Synthesis of polyhydroxylated quinolizidine and indolizidine scaffolds from sugar-derived lactams via a one-pot reduction/Mannich/Michael sequence

Article abstract of DOI:10.1021/jo502146z

A direct approach to the synthesis of indolizidine and quinolizidine scaffolds of iminosugars is described. The presented strategy is based on a one-pot sugar lactam reduction with Schwartz's reagent followed by a diastereoselective Mannich/Michael tandem reaction of the resulting sugar imine with Danishefsky's diene. The stereochemical course of the investigated reaction has been explained in detail. The obtained bicyclic products are attractive building blocks for the synthesis of various naturally occurring polyhydroxylated alkaloids and their derivatives.

Full text of DOI:10.1021/jo502146z

Article
pubs.acs.org/joc
Synthesis of Polyhydroxylated Quinolizidine and Indolizidine
Scaffolds from Sugar-Derived Lactams via a One-Pot Reduction/
Mannich/Michael Sequence
Piotr Szczesniak, Sebastian Stecko,* Elzbieta Maziarz, Olga Staszewska-Krajewska,
́
̇
and Bartłomiej Furman*
Institute of Organic Chemistry, Polish Academy of Sciences Kasprzaka 44/52, 01-224 Warsaw, Poland
S
* Supporting Information
ABSTRACT: A direct approach to the synthesis of indolizidine and quinolizidine scaffolds of iminosugars is described. The
presented strategy is based on a one-pot sugar lactam reduction with Schwartz’s reagent followed by a diastereoselective
Mannich/Michael tandem reaction of the resulting sugar imine with Danishefsky’s diene. The stereochemical course of the
investigated reaction has been explained in detail. The obtained bicyclic products are attractive building blocks for the synthesis
of various naturally occurring polyhydroxylated alkaloids and their derivatives.
Several strategies for the synthesis of bicyclic iminosugar
systems based on either chiral pool or enantio- and
diastereoselective approaches have been developed.2 The first
group of methods employs mainly hydroxyacids and carbohy-
drates as starting materials.1b,c,3,4 The last two approaches
involve linear and stepwise formation of a piperidine or
pyrrolidine ring followed by intramolecular cyclization leading
to a bicyclic pyrrolizidine, indolizidine, or quinolizidine
scaffold.5−7 The most explored strategies rely on 1,3-dipolar
cycloaddition of chiral nitrones with olefins,8−12 developed by
Tufariello13 and extended by Brandi,14 Vasella,15 Vogel,16 and
our group.17
The asymmetric Mannich/Michael tandem reaction (formal
aza-Diels−Alder reaction), which has long proven to be an
invaluable aid in enabling access to highly functionalized six-
membered nitrogen-containing heterocycles,18 can be envi-
sioned as an alternative way. In the past, we demonstrated that
dihydropyridones, generated in situ via a Mannich/Michael
sequence of acyclic imines with electron-rich Danishefsky-type
dienes,19 can be used as building blocks for the construction of
indolizidine and quinolizidine scaffolds through either rhodium-
catalyzed intramolecular conjugate addition of vinylstannanes20
or fluoride ion induced intramolecular conjugate addition of
propargylsilanes.21
INTRODUCTION
■
The synthesis and biological properties of polyhydroxylated
indolizidine alkaloids (iminosugars) such as castanospermine,
swainsonine, lentiginosine, and their synthetic quinolizidine
analogues (1−4) have received considerable interest in recent
years.1 Due to their structural resemblance to sugars,
iminosugars are recognized by glycosidases, the enzymes
responsible for formation or hydrolysis of glycosyl bonds in
carbohydrates and glycoconjugates, which may result in
inhibition of their activity.1b,c Thanks to this feature,
iminosugars have demonstrated a range of biological activity
(e.g., antiviral, anti-HIV, anticancer, antifeedant, immunoregu-
latory activity, and more) that target a wide choice of diseases.1
The approval of Glyset and Zavesca for the treatment of
complications associated with type II diabetes and for
Gaucher’s disease, respectively, within the past decade, is a
testament to their importance as medicines for unmet medical
needs.1 Clearly, the field of iminosugars is a fertile area for
research on both chemical and biological frontiers.
Although the studies on the acyclic imine-involved Mannich/
Michael reactions are advanced,18b−d,22−26 the examples of
analogous reactions that employ nonactivated cyclic imines are
rare.27−31 Despite the fact that the Mannich/Michael process
Received: September 18, 2014
© XXXX American Chemical Society
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Scheme 1
involving cyclic imines provides a direct entry to the
indolizidine or quinolizidine scaffold, its potential as a tool of
synthetic organic chemistry remains unexploited. Such an
approach would be even more attractive if sugar-derived imines
were to be applied, since the resulting products, bicyclic
enaminones, can serve as direct precursors of indolizidine or
quinolizidine iminosugars (Scheme 1). Herein, we wish to
report the use of optically active, sugar-derived imines as
coupling partners to achieve a highly diastereoselective
cyclocondensation as a route to various of bicyclic iminosugars.
Table 1. Synthesis of Imines via Phosphine-Mediated
Deoxygenation of Nitrones
a
RESULTS AND DISCUSSION
■
We started our investigation with the preparation of various
sugar-derived imines. The standard way of preparing simple
cyclic imines is N-chlorination of cyclic amines followed by
elimination.32 However, this approach is less viable in the case
of sugar-derived imines, since it is difficult to control the
regioselectivity of elimination of the corresponding N-chloro-
amines, which leads to the formation of inseparable mixtures of
isomeric imines. Additionally, in many cases the synthesis of
initial amines in not a straightforward task. Therefore, we
considered a more facile approach to the preparation of imines.
On the basis of our previous experience,33 we focused our
attention on sugar-derived nitrones as imine precursors. For
this purpose the pentose-derived nitrones 5a,b34−36 were
prepared according to literature protocols. The additional two
nitrones 5c14b and 5d,14d derived from chiral hydroxyacids,
were also prepared. These compounds were subjected to
phosphine-mediated deoxygenation, leading to corresponding
imines 6a−d in good yields (Table 1).37 All of the imines are
rather unstable molecules; however, careful chromatography on
Florisil allowed us to obtain them in pure form.
a
Reaction conditions: Bu3P (2.0 equiv), THF, 75 °C, 24−48 h.
Isolated yield.
b
Imines 6a−d were submitted to a Yb(OTf)3-catalyzed
addition/cyclization tandem reaction with Danishefsky’s diene
(DD) according to our previous reports.19−21 The correspond-
ing bicyclic enaminones 7a−d were obtained in moderate yields
and with good to high diastereoselectivity (Table 2).
Very recently, we have demonstrated that sugar-derived
imines can be easily generated by the reduction of
carbohydrate-derived lactams with Schwartz’s reagent.39−41
The main advantage of the developed method relies on the
fact that the generated imine can be further functionalized by
direct treatment with a nucleophile in a “one-pot” manner. As
we demonstrated,39 this one-pot reduction/nucleophilic
addition is an attractive way to synthesize monocyclic
iminosugars, particularly in cases when other methods, for
instance those based on nucleophilic addition to nitrones,
cannot be applied. Encouraged by those results, we decided to
apply the same approach in the current studies. Another benefit
of such an approach would be the availability and stability of
sugar-derived lactams. Since they are accessible from
carbohydrate sources, either five- or six-membered lactams
can be prepared. A typical preparation of sugar lactams is
exemplified in Scheme 2.39,42 gluco-Lactam 8 was chosen as a
model starting material for our further studies.
Since imines have limited stability, we wondered if both
steps, deoxygenation and cyclocondensation, could be
performed in a one-pot manner without isolation of the
intermediate imine. However, all attempts to perform the above
sequence in a one-pot manner failed. No formation of the
desired indolizidine product was noticed. Moreover, although
the above approach worked well for five-membered imines, it
was not suitable for the formation of quinolizidines from six-
membered imines. The main problem was the limited
availability of six-membered sugar-derived nitrones; these
compounds are more difficult to prepare and are less stable
than their five-membered congeners.38 In addition, the
formation of the six-membered imines was another challenging;
despite many attempts, these compounds were formed in poor
yields and were highly unstable. Therefore, we decided to revise
our synthetic approach and find another source of cyclic imines
which would provide a straightforward and general route to
polyhydroxylated indolizidines and quinolizidines.
Lactam 8 was treated with Cp2Zr(H)Cl (1.6 equiv) in THF
to afford imine 9, as presented in Scheme 3.39 The progress of
the reaction can be easily followed: the transition of the
reaction mixture from an initially white suspension into a clear
solution indicates the end of the reduction (ca. 30 min). The
B
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various silyl triflates tested, TBSOTf provided the highest yield
for the model reaction (Table 3, entry 8). The catalytic
efficiency of TBSOTf was comparable with the results obtained
for the Yb(OTf)3-catalyzed process (Table 3, entry 8 vs entry
1). Thus, 10 mol% loading of the Lewis acid was optimal. To
confirm that the addition step is catalyzed by an external Lewis
acid and not the zirconium salts present in the reaction mixture,
a blank experiment was performed. In the absence of a Lewis
acid (e.g., Yb(OTf)3) no formation of the desired product was
observed (Table 3, entry 12).
Table 2. Synthesis of Indolizidines and Quinolizidines via
Mannich/Michael Reaction of Cyclic Imines with DD
a
With the optimal reaction conditions (10 mol% of Yb(OTf)3
in THF) in hand, we set out to examine sugar-derived lactams
12−17 as well as simple enantiopure alkoxy-substituted lactams
18−22 to establish the reaction generality.
a
Reaction conditions: diene (2 equiv), Lewis acid (10 mol%), CH2Cl2
b
at −25 °C for 30 min then 3 h at room temperature. Isolated yield.
c
1
Determined by H NMR or HPLC of the crude reaction mixture.
Sugar lactams 12−17 were prepared from commercially
available carbohydrates following the general route presented in
Scheme 2.39,42,43 In the same manner, lactam 19 was prepared
starting from D-erythronolactone. Its diastereomer, lactam 18,
was obtained from tartaric acid derived imide 23,44 via the
reaction sequence depicted in Scheme 5. With L-malic acid as
the starting material, regioisomeric lactams 20 and 21 were
prepared (Scheme 6).45 Finally, lactam 22 was prepared from
ethyl L-pyroglutamate following a literature procedure.45
With various chiral cyclic lactones in hand, we subjected
them to the one-pot reduction/Mannich/Michael tandem
reaction. As shown in Table 4, all investigated examples of
the one-pot reduction/aza-Mannich/Michael tandem reaction
proceeded with good yields and good to high diastereose-
lectivity to provide bicyclic enaminones 10 and 32−41 as the
major isomers. The absolute configuration at the newly formed
bridgehead carbon atom was assigned on the basis of an
analysis of coupling constants and NOE experiments.
resulting imine was directly subjected to the cyclocondensation
reaction. Thus, the diene (2 equiv) and Yb(OTf)3 (10 mol%)
were added at −25 °C, and the reaction mixture was warmed to
room temperature. The desired bicyclic enaminones 10 and 9a-
epi-10 were obtained in 80% yield and with a high level of
stereoselectivity (d.e. 94.6%) (Table 3, entry 1). The absolute
configuration of the major product 10 was confirmed by X-ray
analysis of its hydrogenated derivative 11 (Scheme 4).
Next, the influence of various Lewis acids on the yield and
diastereoselectivity of the investigated process was evaluated.
The replacement of Yb(OTf)3 by scandium or lanthanum
triflates resulted in a decrease of the overall yield and only had a
slight influence on the reaction stereoselectivity (Table 3,
entries 4 and 5 vs entry 1). The reduction of the catalyst
loading resulted only in lowering of the reaction yield (Table 3,
entries 2 and 3). BF3·Et2O displayed only moderate catalytic
activity and provided the desired products 10 and 9a-epi-10 in
66% yield. The stereoselectivity remained very high. Among the
Finally, we decided to ascertain if the size of the silyl group in
the diene could influence the stereoselectivity of the process. As
a
Scheme 2. General Route to Sugar-Derived Lactams 8 and 12−17
a
Reagents and conditions: (a) (COCl)2, DMSO, Et3N, CH2Cl2, −78 °C; (b) (i) NH3(l), Et2O, −78 °C, (ii) SO3·Py, DMSO; (c) Et3SiH, BF3·Et2O,
MeCN, CH2Cl2.
C
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Scheme 3
Table 3. Lewis Acid Effect on the Formation of 10 via
Lactam Reduction/Diene Addition Sequence
sequential reduction/Mannich/Michael reaction, may differ
only at a single bridgehead position, the separation of isomeric
products was not a trivial task. In some cases the separation of
products by classic column chromatography was not effective;
even FCC and preparative HPLC did not give satisfying results
(although the results of analytical HPLC analysis were
promising). Crystallization techniques were also ineffective,
since most of the obtained products were oils and all attempts
to force them to crystallize failed. An alternative approach
involving derivatization of the obtained products by a complete
or partial exchange of O-Bn protecting groups for different
groups, such as Bz, PMB, TBS, THP, etc., also did not give
satisfying results in comparison to the effort expended. The
increase of the selectivity of the process to minimize the
formation of the minor isomer, e.g. by modifying the structure
of the starting materials, could present an alternate solution to
this problem. Unfortunately, the comparison of our data with
those of closely related works by Shao and Yang31 (for example,
for the synthesis of 37) indicates that the replacement of the
benzyl protecting group with the bulkier O-TBS group gives
only a slight increase in the selectivity of the process. In
addition, as demonstrated in Tables 3 and 5, the use of a bulkier
Lewis acid, such as TBSOTf, or a modified diene also provides
only slight changes in the level of diastereoselectivity of the
investigated process. So far, the isolation of products and
increase of diastereoselectivity of the addition step are still an
open question, and our current efforts are focused on
developing a suitable solution.
a
b
c
entry
Lewis acid (amt (mol%))
yield (%)
d.e. (%)
1
Yb(OTf)3 (10)
Yb(OTf)3 (5)
Yb(OTf)3 (1)
Sc(OTf)3 (10)
La(OTf)3 (10)
BF3·Et2O (10)
TMSOTf (10)
TBSOTf (10)
TBSOTf (5)
TBSOTf (2)
TIPSOTf (10)
none
80
51
35
55
77
66
68
75
58
26
53
0
95.8
94.4
94.7
96.4
92.2
96.4
94.2
95.8
94.2
93.0
96.0
2
3
4
5
6
7
8
9
10
11
12
a
Reaction conditions: (step 1) Cp2Zr(H)Cl (1.6 equiv) in THF at
−25 °C for 30 min; (step 2) diene (2 equiv), Lewis acid (10 mol%) at
b
−20 °C for 30 min and then 3 h at room temperature. Isolated yield
c
(overall after two steps). Determined by HPLC of the crude reaction
mixture.
