NMR (125 MHz): d ˆ
18.6 (NCH2CH2), 26.8 (CHCH2), 41.7 [41.9] (NCH2), 53.6 (NCH), 66.0
(OCH3), 75.2 (CH2CHO), 83.1 [83.2] (PhCH), 125.0 [126.1] (Car), 127.7
[128.3] (2 C, Car), 129.5 [129.7] (2C, Car), 136.8 [137.5] (Car), 156.0 [156.7]
1
60:40); H NMR (300 MHz, CDCl3): d ˆ 1.35 (s, 9H; C(CH3)3), 1.61 ± 1.80
(m, 2H; CH2CHOH), 2.87 ± 2.90 (m, 2H; CH2Ph), 3.27 ± 3.38 (m, 1H;
CHHN), 3.64 ± 3.69 (m, 1H; CHHN), 3.96 (ddd, 3J(H,H) ˆ^ 3J(H,H) ˆ^
3J(H,H) ˆ 6.3 Hz, 1H; CHCH2Ph), 4.20 (ddd, 3J(H,H) ˆ^ 3J(H,H) ˆ^
3J(H,H) ˆ 5.9 Hz, 1H; CHOH), 7.11 ± 7.22 (m, 5H; Ph); 13C NMR
(75.5 MHz, CDCl3): d ˆ 28.4 (C(CH3)3), 31.7 (CH2CHOH), 34.8 (CH2Ph),
49.4 (CH2N), 59.9 (CHCH2Ph), 71.7 (C(CH3)3), 79.4 (CHOH), 126.0 (Car),
128.3 (2C, Car), 129.5 (2C, Car), 139.4 (Car), 154.8 (NCOO); IR (film): nÄ ˆ
3420 cmÀ1 (s, b, OH), 3030 (w), 3060 (w), 3085 (w), 2975 (m), 2895 (w;
À
ˆ
C H), 1670 (s, C O), 1410 (s), 1455 (m), 1170 (s), 1115 (m), 735 (m), 770
‡
À
(m), 700 (m, C H); MS (70 eV, EI), m/z (%): 277 (0.3) [M] , 186 (15) [M À
‡
‡
‡
‡
C7H7] , 130 (34) [C9H8N] , 113 (9) [C6H11NO] , 91 (15) [C7H7] , 86 (67)
Chem. Eur. J. 2000, 6, No. 20
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000 0947-6539/00/0620-3845 $ 17.50+.50/0
3845

T. Bach et al.
FULL PAPER
‡
‡
[C4H7O2] , 57 (97) [C3H7N] ; HRMS calcd (u) for C16H23NO3 (277.36):
277.1678; found 277.1683.
(c ˆ 2.0 in CHCl3); 1H NMR (300 MHz): d ˆ 0.84 (d, 3J(H,H) ˆ 6.6 Hz, 3H;
CH3), 1.24 ± 1.26 (m, 14H; (CH2)7), 1.47 ± 1.84 (m, 2H; NCHCH2(CH2)7),
2.21 ± 2.27 (m, 1H; CHHCHN), 2.74 ± 2.80 (m, 1H; CHHCHN), 3.69 (s,
3H; OCH3), 3.96 ± 4.06 (m, 1H; CH2CHN), 4.86 ± 4.94 (m, 1H; CHCHN),
8.36 ± 6.48 (m, 1H; CHCHN); 13C NMR (75.5 MHz): d ˆ 14.0 (CH3), 22.6
(CH2), 24.4 (CH2), 29.3 (CH2), 29.5 (5C, (CH2)5), 31.8 (CHCH2CHN), 52.2
(OCH3), 57.5 (CH2CHN), 107.1 (CHCHN), 128.8 (CHCHN), 182.9
(R)-5-Nonyl-2-pyrrolidinone (13):
A suspension of CuCN (1.97 g,
22.0 mmol) in THF (45 mL) was cooled to À788C. A 0.61m solution of
n-octyllithium in n-hexane (72.0 mL, 44.0 mmol) was added. Subsequent
warming to 08C for 5 min led to a dark, clear solution, which was recooled
to À788C, after which a solution of tosylate 12[26] (2.37 g, 8.88 mmol) in
THF (30 mL) was added dropwise. The mixture was warmed to room
temperature, stirred for 20 h, and subsequently quenched with a saturated
aqueous NH4Cl solution (40 mL). After extraction with dichloromethane
(3 Â 80 mL) the organic layers were collected, washed with brine, and dried
over MgSO4. After removal of the solvent, the residue was purified by flash
chromatography (TBME/EtOAc ˆ 50:50). A quantity of 1.53 g (82%) of
(COOCH3); IR (film): nÄ ˆ 2955 cmÀ1 (s), 2925 (vs), 2855 (s, C H), 1750
À
ˆ
(w), 1715 (s), 1620 (m, C O), 1450 (s), 1395 (s), 1345 (sh), 1265 (m), 1135 (s,
‡
‡
À
C H); MS (70 eV, EI), m/z (%): 253 (9) [M] , 126 (100) [C9H18] , 67 (11)
‡
‡
[C4H5N] , 41 (9) [C2H3N] ; HRMS calcd (u) for C15H27NO2 (253.38):
253.2042; found 253.2038.
