A general strategy for the catalytic, highly enantio- and diastereoselective synthesis of indolizidine-based alkaloids

Article abstract of DOI:10.1002/chem.201304086

Sixteen indolizidine-based alkaloids (IBAs) that were isolated as poison constituents of the skin of frogs were synthesized in a highly flexible and stereoselective manner. As a key step, a three-component, organocatalytic, highly enantio- and diastereose

Full text of DOI:10.1002/chem.201304086

DOI: 10.1002/chem.201304086
Full Paper
&
Natural Products
A General Strategy for the Catalytic, Highly Enantio- and
Diastereoselective Synthesis of Indolizidine-Based Alkaloids
Falko Abels, Chris Lindemann, and Christoph Schneider*[a]
Dedicated to the memory of John W. Daly
Abstract: Sixteen indolizidine-based alkaloids (IBAs) that
were isolated as poison constituents of the skin of frogs
were synthesized in a highly flexible and stereoselective
manner. As a key step, a three-component, organocatalytic,
highly enantio- and diastereoselective vinylogous Mukaiya-
ma–Mannich reaction was employed furnishing optically
highly enriched butyrolactams as central intermediates on
a multigram scale. The attached six-membered ring was con-
structed through cyclization of the pendant enoate moiety
onto the pyrrolidine ring. The absolute configuration of the
bridgehead chiral center and the adjacent 8-position was es-
tablished in the initial vinylogous Mannich reaction, whereas
the 3- and 5-substituents were introduced through organo-
metallic addition at a late stage of the synthesis with full ste-
reochemical control from the substrate. With this strategy,
simple as well as even more complex alkaloids were accessi-
ble in good overall yields as single stereoisomers. These syn-
theses also served to establish the absolute and relative con-
figuration of those IBAs that had never been synthesized
before.
ease, schizophrenia, epilepsy, and Parkinson’s disease.[7] Given
a general synthetic access towards a broad variety of IBAs, ad-
ditional biological testing might uncover further beneficial fea-
tures of this class of natural products.
Introduction
Naturally occurring alkaloids have always attracted the atten-
tion of chemists on the basis of their documented biological
activity and their fascinating chemical structure. It was already
known to Native American huntsmen that certain ingredients
in the skin of peculiar colored frogs from Central and South
American regions (Phyllobates species) can be used as poisons.
During the last five decades, over 80 genera and 11 families of
poison-dart frogs (e.g., Dendrobatidae, Mantelline frogs or Bufo-
nid toads) were systematically investigated[1] and found to ac-
commodate a huge variety of natural products, albeit in only
very little amounts. It is especially due to the enormous efforts
of John W. Daly[2] that we nowadays know about the existence
of no less than 240 indolizidine-based alkaloids (IBAs).[3,4] IBAs
are commonly found in skin glands of poison frogs but empiri-
cal data provided evidence for a dietary source—ants, mites,
and other arthropods.[5] Poison frogs, therefore, must be able
to sequester different IBAs without being intoxicated and use
them on their own to defend themselves against predators.
Some IBAs have been shown to be effective, noncompetitive
blockers for nicotinic receptor channels,[6] which render them
promising candidates against diseases such as Alzheimer’s dis-
IBAs differ in their substituents and their substitution pattern
(Figure 1). In particular, 5-mono (1), as well as 3,5- and 5,8-di-
substituted[8] IBAs (2 and 3) are prominent representatives and
in almost all cases IBAs are substituted with simple alkyl
chains. Additionally, 6,7-dihydro-5,8-disubstituted IBAs, such as
the indolizidine 179 (4) are known and although those natural
products are solely found as trace alkaloids in dendrobatid,
mantellid, and bufonid anurans, they are part of an interesting
class of indolizidines with about 30 members.[3] Even more in-
terestingly, the 5,6,8-trisubstituted indolizidine 195G (5) was
isolated from the mite scheloribates laevigatus and represents
[a] F. Abels, C. Lindemann, Prof. Dr. C. Schneider
Fakultꢀt fꢁr Chemie und Mineralogie, Universitꢀt Leipzig
Institut fꢁr Organische Chemie, Johannisallee 29
04103 Leipzig (Germany)
Fax: (+49)34197-36599
E-mail: schneider@chemie.uni-leipzig.de
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201304086.
Figure 1. Commonly found substitution patterns in IBAs.
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a class of roughly 70 alkaloids found in dendrobatidae.[9] Struc-
ture–activity relationship studies regarding the substitution
pattern and the nature of substituents of the indolizidine core
(e.g., unsaturation in the side chain; length of the side chain)
are ongoing and represent a current research field.[10]
g-lactams as key intermediates.[39] (+)-Coniceine and (+)-indoli-
zidine 167B (1a) as well as (+)-monomorine (2a) and disubsti-
tuted indolizidine (+)-167A (3a) were synthesized from a versa-
tile central building block that was available on a multigram
scale (Figure 2).
Due to their scarcity, most IBAs have solely been character-
ized by means of FTIR- and GCMS-analysis making a stereo-
chemical assignment very difficult. Thus, whereas in some
cases, the relative configuration has been established, the ab-
solute configuration of most IBAs remains unknown to date.
Consequently, efforts directed at the total synthesis of these
natural products not only demonstrates the power and effi-
ciency of new stereoselective synthesis methodology and addi-
tionally provides material for biological testing, but are also im-
portant for their correct stereochemical assignment. It there-
fore comes as no surprise that IBAs have become interesting
and challenging synthetic targets over the last decades and
synthetic endeavors have been reviewed extensively on a regu-
lar basis since 1984.[11]
Figure 2. New strategy to access indolizidine-based alkaloids.
First synthetic approaches toward IBAs date back to the
1970s.[12] With the ongoing discovery of further alkaloids from
anurans, synthetic attempts have become more and more
target-oriented and monomorine (2a), as well as some other
3,5-disubstituted indolizidines, were synthetized in a diastereo-
selective fashion.[13] Subsequently, ex-chiral-pool strategies
were developed to access a select natural product as a single
enantiomer by a specifically tailored total synthesis.[14] Some 5-
mono-[15] and 5,8-disubstituted IBAs[16] were synthesized from
amino acids[17] and their derivatives,[18] as well as from pyroglu-
tamic acid.[19] Alternatively, chiral auxiliary-based strategies
(e.g., with (S)-(ꢀ)- or (R)-(+)-1-amino-2-methoxymethylpyrroli-
dine [SAMP/RAMP]),[20] carbohydrates,[21] amino alcohols,[22] or
N-sulfinylimines)[23] have been developed and used extensively
to furnish optically active IBAs with partially excellent diaste-
reoselectivities. Most recently, highly elegant and creative dia-
stereoselective approaches[24] featuring a hydroamination strat-
egy and a reductive cross-coupling and [3+2] cycloaddition re-
action were reported by Shenvi et al.[25] and the Micalizio
group,[26] respectively. Catalytic, enantioselective approaches
however, to access these important natural products have
been reported much less frequently and are often limited to
a specific substitution pattern within the indolizidine core.[27]
Transition-metal-catalyzed allylic amination,[28] Heck,[29] and di-
hydroxylation[30] reactions have been developed with good
success for this purpose and gave rise to select natural prod-
ucts.[31] Recently, a novel approach that employs the partial hy-
drogenation of a substituted indolizine core with a N-heterocy-
clic carbene (NHC)-based catalyst was published by the Glorius
group.[32] In addition, a few organocatalytic enantioselective
approaches,[33] such as the proline-catalyzed asymmetric a-ami-
nation/Horner–Wadsworth–Emmons olefination sequence[34] or
an a-aminoxylation of aldehydes were developed.[35]
Herein, we wish to report a full account of our work that fur-
ther details our studies and significantly extends beyond our
previous results. We have now developed a general and flexi-
ble strategy for the catalytic, enantioselective synthesis of
highly substituted indolizidines that we have applied towards
the synthesis of more than a dozen diversely substituted natu-
ral products. We are now in a position to address five stereo-
genic centers within the indolizidine core individually and have
completed the synthesis of 5-mono (1a–c), 3,5-disubstituted
(2a,b) as well as many 5,8-disubstituted indolizidines (3a–h),
6,7-dihydro indolizidine 179 (4) as well as the 5,6,8-trisubstitut-
ed indolizidine 195G (5). The flexibility of our strategy allows
us to vary the 3-, 5-, 6-, and 8-substituents in a broad range
rendering our approach a very general one. Our retrosynthetic
approach (Figure 3) called for the late-stage introduction of
the 5- and 6-substituents into the indolizidinone core that
itself was derived from the Boc-protected pyrrolidine. That in
turn was derived from a substrate-controlled, diastereo- and
chemoselective alkylation of the pyrrolidinone. This key inter-
mediate should eventually be accessible following our protocol
for the Brønsted acid catalyzed highly enantioselective VMMR
with the ester-functionalized aldehyde. As chiral Brønsted acid
catalyst 1,1’-bis-2-naphthol (BINOL)-based phosphoric acids (7)
were to be employed to provide the asymmetric induction.[40]
Whereas the three substituents R2–R4 would accordingly be
incorporated at a late stage of the synthesis with a beneficial
effect on the flexibility, both the bridgehead chiral carbon
center and the adjacent C8-center were to be established in
the central VMMR.
Results and Discussion
In 2012 we established a new strategy towards the total syn-
thesis of variously substituted IBAs.[36] As a central key step we
employed a Brønsted acid catalyzed, highly enantioselective vi-
nylogous Mukaiyama–Mannich reaction (VMMR)[37,38] of an acy-
clic silyl dienolate, a g-oxo ester and para-anisidine to furnish
Optimization of the VMMR
In our initial studies we had found an optimal protocol for the
execution of the VMMR that was based on the in situ forma-
tion of the imine at low temperature and subsequent addition
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within the indolizidine core. When the g-methyl-substituted di-
enolate 9b (R1 =CH3) was submitted to the reaction with
imine 8 under the optimized conditions a mixture of re-
gioisomers 10b and 11 b was obtained in a combined yield of
only 34% after 54 h (entry 3). The diastereoselectivity and
enantioselectivity, however, were encouraging with 25:1 (anti/
syn) for the g-product and 95% ee for the major diastereomer,
respectively. We reasoned that the transition state might be
sterically overloaded due to the additional substituent within
the dienolate. Hence, we screened further BINOL-based phos-
phoric acids with smaller substituents in the 3,3’-position. With
the 3,3’-unsubstituted phosphoric acid 7a, the VMMR was al-
ready completed after 30 h and the yield was increased to
65%. However, the regio- and diastereoselectivity was very low
and the products were obtained as racemic mixtures (entry 4).