Stereochemical Proofs and Analysis of the Stereo-
chemistry of the Investigated Reduction/Mannich/
Michael Sequence. The formation of bicyclic enaminones
is a stepwise process involving a Mannich reaction followed by
Michael addition. Therefore, its stereochemical outcome is
governed by the course of the nucleophilic addition to the
imine group. However, such analysis is not as straightforward as
it seems at first glance and both steric and stereoelectronic
effects must be taken into consideration to permit the correct
prediction and rationalization of its stereochemical course. For
this reason in our studies we employed the stereochemical
shown in Table 5, replacement of Danishefsky’s diene by its
analogue with a TBS group let us increase the diasterose-
lectivity of the reaction with lactam 14 derived imine. In the
case of lactam 18 the use of a diene with the bulkier silyl group
resulted in a slight decrease of stereoselectivity and an increase
in the overall reaction yield.
Although the method described above enables the efficient
and highly stereoselective formation of polyhydroxylated
indolizidinones and quinolizidinones, we encountered some
problems during the isolation and purification of the desired
products. Since the products, formed through the described
Scheme 4
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a
Scheme 5. Synthesis of Lactam 18
a
Reagents and conditions: (a) NaBH4, MeOH/CH2Cl2, −78 °C to room temperature, 24 h, 89%; (b) Ac2O, Et3N, CH2Cl2, 24 h, 69%; (c) BF3·
Et2O, Et3SiH, CH2Cl2, −78 to 0 °C, 3 h, 95%; (d) CAN, MeCN/H2O, 0 °C, 6 h, 73%.
a
Scheme 6. Synthesis of Lactams 20 and 21
a
Reagents and conditions: (a) BnBr, Ag2O, Et2O, room temperature, 24 h, 93%; (b) LiEt3BH, Ac2O, CH2Cl2, −78 °C to room temperature, 24 h,
91%; (c) BF3·Et2O, Et3SiH, CH2Cl2, −78 °C to room temperature, 24 h, 87% (30:31 ratio 94:6); (d) CAN, MeCN/H2O, 0 °C to room
temperature, 24 h, 86%; (e) CAN, MeCN/H2O, 0 °C to room temperature, 24 h, 76%.
models proposed by Woerpel and co-workers,46 which describe
the stereochemical course of C-allylation reactions of furanosyl
and pyranosyl oxycarbenium ions. Due to several parallels
between both types of reactions, we assumed that it can applied
as a working model for our process.
Woerpel’s rationalization is based on the conformational
preferences of the intermediate oxocarbenium ions and argues
that the orientation preferences of the ring substituents dictate
the relative stabilities of the possible oxocarbenium ion
conformers and govern the approach of allyl species to
oxycarbenium ions.
For 4,5-disubstituted imines 6b and 43 the observed
outcome of addition also corresponded well with Woerpel’s
model, and compounds 7b and 36 with a 2,8a-cis relative
configuration were obtained as the major products (Scheme 9).
This result also confirmed that the electronic nature of the
substituent at C-4 exerts a powerful effect upon selectivity. At
the same time, it confirmed a small influence of the CH2OBn
substituent at the C-5 position; regardless of the configuration
at the C-5 position the formation of the bridgehead
stereocenter was influenced predominantly by the C-4 center
of the imine.
Stereochemistry of Reactions Involving Five-Membered
Imines. Woerpel’s model assumes that, for furanosyl oxy-
carbenium ions (with an envelope conformation), alkoxy
substituents at C-2 and C-3 preferentially take the equatorial
and axial positions, respectively (Scheme 7).46e The C-4 alkyl
substituent does not have a strong preference for either
orientation but can play an important role in combination with
the other ring substituents through mutual steric interactions.
Nucleophiles would then approach the intermediate envelope
oxocarbenium ions preferentially from the “inside” (the side of
the envelope syn to the carbon atom which lies out of the
envelope plane; Scheme 7) to avoid developing eclipsing
interactions with the neighboring ring substituent.46e
According to the above assumptions, the addition of DD to
the lactam 20 derived imine 42 should result in the formation
of the 2,8a-cis isomer as the major product, as shown in
Scheme 8. Indeed, NOE experiments confirmed the relative cis
configuration of protons at the C-2 and C-8a positions for
compound 39. The same cis selectivity was also observed by
Seebach47 during the allylation of five-membered 3-silylox-
yiminium ions.
As indicated in Table 4, the addition of DD to the 3,4-
disubsituted imines threo-44 and erythro-45 (Schemes 9 and
10) provided compounds 37 and 38, respectively, as the major
products. In both cases the 1,8a-trans relative configuration was
assigned.
As disclosed in Scheme 10, the course of the addition to
imine 44 can be easily explained Woerpel’s stereoelectronic
4
model (via the E conformer). The same course of addition of
DD to imine 44 was observed by Yang and Shao.31
On the other hand, the formation of compound 38 as the
major product is in opposition to the outcome of the allylation
of the corresponding furanosyl oxycarbenium ion,46e which
provides the cis isomer, and suggests that the addition to imine
45 is probably governed by steric effects. This effect may be
associated with steric repulsion of the alkoxy substituent located
at the C-3 position that should favor a syn approach of the
nucleophile through the E4 conformer (Scheme 11).
Another explanation is also possible. Woerpel’s stereo-
chemical model has been based on the results of addition of
allyltrimethylsilane to various five- and six-membered oxy-
carbenium ions and does not take into consideration the
E
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Table 4. Synthesis of Indolizidines and Quinolizidines via One-Pot Reduction/Mannich/Michael Tandem Reaction Starting
a
from Lactams 10 and 12−22
a
Reaction conditions: (step 1) Cp2Zr(H)Cl (1.6 equiv) in THF for 30 min; (step 2) diene (2 equiv), Lewis acid (10 mol%) at −20 °C for 30 min
b
c
and then 3 h at room temperature. Isolated yield (overall after two steps). Determined by 1H NMR or/and HPLC of the crude reaction mixture.
d
Absolute configuration at the bridgehead position of the major product could not be unambiguously assigned.
influence of the nucleophile on the course of the addition.
Surely, Danishefsky’s diene is a sterically bulkier reagent than
the linear allyltrimethylsilane and in certain cases may also
govern the stereochemical outcome of the investigated
reactions. This might be the reason for the formation of
product 38; stereoelectronically favored addition of the
nucleophile to the E4 conformer of 45 is plausibly affected by
steric repulsion between the bulky diene and the alkoxy
substituent at the C-3 position.
Addition to imine 46 (Scheme 12), obtained from lactam 21,
gave compound 40 as the major isomer (Table 4, entry 10).
For both compounds, the assignment of relative configuration
between H-1 and H-8a by NOE experiments was impossible;
the observed enhancement of signals was small and did not
enable unambiguous assignment of a configuration. However,
an inspection of coupling constants of the protons at the C-8
position showed that one of them has an abnormally high value
of 3J to the bridgehead H-8a proton (16.3 Hz). On the basis of
the Karplus equation, it was assumed that both hydrogen atoms
have a plausibly antiperiplanar orientation (H-8a and H-8anti).
The same observation was made for all compounds with an
indolizidine scaffold (7a−d, 17−22). The presence of this
effect proved useful for the structure determination of
compounds 7a−d and 17−22. According to this, for the
major product (40) a 1,8a-trans relation of protons was
determined due to the presence of an NOE effect between H-
8
anti and H-1 protons. In the case of the minor product 8a-epi-
40, there was an interaction between H-1 and H-8a protons
F
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to a poorly selective reaction. Such is not, however, the case for
imine 6a; the high stereoselectivity of the reaction, leading
mainly to product 7a, indicates that the process is stereo-
electronically controlled not only by the imine (”inside”
approach of the nucleophile via E4 conformer) but also by a
steric effect of the bulky nucleophilic reagent.
Table 5. Effect of Diene Type on Stereoselectivity of
Reduction/Mannich/Michael Tandem Reaction of Lactams
a
14 and 18
The addition to imine 47 proceeded syn to the C-3 alkoxy
group to provide compound 35 with a 2,8a-cis arrangement of
protons (Scheme 14), and such an outcome corresponds well
with Woerpel’s rationalization.46e This result is even more
interesting if it is compared with the stereochemical outcome of
the analogous reaction of imine 45 (Scheme 11). As already
discussed, in the latter case the addition was mainly controlled
by the sterics of the alkoxy group at C-3 of the imine, which
resulted in the formation of 1,8a-trans-2,8a-trans product 38. At
this moment there is no reasonable explanation for this
phenomenon. One can assume that observed differences may
be result of the presence or absence of a CH2OBn substituent
at the C-5 position. However, as proved experimentally, this
substituent has a minor influence on the course of the addition
process to either imines (see Scheme 9) or furanosyl
oxycarbenium ions.46e
b
c
entry
lactam
R (diene)
major product
yield (%)
d.r. (%)
1
2
3
4
14
14
18
18
TMS
TBS
TMS
TBS
34
34
37
37
67
62
55
68
87:13
88:12
90:10
87:13
a
Reaction conditions: (step 1) Cp2Zr(H)Cl (1.6 equiv) in THF for 30
min; (step 2) diene (2 equiv), Lewis acid (10 mol%) at −25 °C for 30
min and then 3 h at room temperature. Isolated yield (overall after
b
c
two steps). Determined by HPLC of the crude reaction mixture.
Scheme 7
Stereochemistry of Reactions Involving Six-Membered
Imines. As in the case of five-membered cyclic imines,
Woerpel’s model for addition to pyranosyl oxycarbenium
ions46b,c,f was used as a working model for the rationalization of
the stereochemical outcome of the Mannich/Michael reaction
of six-membered imines.
Nucleophile additions to six-membered oxocarbenium ions
occur through chairlike transition structures, not twistlike ones,
through an axial trajectory (Scheme 15).50 As indicated by
Woerpel and co-workers,46c,f,g their stereochemical course is
also governed by stereoelectronic effects. Thus, substrates
bearing alkoxy groups at C-3, C-4, or C-5 give β isomers as the
major products. Again, the preference to adopt an axial
orientation of substituents at C-4 and C-5 and equatorial
position by groups at C-3 was crucial (for the numbering of
positions see Scheme 16).
As shown in Tables 2−4, the reaction of the model gluco-
lactam 8 with DD gave the bicyclic product 10 with a cis
arrangement of H-9 and H-9a protons (Scheme 16). The
assignment of absolute configuration at H-9a was not easy task
since, as concluded from NMR data, the gluco ring in 10 has a
half-boat conformation. The assignment was proven by X-ray
analysis of a hydrogenated derivative of 10 (compound 11,
Scheme 4).
and no NOE effect between H1/H-8anti; therefore, a 1,8a-cis
relative configuration was assigned.
The formation of the 1,8a-trans product 40 is in opposition
to Woerpel’s model for allylation of furanosyl oxycarbenium
ions,46e which assumes the formation of its epimer through syn
addition to the E4 conformer of imine 46 (Scheme 12). It
seems that for 3-alkoxy-substituted imines, such as 46, the
addition is ruled again mainly by steric factors connected with
steric repulsion of the bulky nucleophile and the substituent at
C-3 position (Scheme 12).
Finally, for both 3,4,5-trisubstituted imines 6a and 47, an
addition of DD provided compounds 7a and 35, respectively.
In both cases the aforementioned compounds were formed
with high stereoselectivity and, as assigned by NOE experi-
ments, had a trans arrangement of protons at positions C-2 and
C-8a (Schemes 13 and 14).
When addition to imine 6a is considered through Woerpel’s
model, the low selectivity of the reaction should be expected, as
is observed for allylation of arabinose-derived acetals.46e,48 For
the C-4 alkoxy group to occupy the preferred pseudoaxial
orientation, all substituents must be also pseudoaxial (E4
conformer of 6a; Scheme 13). However, such an arrangement
is disfavored due to unfavorable syn-butanol interactions.49 As a
result, the reaction course via the all equatorially substituted
conformer 4E should also be possible and, in consequence, lead
The formation of the 9,9a-cis product 10 plausibly results
4
from an axial attack of the nucleophile at the all-equatorial H3
conformer (Scheme 16). The 3H4 conformer, which bears
stereoelectronically more preferred axially oriented C-3 and C-4
groups, is strongly destabilized by 1,3-diaxial interactions. The
observed stereochemical outcome corresponds well to our
Scheme 8
G
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Scheme 9
The stereochemistry of the addition of DD to manno-imine
48 (Table 4, entry 2) differed from the outcome observed
during its allylation (Scheme 17, eq 2)39 and led to compound
32, with a 9,9a-trans relative configuration, as the major isomer.