(2S,3S,5R)-N-Methoxycarbonyl-2-benzyl-5-nonyl-3-pyrrolidinol (17): Ac-
cording to the typical hydrogenolysis procedure, oxetane 9d (420 mg,
1.17 mmol) was cleaved hydrogenolytical in 3 h. Flash chromatography
(P/TBME ˆ 60:40) yielded 343 mg (81%) pyrrolidinol 17 as a colorless oil.
The analytical data were in accordance with those reported in the
literature:[10a] Rf ˆ 0.17 (P/EtOAc ˆ 3:1); [a]D25 ˆ À69.5 (c ˆ 2.5 in CHCl3);
1H NMR (300 MHz): d ˆ 0.82 (t, 3J(H,H) ˆ 6.9 Hz, 3H; CH2CH3), 1.17 ±
1.39 (m, 16H; [CH2]8), 1.54 ± 1.68 (m, 1H; CHHCHOH), 1.97 (bs, 1H; OH),
2.17 (m, 1H; CHHCHOH), 2.89 ± 2.94 (m, 2H; CH2Ph), 3.48 (s, 3H;
OCH3), 3.67 ± 3.74 (m, 1H; NCHCH2), 4.10 (ddd, 3J(H,H) ˆ^ 3J(H,H) ˆ^
3J(H,H) ˆ 6.8 Hz, 1H; NCHCHOH), 4.23 (ddd, 3J(H,H) ˆ^ 3J(H,H) ˆ^
3J(H,H) ˆ 6.6 Hz, 1H; CHOH), 7.09 ± 7.23 (m, 5H; Ph); 13C NMR
(75.5 MHz): d ˆ 14.0 (CH2CH3), 22.6 (CH2), 26.4 (CH2), 29.3 (CH2), 29.5
(CH2), 29.5 (CH2), 29.6 (CH2), 31.9 (CH2Ph), 36.0 (CH2), 36.4 (CH2), 37.5
(CH2CHOH), 52.0 (OCH3), 56.8 (CHOH), 62.9 (NCHCH2), 71.4
(CHCH2Ph), 126.0 (Car), 128.3 (2C, Car), 129.4 (2C, Car), 139.4 (Car),
156.0 (NCOO).
compound 13 was obtained as a white solid: Rf ˆ 0.22 (EtOAc); [a]D25
ˆ
‡9.40 (c ˆ 1.3 in EtOH); m.p. 61 ± 638C; 1H NMR (400 MHz): d ˆ 0.78 (t,
3J(H,H) ˆ 6.9 Hz, 3H; CH3), 1.16 ± 1.20 (m, 14H; (CH2)7), 1.36 ± 1.63 (m,
3H; CHHCHNCH2), 2.13 ± 2.25 (m, 3H; COCH2CHH), 3.50 (ddd,
3J(H,H) ˆ^ 3J(H,H) ˆ^ 3J(H,H) ˆ 6.5 Hz, 1H; CHN), 6.10 (brs, 1H; NH);
13C NMR (100 MHz): d ˆ 14.1 (CH3), 22.6 (CH2), 25.9 (CH2), 27.3 (CH2),
29.3 (CH2), 29.5 (3C, (CH2)3), 30.1 (CH2), 31.8 (CH2CH2CO), 36.7
(CH2CON), 54.5 (CHN), 178.2 (CON); IR (KBr): nÄ ˆ 3180 cmÀ1 (m,
À
ˆ
NH), 2920 (vs), 2855 (s, C H), 1715 (vs), 1655 (s, C O); MS (70 eV, EI):
‡
‡
‡
m/z (%): 211 (6) [M] , 85 (5) [C5H11N] , 84 (100) [C5H10N] ; elemental
analysis calcd (%) for C13H25NO (211.34): C 73.88, H 11.92, N 6.63; found C
73.97, H 11.70, N 6.47.