Compared to the TRIP-catalyst (7b), phosphoric acid 7c with
an increased steric demand in the para-position of the aryl
substituent and a decreased steric demand in both ortho-posi-
tions, gave superior results. The product was obtained with an
excellent enantioselectivity of 97% and a diastereoselectivity
of 39:1. Merely the reaction time and the yield needed to be
further optimized (entry 5). As slim substituents on the aryl
substituents seemed to have a beneficial effect, we tested the
3,3’-mesityl-substituted phosphoric acid 7d. The enantioselec-
tivity was still excellent and a complete g-selectivity was ob-
served. The reaction was also comparably fast and afforded
the anti-product 11 b in 74% yield with a very good diastereo-
selectivity of 22:1 after 30 h. By further slightly increasing the
steric bulk of the aryl substituent, the best result was eventual-
ly obtained with the 2,4,6-triethylphenyl-substituted phospho-
Figure 3. Retrosynthetic approach.
of the catalyst and freshly distilled nucleophile. Thus, the aldi-
mine 8 was formed at ꢀ508C within typically 30 min from the
corresponding aldehyde and para-anisidine (HPLC-control).
Subsequently, 3,3’-triisopropylphenyl-substituted BINOL-based
phosphoric acid, the TRIP-phosphoric acid[41] (7b, 10 mol%)
and vinylketene silyl acetal 9a (R1 =H) were added one after
another and the open-chain vinylogous Mannich product 11 a
was obtained in 70% yield with 99% ee within 15 min on a lab-
oratory scale (0.1 mmol) (Table 1, entry 1). No regioisomeric a-
product (10a) was formed under these conditions. A previous
catalyst screening had revealed that the TRIP catalyst (7b) was
the chiral Brønsted acid of
choice for this particular trans-
formation, both in terms of yield
and enantioselectivity.[39] Inter-
Table 1. Optimization of the VMMR.
estingly, we observed that upon
prolonged reaction times, the
open-chain product slowly cy-
clized to furnish lactam 12a that
could be easily purified by chro-
matography.
We
eventually
found that this cyclization was
accelerated when the crude mix-
ture—after completion of the
carbon–carbon
bond-forming
event—was treated directly
with acetic acid for one hour
Entry
9 (R1)
Cat.
t [h]
Yield [%]
g/a[a]
d.r.[b]
ee[b] [%]
at reflux.
A simple filtration
through a silica gel pad deliv-
ered the desired lactam 12a in
an enhanced yield of 80% over
the two steps and with identical
ee (entry 2).
1
2
3
4
5
6
7
8
9
9a (H)
9a (H)
7b
7b
7b
7a
7c
7d
7e
7b
7d
7e
0.25
0.25
54
30
72
30
120
18
72
18
70 (11 a)
80 (12a)
34 (11 b)
65 (11 b)
47 (11 b)
74 (12b)
63 (11 b)
59 (12c)
80 (12c)
84 (12c)
1:0
1:0
3.9:1
1:1.7
n.d.
1:0
1:0
1:0
1:0
1:0
–
–
25:1
1:1.6
39:1
22:1
>99:1
18:1
20:1
99
99
95
rac
97
93
98
99
97
>99
9b (Me)
9b (Me)
9b (Me)
9b (Me)
9b (Me)
9c (nBu)
9c (nBu)
9c (nBu)
We then focused our attention
on g-alkyl substituted vinylke-
tene silyl acetals as nucleophiles
in the light of the role of this
substituent for the 8-position
10
22:1
1
[a] Determined from crude H NMR spectroscopy. [b] Determined by chiral HPLC analysis.
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ric acid 7e. Thus, the product was obtained as one single
regio- and diastereomer with an excellent enantioselectivity of
98% in 63% yield.
with very good diastereoselectivity. However, we were pleased
to find that both 12a and 12b solidified upon standing at
room temperature and could be recrystallized from methyl-
tert-butyl ether, which gave us the lactams in multigram
amounts as single diastereomers and enantiomers, respectively
(Figure 4). The relative and absolute configuration was unam-
biguously assigned based on X-ray-crystallography of single
crystals of 12a and 12b, respectively (for further information,
please see the Supporting Information).
The reaction optimization and catalyst screening with the di-
enolate 9c (R1 =C4H9) went comparably well. A first reaction
with the catalyst 7b gave the g-lactam 12c as a single regio-
isomer in excellent enantioselectivity (99%) and high diaste-
reoselectivity (18:1) after 18 h. However, the yield was only
moderate at 59% (Table 11, entry 8). With catalyst 7d the yield
improved to 80% while maintaining excellent levels of regio-,
diastereo-, and enantioselectivity (entry 9). The best result was
eventually obtained with catalyst 7e that gave rise to VMMR-
product 12c with a very good yield over two steps and out-
standing levels of regio-, diastereo-, and enantioselectivity
(entry 10).
Scaling up
After we had carefully investigated optimal conditions, we en-
visaged a scaling-up of this key transformation (Table 2). In
some cases merely a prolongation of the reaction time was
necessary. More importantly, it became apparent that isolation
of the respective lactam 12 instead of the open-chain VMMR-
Figure 4. X-ray-crystal structure of 12b.[52]
Table 2. Large-scale experiments.
Fortunately, in the case of the dienolate 9c the enantioselec-
tivity of the reaction was not affected by the scaling-up pro-
cess and 11.0 g of lactam 12c were obtained over two steps
(93% yield) in a single run as a homogenous regioisomer and
enantiomer with excellent diastereoselectivity (entry 4).
5-Monosubstituted IBAs
With enantiomerically and diastereomerically pure 12a–c in
hand we first attempted the synthesis of 5-monosubstituted
IBAs. For this purpose it was necessary that lactam 12a was
first hydrogenated, subsequently PMP-deprotected, and finally
Boc-protected to furnish the corresponding imide 13a in ex-
cellent overall yield (Scheme 1).
Entry Product (R1) Cat. Scale
[mmol]
t [h] Yield [%] d.r.[a] ee[a] [%]
1
2
3
4
12a (H)
12a (H)
12b (Me)
12c (nBu)
7b
7b
7d
7e
0.1
0.25 80
–
–
99
32
35
33
16
28
41
86 (67)[b]
96 (>99)[b]
96 (>99)[b]
77 (61)[b] 28:1
93
22:1 >99
Unfortunately, this deprotecting/reprotecting sequence was
inevitable since all attempts to employ a Boc-protected imine
in the key step failed. Fortunately and in contrast to the poly-
methylpentene (PMP)-protected tertiary lactam, the imide 13a
now offered the possibility to undergo chemoselective trans-
formations at the imide carbonyl group, such as reduction
[a] Determined by chiral HPLC analysis. [b] After recrystallization.
product 11 was advantageous (vide supra). Therefore, the
open-chain products 11 a–c were directly transformed into the
corresponding lactams 12a–c through addition of acetic acid
and the heating of this mixture for 1 h at reflux.
In the case of unsubstituted dienolate 9a, the yield was in-
creased but the enantioselectivity slightly eroded. Noteworthy,
is that the concentration of the reaction mixture had to be
maintained at 0.1m to avoid further loss in selectivity. In the
case of dienolate 9b the enantioselectivity and yield increased
slightly relative to the reaction on a laboratory scale (compare
Table 1, entry 6 and Table 2, entry 3). A prolongation of the re-
action time was not necessary and the product was obtained
Scheme 1. Formation of imides 13a–c. Boc=tert-butoxycarbonyl; DMAP=4-
dimethylaminopyridine.
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and/or alkylation reactions in the presence of the ester moiety.
Thus, 13a was converted into the pyrrolidine by sequential re-
duction with superhydride and a combination of triethyl silane
and boron trifluoride etherate (Scheme 2).[42] Subsequent Boc-
and 8a-CH cannot be measured in a reliable and reproducible
manner. However, in the case of the 1c, all crucial proton sig-
nals were separated and a strong NOE was observed between
the 5-CH- and the 8a-CH-proton.
It is important to note that all IBAs were isolated as TFA-salts
because the free indolizidines were very volatile, extremely
prone to oxidation and thus difficult to analyze. In combina-
tion with their high lipophilicity (and ability to penetrate the
skin) and potential biological activities, a non-volatile, air-
stable, less lipophilic form was more convenient to handle. Fur-
thermore, opposed to the commonly used routine found in
the literature (i.e., proton NMR spectroscopic studies of the
free amine in for example, deuterated chloroform), all TFA salts
were measured in deuterated methanol or dimethyl sulfoxide
and sharp spectra were obtained that clearly showed the ab-
sence of further diastereomeric signals or byproducts. 19F-spec-
tra supplemented our findings. As a beneficial side effect, this
way, for example, the TFA salt 2a could be stored at room
temperature for over one year without any signs of decompo-
sition and the yields exceeded those reported in the literature
quite significantly in all cases. Conclusively, through the above
mentioned route, indolizidine 167B (1a), indolizidine 139 (1b),
and the phenyl-substituted indolizidine 201 (1c) were obtained
in excellent overall yields of 56, 54, and 42% over ten steps, re-
spectively, by a unified, catalytic strategy and as single diaste-
reomers and enantiomers.
Scheme 2. Conversion into the indolizidinone core. TFA=trifluoroacetic acid.
deprotection and cyclization gave rise to indolizidinone 14a in
almost quantitative yield over four steps.[43]
With 14a in hand, its conversion into the indolizidines
1a–c was undertaken (Scheme 3).[44] A sequence comprising
Grignard addition, acid-catalyzed dehydration and subsequent
reduction of the formed iminium ion under substrate-control
furnished 1a–c after trifluoroacetic acid (TFA) treatment as TFA
3,5-Disubstituted IBAs
Scheme 3. Synthesis of 5-monoubsituted IBAs.