Scheme 10
Scheme 11
Scheme 12
3
Conformational analysis showed that the H4 conformer of
4
48 is only slightly less favored than the H3 form (by 0.3 kcal/
mol), what probably arises from destabilizing 1,3-diaxial
interactions between substituents at C-3 and C-5. The
nucleophile’s approach from the more stereoelectronically
3
favored face of H4 (from the top, Scheme 18) would result
in the development of a syn-pentane51 interaction between the
nucleophile and the substituent at C-5 as well as a smaller syn-
butanol49 interaction with the substituent at C-3. Such
destabilizing interactions, as well as the small energy difference
between both conformers, plausibly result in an interconverting
mixture of conformers, and the reaction proceeds through the
lowest-energy transition state via conformer 4H3, in accordance
with the Curtin−Hammett principle, leading to compound 32
as the major product (Scheme 18). The different stereo-
chemical preferences of the addition of Danishefsky’s diene and
allyltributylstannane indicate that the type of nucleophile and
its size and reactivity may also influence the course of the
reaction. For the more bulky diene, the addition is plausibly
4
governed by steric factors. Thus, the approach through H3 is
3
preferred. In the case of the H4 conformer of 48, an axial
approach of the nucleophile may be effected by steric repulsion
between the alkoxy group at C-3 or/and C-4. In the case of the
more linear allylstannane, such an interaction may be weaker
and, as a result, the addition proceeds through the stereo-
3
electronically more preferred conformer H4.
Interestingly, in contrast to gluco-imine 9, nucleophile
addition to galacto-imine 49 followed by intramolecular
Michael conjugate addition gave product 9c as the major
isomer, with a trans arrangement of H-9 and H-9a protons
(Table 4, entry 3). Such an outcome also differs from the result
of allylation of galacto-imine 49 (Scheme 17, eq 3)39 as well as
syntheses of analogous C-glycosides of galactose.46f,52,53
Computational studies showed a 1.5 kcal/mol energy
difference between both conformers of imine 49 (Scheme
19). The addition of DD plausibly proceeds via the stereo-
3
electronically more favored face of the H4 conformer, which
should result in the formation of the 9,9a-trans isomer as the
predominant product.
In comparison to imines 9, 48, and 49, the reaction of imine
50 with DD was slightly less selective (Table 4, entry 4). The
major product was compound 34, with a trans arrangement of
H-9 and H-9a protons. Again, such a result was in opposition to
the allylation of the same imine with allyltributylstannane
(Scheme 17, eq 4).39
previous studies of allylation of in situ generated sugar-derived
imines (Scheme 17, eq 1)39 as well as allylation of the gluco-
oxycarbenium ion.46b,c,f
The calculated energy difference between the two con-
formers of imine 50 is low and indicates the presence of their
H
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Scheme 13
Scheme 14
the energy of the transition state, making it less preferred. Such
experimental results additionally support the statement that the
course of the investigated addition reaction depends on the size
of the nucleophile as well.
Scheme 15
CONCLUSION
■
In conclusion, an attractive method for the formation of
indolizidine and quinolizidine scaffolds was developed. The
presented strategy is based on a one-pot sugar-derived lactam
reduction/Mannich/Michael tandem reaction. The availability
of starting materialssugar lactamsand the high stereo-
selectivity of the cyclocondensation step open a straightforward
and general route to polyhydroxylated indolizidines and
quinolizidines which not only provides complex 5,6- and 6,6-
fused systems in a one-pot manner but also allows diverse
iminosugars to be constructed in a common pathway. It is also
worth emphasizing that the presence of an enaminone moiety
in the resulting bicyclic products gives an opportunity for their
further transformation/functionalization.
Scheme 16
The use of sugar-derived lactams, as cyclic imine precursors,
shows the crucial benefit of the disclosed synthetic method.
These compounds are more easily and readily prepared,
handled, and stored than the alternative precursors of cyclic
imines such as nitrones, N-chloroamines, and azido aldehydes.
As demonstrated, there is no need to isolate in situ generated
imines, which can be directly used in subsequent reactions with
Danishevsky’s diene in the presence of a catalytic amount of a
Lewis acid, such as Yb(OTf)3 or TMSOTf.
As shown in the second part of the article, the stereochemical
course of the investigated process, which is a stepwise aza-
Mannich/Michael sequence, is determined by nucleophilic
addition of DD to the in situ generated imines and is ruled not
only by steric but also by stereoelectronic factors, as in the case
of allylation of five- and six-membered oxycarbenium ions
investigated in detail by the Woerpel group. As we pointed out,
on the basis of a comparison of the current results with studies
on the allylation of cyclic imines, the structure of the
nucleophile is an additional factor which has an influence on
the stereochemical outcome of the investigated process, giving
new insights into the knowledge about addition to cyclic
imines.
interconverting mixture (Scheme 20). Woerpel’s model
assumes the axial approach of the nucleophile to the top face
of 3H4 conformer of 50 leading, as a result, to the formation of
the 9,9a-cis isomer. Such an outcome was observed by us
previously in the case of allylation of imine 50 (Scheme 17, eq
4).39 However, the formation of compound 34 as the major
isomer indicates that in the case of addition of DD to imine 50
4
the axial attack of the nucleophile through the H3 conformer
seems to be preferred. Although in this case the C-2 group
occupies the disfavored axial position, such a location of the
substituent minimizes any steric interaction which might occur
during the axial approach of a rather bulky nucleophile (e.g.,
Danishefsky’s diene). In case of the 3H4 conformer of 50, steric
repulsion during the syn approach of the nucleophile may affect
I
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Scheme 17
Scheme 18
Scheme 19
TOF) m/z calcd for C19H21NO3Na [M + Na+] 334.1419, found
334.1423; IR (film) ν 3400, 3031, 2921, 2866, 1585, 1454, 1366, 1249,
1110, 738, 698 cm−1.
Deoxygenation of Nitrones: General Procedure. To a stirred
solution of nitrone (1.2 mmol) in THF (20 mL) under argon was
added n-Bu3P (2.0 equiv, 600 μL, 2.4 mmol) in one portion. The
reaction mixture was heated to 75 °C for 24−72 h. The progress of the
reaction was followed by TLC. After removal of the solvent, the crude
product was chromatographed on Florisil.
EXPERIMENTAL SECTION
■
Synthesis of Nitrones 5a−d. The known nitrones 5a,34 5c,14b
and 5d14d were prepared according to literature procedures.
Compound 5b was prepared following the synthetic procedure
described by Maciejko et al.36
(2R,3R,4R)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-3,4-dihydro-
2H-pyrrole (6a): colorless oil; isolated yield 400 mg (83%) starting
from 500 mg (1.2 mmol) of nitrone 5a; [α]D −9.9 (c 0.8, CH2Cl2)
(lit.54 [α]D −10.4 (c 0.8, CHCl3)); Rf = 0.35 (100% Et2O); column
(2S,3S)-3-(Benzyloxy)-2-(benzyloxymethyl)-3,4-dihydro-2H-pyr-
role N-oxide (5b): prepared according to literature procedure;36 white
waxy solid; [α]D +22.4 (c 1.39, CHCl3); 1H NMR (600 MHz, CDCl3)
δ 7.34−7.23 (m, 10H), 6.88 (d, J 1.3 Hz, 1H), 4.62−4.58 (m, 2H),
4.58−4.54 (m, 2H), 4.48 (td, J 6.9, 4.9 Hz, 1H), 4.14−4.08 (m, 2H),
4.05−4.01 (m, 1H), 2.82 (ddd, J 17.9, 6.9, 2.6 Hz, 1H), 2.77−2.70 (m,
1H); 13C NMR (151 MHz, CDCl3) δ 137.5, 137.4, 134.1, 128.5,
128.0, 127.9, 127.6, 127.5, 71.9, 71.8, 71.4, 70.4, 60.1; HRMS (ESI-
1
chromatography (100% Et2O); H NMR (600 MHz, CDCl3) δ 7.60
(d, J 2.3 Hz, 1H), 7.37−7.25 (m, 15H), 4.62−4.52 (m, 7H), 4.16 (dt, J
7.8, 6.3 Hz, 1H), 4.11 (t, J 3.8 Hz, 1H), 3.76 (dd, J 9.8, 4.6 Hz, 1H),
3.54 (dd, J 9.8, 6.3 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 165.9,
138.1, 137.8, 137.5 128.5, 128.4, 128.3, 128.0, 127.9, 127.8, 127.7,
127.6, 127.5, 90.6, 84.3, 73.3, 72.2, 71.9, 70.9; HRMS (ESI-TOF) m/z
J
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1
The compound was stored under argon in a freezer: H NMR (400
MHz, CDCl3) δ 6.82 (d, J 12.4 Hz, 1H), 5.35 (d, J 12.4 Hz, 1H), 4.10
(s, 1H), 4.06 (s, 1H), 3.58 (s, 3H), 0.23 (s, 9H).
Scheme 20
TBS-Danishefsky’s Diene. To a solution of 4-methoxybut-3-en-2-
one (505 μL, 5.0 mmol) in dry Et2O (20 mL) was added Et3N (1.75
mL, 12.6 mmol) under argon. The reaction mixture was cooled to 0
°C, and a solution of TBSOTf (1.3 mL, 5.74 mmol) in Et2O (1 mL)
was added dropwise. After it was stirred overnight at 0 °C, the reaction
mixture was quenched with addition of saturated aqueous NaHCO3
(10 mL, at 0 °C) followed by addition of pentane (20 mL). The
organic layer was separated, and the aqueous layer was extracted with
pentane (10 mL). The combine organic extracts were washed with
aqueous NaHCO3 (2 × 10 mL), water (2 × 10 mL), and brine (2 × 10
mL) and dried over Na2SO4. The solvent was removed, and the
resulting brown oil was distillated under diminished pressure (71−72
°C, 3.8 Torr) to afford 808 mg of the diene (82%) as a colorless liquid.
1
The reagent was stored under argon in the freezer: H NMR (200
MHz, CDCl3) δ 7.11 (d, J 12.3 Hz, 1H), 5.58 (d, J 12.3 Hz, 1H), 4.30
(d, J 6.2 Hz, 2H), 3.81 (s, 3H), 1.19 (s, 9H), 0.42 (s, 6H).
Mannich/Michael Reaction of Cyclic Imines with Danishef-
sky-Type Dienes: General Procedure. To a solution of the imine
(0.5 mmol) in dry CH2Cl2 (5 mL) was added Yb(OTf)3 (10 mol%, 31
mg, 0.05 mmol) at −25 °C under argon. The mixture was stirred for
10 min at the same temperature, and then Danishefsky’s diene (1.2
equiv, 117 μL, 0.6 mmol) was added dropwise. The mixture was
warmed gradually to room temperature. After it was stirred for 2.5 h at
room temperature (TLC monitoring), the reaction mixture was
quenched with 1 M aqueous HCl (1 mL) and diluted with CH2Cl2 (3
mL). After phase separation, the organic layer was washed with water
(3 mL) and brine (3 mL), dried over Na2SO4, and filtered. The filtrate
was concentrated under reduced pressure to give the crude product,
which was purified by silica gel column chromatography to give the
corresponding bicyclic product(s).
calcd for C26H27NO3Na [M + Na+] 424.1883, found 424.1894; IR
(film) ν 2925, 2862, 1496, 1454, 1362, 1206, 1097, 1028, 736, 697
cm−1.
(2S,3S)-3-(Benzyloxy)-2-(benzyloxymethyl)-3,4-dihydro-2H-pyr-
role (6b): colorless oil; isolated yield 198 mg (67%) starting from 375
mg (1.2 mmol) of nitrone 5b; [α]D +14.7 (c 1.0, CH2Cl2); Rf = 0.22
(5% MeOH in CH2Cl2); column chromatography (4/1 AcOEt/
1
hexanes then 100% AcOEt); H NMR (400 MHz, CDCl3) δ 7.69 (s,
1H), 7.41−7.24 (m, 11H), 4.66 (d, J 11.8 Hz, 1H), 4.60 (d, J 11.9 Hz,
1H), 4.54 (d, J 12.0 Hz, 1H), 4.47 (d, J 12.1 Hz, 1H), 4.25 (t, J 5.1 Hz,
1H), 4.07 (s, 1H), 4.00−3.90 (m, 2H); HRMS (ESI-TOF) m/z calcd
for C19H21NO2Na [M + Na+] 318.1456, found 318.1457; IR (film) ν
3029, 2913, 2861, 1496, 1453, 1362, 1099, 734, 696 cm−1.
(3R,4R)-3,4-Di-tert-butoxy-3,4-dihydro-2H-pyrrole (6c): colorless
oil; isolated yield 181 mg (85%) starting from 275 mg (1.2 mmol) of
nitrone 5c; [α]D +68.9 (c 1.5, CH2Cl2); Rf = 0.43 (100% AcOEt);
column chromatography (7/3 AcOEt/hexanes); 1H NMR (600 MHz,
CDCl3) δ 7.50−7.49 (m, 1H), 4.49 (d, J 4.0 Hz, 1H), 4.09−4.04 (m,
2H), 3.57−3.51 (m, 1H), 1.25 (s, 9H), 1.19 (s, 9H); 13C NMR (151
MHz, CDCl3) δ 168.6, 84.2, 77.9, 74.5, 73.8, 66.7, 28.5, 28.4; HRMS
(ESI-TOF) m/z calcd for C12H24NO2 [M + H+] 214.18016, found
214.1799; IR (film) ν 2975, 1722, 1472, 1390, 1365, 1193, 1100, 888
cm−1.