(R)-N-Methoxycarbonyl-5-nonyl-2-pyrrolidinone (14): A solution of n-
butyllithium in n-hexane (5.60 mL, 1.50m, 8.40 mmol) was added dropwise
to a cooled solution of pyrrolidinone 13 (1.70 g, 8.04 mmol) in THF (30 mL)
at À788C. The mixture was stirred for 1 h at this temperature, then methyl
chloroformate (0.80 mL, 10.3 mmol) was added and the reaction mixture
was allowed to warm slowly to room temperature. After 3 h it was
quenched with saturated aqueous NH4Cl solution (25 mL). The aqueous
phase was extracted with TBME (3 Â 30 mL), then the combined organic
layers were dried with MgSO4 and concentrated in vacuo. The rawproduct
was purified by flash chromatography (TBME). A total of 2.10 g (97%) of
(2S,3S,5R)-N-Methyl-2-benzyl-5-nonyl-3-pyrrolidinol [(‡)-preussin] (1):
A solution of pyrrolidinol 17 (147 mg, 407 mmol) in THF (4 mL) was
added dropwise to a stirred solution of lithium aluminum hydride (75.9 mg,
2.00 mmol) in THF (10 mL). The reaction mixture was refluxed for 2 h,
cooled to 08C, and quenched by addition of saturated aqueous NH4Cl
solution (5 mL). The aqueous phase was extracted with TBME (3 Â
10 mL), then the combined organic layers were dried with MgSO4 and
concentrated in vacuo. The crude product was purified by flash chroma-
tography (CH2Cl2/methanol ˆ 9:1) to give 117 mg (91%) of (‡)-preussin
(1) as a pale yellowoil: Rf ˆ 0.44 (EtOAc); [a]2D5 ˆ ‡22.1 (c ˆ 1.0 in
CHCl3); 1H NMR (500 MHz): 0.88 (t, 3J(H,H) ˆ 6.9 Hz, 3H; CH2CH3),
1.19 ± 1.34 (m, 16H; (CH2)8), 1.42 (ddd, 2J(H,H) ˆ 13.9 Hz, 3J(H,H) ˆ
pyrrolidinone 14 was obtained as a colorless oil: Rf ˆ 0.46 (TBME); [a]D25
ˆ
À85.43 (c ˆ 1.4 in CHCl3); 1H NMR (400 MHz): d ˆ 0.86 (d, 3J(H,H) ˆ
7.1 Hz, 3H; CH3), 1.17 ± 1.29 (m, 14H; (CH2)7), 1.41 ± 1.85 (m, 3H;
CHHCHNCH2), 2.04 ± 2.18 (m, 1H; COCH2CHH), 2.43 (ddd, 2J(H,H) ˆ
17.8, 3J(H,H) ˆ 9.5 Hz, 3J(H,H) ˆ 2.7 Hz, 1H; COCHH), 2.60 (ddd,
2J(H,H) ˆ 17.8, 3J(H,H) ˆ 9.3 Hz, 3J(H,H) ˆ 9.0 Hz, 1H; COCHH), 3.84
(s, 3H; OCH3), 4.16 (dddd, 3J(H,H) ˆ^ 3J(H,H) ˆ 8.8 Hz, 3J(H,H) ˆ 3.2 Hz,
3J(H,H) ˆ 1.7 Hz, 1H; CHN); 13C NMR (75.5 MHz): d ˆ 13.7 (CH3), 23.3
(CH2), 25.1 (CH2), 28.9 (CH2), 29.0 (CH2), 29.1 (CH2), 31.0 (2 C, (CH2)2),
31.5 (CH2CHN), 33.1 (CH2), 33.3 (CH2CON), 52.9 (OCH3), 57.8 (CHN),
151.8 (COOCH3), 173.4 (CON); IR (film): nÄ ˆ 2955 cmÀ1 (s), 2925 (vs),
3
6.4 Hz, J(H,H) ˆ 1.2 Hz, 1H; CHHCHOH), 1.73 (s, 1H; OH), 2.10 ± 2.13
(m, 1H; NCHCH2), 2.21 (ddd, 2J(H,H) ˆ 13.9 Hz, 3J(H,H) ˆ 9.1 Hz,
3J(H,H) ˆ 6.6 Hz, 1H; CHHCHOH), 2.27 (ddd, 3J(H,H) ˆ 10.2 Hz,
3J(H,H) ˆ^ 3J(H,H) ˆ 4.3 Hz, 1H; CHCH2Ph ), 2.34 (s, 3H; CH3), 2.84
(dd, 2J(H,H) ˆ 13.3 Hz, 3J(H,H) ˆ 4.3 Hz, 1H; CHHPh), 2.91 (dd,
2J(H,H) ˆ 13.3 Hz, 3J(H,H) ˆ 10.2 Hz, 1H; CHHPh), 3.83 ± 3.87 (m, 1H;
CHOH), 7.16 ± 7.31 (m, 5H; Ph); 13C NMR (125.5 MHz): 14.1 (CH2CH3),
22.6 (CH2), 26.3 (CH2), 29.3 (CH2), 29.5 (CH2), 29.6 (CH2), 29.8 (CH2), 31.9
(CH2Ph), 33.5 (CH2), 34.8 (CH2), 38.6 (NCH3), 39.4 (CH2CHOH), 65.9
(NCHCH2), 70.3 (CHOH), 73.7 (CHCH2Ph), 126.0 (Car), 128.3 (2C, Car),
129.3 (2C, Car), 139.4 (Car); IR (film): nÄ ˆ 3430 cmÀ1 (s, b, OH), 3065 (w),
À
ˆ
À
‡
2855 (s, C H), 1790 (s), 1755 (s), 1720 (vs, C O), 1300 (m, C H); MS
‡
(70 eV, EI), m/z (%): 269 (5) [M] , 142 (100) [M À (CH2)8CH3] , 98 (53)
‡
‡
[C5H8NO] , 41 (30) [C2H3N] ; elemental analysis calcd (%) for C15H27NO3
(269.38): C 66.88, H 10.10, N 5.20; found C 66.60, H 10.34, N 5.49.