To access IBAs, such as monomorine (2a) or other 3,5-disubsti-
tuted IBAs, we anticipated that our central building block,
imide 13a, could be ring-opened by addition of a Grignard re-
agent and again ring-closed reductively in a highly diastereose-
lective manner by using substrate control.[46] Indeed, various
Grignard reagents were chemoselectively added to imide 13a
and furnished amino ketones 15a and 15b in good yields. Un-
fortunately, initial attempts to use boron trifluoride etherate as
Lewis acids and sodium borohydride as the reducing agent
failed (Table 3). On the one hand, when kept at low tempera-
tures (ꢀ788C) (Table 3, entry 1), the conversion did not exceed
50% and the product was isolated in 40% yield albeit with ex-
cellent diastereoselectivity (>25:1). On the other hand, when
allowed to warm to room temperature (entry 2), side reactions
occurred and a complex and inseparable mixture of products
was obtained.
salts in typically excellent yields and as single enantio- and dia-
stereomers. To avoid dimerization processes triggered by the
equilibrium of the formed iminium ion with its enamine it was
important to add the reducing agent at low temperatures
prior to the treatment with acetic acid.
For stereoelectronic reasons,[45] the hydride preferentially at-
tacks the iminium ion in such a way (Scheme 4, solid arrow),
that the reaction proceeds through the energetically favored
chair-like transition state to furnish preferentially the kinetic
5,8a-cis products. The rather unfavored pathway would lead
through a twist-boat transition state (Scheme 4, dotted arrow).
To support this stereochemical assignment, we synthesized
the non-naturally occurring 5-phenyl-substituted indolizidine
1c. Usually—as in the case of 5-alkyl-subsituted IBAs—the
signal for the 5-CH-proton is not isolated in the proton NMR
and hence a nuclear Overhauser effect (NOE) between 5-CH
Most likely, at elevated temperatures, partial Boc-deprotec-
tion was an issue that presumably led to several side reactions,
for example, intermolecular attack of the amine onto the ester
and/or ketone carbonyl center. However, Lewis acid supported
cyclization and reduction with a combination of triphenyl
silane and tris-pentafluorophenyl borane[47] proved extremely
successful and gave rise exclusively to the corresponding 2,5-
disubstituted pyrrolidines 16a and 16b that were obtained in
very good to excellent yields as single diastereomers on a mul-
tigram scale (Table 3, entry 6).
The outcome of this substrate-controlled, highly diastereose-
lective transformation is easily explained by the steric influence
Scheme 4. Substrate-controlled reduction of the bicyclic iminium ion and
NOE studies.
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5,8-Disubstituted IBAs
Table 3. Substrate-controlled reductive cyclization.
To access IBAs with a 5,8-substi-
tution pattern, such as (+)-indo-
lizidine 167A (3a), we started
from vinylogous Mannich prod-
ucts 12b and 12c carrying two
stereogenic centers and convert-
ed them into the enantiomeri-
cally and diastereomerically pure
saturated imides 13b and 13c
as described above (Scheme 1).
Applying the same sequence of
events described for the synthe-
sis of 5-mono-substituted IBAs,
the conversion into the 8-substi-
tuted indolizidinones proceeded
without problems and furnished
14d and 14e in excellent overall
Entry R2
Conditions
Reagents
Conversion [%][c] Yield [%] d.r.[b]
1
2
3
4
5
6
C2H5 THF ꢀ788C
BF3·OEt2 (1.1 equiv)/Et3SiH (1.1 equiv)
50
40[a]
n.d.[d]
n.d.
62
>25:1
n.d.
C2H5 THF ꢀ788C!ꢀr.t. BF3·OEt2 (1.1 equiv)/Et3SiH (1.1 equiv) >60
C2H5 THF 3 h, ꢀ788C
BF3·OEt2 (5.0 equiv)/Et3SiH (1.1 equiv) >99
1:1
C2H5 CH2Cl2 ꢀ788C!r.t. B(ArF5)3 (0.2 equiv)/Ph3SiH (3.0 equiv) >99
C2H5 CH2Cl2 ꢀ788C!r.t. B(ArF5)3 (0.3 equiv)/Ph3SiH (0.3 equiv) >99
C4H9 CH2Cl2 ꢀ788C!r.t. B(ArF5)3 (0.3 equiv)/Ph3SiH (0.3 equiv) >99
>25:1
>25:1
>25:1
79
96[a]
1
[a] Based on recovered starting material. [b] Determined from crude H NMR spectroscopy. [c] Determined from
TLC analysis. [d] n.d.=not determined.
yields on
a multigram scale
(Scheme 7).
As anticipated, Grignard addition onto the lactam carbonyl
moiety went smoothly and subsequent reduction of the bicy-
clic iminium ion gave exclusively the 5,8-trans and 5,8a-cis-con-
figured IBAs 3a–h as TFA salts in excellent overall yields
(Scheme 8).[49] According to the Schlenk equilibrium, it was of
crucial importance for the success of this transformation to
employ the more reactive Grignard reagent in diethyl ether
rather than in tetrahydrofuran.
Scheme 5. Reduction of the cyclic iminium ion.
of the 2-substituent (Scheme 5). In the likely transition-state
17a the upper side of the cyclic iminium ion is effectively
shielded by the axially oriented alkyl substituent leading the
hydride attack to the opposite side. After the attack from the
bottom side, 2,5-cis-configured pyrrolidines 16a and 16b were
obtained. Following our previously established protocol, lac-
tams 14b and 14c were obtained through deprotection and
cyclization and further converted into indolizidines 2a and 2b
through Grignard addition with the requisite organometallic
reagent, dehydration, and iminium ion reduction, all of which
proceeded in excellent yields (Scheme 6).
Scheme 6. Formation of 3,5-disubstituted IBAs and NOE studies.
At the stage of the final monomorine TFA salt, NOE experi-
ments provided evidence for the relative configuration. A
strong NOE between all three cis-configured protons
(Scheme 6) was measured in both directions, respectively,
proving the highly cis-stereoselective formation of the pyrroli-
dines 16a and 16b. Whereas monomorine (2a) has been syn-
thesized before,[48] this study represents the first total synthesis
of indolizidine 181A (2b).
Scheme 7. Formation of 8-substituted indolizidinones 14d and 14e. DIBAL-
H=diisobutylaluminum hydride.
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Scheme 10. Conversion into indolizidine 179 and NOE experiments.
Scheme 8. Formation of 5,8-disubstituted IBAs.
indolizidinone can also be used as a latent nucleophile and
alkyl substituents can be introduced to the 6-position by eno-
late alkylation. The stereogenic centers at C8 and the bridge-
head carbon center were expected to have an impact on the
diastereoselectivity of this transformation. To test this hypothe-
sis and establish conditions for the alkylation, 1,5-dimethylpi-
peridinone 19 was employed as model compound and treated
with methylating agents under various conditions (Table 4).
It turned out that more than stoichiometric amounts of base
and methylating agent were essential to convert all starting
materials into product and 1.5 equivalents of both LDA and
methyl iodide were optimal to produce the desired lactam
20a in quantitative yield (Table 4, entry 3). With only stoichio-
metric amounts, roughly 50% of the starting material was re-
covered, whereas with 3 equivalents of both LDA and methyl
iodide, 53% of the dialkylated product 20b was obtained
along with only 34% of the desired monoalkylated lactam 20a
(compare entries 1 and 3). Reactions with alkali-metal hexame-
thyldisilazides (LiHMDS, NaHMDS, and KHMDS) when em-
ployed as bases failed to furnish any product. The presence of
DMPU had no effect on either the yield or selectivity. The dia-
stereoselectivity of the reaction, however, was only very mod-
erate in all cases studied.
Conclusively, eight 5,8-disubstituted IBAs were obtained
from indolizidinone 14d and 14e, respectively, some of which
were synthesized for the first time (indolizidine 167A (3a),
181B (3b), 195I (3c), and 265P (3g)).
6,7-Dihydro IBA
Indolizidine 179 (4), a trace alkaloid isolated from anurans,
contains an unsaturation in the six-membered ring that we ex-
pected to be synthetically accessible from lactam 14d. In the
event, the enolate was formed with LDA and trapped with
phenyl selenic bromide, which furnished the corresponding a-
seleno lactam. Upon oxidation with hydrogen peroxide an
elimination process was triggered and gave rise to a,b-unsatu-
rated lactam 18 in 64% overall yield (Scheme 9).[50]
When the above-established conditions were applied to in-
dolizidinone 14d as the substrate, the a-methylated lactam 21
was obtained in almost quantitative yield as a 2:1-mixture of
diastereomers that were separable by column chromatography
(Scheme 11). Finally, individual C5-alkylation of 21a and 21b
with propylmagnesium chloride followed by acid-catalyzed
dehydration and iminium-ion reduction with sodium borohy-
dride delivered indolizidine 195G (5) and epi-195G (epi-5) in
quantitative yield and as single diastereomers, respectively
Scheme 9. Formation of the a,b-unsaturated bicyclic lactam. LDA=lithium
diisopropylamide.
Addition of a propyl cerium chloride reagent[51] in THF at
ꢀ788C gave rise to the hemiaminal that under acidic condi-
tions led to the bicyclic iminium ion. Reduction of the latter
with sodium borohydride proceeded again with complete dia-
stereoselectivity and indolizidine 179 (4) was obtained as the
TFA salt in moderate yield. A
strong NOE between 5-CH and
8a-CH was observed in both di-
Table 4. Model studies for amide enolate alkylation.
rections that confirmed the 5,8a-
cis-relationship (Scheme 10).
The comparably low yield of
this last transformation was
most likely due to the formation
of the dialkylated indolizidine
that we could isolate in 10%
yield additionally.
Entry
Base
Methylating reagent
t [h]
Yield [%][a]
d.r.[b]
1
2
3
4
5
LDA (1.1 equiv)
LDA (3.0 equiv)
LDA (1.5 equiv)
LHMDS[c] (1.2 equiv)
LDA (1.5 equiv)
CH3I (1.5 equiv)
CH3I (3.0 equiv)
CH3I (1.5 equiv)
CH3I (2.0 equiv)
CH3I (1.5 equiv)/DMPU[c] (1.5 equiv)
3
2
2
4
2
42
2:1
1:1
2:1
n.d.