(1R,2R,3R,8aR)-1,2-Bis(benzyloxy)-3-(benzyloxymethyl)-2,3,8,8a-
tetrahydroindolizin-7(1H)-one (7a and 8a-epi-7a): inseparable
mixture of diasteromers; colorless oil; for yield and d.r. see Tables 2
and 4; column chromatography (7/3 AcOEt/hexanes); major isomer
7a (pure sample obtained by preparative TLC, Merck preparative TLC
plates Si60 F254, 20 × 20 cm, hexanes/AcOEt 1/1) [α]D −191.7 (c
0.15, CH2Cl2); Rf = 0.32 (7/3 AcOEt/hexanes); 1H NMR (600 MHz,
C6D6) δ 6.94−6.80 (m, 15H, 3 × Ph), 6.48 (d, J 7.3 Hz, 1H, CH
CHCO), 4.82 (d, J 7.3 Hz, 1H, CHCHCO), 4.09 (d, J 11.9
Hz, 1H, PhCHHO), 4.04 (d, J 11.9 Hz, 1H, PhCHHO), 4.02 (d, J 11.7
Hz, 1H, PhCHHO), 3.97 (d, J 11.7 Hz, 1H, PhCHHO), 3.85 (m, 2H,
PhCH2O), 3.53 (ps t, J 4.3, 4.0, 1H, H-2), 3.43 (dd, J 6.9, 4.3 Hz, 1H,
H-1), 3.38 (dt, J 16.1, 6.7, 5.1 Hz, 1H, H-8a), 3.17−3.13 (m, J 6.5, 4.8,
4.0 Hz, 1H, H-3), 2.82 (dd, J 10.0, 4.8 Hz, 1H, CHHOBn), 2.79 (dd, J
10.0, 6.5 Hz, 1H, CHHOBn), 2.24 (dd, J 15.9, 5.1 Hz, 1H, H-8syn),
2.03 (ps t, J 16.1, 15.9 Hz, 1H, H-8anti); 13C NMR (126 MHz, CDCl3)
δ 191.2, 149.8, 137.3, 137.2, 128.6, 128.5, 128.12, 128.07, 128.0, 127.8,
127.7, 98.1, 87.9, 84.2, 73.4, 72.6, 72.3, 69.3, 64.6, 61.4, 40.6; minor
(S)-4-tert-Butoxy-3,4-dihydro-2H-pyrrole (6d): colorless oil; iso-
lated yield 97 mg (69%) starting from 190 mg (1.2 mmol) of nitrone
5d; [α]D +20.1 (c 0.6, CH2Cl2); Rf = 0.35 (100% acetone); column
1
chromatography (1/1 AcOEt/hexanes then 100% AcOEt); H NMR
1
isomer 8a-epi-7a selected signals H NMR (500 MHz, C6D6) δ 6.61
(600 MHz, CDCl3) δ 7.49 (t, J 2.2 Hz, 1H), 4.65 (dd, J 8.1, 6.4 Hz,
1H), 4.06−4.00 (m, 1H), 3.75−3.68 (m, 1H), 2.24−2.13 (m, 1H),
1.69−1.54 (m, 2H), 1.25 (s, 6H), 1.20 (s, 3H); 13C NMR (151 MHz,
CDCl3) δ 168.2, 78.1, 74.1, 60.1, 31.5, 28.7, 28.3; HRMS (ESI-TOF)
m/z calcd for C8H16NO [M + H+] 142,1232, found 142,1248; IR
(film) ν 2975, 1389, 1363, 1197, 1097, 1098, 888 cm−1.
Danishefsky’s Diene. To a solution of 4-methoxybut-3-en-2-one
(9.5 mL, 94.0 mmol) in dry Et2O (400 mL) was added Et3N (32.9 mL,
236.0 mmol) under argon. The reaction mixture was cooled to 0 °C,
and a solution of TMSOTf (19.6 mL, 108.0 mmol) in Et2O (20 mL)
was added dropwise. After it was stirred overnight at 0 °C, the reaction
mixture was quenched by addition of saturated aqueous NaHCO3
(100 mL, at 0 °C) followed by addition of pentane (100 mL). The
organic layer was separated, and the aqueous layer was extracted with
pentane (100 mL). The combined organic extracts were washed with
saturated aqueous NaHCO3 (2 × 100 mL), water (2 × 100 mL), and
brine (2 × 100 mL) and dried over Na2SO4. The solvent was removed,
and the resulting brown oil was distilled under reduced pressure (70
°C, 15 mbar) to afford 14.4 g of the diene (89%) as a colorless liquid.
(d, J 7.3 Hz, 1H, CHCHCO), 4.88 (d, J 7.3 Hz, 1H, CH
CHCO), 3.26 (m, 1H, H-8a), 2.95 (dd, J 7.4, 2.7 Hz, 1H,
CHHOBn) 2.53 (t, J 16.3, 16.0 Hz, 1H, H-8anti), 1.97 (dd, J 16.0, 4.6
Hz, 1H, H-8syn); HRMS (ESI-TOF) m/z calcd for C30H31NO4Na [M
+ Na+] 492.2145, found 492.2167; IR (film) ν 2864, 1638, 1577, 1454,
1115, 1096, 740, 698 cm−1; HPLC Chiralpak AD-H, 20% i-PrOH in
hexanes, flow 0.5 mL/min, UV 313 nm, Rt 23.1 min (7a major
isomer), 35.8 min (8a-epi-7a minor isomer).
(2S,3S,8aS)-2-(Benzyloxy)-3-(benzyloxymethyl)-2,3,8,8a-tetrahy-
droindolizin-7(1H)-one (7b and 8a-epi-7b): inseparable mixture of
diasteromers; colorless oil; isolated yield 99 mg (55%, both isomers)
starting from 150 mg (0.5 mmol) of imine 6b; d.r. 86:14 (determined
by 1HNMR of crude reaction mixture); column chromatography
(100% AcOEt); major isomer 7b (pure sample after preparative TLC,
Merck preparative TLC plates Si60 F254, 20 × 20 cm, hexanes/AcOEt
1
1/9) [α]D −190.7 (c 2.87, CH2Cl2); Rf = 0.22 (100% AcOEt); H
NMR (600 MHz, CDCl3) δ 7.39−7.19 (m, 11H, 2 × Ph, CH
CHCO), 4.99 (d, J 7.2 Hz, 1H, CHCHCO), 4.58−4.56 (m,
K
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2H, OCH2Ph), 4.53−4.49 (m, 2H, OCH2Ph), 4.26−4.20 (m, 1H, H-
8a), 3.86 (td, J 8.5, 7.1, 3.3 Hz, 1H, H-3), 3.77 (dd, J 10.0, 3.3 Hz, 1H,
CHHOBn), 3.75−3.71 (m, 1H, H-2), 3.52 (dd, J 10.0, 8.5 Hz, 1H,
CHHOBn), 2.41 (dt, J 12.3, 6.2 Hz, 1H, H-1), 2.38−2.34 (m, 2H, H-
8′, H-8″), 1.85−1.75 (m, 1H, H-1′); 13C NMR (151 MHz, CDCl3) δ
192.3, 150.7, 137.7, 137.4, 128.53, 128.45, 128.0, 127.8, 127.7, 127.5,
98.5, 73.6, 72.3, 70.4, 60.8, 55.7, 42.1, 36.3; minor isomer 8a-epi-7b
selected signals 1H NMR (600 MHz, CDCl3) δ 4.95 (d, J 7.3 Hz, 1H),
4.15−4.10 (m, 1H, H-3); minor isomer 8a-epi-7b selected signals 13C
NMR (151 MHz, CDCl3) δ 191.5, 149.8, 137.6, 137.5, 97.6, 78.0, 73.6,
71.5, 69.7, 63.5, 55.9, 41.4, 36.7; HRMS (ESI-TOF) m/z calcd for
C23H25NO3Na [M + Na+] 386.1745, found 386.1745; IR (film) ν
2922, 2866, 1634, 1571, 1453, 1335, 1096, 738, 698 cm−1.
(1R,2R,8aR)-1,2-Di-tert-butoxy-2,3,8,8a-tetrahydroindolizin-
7(1H)-one (7c and 8a-epi-7c): inseparable mixture of diasteromers;
isolated yield 96 mg (69%, both isomers) sterting from 135 mg (0.5
mmol) of imine 6c; d.r. 86:14 (determined by HPLC of crude reaction
mixture); Rf = 0.22 (100% AcOEt); column chromatography (4/1
AcOEt/hexanes); major isomer 7c (pure sample prepared by
preparative TLC, Merck preparative TLC plates Si60 F254, 20 × 20
cm, hexanes/AcOEt 1/1); colorless oil; [α]D +280.6 (c 0.9, CH2Cl2);
1H NMR (600 MHz, CDCl3) δ 7.05 (d, J 7.1 Hz, 1H), 4.95 (d, J 7.1
CDCl3) δ 169.9, 159.2, 137.2, 137.1, 129.8, 128.5, 128.4, 128.3, 128.0,
127.9, 127.7, 127.7, 114.1, 84.7, 83.9, 79.6, 72.9, 72.1, 55.3, 42.4; 5-epi-
24 selected signals 1H NMR (600 MHz, CDCl3) δ 5.05 (d, J 11.7 Hz,
1H); HRMS (ESI-TOF) m/z calcd for C26H27NO5Na [M + Na+]
456.1787, found 456.1789; IR (film) ν 3348, 2925, 1683, 1513, 1454,
1247, 1105, 738, 697 cm−1.
(2S,3R,4R)-3,4-Bis(benzyloxy)-1-(4-methoxybenzyl)-5-oxopyrroli-
din-2-yl acetate (25 and 2-epi-25). To a solution of 24/5-epi-24
(1.57g, 3.62 mmol) in dry CH2Cl2 (35 mL) were added Et3N (9.0
equiv, 3.24 mL, 21.73 mmol) and Ac2O (6.0 equiv, 2.0 mL, 21.73
mmol). The reaction mixture was stirred at room temperature for 12
h. The progress of the reaction was followed by TLC (1/3 AcOEt/
hexanes, Rf = 0.35). Afterward, the solvent was removed under
diminished pressure and the residue was chromatographed on silica gel
(1/5 AcOEt/hexanes) to afford 1.19 g of the product (69%
1
diastereoisomeric mixture, d.r. 89.2:10.8 based on H NMR spectra
1
of crude mixture) as a colorless oil: major isomer 25 H NMR (600
MHz, CDCl3) δ 7.40−7.34 (m, 5H), 7.32−7.27 (m, 4H), 7.21−7.17
(m, 2H), 7.17−7.14 (m, 2H), 6.84−6.81 (m, 2H), 4.97 (d, J 11.9 Hz,
1H), 4.77 (d, J 11.9 Hz, 1H), 4.62 (d, J 12.9 Hz, 1H), 4.54 (d, J 7.3 Hz,
1H), 4.48−4.46 (m, 1H), 4.20 (d, J 14.9 Hz, 1H), 4.07 (d, J 2.8 Hz,
1H), 3.91 (dd, J 2.8, 1.5 Hz, 1H), 3.77 (s, 3H), 1.90 (s, 3H); 13C NMR
(151 MHz, CDCl3) δ 171.2, 170.1, 159.2, 137.2, 136.9, 129.5, 128.4,
128.2, 128.0, 127.9, 127.8, 127.7, 114.0, 84.7, 81.6, 79.4, 72.7, 71.9,
55.2, 43.9, 20.8; minor isomer 2-epi-25 selected signals 1H NMR (600
MHz, CDCl3) δ 4.94 (d, J 11.8 Hz, 1H), 4.82 (d, J 11.7 Hz, 1H), 4.66
(d, J 14.7 Hz, 1H), 3.93 (dd, J 2.7, 1.4 Hz, 1H); HRMS (ESI-TOF) m/
z calcd for C28H29NO6Na [M + Na+] 498.1893, found 498.1894; IR
(film) ν 3032, 2934, 1716, 1514, 1248, 1226, 1177, 1108, 1019, 738,
698 cm−1.
Hz, 1H), 3.98 (dd, J 12.3, 5.9 Hz, 1H), 3.88−3.84 (m, 1H), 3.73−3.68
(m, 1H), 3.57 (dt, J 15.5, 6.3 Hz, 1H), 3.26 (dd, J 10.7, 5.8 Hz, 1H),
2.55−2.44 (m, 2H), 1.20 and 1.18 (2 × s, 18H); 13C NMR (151 MHz,
CDCl3) δ 191.9, 150.4, 97.7, 75.5, 74.6, 74.2, 61.0, 54.9, 39.5, 29.0,
1
28.4; minor isomer 8a-epi-7c selected signals: H NMR (600 MHz,
CDCl3) δ 7.15 (d, J 7.0 Hz, 1H); HRMS (EI) m/z calcd for
C16H27O3N [M+] 281.1990, found 281.1985; IR (film) ν 2975, 1637,
1579, 1364, 1191, 1092 cm−1; HPLC Chiralpak OD-H, 20% i-PrOH in
hexanes, flow 1.0 mL/min, UV 335 nm, Rt 4.9 min (minor isomer 8a-
epi-7c), 8.1 min (major isomer 7c).
(3R,4R)-5-Acetoxy-3,4-bis(benzyloxy)-N-(4-methoxybenzyl)-pyr-
rolidin-2-one (26). To a 25/2-epi-25 mixture (709 mg 1.49 mmol) in
dry CH2Cl2 (20 mL) at −78 °C was added BF3·Et2O (2.0 equiv, 374
μL, 2.98 mmol). The mixture was stirred for 30 min, and then Et3SiH
(5.0 equiv, 1.2 mL, 7.45 mmol) was added. The mixture was warmed
to room temperature and quenched by saturated aqueous Na2CO3 (5
mL). After phase separation, the aqueous phase was washed with
CH2Cl2 (10 mL). The combined organic phases were dried over
Na2SO4. The crude product (590 mg, 95%, colorless oil) was used
directly in the next step. A pure sample was obtained by filtration
through a short pad of silica gel (CH2Cl2): [α]D +73.8 (c 6.1, CHCl3);
(1S,8aR)-1-tert-Butoxy-2,3,8,8a-tetrahydroindolizin-7(1H)-one
(7d and 8a-epi-7d): mixture of diasteroisomers; isolated yield 67 mg
(64%, both isomers) starting from 70 mg (0.5 mmol) of imine 6d; d.r.