(R)-N-Methoxycarbonyl-2-nonyl-2,3-dihydropyrrole (8d): General proce-
dure A: A 1.0m solution of LiEt3BH in THF (4.20 mL, 4.20 mmol) was
added dropwise to
À
3030 (w), 2960 (m), 2925 (s), 2855 (s), 2790 (m, C H), 1495 (w), 1455 (s,
a cooled solution of 2-pyrrolidinone 14 (1.05 g,
‡
‡
À
C H); MS (70 eV, EI); m/z (%): 317 (0.1) [M] , 316 (0.7) [M À H] , 227
3.90 mmol) in CH2Cl2 (40 mL) at À788C. The reaction mixture was
allowed to reach 08C and it was subsequently stirred for 4 h at this
temperature. A 1m NaOH solution (6.00 mL, 6.00 mmol) and a 35% H2O2
solution (3.0 mL) were added successively. The organic layer was separated
and filtered through a Celite pad. The solution thus obtained was cooled to
08C. 2,2-Dimethoxypropane (2.55 g, 3.00 mL, 24.6 mmol) and camphor-
sulfonic acid (CSA) (75.0 mg, 0.30 mmol) were added. After 30 min a
saturated aqueous NaHCO3 solution (20 mL) was added. The aqueous
layer was extracted with CH2Cl2 (3 Â 20 mL). The combined organic layers
were filtered through a Celite pad and concentrated in vacuo. The
diastereomeric mixture of 2-methoxypyrrolidines was dissolved in CH2Cl2
(20 mL) and cooled to 08C. Diisopropylethylamine (0.68 g, 0.90 mL,
5.16 mmol) and TMSOTf (1.11 g, 0.90 mL, 4.80 mmol) were added
successively. After 30 min the reaction was stopped by adding pentane
(40 mL). The reaction mixture was filtered and concentrated under
reduced pressure. The crude product was purified by flash chromatography
(PE/TBME ˆ 90/10). A total of 602 mg (61%) of dihydropyrrole 8d was
obtained as a colorless oil: Rf ˆ 0.55 (P/TBME ˆ 80:20); [a]2D5 ˆ À245.7
(15) [M À 13CC6H7] , 226 (100) [M À C7H7] ; HRMS calcd (u) for
‡
‡
C21H35NO (317.51): 317.2719, found 317.2711.