2:1
34 (20a)/53 (20b)
>99
n.c.[c]
>99
5,6,8-Trisubstituted IBAs
[a] Isolated yield. [b] Determined from crude 1H NMR spectroscopy. [c] DMPU = 1,3-Dimethyltetrahydropyrimi-
din-2(1H)-one; LHMDS=lithium hexamethyl disilazide; n.c. =no conversion.
Based on our retrosynthetic ap-
proach, we envisaged that the
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has been found optimal in terms of yield, analysis, and long-
term storage of these highly valuable alkaloids and is therefore
strongly recommended for future endeavors. Finally, we expect
this strategy to be applicable towards the synthesis of even
more complex indolizidines.
Scheme 11. Methylation of indolizidinone 14d.
Experimental Section
General
All reactions were performed in flame-dried glassware under an at-
mosphere of dry nitrogen or argon. Tetrahydrofuran and diethyl-
ether were dried over Na and benzophenone, CH2Cl2 was dried
over CaH. Abs. ethanol (<99.8%) was purchased from VWR and
used directly. All reactions were monitored by TLC analysis on pre-
coated silica gel SIL G/UV254 plates (Machery, Nagel) or HPLC anal-
ysis. Flash column chromatography was performed by using Merck
1
silica gel 60 230–400 mesh. H and 13C NMR spectra were recorded
by using VARIAN Gemini 300 (300 MHz) spectrometer or a Bruker
Avance DRX 400 (400 MHz) spectrometer at 258C if not stated oth-
erwise. IR spectra were obtained by using a FTIR spectrometer
(Genesis ATI, Mattson/Unicam). Melting points are uncorrected. Op-
tical rotations were measured by using a Polarotronic polarometer
(Schmidt & Haensch). HPLC analyses were performed by using
a JASCO MD-2010 plus instrument with a chiral stationary phase
column (Chiralcel ODH, purchased from Daicel). Mass spectra were
measured at 70 eV (EI) by using a Finnigan MAT 95A spectrometer.
HRMS (ESI/Na+) were measured by using a Bruker Daltonics APEX
II. GCMS measurements were performed on an AGILENT 5975B
VL.MSD (mass) combined with an AGILENT 6890N (GC) equipped
with an injector (7683B) and autosampler (7683) from AGILENT.
Samples were run starting with an initial temperature of 100
(DB100S) or 508C (DB50S) (initial time 1.0 min). Temperature was
raised by 508Cminꢀ1 up to a final temperature of 3008C. Analytic
data is presented as follows: retention time (m/z values with de-
scending order in rel. intensity). Compound 9a, 9b, and 9c,[38]
B(ArF5)3,[47] and catalysts (7a–e)[38] were synthesized by following
literature procedures or along the lines.
Scheme 12. Synthesis of indolizidine 195G and epi-195G.
(Scheme 12). Comparison of the chemical shifts for the methyl
group at C6 in 5 and epi-5, respectively provided evidence for
the relative configuration as depicted (g-effect). Most notably,
the diastereoselectivity of the iminium-ion reduction was
solely governed by the configuration of the bridgehead chiral
center and was not affected by the additional chiral center at
C6 at all.
Accordingly, this general strategy is applicable to 6-alkylated
indolizidines as well although the modest selectivity of the
enolate alkylation appears as a current limitation.
Conclusions
In conclusion, we have established a general, catalytic, and
highly stereoselective synthetic access toward a broad range
of diversely substituted indolizidine-based alkaloids. 5-Mono-
substituted, 3,5- and 5,8-disubsituted, 5,6,8-trisubstituted indo-
lizidines, and one 6,7-dihydroindolizidine were easily accessible
by a unified synthetic strategy. As a key step, we employed the
Brønsted acid catalyzed vinylogous Mukaiyama–Mannich reac-
tion that we had developed earlier in our laboratories and
which was easily run on a multigram scale and set the first
two stereogenic enters with typically excellent stereocontrol.
The remaining chiral centers and substituents were incorporat-
ed at a late stage of the synthesis under substrate control ren-
dering our approach highly flexible and general. Overall, we
have disclosed the total synthesis of three 5-monosubstituted
IBAs (indolizidine 139, 167B, and 209), two 3,5-disubstituted
IBAs (monomorine and indolizidine 181A), and eight 5,8-disub-
situted IBAs (indolizidine 167A, 181B, 195I, 207A, 221K, 223V,
251N, and 265P) some of which were synthesized for the first
time. Furthermore, even more complex IBAs, such as the 5,6,8-
trisubsituted indolizidine 195G (5) and its epimer or the 6,7-di-
hydro indolizidine 179 were accessible with slight adjustments
according to our protocol. The isolation of IBAs as TFA salts
General X-ray crystallography
The data were collected on a Gemini diffractometer (Agilent Tech-
nologies) by using CuKa radiation (l=1.5418 ꢁ), w-scan rotation.
Data reduction was performed with the CrysAlisPro (CrysAlisPro:
Data collection and data reduction software package, Agilent Tech-
nologies) including the program SCALE3 ABSPACK (SCALE3 AB-
SPACK: empirical absorption correction by using spherical harmon-
ics) for empirical absorption correction. The structures were solved
by direct methods with SIR2004. The refinement of all non-hydro-
gen atoms was performed anisotropically, the hydrogen atoms iso-
tropically with SHELXL-97. The structure figure was generated with
ORTEP.
General methods
Compound 12a: 4-Methoxyaniline (3.97 g, 32.3 mmol, 1.05 equiv)
was dissolved in THF (300 mL) in a 500 mL round-bottomed flask
to give a pale yellow solution and cooled to ꢀ558C. After 30 min,
ethyl-4-oxobutanoate (4.00 g, 30.7 mmol, 1.00 equiv) was added by
a syringe and the corresponding solution was allowed to stir for
a
further 30 min. Then TRIP-catalyst (7b) (1.74 g, 2.31 mmol,
7.5 mol%) was added and the resulting suspension was stirred for
30 min until a pale reddish solution was formed. Subsequently ice-
Chem. Eur. J. 2014, 20, 1964 – 1979
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cold 9a (21 g, 92 mmol, 3.0 equiv) was added slowly over a period
of 20 min. The reaction mixture was allowed to stir over night and
was subsequently concentrated to give a dark-yellow/brown oil.
The crude product was further dissolved in glacial acetic acid
(80 mL), heated to reflux conditions, and stirred for 1 h. The result-
ing dark-red solution was concentrated, and the crude product fur-
ther subjected to a silica gel column and eluted with methyl tert-
butyl ether (MTBE) to give a pale-grey solid: 8.1 g (87%, 96% ee).
The solid was then either recrystallized from MTBE or from layering
a toluene solution with hexane to give colorless needles: 6.24 g
(67%, >99% ee). Rf =0.2 (MTBE); m.p.=72–738C; [a]2D4 = +76.2 (>
oxobutanoate (4.28 g, 32.9 mmol, 1.00 equiv) was added by a sy-
ringe and the corresponding solution was allowed to stir for a fur-
ther 15 min. Then, 7e (2.20 g, 3.29 mmol, 10 mol%) was added
and the resulting suspension was stirred for 15 min until a pale-
reddish solution was formed. Subsequently ice-cold 9c (18.7 g,
65.8 mmol, 2.00 equiv) was added slowly over a period of 10 min.
The reaction mixture was allowed to stir for 41 h and subsequently
allowed to warm to room temperature. Glacial acetic acid (40 mL)
was added to the crude product and the mixture was heated to
reflux conditions and stirred for 4 h. The resulting dark-red solution
was concentrated and the crude product further subjected to
a silica gel column and eluted with MTBE!EtOAc to give a yellow
oil: 11.0 g (93%, d.r.=22:1, >99% ee). Rf =0.34 (MTBE); [a]2D2 = +
1.4 (d.r.=22:1, >99% ee, c=1.02 in CHCl3); 1H NMR (300 MHz,
CDCl3): d=7.21 (d, J=9.0 Hz, 2H), 6.92 (d, J=9.0 Hz, 2H), 6.72 (dd,
J=16.0, 9.0 Hz, 1H), 5.79 (d, J=16.0 Hz, 1H), 4.28–4.20 (m, 1H),
4.18 (q, J=7.0 Hz, 2H), 3.81 (s, 3H), 2.67–2.47 (m, 2H), 2.47–2.36
(m, 1H), 2.28–2.13 (m, 1H), 2.04–1.88 (m, 1H), 1.48–1.35 (m, 1H),
1.29 (t, J=7.0, 3H), 1.31–1.23 (m, 1H), 1.21–1.07 (m, 3H), 0.91 (m,
1H), 0.80 ppm (t, J=7.0 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): d=
174.7, 166.1, 157.9, 148.1, 130.0, 126.3, 123.5, 114.5, 63.25, 60.48,
55.47, 44.43, 31.15, 29.47, 26.14, 22.56, 19.75, 14.26, 13.91 pm; IR
(film): n˜ =2956, 2932, 2871, 2859, 2838, 1716, 1697, 1652, 1610,
1513, 1465, 1443, 1425, 1398, 1368, 1293, 1250, 1179, 1138, 1121,
1105, 1036, 984, 913, 832, 731 ppm; HRMS (ESI): m/z: calcd for
C21H30NO4: 360.21693 [M+H]+; found: 360.21670; calcd for
C21H30NO4 [M+Na]+: 382.19888; found: 382.19871; HPLC Chiralcel-
AS-H isocratic (hexane/iPrOH 70:30, flow: 1.0 mLminꢀ1): l=220
1
99% ee, c=0.99 in EtOH); H NMR (400 MHz, CDCl3): d=7.34–7.10
(m, 2H), 7.00–6.82 (m, 2H), 6.77 (dt, J=15.0, 7.5 Hz, 1H), 5.80 (d,
J=15.0 Hz, 1H), 4.24 (tdd, J=8.5, 5.0, 3.5 Hz, 1H), 4.16 (q, J=
7.0 Hz, 2H), 3.79 (s, 3H), 2.65–2.43 (m, 3H), 2.39–2.23 (m, 2H), 1.85
(dddd, J=13.0, 9.5, 7.0, 5.0 Hz, 1H), 1.26 ppm (t, J=7.0 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3): d=174.4, 166.0, 158.2, 142.8, 130.1,
126.7, 126.4, 125.1, 114.8, 60.65, 59.18, 55.68, 36.45, 31.01, 23.76,
14.43 ppm; IR (KBr): n˜ =3306, 2978, 2955, 2837, 1707, 1678, 1608,
1584, 1512, 1466, 1444, 1428, 1415, 1396, 1367, 1314, 1294, 1264,
1246, 1220, 1174, 1141, 1120, 1107, 1092, 1061, 1023, 830, 814, 791,
773, 713, 663, 641, 617, 578 cmꢀ1; HRMS (ESI): m/z: calcd for
C17H21NO4: 326.1368 [M+Na]+; found: 326.1363; HPLC Chiralcel-
OD-H isocratic (hexane/iPrOH 70/30, flow: 1.0 mLminꢀ1: l=204
tR(minor enantiomer)=13.29. tR(major enantiomer)=19.87 min;
GCMS (DB100S): 6.64 min (190.1, 134.1, 303.2).