92:8 (determined by HPLC of crude reaction mixture); column
chromatography (100% AcOEt); major isomer 7d; colorless oil; [α]D
−25.6 (c 0.9, CH2Cl2); (Lit.55 [α]D −28.3 (c 0.5, CH2Cl2)); Rf = 0.20
(100% AcOEt); 1H NMR (600 MHz, CDCl3) δ 7.08 (t, J 9.4 Hz, 1H),
4.94 (d, J 7.1 Hz, 1H), 3.98 (dd, J 15.2, 7.8 Hz, 1H), 3.60 (td, J 10.2,
3.6 Hz, 1H), 3.57−3.52 (m, 1H), 3.47 (dd, J 18.3, 9.2 Hz, 1H), 2.56
(dd, J 15.9, 5.0 Hz, 1H), 2.33 (t, J 16.2 Hz, 1H), 2.27 (dtd, J 12.4, 7.4,
3.5 Hz, 1H), 1.90 (ddd, J 17.7, 12.7, 9.2 Hz, 1H), 1.20 (s, 9H); 13C
NMR (151 MHz, CDCl3) δ 191.8, 150.3, 97.6, 76.4, 74.0, 62.1, 47.3,
(lit.56 [α]D +77.5 (c 7.0, CHCl3)); H NMR (600 MHz, CDCl3) δ
1
7.44−7.41 (m, 2H), 7.37−7.22 (m, 7H), 7.16−7.13 (m, 2H), 6.85−
6.83 (m, 2H), 5.12 (d, J 11.6 Hz, 1H), 4.84 (d, J 11.6 Hz, 1H), 4.53 (d,
J 11.6 Hz, 1H), 4.47 (d, J 11.6 Hz, 1H), 4.38 (s, 2H), 4.23 (d, J 5.7 Hz,
1H), 4.14 (dt, J 7.5, 5.8 Hz, 1H), 3.78 (s, 3H), 3.40 (dd, J 10.0, 7.6 Hz,
1H), 3.06 (dd, J 10.1, 5.8 Hz, 1H); 13C NMR (151 MHz, CDCl3) δ
170.6, 159.2, 137.7, 137.4, 129.6, 128.4, 128.4, 128.3, 127.9, 127.9,
127.7, 127.6, 114.1, 80.8, 77.5, 72.5, 71.8, 55.3, 48.5, 45.8; HRMS
(ESI-TOF) m/z calcd for C26H27NO4Na [M + Na+] 440.1838, found
440.1838; IR (film) ν 2869, 1701, 1513, 1248, 1109, 1029, 738, 698
cm−1.
1
39.5, 33.3, 28.4; minor isomer 8a-epi-7d selected signals H NMR
(600 MHz, CDCl3) δ 7.19 (d, J 7.2 Hz, 1H), 4.92 (d, J 7.0 Hz, 1H);
HRMS (ESI-TOF) m/z calcd for C12H19NO2Na [M + Na+] 232.1308,
found 232.1305; IR (film) ν 2974, 1634, 1578, 1097 cm−1; HPLC
Chiralpak OD-H, 20% i-PrOH in hexanes, flow 1.0 mL/min, UV 329
nm, Rt 9.3 min (major isomer 7d), 15.5 min (minor isomer 8a-epi-7d).
(3R,4R)-3,4-Bis(benzyloxy)-1-(4-methoxybenzyl)pyrrolidine-2,5-
dione (23): prepared according to the literature procedure.44
(3R,4R,5S)-3,4-Bis(benzyloxy)-5-hydroxy-1-(4-methoxybenzyl)-
pyrrolidin-2-one (24 and 5-epi-24). To a solution of 23 (1.764 g,
4.09 mmol) in dry MeOH (14 mL) and CH2Cl2 (25 mL) was added
NaBH4 (1.2 equiv, 186 mg, 4.91 mmol) in small portions at −78 °C.
The reaction mixture was warmed quickly to room temperature and
stirred for 12 h. When the reaction was complete (TLC 2/5 AcOEt/
hexanes; Rf = 0.45), it was quenched by slow addition of H2O (10 mL)
at 0 °C. After phase separation, the aqueous phase was washed with
CH2Cl2 (3 × 10 mL). The combined organic solutions were washed
with H2O (10 mL) and dried over Na2SO4. The crude mixture of
products was used directly in the next step: inseparable mixture of
diasteroisomers; colorless oil; isolated yield 89% (both isomers); d.r.
(3R,4S)-3,4-Bis(benzyloxy)pyrrolidin-2-one (18). To a solution of
26 (408 mg, 0.89 mmol) in dry acetonitrile (9 mL) at 0 °C was added
a solution of cerium ammonium nitrate (5.0 equiv, 2.44 g, 4.46 mmol)
in H2O (1 mL). After it was stirred for 6 h at 0 °C (TLC 1/2 AcOEt/
hexanes), the reaction mixture was warmed to room temperature, and
the organic layer was separated. The aqueous phase was washed with
AcOEt (3 × 5 mL). The combined organic layers were washed with
saturated aqueous NaHCO3 (10 mL) and dried over Na2SO4. The
crude product was purified by column chromatography on silica gel
(1/2 AcOEt/hexanes) to give 177 mg of 18 (73%) as a yellow waxy
1
solid: Rf = 0.15; [α]D +81.7 (c 1.23, CHCl3); H NMR (600 MHz,
1
CDCl3) δ 7.42−7.39 (m, 2H), 7.36−7.32 (m, 3H), 7.31−7.27 (m,
5H), 6.39 (s, 1H), 5.07 (t, J 9.7 Hz, 1H), 4.80 (d, J 11.7 Hz, 1H), 4.59
(d, J 11.7 Hz, 1H), 4.52 (d, J 11.7 Hz, 1H), 4.27 (dd, J 13.8, 6.3 Hz,
1H), 4.17 (d, J 6.3 Hz, 1H), 3.57−3.52 (m, 2H), 3.17 (dd, J 9.8, 6.3
Hz, 1H); 13C NMR (151 MHz, CDCl3) δ 173.9, 137.5, 137.4, 128.5,
128.4, 128.2, 127.90, 127.86, 127.80, 79.8, 79.6, 72.5, 71.9, 44.5;
86:14 (determined by H NMR of crude reaction mixture); major
1
isomer 24 H NMR (600 MHz, CDCl3) δ 7.40−7.24 (m, 8H), 7.20
(dd, J 7.2, 4.8 Hz, 4H), 6.84−6.81 (m, 2H), 4.98 (d, J 11.7 Hz, 1H),
4.84 (d, J 14.6 Hz, 1H), 4.76 (d, J 11.6 Hz, 2H), 4.55 (d, J 11.7 Hz,
1H), 4.49 (d, J 11.7 Hz, 1H), 4.11 (d, J 14.6 Hz, 1H), 4.08 (d, J 4.6 Hz,
1H), 3.90 (dd, J 4.5, 2.9 Hz, 1H), 3.76 (s, 3H); 13C NMR (151 MHz,
L
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Article
HRMS (ESI-TOF) m/z calcd for C18H19NO3Na [M + Na+] 320.1263,
found 320.1266; IR (film) ν 3245, 2874, 1714, 1111, 737, 697 cm−1.
(3R,4R)-3,4-Bis(benzyloxy)pyrrolidin-2-one (19). prepared accord-
ing to the literature procedure;39 white waxy solid, [α]D +57.6 (c 0.61,
CHCl3); Rf = 0.47 (100% AcOEt); column chromatography (1/1 then
was monitored by TLC (2/3 AcOEt/hexanes). The reaction was
quenched with saturated aqueous Na2CO3 (50 mL). The organic layer
was separated, and the aqueous layer was extracted with CH2Cl2 (50
mL). The combined organic extracts were dried over Na2SO4. After
removal of solvent the residue was chromatographed on silica gel (2/3
AcOEt/hexanes) to give 2.248 g of 30 (yield 82%) and 143 mg of 31
(yield 5%) Compound 30: Rf = 0.1 (2/3 AcOEt/hexanes); [α]D +8.4
(c 0.36, CHCl3); 1H NMR (600 MHz, CDCl3) δ 7.35−7.30 (m, 2H),
7.29−7.21 (m, 3H), 7.18−7.12 (m, 2H), 6.87−6.81 (m, 2H), 4.48 (d, J
11.7 Hz, 1H), 4.42 (d, J 11.7 Hz, 1H), 4.40 (s, 2H), 4.18 (m, 1H), 3.78
(s, 3H), 3.43 (dd, J 10.8, 6.2 Hz, 1H), 3.28 (dd, J 10.8, 2.9 Hz, 1H),
2.67 (dd, J 17.3, 7.0 Hz, 1H), 2.57 (dd, J 17.3, 3.4 Hz, 1H); 13C NMR
(151 MHz, CDCl3) δ 172.2, 159.1, 137.4, 129.4, 128.5, 128.2, 127.9,
127.6, 114.1, 70.9, 70.8, 55.3, 52.6, 45.6, 38.2; HRMS (ESI-TOF) m/z
calcd for C19H21NO3Na [M + Na+] 334.1419, found 334.1422; IR
(film) ν 2932, 1687, 1513, 1247, 1031 cm−1. Compound 31: Rf = 0.31
1
4/1 AcOEt/hexanes); H NMR (600 MHz, CDCl3) δ 7.42−7.26 (m,
10H), 6.57 (s, 1H), 5.05 (d, J 11.7 Hz, 1H), 4.80 (d, J 11.7 Hz, 1H),
4.58 (d, J 11.7 Hz, 1H), 4.52 (d, J 11.7 Hz, 1H), 4.26 (dd, J 13.7, 6.4
Hz, 1H), 4.17 (d, J 6.4 Hz, 1H), 3.54 (ddd, J 9.3, 7.6, 1.4 Hz, 1H), 3.15
(dd, J 9.8, 6.4 Hz, 1H); 13C NMR (151 MHz, CDCl3) δ 173.9, 137.6,
137.4, 128.5, 128.4, 128.2, 128.0, 127.9, 127.8, 79.9, 79.6, 72.5, 71.9,
44.5; HRMS (ESI-TOF) m/z calcd for C18H19NO3Na [M + Na+]
320.1263, found 320.1263; IR (film) ν 3243, 2873, 1712, 1110, 738,
697 cm−1.
(R)-3-Hydroxy-1-(4-methoxybenzyl)pyrrolidine-2,5-dione (27).
prepared according to the literature procedure;57 [α]D −66.0 (c
1
1
0.84, CHCl3); H NMR (500 MHz, CDCl3) δ 7.34−7.29 (m, 2H),
(2/3 AcOEt/hexanes); [α]D −73.1 (c 1.02, CHCl3); H NMR (600
6.95−6.70 (m, 2H), 4.69−4.52 (m, 3H), 3.78 (s, 3H), 3.29 (s, 1H),
3.04 (dd, J 18.2, 8.4 Hz, 1H), 2.66 (dd, J 18.2, 4.8 Hz, 1H); 13C NMR
(126 MHz, CDCl3) δ 177.9, 173.7, 159.4, 130.4, 127.5, 114.0, 67.0,
55.3, 42.0, 37.1; HRMS (ESI-TOF) m/z calcd for C18H19NO3Na [M +
Na+] 320.1263, found 320.1263; IR (film) ν 3435, 2943, 1698, 1514,
1248, 1107 cm−1.
MHz, CDCl3) δ 7.42−7.37 (m, 2H), 7.36−7.31 (m, 2H), 7.29−7.24
(m, 1H), 7.18−7.13 (m, 2H), 6.87−6.81 (m, 2H), 5.00 (d, J 11.9 Hz,
1H), 4.77 (d, J 11.9 Hz, 1H), 4.40 (d, J 14.5 Hz, 1H), 4.37 (d, J 14.5
Hz, 1H), 4.13 (dd, J 7.7, 6.9 Hz, 1H), 3.77 (s, 3H), 3.24 (ddd, J 9.7,
8.8, 3.9 Hz, 1H), 3.11−3.01 (m, 1H), 2.27−2.17 (m, 1H), 1.98−1.90
(m, 1H); 13C NMR (151 MHz, CDCl3) δ 172.4, 159.1, 137.9, 129.5,
128.4, 128.1, 128.0, 127.7, 114.1, 75.9, 72.0, 55.3, 46.1, 43.1, 26.4;
HRMS (ESI-TOF) m/z calcd for C19H21NO3Na [M + Na+] 334.1419,
found 334.1414; IR (film) ν 2935, 1693, 1513, 1247, 1030 cm−1.
(R)-4-(Benzyloxy)pyrrolidin-2-one (20). To a solution of 30 (2.248
g, 7.22 mmol) in MeCN (70 mL) was added a mixture of CAN (5
equiv, 19.8 g, 36.1 mmol) and water (8.4 mL) portionwise at 0 °C.
The reaction mixture was warmed to room temperature and stirred
overnight. The progress of the reaction was monitored by TLC (100%
AcOEt). The reaction mixture was diluted with H2O (20 mL) and
extracted with AcOEt (20 mL). The organic layer was washed with
saturated aqueous NaHCO3 (20 mL) and dried over Na2SO4, and the
solvent was removed under diminished pressure. The crude product
was purified by column chromatography (1/1 AcOEt/hexanes, 100%
AcOEt, and then 5/95 MeOH/CH2Cl2) to give 1.187 g of product 20:
(R)-3-(Benzyloxy)-1-(4-methoxybenzyl)pyrrolidine-2,5-dione (28).