(2S,3S,5R)-N-Methoxycarbonyl-2-benzyl-5-methyl-3-pyrrolidinol
(18):
The reaction was carried out as described for the typical hydrogenolysis
procedure, starting from oxetane 9a on a 0.16-mmol scale. The crude
product was purified by flash chromatography (P/TBME ˆ 80/20). A total
of 36 mg (89%) of pyrrolidinol 18 was obtained as a colorless oil: Rf ˆ 0.42
(TBME); [a]2D5 ˆ À48.1 (c ˆ 2.1 in CHCl3); H NMR (400 MHz): d ˆ 1.34
1
(t, 3J(H,H) ˆ 6.3 Hz, 3H; CH3), 1.60 ± 1.69 (m, 1H; CHHCHOH), 2.24 ±
2.30 (m, 1H; CHHCHOH), 2.94 ± 3.01 (m, 2H; CH2Ph), 3.55 (s, 3H;
OCH3), 3.87 (m, 1H; CHCH3), 4.14 (dd, 3J(H,H) ˆ 13.7 Hz, 3J(H,H) ˆ
6.8 Hz, 1H; CHCH2Ph), 4.28 (dd, 3J(H,H) ˆ 13.7 Hz, 3J(H,H) ˆ 6.7 Hz,
1H; CHOH), 7.15 ± 7.31 (m, 5H; Ph); 13C NMR (100 MHz): d ˆ 22.2 (CH3),
35.9 (CH2Ph), 39.5 (CH2CHOH), 52.0 (OCH3), 52.4 (CHCH3), 63.1
(CHCH2Ph), 71.3 (CHOH), 126.1 (Car), 128.3 (2C, Car), 129.7 (2C, Car),
139.4 (Car), 156.1 (COOCH3); IR (film): nÄ ˆ 3435 cmÀ1 (s, OH), 3060 (m),
À
À
ˆ
À
3030 (m, Car H), 2930 (s, C H), 1675 (vs, C O), 1455 (m), 1130 (m, C H);
3846
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000 0947-6539/00/0620-3846 $ 17.50+.50/0 Chem. Eur. J. 2000, 6, No. 20

Asymmetric Synthesis
3838±3848
‡
‡
MS (70 eV, EI), m/z (%): 249 (0.4) [M] , 158 (100) [M À CH2Ph] , 91 (6)
NCH), 3.92 ± 4.04 (m, 1H; CHOH), 4.60 (s, 1H; OH), 7.13 ± 7.29 (m, 5H;
Ph); 13C NMR (75.5 MHz, CDCl3): d ˆ 24.2 (NCH2CH2), 27.8
(CH2CHOH), 29.5 (CH2Ph), 37.8 (CHN), 41.5 (NCH2), 52.2 (OCH3), 69.2
(CHOH), 126.0 (Car), 128.2 (2C, Car), 129.1 (2C, Car), 138.9 (Car), 156.2
(NCOO); IR (film): nÄ ˆ 3430 cmÀ1 (s, b, OH), 3085 (w), 3065 (w), 3030 (w),
‡
‡
[C7H7] , 42 (17) [C2H4N] ; HRMS calcd (u) for C14H19NO3 (249.31):
249.1365; found: 249.1371.
(2R,3R,5R)-N-Methoxycarbonyl-2-benzyl-5-nonyl-3-pyrrolidinol (19): Ac-
cording to the typical hydrogenolysis procedure, oxetane 10d (25.1 mg,
0.07 mmol) was cleaved hydrogenolytical in 3 h. Flash chromatography
(P/TBME ˆ 60:40) yielded 22.3 mg (88%) pyrrolidinol 19 as a colorless oil:
Rf ˆ 0.33 (P/EtOAc ˆ 3:1); [a]2D5 ˆ ‡13.7 (c ˆ 1.9 in CHCl3); 1H NMR
(300 MHz): d ˆ 0.88 (t, 3J(H,H) ˆ 6.8 Hz, 3H; CH2CH3), 1.18 ± 1.36 (m,
16H; (CH2)8), 1.57 (s, 1H; OH), 1.76 ± 1.91 (m, 2H; CH2CHOH), 2.89 ± 3.04
(m, 2H; CH2Ph), 3.67 ± 3.78 (m, 1H; NCHCH2), 3.68 (s, 3H; OCH3), 4.15
(ddd, 3J(H,H) ˆ^ 3J(H,H) ˆ^ 3J(H,H) ˆ 6.1 Hz, 1H; NCHCHOH), 4.46
À
ˆ
À
2955 (m), 2935 (s), 2870 (s, C H), 1680 (s, C O), 1455 (s, C H); MS (EI),
‡
‡
‡
m/z (%): 249 (0.7) [M] , 158 (100) [M À C7H7] , 142 (24) [M À C7H7O] ,
‡
‡
126 (88) [M À PhCHO À CH3] , 91 (19) [C7H7] ; HRMS calcd (u) for
C14H19NO3 (249.31): 249.1365; found 249.1361.
(ddd, J(H,H) ˆ 10.3 Hz, J(H,H) ˆ^ 3J(H,H) ˆ 6.9 Hz, 1H; CHOH), 7.15 ±
7.29 (m, 5H; Ph); 13C NMR (75.5 MHz): d ˆ 14.1 (CH2CH3), 22.6 (CH2),
26.3 (CH2), 29.3 (CH2), 29.4 (CH2), 29.5 (CH2), 29.6 (CH2), 31.9 (CH2Ph),
35.7 (CH2), 36.2 (CH2), 37.5 (CH2CHOH), 52.0 (OCH3), 55.5 (CHOH), 61.7
(NCHCH2), 70.8 (CHCH2Ph), 126.1 (Car), 128.3 (2C, Car), 129.7 (2C, Car),
139.9 (Car), 155.1 (NCOO); IR (film): nÄ ˆ 3420 cmÀ1 (s, OH), 3060 (m),
3
3
Acknowledgements
This project was supported by the Deutsche Forschungsgemeinschaft
(Ba 1372-3/1 and 3/2) and by the Fonds der Chemischen Industrie. We
would like to thank Christian Jasper (undergraduate research participant)
for skilful technical assistance. The donation of chemicals by Witco GmbH
and Degussa-Hüls AG is gratefully acknowledged.