Compound 12b: 4-Methoxyaniline (2.08 g, 16.9 mmol, 1.00 equiv)
was dissolved in THF (0.1m) in a 250 mL round-bottomed flask to
give a pale-yellow solution and cooled to ꢀ508C. After 10 min,
ethyl-4-oxobutanoate (2.20 g, 16.9 mmol, 1.00 equiv) was added by
a syringe and the corresponding solution was allowed to stir for
a further 10 min. Then 3,3’-mesityl substituted BINOL-bases phos-
phoric acid 7e, the Mes-catalyst (7e) (988 mg, 1.69 mmol,
10 mol%) was added and the resulting suspension was stirred for
15 min until a pale-reddish solution was formed. Subsequently ice-
cold 9b (8.2 g, 33.8 mmol, 2.0 equiv) was added slowly over
a period of 10 min. The reaction mixture was allowed to stir for
26 h and subsequently allowed to warm to room temperature. Gla-
cial acetic acid (20 mL) was added to the crude product and the
mixture heated to reflux conditions and stirred for 1 h. The result-
ing dark-red solution was concentrated and the crude product fur-
ther subjected to a silica gel column and eluted with MTBE!
EtOAc to give a white solid: 3.66 g (68%, d.r.=37:1, 93% ee). The
solid was then recrystallized from MTBE to give a colorless solid:
2.63 g (49%, d.r.= >99:1, >99% ee). Rf =0.52 (MTBE); m.p.=63–
658C; [a]2D4 =ꢀ5.4 (d.r.= >99:1, >99% ee, c=1.05 in CHCl3);
1H NMR (400 MHz, CDCl3): d=7.24 (d, J=9.0 Hz, 2H); 6.91 (d, J=
9.0 Hz, 2H); 6.82 (dd, J=16.0, 6.5 Hz, 1H); 5.80 (dd, J=16.0, 1.5 Hz,
1H); 4.32 (dt, J=8.5, 4.0 Hz, 1H); 4.16 (q, J=7.0 Hz, 2H); 3.78 (s,
3H); 2.68 (mc, 1H); 2.61–2.46 (m, 2H); 2.14 (mc, 1H); 1.85 (mc,
1H); 1.26 (t, J=7.0 Hz, 3H); 0.94 ppm (d, J=7.0 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3): d=174.5; 166.3; 157.9; 149.1; 130.0;
126.1; 122.2; 114.6; 62.70; 60.53; 55.54; 37.51; 31.31; 18.75; 14.32;
11.12 ppm; IR (KBr): n˜ =3445, 2979, 2961, 2920, 2863, 2844, 1713,
1682, 1656, 1612, 1583, 1517, 1464, 1448, 1426, 1404, 1368, 1316,
1293, 1256, 1232, 1195, 1162, 1138, 1116, 1038, 1029, 983, 909, 866,
831, 749, 648, 564, 540, 512 ppm; HRMS (ESI): m/z: calcd for
C18H23NO4: 340.15193 [M+Na]+; found: 340.15209; HPLC Chiralcel-
OD-H isocratic (hexane/iPrOH 70:30, flow: 1.0 mLminꢀ1): l=220
t
R1 =24.43, tR2 =55.53 min; GCMS (DB50S): 9.31 min m/z: 359.3
[M]·+, 190.1 [MꢀC10H17O2]·+
.
Towards compound 13a (three-step synthesis): Compound 12a
(6.24 g, 20.6 mmol, 1 equiv) was dissolved in ethanol (40 mL) in
a 100 mL round-bottomed flask to give a colorless solution. Pd/C
(1.10 g, 1.00 mmol) was added and the dark suspension treated
with hydrogen by a balloon. The crude mixture was stirred for
10 min and subsequently filtered over Celite to give a colorless
solid (12a-1): 6.30 g (>99%); Rf =0.50 (EtOAc/MeOH, 25:1); m.p.=
348C; [a]2D4 = +45.8 (c=1.01 in EtOH); 1H NMR (300 MHz, DMSO):
d=7.35–7.20 (m, 2H), 7.02–6.88 (m, 2H), 4.26–4.11 (mc, 1H), 3.99
(q, J=7.0 Hz, 2H), 3.74 (s, 3H), 2.49–2.29 (m, 2H), 2.26–2.18 (m,
3H), 1.83–1.66 (mc, 1H), 1.57–1.35 (m, 3H), 1.33–1.22 (m, 1H),
1.11 ppm (t, J=7.0 Hz, 3H); 13C{1H} NMR (75 MHz, DMSO): d=
173.2, 172.5, 156.7, 130.7, 125.4, 113.9, 59.7, 58.57, 55.18, 33.22,
32.23, 30.58, 23.21, 19.71, 14.04 ppm; IR (film): n˜ =3437, 2938,
2838, 2359, 1731, 1662, 1609, 1586, 1513, 1444, 1321, 1250, 1181,
1120, 1033, 834, 780, 734, 660, 614, 556, 520 cmꢀ1; HRMS (ESI): m/z:
calcd for C17H23NO4: 328.1519 [M+Na]+; found: 340.1520; GCMS:
(DB100S): 6.51 min (190, 305, 260).
Compound 12a-2: Compound 12a-1 (6.28 g, 20.6 mmol,
1.00 equiv) was dissolved in a 1 L round-bottomed flask in a mix-
ture of acetonitrile/water (5:1 [0.04m]) to give a colorless solution
and cooled to 08C. After 10 min, ceric ammonium nitrate (CAN)
(24.8 g, 45.3 mmol, 2.20 equiv) was added in small portions where-
upon the colorless solution turned yellow, purple, then dark red.
After complete addition, the reaction mixture was allowed to stir
for 10 min and was subsequently quenched at 08C by addition of
sat. sodium bicarbonate solution (75 mL). Additional solid potassi-
um carbonate (2 g) was added to basify the crude reddish, grey
suspension. The suspension was filtered and the residual solid
washed extensively with EtOAc. The phases were separated and
the aqueous layer extracted with EtOAc (5ꢂ50 mL) until TLC analy-
sis suggested completion. The combined organic layers were con-
centrated and subsequently dried over Na2SO4, filtered, concentrat-
t
R1 =41.91, tR2 =64.54 min; GCMS: (DB50S): 8.99 min (190).
Compound 12c: 4-Methoxyaniline (4.05 g, 32.9 mmol, 1.00 equiv)
was dissolved in THF (0.1m) in a 1 L round-bottomed flask to give
a pale-yellow solution and cooled to ꢀ508C. After 10 min, ethyl-4-
Chem. Eur. J. 2014, 20, 1964 – 1979
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ed in vacuum, and subsequently subjected to a silica gel column.
Chromatography of the crude product by using an eluent system
with a gradient from EtOAc!EtOAc/MeOH (30:1)!EtOAc/MeOH
(9:1) yielded the deprotected lactam 12a-2 as a white solid: 3.6 g
(87%). Rf =0.3 (EtOAc/MeOH, 9:1); m.p.=538C; [a]2D4 =ꢀ14.9 (c=
1697, 1654, 1476, 1455, 1444, 1424, 1395, 1369, 1354, 1337, 1293,
1259, 1200, 1174, 1115, 1076, 1036, 1002, 984, 910, 871, 764, 729,
671, 501 cmꢀ1; GCMS (DB50S): 7.28 min: m/z: 84.0 [MꢀC7H11O2]·+
;
HRMS (ESI): m/z: calcd for C11H17NO3: 234.11006 [M+Na]+; found:
234.11021.
1
0.40 in EtOH); H NMR (300 MHz, DMSO): d=7.72 (brs, 1H), 4.05 (q,
Compound 12b-2: Compound 12b-1 (895 mg, 4.24 mmol,
1.00 equiv) was dissolved in acetonitrile (10 mL) in a 50 mL round-
bottomed flask and the mixture was cooled to 08C. Boc2O (2.77 g,
12.7 mmol, 3.0 equiv) and DMAP (52 mg, 424 mmol, 0.10 equiv)
were added and the crude mixture subsequently allowed to warm
to room temperature and stirred overnight. After 1 d TLC analysis
suggested complete conversion and hence the crude mixture was
concentrated in vacuum and subjected to a silica gel column.
Chromatography with MTBE/Hex (1:1) yielded the imide (12b-2) as
a pale-yellow oil in quantitative yield: 1.31 g (>99%); Rf =0.24
(Hex/MTBE=1:1); [a]2D6 = +31.48 (c=1.02 in CHCl3, d.r.>99/1,
J=7.0 Hz, 2H), 3.55–3.39 (mc, 1H), 2.29 (t, J=7.0 Hz, 2H), 2.15–2.05
(m, 3H), 1.70–1.24 (m, 5H), 1.18 ppm (t, J=7.0 Hz, 3H);
13C{1H} NMR (75 MHz, DMSO): d=176.5, 172.7, 59.70, 53.24, 35.73,
33.35, 29.95, 26.60, 20.77, 14.33 ppm; IR (film): n˜ =3341, 2933,
1732, 1683, 1377, 1315, 1251, 1180, 1096, 1034, 825, 651, 505 cmꢀ1
;
HRMS (ESI): m/z: calcd for C10H17NO3: 222.1101 [M+Na]+; found:
222.1102; calcd for C20H34N2O6: 421.2309 [2M+Na]+; found:
421.2309; GCMS (DB100S): 4.83 min (84, 154, 199).