To a solution of 27 (2.74 g, 11.65 mmol) in dry Et2O (100 mL) were
added BnBr (3.0 equiv, 4.15 mL, 34.89 mmol) and Ag2O (3.6 equiv,
9.80 g, 42.29 mmol). After it was stirred overnight in the dark, the
mixture was filtered through a pad of Celite. The collected solid was
washed with AcOEt (50 mL), and the solvent was evaporated. The
residue was chromatographed on silica gel (1/4 than 1/3 AcOEt/
hexanes) to give 3.524 g of product 28 as a colorless oil: isolated yield
93%; [α]D −73.3 (c 0.81, CHCl3); Rf = 0.57 (4/6 AcOEt/hexanes);
1H NMR (600 MHz, CDCl3) δ 7.37−7.29 (m, 7H), 6.84−6.79 (m,
2H), 4.97 (d, J 11.7 Hz, 1H), 4.77 (d, J 11.7 Hz, 1H), 4.63−4.54 (m,
2H), 4.33 (dd, J 8.2, 4.2 Hz, 1H), 3.77 (s, 3H), 2.91 (dd, J 18.2, 8.2
Hz, 1H), 2.63 (dd, J 18.2, 4.2 Hz, 1H); 13C NMR (151 MHz, CDCl3)
δ 175.6, 173.8, 159.3, 136.7, 130.4, 128.6, 128.23, 128.18, 127.7, 114,0,
73.0, 72.1, 55.2, 41.7, 36.3; HRMS (ESI-TOF) m/z calcd for
C19H19NO4Na [M + Na+] 348.1212, found 348.1210; IR (film) ν
2937, 1709, 1514, 1249, 699 cm−1.
1
yield 86%; [α]D +2.4 (c 0.88, CHCl3); Rf = 0.4 (100% AcOEt); H
NMR (600 MHz, CDCl3) δ 7.35−7.26 (m, 5H), 6.86 (s, 1H), 4.48 (q,
J 11.7 Hz, 2H), 4.27 (dq, J 9.5, 3.2 Hz, 1H), 3.56 (dd, J 10.6, 6.2 Hz,
1H), 3.40 (dd, J 10.6, 2.6 Hz, 1H), 2.55 (dd, J 17.3, 6.9 Hz, 1H), 2.43
(dd, J 17.3, 3.6 Hz, 1H); 13C NMR (151 MHz, CDCl3) δ 176.6, 137.5,
128.5, 127.9, 127.7, 73.8, 71.0, 48.8, 37.3; HRMS (ESI-TOF) m/z
calcd for C11H13NO2Na [M + Na+] 214.0844, found 214.0842; IR
(film) ν 3236, 2916, 1693, 1667, 1354, 1095, 728 cm−1.
(3R)-3-(Benzyloxy)-1-(4-methoxybenzyl)-5-oxopyrrolidin-2-yl Ac-
etate (29). To a solution of 28 (3.12 g, 9.59 mmol) in dry CH2Cl2 (41
mL) was added a 1 M solution of LiEt3BH in THF (11.3 mL, 95
mmol) dropwise at −78 °C. After the mixture was stirred for 15 min at
−78 °C, Ac2O (1.26 mL, 13.3 mmol) was added dropwise. Then the
reaction mixture was warmed to ambient temperature and stirred
overnight. The reaction progress was monitored by TLC (2/3 AcOEt/
hexanes). At the end of the reaction activated carbon was added and
the mixture was stirred for 15 min and then filtered through a pad of
Celite. The collected solid was washed with AcOEt (30 mL), and the
solvent was evaporated. The residue was chromatographed on silica gel
(3/7 AcOEt/hexanes) to give 3.224 g of acetate 29 as a colorless oil:
(R)-3-(Benzyloxy)pyrrolidin-2-one (21): prepared following the
procedure for the synthesis of 20: isolated yield 76%; [α]D −125.2
1
(c 0.29, CHCl3); Rf = 0.19 (100% AcOEt); H NMR (600 MHz,
CDCl3) δ 7.41−7.24 (m, 5H), 6.64 (s, 1H), 4.94 (d, J 11.9 Hz, 1H),
4.74 (d, J 11.9 Hz, 1H), 4.10−4.03 (m, 1H), 3.43 (td, J 9.0, 3.8 Hz,
1H), 3.27 (dt, J 9.7, 7.2 Hz, 1H), 2.36 (dtd, J 13.0, 7.6, 3.8 Hz, 1H),
2.11 (ddt, J 13.5, 8.4, 7.0 Hz, 1H); 13C NMR (151 MHz, CDCl3) δ
176.3, 137.8, 128.4, 128.0, 127.8, 74.8, 72.1, 39.0, 28.8; HRMS (ESI-
TOF) m/z calcd for C11H13NO2Na [M + Na+] 214.0844, found
214.0843; IR (film) ν 3244, 2894, 1708, 1454, 1297, 1125, 741, 699
cm−1.
1
isolated yield 91%; Rf = 0.34; [α]D −50.6 (c 0.90, CHCl3); H NMR
(600 MHz, CDCl3) δ 7.34−7.29 (m, 2H), 7.29−7.23 (m, 3H), 7.19−
7.14 (m, 2H), 6.86−6.80 (m, 2H), 6.23 (d, J 5.0 Hz, 1H), 4.67 (d, J
14.6 Hz, 1H), 4.52 (d, J 11.7 Hz, 1H), 4.44 (d, J 11.7 Hz, 1H), 4.13−
4.05 (m, 2H), 3.78 (s, 3H), 2.61 (d, J 8.6 Hz, 2H), 1.97 (s, 3H); 13C
NMR (151 MHz, CDCl3) δ 172.3, 170.7, 159.2, 137.1, 129.8, 128.5,
128.1, 128.0, 127.6, 114.1, 81.5, 72.17, 72.16, 55.3, 44.0, 35.0, 20.8;
HRMS (ESI-TOF) m/z calcd for C21H23NO5Na [M + Na+] 392.1474,
found 392.1472; IR (film) ν 2934, 1742, 1715, 1514, 1248, 1230,
1179, 1029, 966 cm−1.
(4S,5R)-4-Benzyloxy-5-benzyloxymethylpyrrolidin-2-one (17):
prepared according to the literature procedure.39,58
(S)-5-((tert-Butyldiphenylsilyloxy)methyl)pyrrolidin-2-one
(22): prepared according to the literature procedure.59−62
Dicyclopentadienylzirconium Hydrochloride (Schwartz’s
Reagent).63 A solution of Cp2ZrCl2 (10.0 g, 34.2 mmol) in dry
THF (65 mL) was stirred under argon in a Schlenk tube (covered with
aluminum foil) until all solids dissolved. Then a 2 M solution of
LiAlH4 in THF (4.6 mL, 9.23 mmol) was added dropwise. The
mixture was stirred for 90 min at room temperature. The white
precipitate was filtered off under argon and, under argon, washed with
dry THF (4 × 20 mL), dry CH2Cl2 (2 × 20 mL), and dry Et2O (4 ×
20 mL), sequentially. The resulting white solid was dried under
(R)-4-(Benzyloxy)-1-(4-methoxybenzyl)pyrrolidin-2-one (30) and
(R)-3-(Benzyloxy)-1-(4-methoxybenzyl)pyrrolidin-2-one (31). To a
solution of 29 (3.26 g, 8.83 mmol) in dry CH2Cl2 (117 mL) was
added BF3·Et2O (2.0 equiv, 2.2 mL, 17.5 mmol) dropwise at −78 °C.
After the mixture was stirred for 30 min, Et3SiH (5 equiv, 7.0 mL, 31.3
mmol) was added dropwise. After this mixture was stirred for an
additional 30 min, the cooling bath was removed and the reaction
mixture was left overnight at room temperature. The reaction progress
M
dx.doi.org/10.1021/jo502146z | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
vacuum and stored under argon in a flask covered with aluminum foil
at −10 °C.
mg (81%, both isomers) starting from 135 mg (0.25 mmol) of lactam
13; d.r. 90:10 (determined by 1H NMR of crude reaction mixture); Rf
= 0.26 (50% AcOEt in hexanes); column chromatography (50%
One-Pot Lactam Reduction/Mannich/Michael Reaction:
General Procedure. To a solution of Cp2Zr(H)Cl (Schwartz’s
reagent; 1.6 equiv, 206 mg, 0.8 mmol) in THF (5 mL) was added a
solution of the sugar lactam (0.5 mmol) in THF (5 mL). The initially
formed white suspension disappeared during the reaction progress;
formation of a clear solution indicated the end of the reaction (ca. 1.5
h, TLC monitoring). Then the solution was cooled to −25 °C and
Yb(OTf)3 was added (10 mol%, 31 mg, 0.05 mmol). After 10 min neat
diene (2.0 equiv 194 μL, 1.0 mmol) was added dropwise. The mixture
was warmed gradually to room temperature and stirred for 2.5 h (TLC
monitoring). The reaction was quenched with saturated aqueous
NaHCO3 (5 mL) and diluted with Et2O (5 mL). The organic layer
was separated, and the aqueous layer was washed with Et2O (3 × 5
mL). The combined organic layers were dried over anhydrous
Na2SO4, and the solvent was removed. The residue was purified by
chromatography on silica gel to give the corresponding enaminone.
(6R,7R,8R,9S,9aR)-7,8,9-Tris(benzyloxy)-6-(benzyloxymethyl)-
7,8,9,9a-tetrahydro-1H-quinolizin-2(6H)-one (10 and 9a-epi-10):
for yield and de see Table 3; column chromatography (50% AcOEt in
hexanes); major isomer 10 (pure sample obtained by preparative TLC,
Merck preparative TLC plates Si60 F254, 20 × 20 cm, hexanes/AcOEt
2/1); colorless oil; [α]D −49.3 (c 0.3, CH2Cl2); Rf = 0.24 (50% AcOEt
1
AcOEt in hexanes); major isomer 33 H NMR (600 MHz, CDCl3) δ
7.40−7.23 (m, 18H), 7.26−7.21 (m, 2H), 6.89 (d, J 7.8 Hz, 1H, CH
CHCO), 5.02 (d, J 7.7 Hz, 1H, CHCHCO), 4.91 (d, J 10.5 Hz, 1H,
OCHHPh), 4.76 (d, J 12.3 Hz, 1H, OCHHPh), 4.66 (d, J 12.3 Hz, 1H,
OCHHPh), 4.62 (d, J 10.5 Hz, 1H, OCHHPh), 4.60−4.58 (m, 2H,
OCH2Ph), 4.44 (s, 2H, OCH2Ph), 3.97 (t, J 9.3 Hz, 1H, H-9), 3.89 (t,
J 2.8 Hz, 1H, H-7), 3.68 (dt, J 6.2, 5.8, 2.8 Hz, 1H, H-6), 3.63 (dd, J
8.8, 2.7 Hz, 1H, H-8), 3.53−3.46 (m, 2H, CHHOBn, H-9a), 3.38 (dd,
J 9.9, 5.8 Hz, 1H, CHHOBn), 2.82 (dd, J 16.5, 6.2 Hz, 1H, H-1′), 2.62
(dd, J 16.5, 9.9 Hz, 1H, H-1″); 13C NMR (151 MHz, CDCl3) δ 191.2,
155.2, 137.9, 137.8, 137.2, 128.6, 128.5, 128.5, 128.2, 128.1, 128.0,
127.9, 127.87, 127.8, 127.7, 99.3, 79.7, 77.6, 75.8, 73.6, 73.4, 72.4, 72.3,
67.5, 64.1, 56.2, 38.4; minor isomer 9a-epi-33 selected signals 1H
NMR (600 MHz, CDCl3) δ 7.13 (d, J 7.7 Hz, 1H), 5.00 (d, J 7.8 Hz,
1H); HRMS (ESI-TOF) m/z calcd for C38H39NO5Na [M + Na+]
612.2721, found 612.2739; IR (film) ν 3443, 2923, 2867, 1638, 1587,
1453, 1095, 738, 698 cm−1.
(7R,8R,9R,9aR)-7,8,9-Tris(benzyloxy)-7,8,9,9a-tetrahydro-1H-qui-
nolizin-2(6H)-one (34 and 9a-epi-34): mixture of diasteroisomers;
yield 78 mg (67%) starting from 100 mg (0.25 mmol) of lactam 14;
d.r. 88:12; Rf = 0.36 (100% AcOEt); column chromatography (100%
AcOEt); major isomer 34 (pure sample obtained by preparative TLC,
Merck preparative TLC plates Si60 F254, 20 × 20 cm, hexanes/AcOEt
1
in hexanes); H NMR (600 MHz, CDCl3) δ 7.36−7.21 (m, 18H),
7.11−7.05 (m, J 6.6, 2.8 Hz, 2H), 7.01 (d, J 7.7 Hz, 1H, CH
CHCO), 4.98 (d, J 7.7 Hz, 1H, CHCHCO), 4.60 (d, J 12.0 Hz, 1H,
OCHHPh), 4.58−4.51 (m, 2H, OCH2Ph), 4.45 (d, J 12.0 Hz, 1H,
OCHHPh), 4.41−4.38 (m, 2H, OCH2Ph), 4.31 (d, J 12.0 Hz, 1H,
OCHHPh), 4.26 (d, J 12.0 Hz, 1H, OCHHPh), 3.80 (ddd, J 13.4, 6.2,
2.5 Hz, 1H, H-9a), 3.78−3.74 (m, J 8.0, 5.3, 1.6 Hz, 1H, H-6), 3.73−
3.70 (m, J 3.0, 2.8 Hz, 1H, H-8), 3.70−3.67 (dd, J 10.0, 8.0 Hz, 1H,
CHHOBn), 3.65−3.62 (m, J 3.0, 2.1 Hz, 1H, H-7), 3.52 (dd, J 10.0,
5.3 Hz, 1H, CHHOBn), 3.34−3.30 (m, J 2.8, 2.5 Hz, 1H, H-9), 3.02
(dd, J 16.4, 13.5 Hz, 1H, H-1′), 2.19 (dd, J 16.4, 6.2 Hz, 1H, H-1″);
13C NMR (151 MHz, CDCl3) δ 192.6, 155.3, 137.6, 137.5, 137.2,
1
1/9): colorless oil; [α]D −162.7 (c 0.16, CH2Cl2); H NMR (600
MHz, CDCl3) δ 7.36−7.26 (m, 15H), 6.80 (d, J 7.6 Hz, 1H, CH
CHCO), 5.05 (d, J 7.6 Hz, 1H, CHCHCO), 4.96 (d, J 10.5 Hz, 1H,
OCHHPh), 4.77 (d, J 12.4 Hz, 1H OCHHPh), 4.68−4.62 (m, 4H, 2 ×
OCH2Ph), 3.97 (ps t, J 9.9, 9.3 Hz, 1H, H-9), 3.86−3.83 (m, 1H, H-
7), 3.49 (dd, J 9.3, 2.9 Hz, 1H, H-8), 3.40 (dd, J 13.9, 2.8 Hz, 1H, H-
6′), 3.28 (dt, J 9.9, 7.2, 6.8 Hz, 1H, H-9a), 3.03 (d, J 13.9 Hz, 1H, H-
6″), 2.83 (dd, J 16.8, 6.8 Hz, 1H, H-1′), 2.70 (dd, J 16.8, 7.2 Hz, 1H,
H-1″); 13C NMR (151 MHz, CDCl3) δ 155.1, 137.9, 137.8, 137.7,
128.5, 128.4, 128.2, 127.9, 127.8, 127.65, 127.64, 99.1, 83.3, 76.2, 75.9,
72.6, 72.2, 72.1, 60.0, 54.7, 36.8; HRMS (ESI-TOF) m/z calcd for
C30H31NO4Na [M + Na+] 492.2145, found 492.2122; IR (film) ν
2900, 1623, 1574, 1455, 1383, 1200, 1173, 1125, 1105, 739, 718, 697
cm−1; HPLC Chiralpak AD-H, 20% i-PrOH in hexanes, flow 0.5 mL/
min, UV 304 nm, Rt 18.4 min (9a-epi-34 minor isomer), 22.9 min (34
major isomer).