À
À
ˆ
2955 (m, Car H), 2925 (s, C H), 1655 (vs, C O), 1450 (m), 1190 (m), 1120
‡
À
(w), 1075 (m, C H); MS (70 eV, EI); m/z (%): 270 (100) [M À C7H7] , 254
‡
‡
‡
‡
(21) [C22H35NO2] , 128 (73) [C6H12NO2] , 41 (20) [C2H3N] , 28 (29) [CO] ;
‡
HRMS calcd (u) for C15H29NO3 ([M-C7H7] ): 270.2069, found 270.2064.
[1] E. Winterfeldt, Stereoselektive SyntheseÐPrinzipien und Methoden,
Vieweg, Braunschweig, 1988, pp. 13 ± 29.
(2S,3S,5R)-N-Methyl-2,5-dibenzyl-3-pyrrolidinol (20): The reaction was
carried out as described in typical hydrogenolysis procedure starting from
oxetane 9c on a 0.53-mmol scale. The crude product was dissolved in THF
(25 mL) and lithium aluminum hydride (95.0 mg, 2.50 mmol) was added at
08C. The reaction mixture was refluxed for 3 h and quenched at 08C by
addition of saturated aqueous NH4Cl solution (10 mL). TBME (50 mL)
was added and the layers were separated. The aqueous phase was extracted
with TBME (3 Â 20 mL); the combined organic layers were dried with
MgSO4 and concentrated in vacuo. The crude product was purified by flash
chromatography (hexane/EtOAc ˆ 3:1). A total of 107 mg (72%) of
pyrrolidinol 20 was obtained as a colorless solid: Rf ˆ 0.32 (EtOAc);
[a]2D5 ˆ ‡23.6 (c ˆ 1.0 in CHCl3); m.p. 798C; 1H NMR (300 MHz): d ˆ 1.50
(ddd, 2J(H,H) ˆ 14.4 Hz, 3J(H,H) ˆ 6.0 Hz, 3J(H,H) ˆ 1.2 Hz, 1H;
CHHCHOH), 1.64 (brs, 1H; OH), 2.33 (ddd, 2J(H,H) ˆ 14.4 Hz,
3J(H,H) ˆ 9.3 Hz, 3J(H,H) ˆ 6.4 Hz, 1H; CHHCHOH), 2.33 (dt,
3J(H,H) ˆ 3.6 Hz, 3J(H,H) ˆ 7.5 Hz, 1H; CHCHOH), 2.44 (s, 3H; CH3),
2.48 ± 2.56 (m, 1H; NCHCH2), 2.64 (dd, 2J(H,H) ˆ 13.2 Hz, 3J(H,H) ˆ
8.5 Hz, 1H; CHHPh), 2.84 (d, 3J(H,H) ˆ 7.5 Hz, 2H; CH2CHCHOH),
3.00 (dd, 2J(H,H) ˆ 13.2 Hz, 3J(H,H) ˆ 3.7 Hz, 1H; CHHPh), 3.69 ± 3.71
(m, 1H; CHOH), 7.18 ± 7.29 (m, 10H; 2Ph); 13C NMR (75.5 MHz): d ˆ 33.8
(CH2Ph), 38.1 (CH2Ph), 38.6 (CH3), 40.8 (CH2CHOH), 66.4 (CH2CHN),
70.3 (CHOH), 73.3 (CHOHCHN), 126.0 (Car), 126.1 (Car), 128.2 (2C, Car),
128.3 (2C, Car), 129.2 (2C, Car), 129.6 (2C, Car), 139.0 (Car), 139.4 (Car); IR
Á
[2] a) E. Paterno, G. Chieffi, Gazz. Chim. Ital. 1909, 39 ± 1, 341 ± 361; b) G.
Büchi, C. G. Inman, E. S. Lipinsky, J. Am. Chem. Soc. 1954, 76, 4327 ±
4331.
[3] Reviews: a) J. Mattay, R. Conrads, R. Hoffmann, in Methoden Org.
Chem. (Houben-Weyl) 4th ed., Vol. E21c (Eds.: G. Helmchen, R. W.