Compound 13a: Compound 12a-2 (3.30 g, 16.6 mmol, 1.00 equiv)
was dissolved in acetonitrile (20 mL) in a 50 mL round-bottomed
flask to give a yellow solution and cooled to 08C. Boc2O (3.98 g,
4.23 mL, 18.2 mmol, 1.1 equiv) and DMAP (202 mg, 1.66 mmol,
0.10 eq) were added and the crude mixture subsequently allowed
to warm to room temperature and stirred overnight. After 18 h
TLC analysis suggested complete conversion and hence the crude
mixture was concentrated in vacuum and subjected to a silica gel
column. Chromatography with MTBE/Hex (1:1) yielded the imide as
a colorless oil in quantitative yield: 4.96 g (>99%); Rf =0.15
1
>99% ee,); H NMR (300 MHz, CDCl3): d=6.88 (dd, J=15.5, 7.0 Hz,
1H); 5.86 (dd, J=15.5, 1.5 Hz, 1H); 4.27 (ddd, J=9.0, 5.0, 2.0 Hz,
1H); 4.19 (q, J=7.0 Hz, 2H); 2.96 (mc, 1H); 2.62–2.36 (m, 2H); 2.05
(mc, 1H); 1.79 (mc, 1H); 1.56 (s, 9H); 1.29 (t, J=7.0 Hz, 3H);
1.05 ppm (d, J=7.0 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): d=
174.4; 166.4; 150.1; 149.2; 122.4; 83.43; 60.62; 60.48; 39.49; 32.13;
28.15; 19.27; 14.39; 12.90 ppm; IR (film): n˜ =3420, 2979, 2936,
1787, 1751, 1716, 1653, 1458, 1368, 1307, 1256, 1188, 1155, 1034,
984, 955, 919, 849, 777, 599 cmꢀ1; HRMS (ESI): m/z: calcd for
C16H25NO5: 334.16249 [M+Na]+; found: 334.16263.
1
(MTBE/Hex 1:1); [a]2D4 = +59.7 (c=1.00 in EtOH); H NMR (400 MHz,
CDCl3): d=4.13–4.02 (m, 3H), 2.54 (ddd, J=18.0, 11.0, 9.0 Hz, 1H),
2.38 (ddd, J=18.0, 9.0, 3.5 Hz, 1H), 2.30 (td, J=7.0, 3.5 Hz, 2H),
2.15–1.99 (m, 1H), 1.82–1.71 (m, 2H), 1.71–1.51 (m, 4H), 1.48 (s,
9H), 1.21 ppm (t, J=7.0 Hz, 3H); 13C{1H} NMR(100 MHz, CDCl3): d=
174.3, 173.2, 150.1, 82.99, 60.58, 57.86, 34.06, 33.42, 31.52, 28.22,
22.65, 21.24, 14.43 ppm; IR (KBr): n˜ =3383, 2978, 2934, 1782, 1732,
1698, 1597, 1586, 1547, 1474, 1456, 1437, 1410, 1383, 1371, 1352,
1312, 1299, 1252, 1183, 1083, 1069, 1042, 1020, 902, 848, 833, 792,
756, 690, 650, 614, 581 cmꢀ1; HRMS (ESI): m/z: calcd for C15H25NO5:
322.1625 [M+Na]+; found: 322.1624.
Compound 13b: Compound 12b-2 (1.03 g, 3.31 mmol, 1.00 equiv)
was dissolved in ethanol (50 mL) in a 100 mL round-bottomed
flask to give
a colorless solution. Pd/C (176 mg, 10 wt.%,
0.05 equiv) was added and the dark suspension treated with hy-
drogen by a balloon. The crude mixture was stirred for 40 min and
subsequently filtered over Celite to give a colorless solid that was
subjected to a silica gel column chromatograph with MTBE as the
eluent. The purified product was obtained as a yellow oil: 1.03 g
(>99%); Rf =0.39 (Hex/MTBE=1:1); [a]2D5 = +50.08 (c=1.04 in
CHCl3, d.r.>99:1, >99% ee); 1H NMR (300 MHz, CDCl3): d=4.15
(mc, 1H); 4.10 (q, J=7.0 Hz, 2H); 2.57–2.21 (m, 4H); 2.11 (mc, 1H);
1.98 (mc, 1H); 1.78 (mc, 1H); 1.64 (mc, 1H); 1.50 (mc, 1H); 1.49 (s,
9H); 1.23 (t, J=7.0 Hz, 3H); 0.82 ppm (d, J=7.0 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3): d=174.9; 173.3; 150.0; 82.96; 61.01;
60.52; 35.24; 32.39; 32.34; 28.51; 28.10; 17.74; 14.29; 12.97 ppm; IR
(film): n˜ =2978, 2935, 1784, 1736, 1716, 1707, 1472, 1422, 1391,
1369, 1305, 1258, 1157, 1093, 1042, 1022, 917, 850, 780, 599,
Toward compound 13b (three-step synthesis): Compound 12b
(77.0 mg, 234 mmol, 1.00 equiv) was dissolved in a mixture of ace-
tonitrile/water (5:1, 0.04m) in a 25 mL round-bottomed flask to
give a colorless solution and the mixture was cooled to 08C. After
5 min, CAN (293 mg, 534 mmol, 2.20 equiv) was added in small por-
tions whereupon the colorless solution turned yellow, then purple,
then dark red. After complete addition, the reaction mixture was
allowed to stir for 10 min and was subsequently quenched at 08C
by addition of sat. sodium bicarbonate solution (10 mL). Additional
solid potassium carbonate (~0.5 g) was added to basify the crude
reddish, grey suspension. The crude mixture was diluted with
EtOAc (20 mL) and stirred for 5 min at 08C and then a further
5 min at room temperature. The suspension was filtered and the
residual solid washed extensively with EtOAc. The phases were
separated and the aqueous layer extracted with EtOAc (4ꢂ20 mL)
until TLC analysis suggested completion. The combined organic
layers were concentrated and subsequently dried over Na2SO4, fil-
tered, concentrated in vacuum, and subsequently subjected to
a silica gel column. Chromatography of the crude product using
EtOAc as the eluent yielded the deprotected lactam (12b-1) as
a white solid: 41 mg (80%); Rf =0.21 (EtOAc); m.p.=89–918C;
[a]2D8 = +57.78 (c=1.01 in d.r.>99/1, >99% ee, CHCl3); 1H NMR
(300 MHz, CDCl3): d=6.77 (dd, J=15.5, 8.5 Hz, 1H); 6.50 (brs, 1H);
5.86 (d, J=15.5 Hz, 1H); 4.17 (q, J=7.0 Hz, 2H); 3.56 (q, J=7.0 Hz,
1H); 2.42–2.12 (m, 4H); 1.76 (mc, 1H); 1.27 (t, J=7.0 Hz, 3H);
1.06 ppm (d, J=7.0 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): d=
178.2, 166.2, 148.9, 123.0, 60.57, 58.04, 42.61, 30.31, 24.77, 15.26,
14.32 ppm; IR (KBr): n˜ =3447, 3206, 2985, 2942, 2905, 2878, 1717,
460 cmꢀ1
; HRMS (ESI): m/z: calcd for C16H27NO5: 336.17814
[M+Na]+; found: 336.17832; calcd for C32H54N2O10: 649.36707
[2M+Na]+; found: 649.36716.
Toward 13c (three-step synthesis): Compound 12c (10.3 g,
28.5 mmol, 1.00 equiv) was dissolved in a mixture of acetonitrile/
water (5:1, 0.04m) in a 2 L round-bottomed flask to give a colorless
solution and the mixture was cooled to 08C. After 5 min, CAN
(34.4 g, 62.7 mmol, 2.20 equiv) was added in small portions where-
upon the colorless solution turned yellow, then purple, then dark
red. After complete addition, the reaction mixture was allowed to
stir for 10 min and was subsequently quenched at 08C by addition
of sat. sodium bicarbonate solution (500 mL). The crude mixture
was diluted with EtOAc (200 mL) and stirred for 5 min at 08C and
for a further 5 min at room temperature. The suspension was fil-
tered over Celite and the residual solid washed extensively with
EtOAc. The phases were separated and the aqueous layer extracted
with EtOAc (5ꢂ150 mL) until TLC analysis suggested completion.
The combined organic layers were concentrated and subsequently
dried over Na2SO4, filtered, concentrated in vacuum and subse-
quently subjected to a silica gel column. Chromatography of the
Chem. Eur. J. 2014, 20, 1964 – 1979
www.chemeurj.org
1973
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
crude product by using EtOAc as the eluent yielded the deprotect-
treated with hydrogen peroxide (1.57 mL, 35 wt.% in water,
1.00 equiv) and stirred for 30 min. The organic layer was removed
in vacuum and the aqueous layer extracted with CH2Cl2 (5ꢂ50 mL).