137.1, 128.6, 128.5, 128.4, 128.1, 128.1, 123.0, 127.9, 127.8, 127.7,
98.7, 75.0, 73.3, 72.9, 72.7, 72.2, 72.0, 71.9, 67.5, 63.0, 51.3, 37.4;
HRMS (ESI-TOF) m/z calcd for C38H39NO5Na [M + Na+] 612.2721,
found 612.2700; IR (film) ν 3433, 2923, 2863, 1637, 1586, 1454,
1092, 738, 698 cm−1; HPLC Chiralpak AD-H, 20% i-PrOH in hexanes,
flow 0.5 mL/min, UV 315 nm, Rt 19.8 min (10 major isomer), 24.5
min (9a-epi-10 minor isomer).
(1S,2R,3R,8aR)-1,2-Bis(benzyloxy)-3-(benzyloxymethyl)-2,3,8,8a-
tetrahydroindolizin-7(1H)-one (35): isolated yield 72 mg (62%, both
isomers) starting from 100 mg (0.25 mmol) of lactam 15; d.r. 96:4
(determined by HPLC of crude reaction mixture); column
chromatography (100% AcOEt); pure sample of 35 obtained by
preparative TLC (Merck preparative TLC plates Si60 F254, 20 × 20
cm, hexanes/AcOEt 1/9); colorless oil; [α]D −181.4 (c 1.1, CH2Cl2);
(6R,7R,8R,9R,9aR)-7,8,9-Tris(benzyloxy)-6-(benzyloxymethyl)-
7,8,9,9a-tetrahydro-1H-quinolizin-2(6H)-one (32 and 9a-epi-32):
mixture of diasteroisomers; isolated yield 107 mg (73%, both isomers)
starting from 135 mg (0.25 mmol) of lactam 12; d.r. 94:6 (determined
by HPLC of crude reaction mixture); Rf = 0.34 (3/2 AcOEt/hexanes);
column chromatography (1/1 AcOEt/hexane); major isomer 32 (pure
sample obtained by preparative TLC, Merck preparative TLC plates
Si60 F254, 20 × 20 cm, hexanes/AcOEt 2/1): colorless oil; [α]D
−67.6 (c 1.3, CH2Cl2); 1H NMR (600 MHz, CDCl3) δ 7.36−7.22 (m,
16H), 7.19−7.14 (m, 4H), 6.93 (d, J 7.7 Hz, 1H, CHCHCO), 4.98
(d, J 7.7 Hz, 1H, CHCHCO), 4.57 (d, J 12.0 Hz, 1H, OCHHPh),
4.48−4.37 (m, 6H, 3 × OCH2Ph) 4.35 (d, J 12.2 Hz, 1H, OCHHPh),
3.91−3.87 (m, J 10.2, 8.2, 6.7 Hz, 1H, H-9a), 3.83−3.75 (m, 3H, H-6,
H-8, H-9), 3.66 (d, J 3.7 Hz, 1H, H-7), 3.60−3.55 (m, 2H, CH2OBn),
2.77 (dd, J 16.7, 6.7 Hz, 1H, H-1′), 2.60 (dd, J 16.7, 8.2 Hz, 1H, H-
1″); 13C NMR (151 MHz, CDCl3) δ 155.4, 137.7, 137.5, 137.4, 128.6,
128.5, 128.4, 128.2, 128.0, 128.0, 127.9, 127.9, 127.9, 127.7, 127.5,
98.7, 74.5, 74.3, 73.29, 73.25, 73.1, 72.5, 71.7, 67.9, 64.8, 51.5, 37.2;
minor isomer 9a-epi-32 selected signals 1H NMR (600 MHz, CDCl3)
δ 6.85 (d, J 7.9 Hz, 1H); HRMS (ESI-TOF) m/z calcd for
C38H39NO5Na [M + Na+] 612.2721, found 612.2734; IR (film) ν
2924, 2866, 1640, 1588, 1453, 1100, 737, 698 cm−1; HPLC Chiralpak
AD-H, 20% i-PrOH in hexanes, flow 0.5 mL/min, UV 313 nm, Rt 14.4
min (9a-epi-32 minor isomer), 15.8 min (32 major isomer).
1
Rf = 0.28 (100% AcOEt); H NMR (600 MHz, 5% CDCl3 in PhMe-
d7) δ 7.19−6.95 (m, 15H, 3 × Ph), 6.76 (d, J 7.3 Hz, 1H, CH
CHCO), 4.98 (d, J 7.3 Hz, 1H, CHCHCO), 4.48 (d, J 11.7 Hz, 1H,
OCHHPh), 4.34 (d, J 11.7 Hz, 1H, OCHHPh), 4.30 (d, J 11.9 Hz, 1H,
OCHHPh), 4.10−4.06 (m, 3H, 3× OCHHPh), 3.59−3.55 (m, 2H, H-
2, H-3), 3.40−3.36 (m, 1H, H-1), 3.33 (dt, J 16.4, 3.9 Hz, 1H, H-8a),
3.24 (dd, J 10.5, 1.6 Hz, 1H, CHHOBn), 3.15 (dd, J 10.5, 3.5 Hz, 1H,
CHHOBn), 2.86 (t, J 16.4, 15.7 Hz, 1H, H-8anti), 2.06 (dd, J 15.7, 4.7
Hz, 1H, H-8syn); 13C NMR (151 MHz, toluene-d7) δ 189.8, 146.2,
137.1, 128.6, 128.5, 128.3, 128.2, 127.7, 127.5, 127.4, 124.9, 124.7,
124.6, 97.6, 79.6, 75.2, 67.2, 60.7, 60.0, 36.1, 20.4, 20.3, 20.1, 20.0,
19.9, 19.8, 19.6; HRMS (ESI-TOF) m/z calcd for C30H31NO4Na [M +
Na+] 492.2145, found 492.2126; IR (film) ν 2920, 2864, 1574, 1454,
1260, 1172, 1030, 738, 698, 638 cm−1; HPLC Chiralpak AD-H, 20% i-
PrOH in hexanes, flow 0.5 mL/min, UV 329 nm, Rt 22.3 min (35
major isomer), 28.4 min (8a-epi-35 minor isomer).
(1S,2S,8aS)-1,2-Bis(benzyloxy)-2,3,8,8a-tetrahydroindolizin-
7(1H)-one (37 and 8a-epi-37): inseparable mixture of diaster-
oisomers; colorless oil; yield 48 mg (55%) starting from 75 mg
(0.25 mmol) of lactam 18; d.r. 90:10; Rf = 0.22 (100% AcOEt);
(6R,7S,8R,9S,9aS)-7,8,9-Tris(benzyloxy)-6-(benzyloxymethyl)-
7,8,9,9a-tetrahydro-1H-quinolizin-2(6H)-one (33 and 9a-epi-33):
inseparable mixture of diasteroisomers; colorless oil; isolated yield 120
1
column chromatography (100% AcOEt); major isomer 37 H NMR
N
dx.doi.org/10.1021/jo502146z | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(600 MHz, CDCl3) δ 7.40−7.22 (m, 10H), 7.03 (d, J 7.2 Hz, 1H,
CHCHCO), 4.96 (d, J 7.2 Hz, 1H, CHCHCO), 4.64−4.55 (m,
6H, OCH2Ph), 4.14 (dt, J 5.9, 4.0 Hz, 1H, H-2), 3.95 (dd, J 5.8, 4.1
Hz, 1H, H-1), 3.81−3.75 (m, 1H, H-8a), 3.68 (dd, J 11.3, 6.1 Hz, 1H,
H-3′), 3.45 (dd, J 11.3, 3.9 Hz, 1H, H-3″), 2.53−2.50 (m, 2H, H-8, H-
8″); 13C NMR (151 MHz, CDCl3) δ 191.4, 150.1, 137.3, 137.2,
128.59, 128.57, 128.11, 128.09, 127.74, 127.72, 98.3, 87.0, 82.0, 72.4,
2.42 (dt, J 10.0, 7.6 Hz, 1H, H-3″), 2.07 (ps t, J 16.2, 15.6 Hz, 1H, H-
8″), 1.51−1.48 (m, 1H, H-2′), 1.33−1.27 (m, 1H, H-2″); 13C NMR
(151 MHz, C6D6) δ 189.5, 148.4, 138.1, 128.2, 127.5, 127.3, 98.0, 82.6,
71.2, 62.0, 46.6, 40.5, 30.5; HRMS (ESI-TOF) m/z calcd for
C15H18NO2 [M + H+] 244.1338, found 244.1337; IR (film) ν 3437,
2877, 1633, 1576, 1456, 1361, 1248, 1110, 742, 699 cm−1.
(1R,8aR)-1-(Benzyloxy)-2,3,8,8a-tetrahydroindolizin-7(1H)-one
(8a-epi-40): colorless oil; isolated yield 10 mg (8%) starting from 100
mg (0.52 mmol) of lactam 21; [α]D +276.7 (c 0.5, CHCl3); Rf = 0.38
(100% acetone); column chromatography (35% acetone in hexanes);
1H NMR (600 MHz, C6D6) δ 7.13−7.01 (m, 5H), 6.33 (d, J 7.2 Hz,
1H, CHCHCO), 5.14 (d, J 7.2 Hz, 1H, CHCHCO), 4.05 (d, J
12.1 Hz, 1H, OCHHPh), 3.95 (d, J 12.1 Hz, 1H, OCHHPh), 3.20 (ps
t, J 3.9, 3.7 Hz, 1H, H-1), 3.11 (dt, J 16.0, 4.6, 3.9 Hz, 1H, H-8a), 2.88
(ps t, J 16.0, 15.6 Hz, 1H, H-8′), 2.85−2.80 (m, 1H, H-3′), 2.41 (t, J
9.4 Hz, 1H, H-3″), 2.23 (dd, J 15.6, 4.6 Hz, 1H, H-8″), 1.41 (dd, J
13.5, 7.0 Hz, 1H, H-2′), 1.31−1.25 (m, 1H); 13C NMR (151 MHz,
C6D6) δ 190.5, 147.9, 138.1, 128.2, 127.9−127.4 (Ar), 127.2, 97.4,
78.0, 70.9, 61.2, 46.3, 36.2, 29.4; HRMS (ESI-TOF) m/z calcd for
C15H18NO2 [M + H+] 244.1338, found 244.1339; IR (film) ν 3434,
2921, 1625, 1573, 1455, 1356, 1256, 1172, 1115, 1064, 1030, 742, 699
cm−1.
1
72.1, 61.7, 53.4, 40.0; minor isomer 8a-epi-37 H NMR (600 MHz,
CDCl3, selected signals) δ 4.06 (m, 1H, H-8a), 2.88 (ps t, J 16.7, 16.2,
Hz, H-8anti), 2.22 (dd, J 16.2, 4.8 Hz, 1H, H-8syn); HRMS (ESI-TOF)
m/z calcd for C22H24NO3 [M + H+] 350.1756, found 350.1716; IR
(film) ν 3031, 2923, 2868, 1634, 1580, 1454, 1359, 1353, 1250, 1096,
738, 698 cm−1; HPLC LiChrosphere Si60, 40% i-PrOH in hexanes,
flow 1.0 mL/min, UV 329 nm, Rt 9.8 min (8a-epi-37 minor isomer);
12.1 min (37 major isomer).