Hoffmann, J. Mulzer, E. Schaumann), Thieme, Stuttgart, 1995,
pp. 3133 ± 3178; b) J. A. Porco, S. L. Schreiber, in Comprehensive
Organic Synthesis, Vol. 5 (Ed.: B. Trost), Pergamon, Oxford, 1991,
pp. 151 ± 192; c) H. A. J. Carless, in Synthetic Organic Photochemistry
(Ed.: W. M. Horspool), Plenum, NewYork, 1984, pp. 425 ± 487; c) G.
Jones II, in Organic Photochemistry, Vol. 5 (Ed.: A. Padwa), Dekker,
NewYork, 1981, pp. 1 ± 123.
[4] Reviews: a) T. Bach, Synthesis 1998, 683 ± 703; b) T. Bach, Liebigs
Ann./Recueil 1997, 1627 ± 1634.
[5] D. R. Morton, R. A. Morge, J. Org. Chem. 1978, 43, 2093 ± 2101.
[6] a) T. Bach, Tetrahedron Lett. 1994, 35, 1855 ± 1858; b) T. Bach, Liebigs
Ann. 1995, 1045 ± 1053.
[7] a) T. Bach, K. Jödicke, K. Kather, R. Fröhlich, J. Am. Chem. Soc. 1997,
119, 2437 ± 2445; b) T. Bach, F. Eilers, K. Kather, Liebigs Ann./Recueil
1997, 1529 ± 1536.
[8] a) T. Bach, Angew. Chem. 1996, 108, 976 ± 977; Angew. Chem. Int. Ed.
Engl. 1996, 35, 884 ± 886; b) T. Bach, J. Schröder, Tetrahedron Lett.
1997, 38, 3707 ± 3710; c) T. Bach, J. Schröder, Liebigs Ann./Recueil
1997, 2265 ± 2267; d) T. Bach, J. Schröder, T. Brandl, J. Hecht, K.
Harms, Tetrahedron 1998, 54, 4507 ± 4520; e) J. Schröder, T. Bach, J.
Inf. Recording 1998, 24, 285 ± 288; f) T. Bach, J. Schröder, J. Org.
Chem. 1999, 64, 1265 ± 1273.
(KBr): nÄ ˆ 3465 cmÀ1 (vs, OH), 3025 (m), 3030 (m, Car H), 2975 (m), 2920
À
À
(m), 2780 (m, C H), 1495 (m), 1450 (m), 1030 (m), 935 (m), 755 (m), 700 (s,
‡
À
C H); MS (70 eV, EI), m/z (%): 280 (0.6) [M À H] , 190 (100) [M À
‡
‡
‡
C7H7] , 174 (27) [C12H15N] , 91 (35) [C7H7] ; HRMS calcd (u) for
‡
C19H22NO ([M À H]): 280.1701; found: 280.1707.
N-Methoxycarbonyl-4,5,6-trihydropyridine (21): The reaction was carried
out folowing general procedure A starting from N-methoxycarbonyl-2-
piperidinone[44] on a 20-mmol scale. After work-up, the residue was purified
by flash chromatography (P/TBME ˆ 90:10). A total of 1.78 g (63%) of
trihydropyridine 21 was obtained as a colorless oil. The analytical data were
in accordance with those reported in the literature:[45] Rf ˆ 0.62 (TBME);
1H NMR (300 MHz): d ˆ 1.72 ± 2.05 (m, 4H; NCH2CH2CH2), 3.48 ± 3.61
(m, 2H; NCH2), 3.71 (s, 3H; OCH3), 4.77 ± 4.98 (m, 1H; NCHCH), 6.69
[6.83] (d, 1H; 3J(H,H) ˆ 8.3 Hz; NCH); 13C NMR (75.5 MHz): d ˆ 21.4
[21.2] (NCH2CH2), 21.6 (NCHCHCH2), 42.3 [42.1] (NCH2), 52.8 (OCH3),
106.2 [106.4] (NCHCH), 125.3 [124.9] (NCHCH), 13C signal for NCOO was
not obtained.
[9] a) R. E. Schwartz, J. Liesch, O. Hensens, L. Zitano, S. Honeycutt, G.
Garrity, R. A. Fromtling, J. Onishi, R. Monaghan, J. Antibiot. 1988, 41,
1774 ± 1779; b) J. H. Johnson, D. W. Phillipson, A. D. Kahle, J.
Antibiot. 1989, 42, 1184 ± 1185.