The recombined organic phases were dried over Na2SO4, filtered,
and concentrated in vacuum. The crude hemiaminal product was
further used without any purification. The crude product was dis-
solved in CH2Cl2 (300 mL), treated with triethylsilane (2.70 mL,
16.9 mmol, 1.10 equiv), and cooled to ꢀ788C. After 10 min boron
trifluoride etherate (2.14 mL, 16.9 mmol, 1.10 equiv) was added
and the reaction mixture stirred for 30 min. Then again triethylsi-
lane (2.70 mL, 16.9 mmol, 1.10 equiv) and boron trifluoride ether-
ate (2.14 mL, 16.9 mmol, 1.10 equiv) were added to force the reac-
tion to completion. The resulting mixture was stirred for 2 h and
was then quenched by addition of sat. sodium bicarbonate solu-
tion (50 mL). Layers were separated and the aqueous layer extract-
ed with CH2Cl2 (5ꢂ50 mL). The recombined organic layers were
dried over Na2SO4, filtered, subjected to a silica gel column and
eluted with MTBE/Hex (1:3) to give a pale-yellow oil (13a-1): 3.67 g
(84%). Rf =0.36 (MTBE/Hex 2:1); [a]2D4 = +41.9 (c=1.00 in EtOH);
1H NMR (300 MHz, [D6]DMSO [908C]): d=4.05 (q, J=7.0 Hz, 2H),
3.73–3.58 (m, 1H), 3.29 (dt, J=10.5, 7.5 Hz, 1H), 3.16 (ddd, J=10.5,
7.5, 5.0 Hz, 1H), 2.27 (t, J=7.0 Hz, 2H), 1.99–1.45 (m, 7H), 1.39 (s,
9H), 1.38–1.27 (m, 1H), 1.18 ppm (t, J=7.0 Hz, 3H); 13C{1H} NMR-
(75 MHz, [D6]DMSO [908C]): d=172.1, 153.2, 77.63, 59.06, 56.06,
45.50, 33.23, 33.17, 29.60, 27.78, 22.47, 20.84, 13.57 ppm; IR (film):
n˜ =2973, 2933, 2874, 2360, 1735, 1694, 1653, 1636, 1558, 1540,
1508, 1478, 1455, 1395, 1365, 1341, 1311, 1287, 1251, 1173, 1118,
1103, 1033, 916, 879, 861, 772 cmꢀ1; HRMS (ESI): m/z: calcd for
C15H27NO4: 308.1832 [M+Na]+; found: 308.1832.
ed lactam (12c-1) as a white solid: 6.12 g (85%). Rf =0.34 (EtOAc);
1
[a]2D5 =ꢀ15.28 (c=1.05 in CHCl3); H NMR (400 MHz, CDCl3): d=6.67
(dd, J=15.5, 10.0 Hz, 1H); 6.35 (brs, 1H); 5.87 (d, J=15.5 Hz, 1H);
4.18 (q, J=7.0 Hz, 2H); 3.60 (q, J=7.0 Hz, 1H); 2.35–2.29 (m, 2H);
2.23 (mc, 1H); 2.14 (mc, 1H); 1.77 (mc, 1H); 1.49 (mc, 1H); 1.36–1.07
(m, 5H); 1.28 (t, J=7.0 Hz, 3H); 0.86 ppm (t, J=7.0 Hz, 3H);
13C{1H} NMR (75 MHz, CDCl3): d=178.7, 166.2, 148.2, 124.6, 60.75,
57.57, 48.98, 30.26, 29.91, 29.40, 25.35, 22.66, 14.32, 14.00 ppm; IR
(film): n˜ =3646, 3333, 2956, 2929, 2871, 2860, 2359, 2341, 1715,
1697, 1682, 1652, 1469, 1384, 1369, 1267, 1209, 1179, 1160, 1138,
1095, 1038, 988, 911, 865, 824, 785, 730 cmꢀ1; GCMS (DB50S):
7.51 min m/z: 84.0 [MꢀC10H17O2]·+; HRMS (ESI): m/z: calcd for
C14H23NO3: 276.15701 [M+Na]+; found: 276.15706.
Compound 12c-2: Compound 12c-1 (5.65 g, 22.3 mmol,
1.00 equiv) was dissolved in acetonitrile (50 mL) in a 250 mL
round-bottomed flask and the mixture was cooled to 08C. Boc2O
(14.6 g, 66.9 mmol, 3.00 equiv) and DMAP (272 mg, 2.23 mmol,
0.10 equiv) were added and the crude mixture subsequently al-
lowed to warm to room temperature. After 4 d TLC analysis sug-
gested complete conversion and hence the crude mixture was
concentrated in vacuum and subjected to a silica gel column.
Chromatography with MTBE/Hex (1:1) yielded the imide as pale-
yellow oil: 6.75 g (86%); Rf =0.26 (Hex/MTBE=1:1); [a]2D5 = +42.08
1
(c=1.05 in CHCl3); H NMR (300 MHz, CDCl3): d=6.76 (dd, J=15.5,
9.5 Hz, 1H); 5.84 (dd, J=15.5, 0.5 Hz, 1H); 4.20 (mc, 1H); 4.17 (q,
J=7.0 Hz, 2H); 2.64 (mc, 1H); 2.59–2.36 (m, 2H); 2.08 (mc, 1H);
1.88 (mc, 1H); 1.51 (s, 9H); 1.47–1.04 (m, 6H); 1.28 (t, J=7.0 Hz,
3H); 0.86 ppm (t, J=7.0 Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3): d=
174.4; 166.1; 150.1; 148.4; 123.9; 83.33; 60.58; 60.56; 46.23; 31.95;
29.73; 28.20; 28.10; 22.68; 20.36; 14.37; 14.02 ppm; IR (film): n˜ =
2978, 2959, 2933, 2872, 2861, 1787, 1752, 1718, 1653, 1460, 1368,
1308, 1257, 1155, 1041, 985, 930, 910, 849, 778, 598 cmꢀ1; HRMS
(ESI): m/z: calcd for C19H31NO5: 376.20944 [M+Na]+; found:
376.20971; calcd for C38H62N2O10: 729.42967 [2M+Na]+; found:
729.42954.
Compound 14a: Compound 13a–1 (3.00 g, 10.5 mmol) was dis-
solved in CH2Cl2 (105 mL) in a 250 mL round-bottomed flask to
give a pale-yellow solution and cooled to 08C. TFA (10.0 mL,
130 mmol) was added slowly by a syringe and the resulting mix-
ture was allowed to warm to room temperature and was stirred
for 30 min. The mixture was concentrated in vacuum to give
yellow oil that was directly suspended in aqueous sodium bicar-
bonate solution (100 mL) and stirred for 2 h at room temperature.
The aqueous layer was further basified (pH~14) by addition of 2m
NaOH and extracted with CH2Cl2 (3ꢂ30 mL). The recombined or-
ganic layers were dried over Na2SO4, filtered, and subjected to
a silica gel column. Elution with CH2Cl2 and 5% MeOH yielded the
product as colorless liquid that solidifies upon cooling to tempera-
Compound 13c: Compound 12c-2 (6.40 g, 18.1 mmol, 1.00 equiv)
was dissolved in ethanol (90 mL) in a 250 mL round-bottomed
flask to give
a colorless solution. Pd/C (867 mg, 10 wt%,
0.05 equiv) was added and the dark suspension treated with hy-
drogen by a balloon. The crude mixture was stirred for 2.5 h and
subsequently filtered over Celite to give a yellow oil that was sub-
jected to a silica gel column chromatograph with MTBE as the
eluent. The purified product was obtained as pale-yellow oil:
6.40 g (>99%); Rf =0.26 (Hex/MTBE=1:1); [a]2D5 = +63.68 (c=1.00
in CHCl3); 1H NMR (300 MHz, CDCl3): d=4.20 (dt, J=9.5, 3.0 Hz,
1H); 4.13 (q, J=7.0 Hz, 2H); 2.59–2.42 (m, 2H); 2.42–2.26 (m, 2H);
2.08–1.88 (m, 2H); 1.87–1.72 (m, 2H); 1.52 (s, 9H); 1.49–1.04 (m,
7H); 1.25 (t, J=7.0 Hz, 3H); 0.86 ppm (d, J=7.0 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3): d=175.0, 173.4, 149.96, 82.96, 60.56,
59.66, 40.20, 32.52, 32.31, 29.93, 28.13, 27.93, 25.98, 22.94, 17.97,
14.32, 14.06 ppm; IR (film): n˜ =2977, 2958, 2932, 2872. 2862, 1785,
1737, 1715, 1458, 1422, 1369, 1305, 1256, 1159, 1098, 1041, 1021,
917, 850, 781, 599, 459 cmꢀ1; HRMS (ESI): m/z: calcd for C19H33NO5:
378.22509 [M+Na]+; found: 378.22500.
tures below 08C: 1.45 g (99%); Rf =0.5 (CH2Cl2/5% MeOH); [a]D24
=
1
+18.8 (c=1.28 in CH2Cl2); H NMR (400 MHz, CDCl3): d=3.67–3.52
(m, 1H), 3.51–3.31 (m, 2H), 2.51–2.36 (m, 1H), 2.34–2.18 (m, 1H),
2.16–2.03 (m, 2H), 1.99–1.88 (m, 2H), 1.82–1.62 (mc, 2H), 1.51–1.35
(mc, 1H), 1.33–1.17 ppm (mc, 1H); 13C{1H} NMR(100 MHz, CDCl3):
d=169.2, 59.4, 44.93, 33.67, 31.13, 29.26, 22.25, 21.28 ppm; IR
(film): n˜ =3452, 2944, 2880, 1731, 1626, 1455, 1414, 1383, 1372,
1328, 1308, 1252, 1213, 1168, 1143, 1119, 1099, 1071, 1053, 1016,
992, 917, 841, 636, 566, 452, 425 cmꢀ1; HRMS (EI): m/z: calcd for
C8H13NO: 139.0997 [M]+; found: 139.0999; GCMS (DB100S):
5.68 min (83, 139, 70).
Compound 14b: This compound was synthesized along the lines
of the synthesis toward 14a by starting from 16a (for further infor-
mation please see the Supporting Information). Yield: 89%; Rf =
0.21 (MTBE); [a]2D4 =ꢀ44.1 (c=0.86 in EtOH); 1H NMR (300 MHz,
CDCl3): d=4.07–3.75 (m, 1H), 3.35 (tdd, J=11.0, 5.0, 3.0 Hz, 1H),
2.54–2.20 (m, 2H), 2.09–1.83 (m, 4H), 1.85–1.45 (m, 4H), 1.45–1.04
(m, 6H), 0.88 ppm (t, J=7.0 Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3):
d=169.6, 60.15, 57.50, 32.69, 31.67, 31.25, 29.55, 29.04, 27.80,
22.93, 21.40, 14.32 ppm; IR (film): n˜ =3475, 3147, 2953, 2869, 2859,
1727, 1643, 1463, 1440, 1409, 1373, 1333, 1317, 1306, 1223, 1213,
Toward 14a (two-step synthesis): Compound 13a (4.60 g,
15.4 mmol, 1.00 equiv) was dissolved in THF (300 mL) in a 500 mL
round-bottomed flask to give a colorless solution and cooled to
ꢀ788C. Lithium triethylborohydride (18.44 mL, 1m in THF,
1.2 equiv) was added slowly over a period of 30 min. The reaction
mixture was then allowed to stir for 30 min at ꢀ788C and subse-
quently quenched by addition of sat. sodium bicarbonate solution
(25 mL). The crude suspension was warmed to 08C and further
Chem. Eur. J. 2014, 20, 1964 – 1979
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1974
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
1201, 1186, 1163, 1127, 1103, 1065, 964, 901, 641, 567, 453 cmꢀ1
;
50.36, 39.04, 36.25, 35.48, 34.10, 29.49, 28.51, 21.46, 14.37,
7.97 ppm; IR (film): n˜ =3365, 2977, 2938, 2360, 1731, 1714, 1519,
1455, 1416, 1390, 1366, 1300, 1247, 1172, 1115, 1097, 1079, 1027,
866, 780, 751, 667, 641, 626 cmꢀ1; HRMS (ESI): m/z: calcd for
C17H31NO5: 352.20944 [M+Na]+; found: 352.20920; GCMS (DB50S):
7.17 min (184, 240, 126, 260).