(1S,2R,8aS)-1,2-Bis(benzyloxy)-2,3,8,8a-tetrahydroindolizin-
7(1H)-one (38 and 8a-epi-38): inseparable mixture of diaster-
oisomers; colorless oil; isolated yield 55 mg (63%, both isomers)
starting from 75 mg (0.25 mmol) of lactam 19; d.r. 86:14 (determined
by HPLC of crude reaction mixture); Rf = 0.27 (100% AcOEt);
1
column chromatography (100% AcOEt); major isomer 38 H NMR
(600 MHz, C6D6) δ 7.17−7.09 (m, 7H), 7.09−7.03 (m, 3H), 6.19 (d,
J 7.3 Hz, 1H, CHCHCO), 5.08 (d, J 7.3 Hz, 1H, CHCHCO),
4.26−4.23 (m, 2H, OCH2Ph), 4.16 (d, J 12.0 Hz, 1H, OCHHPh),
4.11 (d, J 12.0 Hz, 1H, OCHHPh), 3.62 (dt, J 6.3, 4.5 Hz, 1H, H-2),
3.58 (dd, J 6.4, 4.5 Hz, 1H, H-1), 3.43−3.37 (ps dt, J 16.2, 6.4, 4.8 Hz,
1H, H-8a), 2.78 (dd, J 11.0, 6.3 Hz, 1H, H-3′), 2.70 (dd, J 11.0, 4.4 Hz,
1H, H-3″), 2.50 (dd, J 15.6, 4.8 Hz, 1H, H-8′), 2.28 (ps t, J 16.2, 15.6
Hz, 1H, H-8″); 13C NMR (151 MHz, C6D6) δ 189.4, 148.5, 137.91,
137.90, 128.32, 128.25, 127.7, 127.5, 127.4, 98.7, 87.0, 81.8, 71.8, 71.4,
(2S,3R,8aS)-2-(Benzyloxy)-3-(benzyloxymethyl)-2,3,8,8a-tetrahy-
droindolizin-7(1H)-one (36 and 8a-epi-36): mixture of diaster-
oisomers; isolated yield 70 mg (61%, both isomers) starting from 100
1
(0.32 mmol) of lactam 17; d.r. 87:13 (determined by H NMR of
crude reaction mixture); Rf = 0.26 (100% AcOEt); column
chromatography (100% AcOEt); major isomer 36 (pure sample
obtained by preparative TLC, Merck preparative TLC plates Si60
F254, 20 × 20 cm, hexanes/AcOEt 1/8); yellow oil; [α]D −141.3 (c
0.6, CHCl3); 1H NMR (500 MHz, C6D6) δ 7.15−7.04 (m, 10H), 6.72
(d, J 7.1 Hz, 1H, CHCHCO), 5.18 (d, J 7.0 Hz, 1H, CHCHCO),
4.15 (d, J 12.0 Hz, 1H, OCHHPh), 4.09−4.06 (m, 2H, OCH2Ph),
4.04 (d, J 12.0 Hz, 1H, OCHHPh), 3.58−3.53 (m, 1H, H-2), 3.37−
3.28 (m, 2H, H-3, H-8a), 3.01 (dd, J 10.3, 3.8 Hz, 1H, H-3′), 2.96 (dd,
J 10.3, 5.5 Hz, 1H, H-3″), 2.27 (dd, J 15.6, 4.8 Hz, 1H, H-8′), 2.19 (t, J
15.6 Hz, 1H, H-8″), 1.68 (dt, J 12.3, 6.3 Hz, 1H, H-1′), 1.24−1.15 (m,
1H, H-1″); 13C NMR (126 MHz, C6D6) δ 189.7, 147.1, 138.1, 137.7,
128.3, 128.2, 127.9, 127.7, 127.5, 127.3, 98.4, 78.9, 72.9, 71.1, 69.3,
64.7, 56.5, 42.2, 37.3; minor isomer 8a-epi-36 selected signals 1H
NMR (500 MHz, C6D6) δ 6.61 (d, J 7.4 Hz, 1H, CHCHCO), 5.20
(d, J 7.4 Hz, 1H, CHCHCO); HRMS (ESI-TOF) m/z calcd for
C23H26NO3 [M + H+] 364.1913, found 364.1910; IR (film) ν 3475,
2924, 2862, 1632, 1572, 1455, 1285, 1096, 1031, 740, 699, 638 cm−1.
(3S)-3-((tert-Butyldiphenylsilyloxy)methyl)-2,3,8,8a-tetrahydroin-
dolizin-7(1H)-one (41 and 8a-epi-41): inseparable mixture of
diasteroisomers; colorless oil; isolated yield 57 mg (55%, both
isomers) starting from 90 mg (0.25 mmol) of lactam 22; d.r. 82:18
(determined by HPLC of crude reaction mixture); Rf = 0.44 (100%
AcOEt); column chromatography (100% Et2O then 100% AcOEt);
1
61.2, 52.4, 40.5; minor isomer 8a-epi-38 selected signals H NMR
(600 MHz, C6D6) δ 6.38 (d, J 7.2 Hz, 1H, CHCHCO), 5.12 (d, J
7.2 Hz, 1H, CHCHCO), 3.73 (dt, J 16.9, 4.7, 3.2 Hz, H-8a), 3.46
(d, J 3.2 Hz, H-1), 3.07 (dd, J 11.6, 4.8 Hz, H-3′), 2.87 (ps t, J 16.9,
15.6 Hz, H-8′), 2.23 (dd, J 15.6, 4.7 Hz, H-8″); 13C NMR (151 MHz,
C6D6) δ 190.3, 148.1, 97.7, 80.6, 79.4, 71.9, 70.8, 59.2, 52.7, 35.7;
HRMS (ESI-TOF) m/z calcd for C22H24NO3 [M + H+] 350.1756,
found 350.1750; IR (film) ν 3030, 2868, 1634, 1578, 1455, 1356,
1335, 1250, 1095, 739, 698 cm−1; HPLC Chiralpak AD-H, 40% i-
PrOH in hexanes, flow 1.0 mL/min, UV 340 nm, Rt 10.2 min (8a-epi-
38 minor isomer), 12.8 min (38 major isomer).
(2R,8aR)-2-(Benzyloxy)-2,3,8,8a-tetrahydroindolizin-7(1H)-one
(39 and 8a-epi-39): inseparable mixture of diasteroisomers; colorless
oil; isolated yield 79 mg (63%, both isomers) starting from 100 mg
1
(0.52 mmol) of lactam 20; d.r. 80:20 (determined by H NMR of
crude reaction mixture); Rf = 0.33 (3/2 acetone/hexanes); column
chromatography (100% AcOEt); major isomer 39 1H NMR (600
MHz, C6D6) δ 7.15−7.07 (m, 5H), 6.22 (d, J 7.3 Hz, 1H, CH
CHCO), 5.10 (d, J 7.3 Hz, 1H, CHCHCO), 4.08 (d, J 12.1 Hz, 1H,
OCHHPh), 3.99 (d, J 12.1 Hz, 1H, OCHHPh), 3.40 (dt, J 13.2, 6.6
Hz, 1H, H-2), 3.03 (m, 1H, H-8a), 2.73 (dd, J 10.6, 5.7 Hz, 1H, H-3′),
2.61 (dd, J 10.6, 6.9 Hz, 1H, H-3″), 2.24 (dd, J 15.6, 4.6 Hz, 1H, H-8′),
2.13 (t, J 15.7 Hz, H-8″), 1.62 (dt, J 12.3, 6.3 Hz, 1H, H-1′), 1.20
(ddd, J 12.3, 10.1, 7.6 Hz, 1H, H-1″); 13C NMR (151 MHz, C6D6) δ
190.0, 148.1, 138.1, 128.3−127.3 (Ar), 98.5, 76.3, 71.1, 56.1, 53.7,
1
major isomer 41 H NMR (600 MHz, CDCl3) δ 7.68−7.57 (m, 5H),
7.47−7.36 (m, 5H), 7.34 (d, J 7.2 Hz, 1H, CHCHCO), 4.93 (d, J
7.2 Hz, 1H, CHCHCO), 3.86 (ddd, J 15.6, 10.7, 5.6 Hz, 1H, H-8a),
3.82−3.78 (m, 1H, H-3), 3.69 (dd, J 11.0, 3.5 Hz, 1H, CHHOSi), 3.61
(dd, J 11.0, 5.8 Hz, 1H, CHHOSi), 2.43 (dd, J 15.9, 6.1 Hz, 1H, H-8′),
2.36 (t, J 15.9 Hz, 1H, H-8″), 2.23−2.19 (m, 1H, H-1′), 2.15−2.09 (m,
1H, H-2′), 1.79−1.72 (m, 1H, H-2″), 1.67−1.62 (m, 1H, H-1″), 1.04
(s, 9H, t-Bu); 13C NMR (151 MHz, CDCl3) δ 191.8, 149.5, 135.6,
135.5, 132.7, 132.6, 130.0, 129.89, 127.85, 127.84, 127.81, 96.9, 65.1,
61.5, 58.5, 41.8, 31.7, 27.0, 26.8, 19.1; minor isomer 8a-epi-41 selected
1
41.9, 38.0; minor isomer 8a-epi-39 selected signals H NMR (600
MHz, C6D6) δ 6.31 (d, J 7.3 Hz, 1H, CHCHCO), 5.14 (d, J 7.2 Hz,
1H, CHCHCO), 2.66 (dd, J 11.6, 5.0 Hz, 1H, H-3′), 2.31 (dd, J
15.6, 4.6 Hz, H-8′); 1.98 (ps t, J 16.2, 15.5 Hz, 1H, H-8″); HRMS
(ESI-TOF) m/z calcd for C15H18NO2 [M + H+] 244.1338, found
244.1339; IR (film) ν 3253, 2926, 2870, 1699, 1632, 1577, 1455, 1330,
1251, 1096, 742, 699 cm−1.
(1R,8aS)-1-(Benzyloxy)-2,3,8,8a-tetrahydroindolizin-7(1H)-one
(40): colorless oil; isolated yield 54 mg (43%) starting from 100 mg
(0.52 mmol) of lactam 21; [α]D −241.5 (c 3.3, CHCl3); Rf = 0.43
(100% acetone); column chromatography (35% acetone in hexanes);
1H NMR (600 MHz, C6D6) δ 7.14−7.04 (m, 5H), 6.21 (d, J 7.2 Hz,
1
signals H NMR (600 MHz, CDCl3) δ 4.99 (d, J 7.1 Hz, 1H), 3.48
(dd, J 10.4, 7.4 Hz, 1H), 2.01−1.95 (m, 2H), 1.82 (dd, J 13.1, 7.1 Hz,
1H); HRMS (ESI-TOF) m/z calcd for C25H31NO2NaSi [M + Na+]
428.20347, found 428.2035; IR (film) ν 2958, 2931, 2857, 1635, 1574,
1427, 1252, 1112, 703, 504 cm−1; HPLC Chiralpak AD-H, 20% i-
PrOH in hexanes, flow 1.0 mL/min, UV 327 nm, Rt 8.9 min (minor
isomer 8a-epi-41), 10.4 min (major isomer 41).
1H, CHCHCO), 5.07 (d, J 7.2 Hz, 1H, CHCHCO), 4.08−4.07
(m, 2H, OCH2Ph), 3.38 (dt, J 16.3, 6.3, 4.8 Hz, 1H, H-8a), 3.24 (m,
H-1), 2.64−2.59 (m, 1H, H-3′), 2.54 (dd, J 15.6, 4.8 Hz, 1H, H-8′),
(6R,7R,8R,9S,9aR)-7,8,9-Tris(benzyloxy)-6-(benzyloxymethyl)-
hexahydro-1H-quinolizin-2(6H)-one (11). To a solution of 10 (58
mg, 0.1 mmol) in dry THF (5 mL) was added a 1 M solution of L-
O
dx.doi.org/10.1021/jo502146z | J. Org. Chem. XXXX, XXX, XXX−XXX

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Article
Selectride in THF (1.3 equiv, 0.13 mmol) dropwise at −25 °C. The
mixture was stirred for 25 min at −25 °C. The reaction progress was
monitored by TLC (1/1 AcOEt/hexanes). Then the mixture was
warmed gradually to 0 °C and was quenched with saturated aqueous
NH4Cl (5 mL). The organic layer was separated, and the aqueous
layer was washed with Et2O (3 × 5 mL). The combined organic layers
were dried over anhydrous Na2SO4, and the solvent was removed. The
residue was chromatographed on silica gel (1/4 AcOEt/hexanes) to
give 36 mg of 11 as a white solid: isolated yield 63%; mp 107−108 °C;
[α]D +19.0 (c 1.0, CHCl3); Rf = 0.54 (1/1 AcOEt/hexanes); 1H NMR
(600 MHz, CDCl3) δ 7.35−7.23 (m, 18H), 7.12 (d, J 7.5 Hz, 2H),
4.89 (dd, J 10.7, 3.6 Hz, 2H), 4.77 (d, J 10.8 Hz, 1H), 4.64−4.60 (m,
2H), 4.54−4.44 (m, 3H), 4.40 (d, J 10.8 Hz, 1H), 3.83 (dd, J 9.3, 5.6
Hz, 1H), 3.75−3.67 (m, 2H), 3.64 (d, J 10.1 Hz, 1H), 3.62−3.54 (m,
2H), 3.51 (dd, J 13.5, 7.6 Hz, 1H), 3.02 (d, J 9.1 Hz, 1H), 2.96 (t, J
12.9 Hz, 1H), 2.51 (d, J 8.0 Hz, 2H), 2.14 (d, J 14.6 Hz, 1H); 13C
NMR (151 MHz, CDCl3) δ 208.3, 138.5, 138.1, 137.9, 137.5, 128.5,
128.40, 128.36, 128.2, 128.0, 127.92, 127.85, 127.8, 127.7, 127.6, 82.4,
78.6, 78.4, 75.5, 75.3, 73.6, 72.7, 66.3, 60.1, 56.1, 48.8, 37.5, 37.1;
HRMS (ESI-TOF) m/z calcd for C11H13NO2Na [M + Na+] 214.0844,
found 214.0842; IR (film) ν 3236, 2916, 1693, 1667, 1354, 1095, 728
cm−1. Absolute configuration was confirmed by X-ray analysis.64
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ASSOCIATED CONTENT
■
S
* Supporting Information
Figures, tables, and a CIF file giving 1H and 13C NMR spectra,
stereochemical proofs, HPLC data for selected compounds, and
X-ray crystallographic data for compound 11. This material is
available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
■
Corresponding Authors
*E-mail for S.S.: sebastian.stecko@icho.edu.pl.
*E-mail for B.F.: bartlomiej.furman@icho.edu.pl.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support by the European Union within the European
Regional Development Fund, Project POIG.01.01.02.-14-102/
09, is gratefully acknowledged. The authors are also grateful for
The Regional Council of Mazovia and European Union within
the European Regional Development Fund for a Ph.D. student
scholarship (P.S.).
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