[10] Previous syntheses: a) C. S. Pak, G. H. Lee, J. Org. Chem. 1991, 56,
1128 ± 1133; b) M. Shimazaki, F. Okazaki, F. Nakajima, T. Ishikawa,
A. Ohta, Heterocycles 1993, 36, 1823 ± 1836; c) P. L. McGrane, T.
Livinghouse, J. Am. Chem. Soc. 1993, 115, 11485 ± 11489; d) M.
Overhand, S. M. Hecht, J. Org. Chem. 1994, 59, 4721 ± 4722; e) W.
Deng, L. E. Overman, J. Am. Chem. Soc. 1994, 116, 11241 ± 11250;
f) H. Yoda, H. Yamazaki, K. Takabe, Tetrahedron Asymmetry 1996, 7,
373 ± 374; g) C. Beier, E. Schaumann, Synthesis 1997, 1296 ± 1300;
h) R. Verma, S. K. Ghosh, Chem. Commun. 1997, 1601 ± 1602; i) P.
de Armas, F. Garcia-Tellado, J. J. Marrero-Tellado, J. Robles, Tetrahe-
dron Lett. 1998, 39, 131 ± 134; j) A. Kanazawa, S. Gillet, P. Delair,
A. E. Greene, J. Org. Chem. 1998, 63, 4660 ± 4663; k) R. Verma, S. K.
Ghosh, J. Chem. Soc. Perkin Trans. 1 1999, 265 ± 270.
(2SR,3SR)-N-Methoxycarbonyl-2-benzyl-3-piperidinol (23): According to
the typical hydrogenolysis procedure oxetane 21 (65.0 mg, 0.19 mmol) was
cleaved hydrogenolytically in 2 h. Flash chromatography (P/TBME ˆ
80:20) yielded 49.0 mg (88%) piperidinol 23 as a colorless oil: Rf ˆ 0.13
(P/TBME ˆ 40:60); 1H NMR (300 MHz, CDCl3): d ˆ 1.22 ± 1.91 (m, 4H;
NCH2CH2CH2), 2.79 (d, 2J(H,H) ˆ 11.2 Hz, 1H; CHHPh), 2.83 (d,
2J(H,H) ˆ 11.2 Hz, 1H; CHHPh), 2.93 (ddd, 2J(H,H) ˆ 13.9 Hz,
3J(H,H) ˆ^ 3J(H,H) ˆ 2.9 Hz, 1H; NCHH), 3.03 (dd, 2J(H,H) ˆ 13.9 Hz,
2J(H,H) ˆ 3.8 Hz, 1H; NCHH), 3.33 (s, 3H; OCH3), 3.82 ± 3.92 (m, 1H;
[11] K. Sakamoto, E. Tsuji, F. Abe, T. Nakanishi, M. Yamashita, N.
Shigematsu, S. Izumi, M. Okuhara, J. Antibiot. 1996, 49, 37 ± 44.
[12] Synthesis: B. B. Snider, H. Lin, J. Am. Chem. Soc. 1999, 121, 7778 ±
7786.
Chem. Eur. J. 2000, 6, No. 20
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3847

T. Bach et al.
FULL PAPER
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[33] Information as to the selectivity-determining step can be drawn from
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0.5  0.3  0.15 mm, monoclinic, space group P2(1)/c, a ˆ 1331.8(1),
b ˆ 683.6(1), c ˆ 1731.8(1) pm, U ˆ 1567.90(12) Š3, 1c ˆ 1.175 gcmÀ3
for Z ˆ 4, F(000) ˆ 600, m ˆ 0.648 mmÀ1, Enraf ± Nonius CAD4 dif-
fractometer, l ˆ 1.54178 Š, w-scan, 3109 reflections (Àh, ‡k, Æl),
Vmax ˆ 69.858, 2976 independent and 2454 observed reflections [F ꢀ
4s(F)], 274 refined parameters, R ˆ 0.0397, wR2 ˆ 0.1093, max. resid-
ual electron density 0.207 eŠÀ3, direct methods, hydrogen atoms
located. Crystallographic data (excluding structure factors) for the
structures reported in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary publica-
tion no. CCDC-142647. Copies of the data can be obtained free of
charge on application to CCDC, 12 Union Road, Cambridge
CB21EZ, UK (fax: (‡44)1223 336-033; e-mail: deposit@ccdc.cam.
ac.uk..
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b ˆ 532.2(1), c ˆ 1348.3(3) pm, U ˆ 796.3(3) Š3, 1c ˆ 1.174 gcmÀ3 for
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0.240 eŠÀ3, direct methods, hydrogen atoms calculated. Crystallo-
graphic data (excluding structure factors) for this structure have been
deposited with the Cambridge Crystallographic Data Centre as
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Received: April 10, 2000 [F2414]
3848
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