HRMS (ESI): m/z: calcd for C12H22NO: 196.16959 [M+H]+; found:
196.16971.
Compound 14c: This compound was synthesized along the lines
of the synthesis toward 14a by starting from 16b (for further infor-
mation please see the Supporting Information). Yield: 74%; Rf =
0.22 (10% MeOH in CH2Cl2); [a]2D4 =ꢀ56.3 (c=0.96 in EtOH);
1H NMR (300 MHz, CDCl3): d=3.98–3.76 (m, 1H), 3.34 (tdd, J=11.0,
5.0, 3.0 Hz, 1H), 2.37–2.15 (m, 2H), 2.12–1.06 (m, 10H), 0.82 ppm (t,
J=7.5 Hz, 3H); 13C{1H} NMR(75 MHz, CDCl3): d=169.56, 60.07,
58.55, 31.49, 31.13, 29.33, 27.12, 25.40, 21.24, 10.72 ppm; IR (film):
n˜ =3420, 2965, 2939, 2876, 1725, 1672, 1615, 1463, 1411, 1382,
Compound 15a: This compound was synthesized along the lines
of the synthesis of 15b (for further information please see the Sup-
porting Information). Yield: 85%; Rf =0.14 (MTBE/Hex 1:2); [a]D24
=
1
ꢀ34.1 (c=1.11 in EtOH); H NMR (300 MHz, CDCl3): d=4.26 (d, J=
9.5 Hz, 1H), 4.12 (q, J=7.0 Hz, 2H), 3.58–3.45 (mc, 1H), 2.47 (td, J=
7.0, 2.0 Hz, 2H), 2.39 (t, J=7.5 Hz, 2H), 2.31 (td, J=7.5, 2.5 Hz, 2H),
1.84–1.52 (m, 8H), 1.43 (s, 9H), 1.37–1.28 (m, 2H), 1.25 (t, J=7.0 Hz,
3H), 0.90 ppm (t, J=7.5 Hz, 3H); 13C{1H} NMR(100 MHz, CDCl3): d=
211.2, 173.6, 156.0, 79.24, 60.43, 50.39, 42.92, 39.48, 35.53, 34.15,
29.38, 28.57, 26.14, 22.53, 21.51, 14.42, 14.04 ppm; IR (film): n˜ =
3367, 2957, 2934, 2873, 1731, 1715, 1519, 1447, 1391, 1366, 1299,
1245, 1173, 1130, 1085, 1028, 975, 862, 835, 780, 751, 637, 598,
1352, 1335, 1246, 1201, 1174, 719, 699, 668, 642, 617, 602 cmꢀ1
,
HRMS (ESI): m/z: calcd for C10H17NONa: 190.12024 [M+Na]+; found:
190.12031; calcd for C20H34N2O2Na: 357.25125 [2M+Na]+; found:
357.25121; GCMS (DB100S): 4.647 min (138, 83.9, 55.0).
Compound 14d: This compound was synthesized along the lines
of the synthesis of 14a by starting from 13b-1 (for further informa-
tion please see the Supporting Information); Yield: 83%; Rf =0.30
(CH2Cl2/MeOH=95:5); M.p.=53–558C; [a]2D2 = +24.28 (c=1.04 in
EtOH, d.r. >99:1, >99% ee); 1H NMR (400 MHz, CDCl3): d=3.56
(mc, 1H); 3.45 (mc, 1H); 2.98 (mc, 1H); 2.44 (mc, 1H); 2.32 (mc, 1H);
2.13 (mc, 1H); 1.94 (mc, 1H); 1.87–1.62 (m, 2H); 1.51–1.28 (m, 3H);
1.01 ppm (dd, J=5.5 Hz, J=2.0 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3): d=169.1; 65.26; 45.36; 35.55; 32.44; 31.64; 30.22; 22.26;
18.34 ppm; IR (KBr): n˜ =3346, 3246, 2943, 2885, 2872, 1707, 1748,
1627, 1469, 1454, 1412, 1381, 1331, 1309, 1291, 1282, 1235, 1226,
1211, 1199, 1161, 1144, 1174, 987, 915, 831, 745, 703, 664, 579, 492,
413 cmꢀ1; GCMS (DB50S): m/z: 153.1 [M]·+, 111.0 [MꢀC3H6]·+; HRMS
(ESI): m/z: calcd for C9H15NO: 176.10459 [M+Na]+; found:
176.10478; calcd for C18H30N2O2: 329.21995 [2M+Na]+; found.:
329.22005.
462, 452, 411 cmꢀ1
; HRMS (ESI): m/z: calcd for C19H35NO5:
380.24074 [M+Na]+; found: 380.24085; calcd for C38H70N2O10:
737.49227 [2M+Na]+; found: 737.49164.
Compound 16b: B(ArF5)3 (787 mg, 1.54 mmol, 0.30 equiv) dis-
solved in CH2Cl2 (10 mL) in a 100 mL round-bottomed flask and
Ph3SiH (4.01 g, 15.4 mmol, 3.00 equiv) was added as a solution in
CH2Cl2 (10 mL) at room temperature. Compound 15a (1.69 g,
5.13 mmol, 1.00 equiv) was dissolved in CH2Cl2 (30 mL), cooled to
ꢀ788C, and treated with the aforementioned freshly prepared mix-
ture of Ph3SiH/B(ArF5)3. The resulting mixture was allowed to
slowly warm to room temperature and stirred for 72 h. The reac-
tion was quenched by addition of sat. sodium bicarbonate solution
(30 mL) and the layers separated. The aqueous layer was extracted
with CH2Cl2 (3ꢂ30 mL), dried over Na2SO4, filtered, and concentrat-
ed in vacuum. The crude product was subjected to a silica gel
column and eluted with MTBE/Hex 1:4!1:2 to give a colorless oil:
1.26 g (79%); Rf =0.45 (MTBE/Hex 1:2); [a]2D4 = +40.4 (c=0.2 in
Compound 14e: This compound was synthesized along the lines
of the synthesis toward 14a by starting from 13c-1 (for further in-
formation please see the Supporting Information). Yield: 74%; Rf =
0.24 (CH2Cl2/MeOH=95:5); [a]2D2 = +55.68 (c=1.47 in EtOH);
1H NMR (300 MHz, CDCl3): d=3.57 (mc, 1H); 3.45 (mc, 1H); 3.06 (mc,
1H); 2.47 (mc, 1H); 2.29 (mc, 1H); 2.16 (mc, 1H); 2.01–1.88 (m, 2H);
1.71 (ttd, J=12.5, 10.0, 6.5 Hz, 1H); 1.56–1.09 (m, 9H); 0.89 ppm
(t,=7.0, 3H); 13C{1H} NMR (75 MHz, CDCl3): d=169.2, 64.22, 45.25,
40.42, 32.49, 32.28, 31.56, 28.80, 27.03, 22.99, 22.25, 14.07 ppm; IR
(film): n˜ =3464, 2954, 2927, 2870, 2861, 1647, 1638, 1459, 1415,
1383, 1324, 1287, 1278, 1233, 1204, 1190, 1147, 960, 837, 728, 667,
1
EtOH); H NMR (300 MHz, [D6]DMSO [908C]): d=4.05 (q, J=7.0 Hz,
2H), 3.78–3.43 (m, 2H), 2.27 (t, J=7.0 Hz, 2H), 1.96–1.82 (m, 2H),
1.77–1.45 (m, 6H), 1.40 (s, 9H), 1.36–1.23 (m, 2H), 1.18 (t, J=7.0 Hz,
3H), 0.82 ppm (t, J=7.5 Hz, 3H); 13C{1H} NMR(75 MHz, [D6]DMSO,
908C): d=172.1, 153.7, 77.55, 58.99, 58.88, 57.22, 34.47, 33.21,
28.63, 28.11, 27.71, 27.56, 20.97, 13.54, 9.59 ppm; IR (film): n˜ =2966,
2934, 2875, 1736, 1692, 1478, 1461, 1455, 1391, 1366, 1324, 1301,
1252, 1174, 1104, 1049, 1030, 914, 873, 858, 772, 710, 701, 512,
459 cmꢀ1, HRMS (ESI): m/z: calcd for C17H32NO4: 314.23258 [M+H]+;
found: 314.23260; calcd for C17H31NO4Na: 336.21453 [M+Na]+;
found: 336.21447.
598, 581, 566 cmꢀ1; GCMS (DB50S): 6.78 min m/z: 195.1 [M]·+
;
HRMS (ESI): m/z: calcd for C12H21NO: 218.15154 [M+Na]+; found.:
218.15173; calcd for C24H42N2O2: 413.31384 [2M+Na]+; found:
413.31364.
Compound 16a: This compound was synthesized along the lines
of the synthesis of 16b (for further information please see the Sup-
Compound 15b: Compound 13a (1.75 g, 5.85 mmol, 1.00 equiv)
was dissolved in THF (117 mL) in a 250 mL round-bottomed flask
to give a colorless solution and cooled to ꢀ788C. Ethyl magnesium
chloride (4.33 mL, 11.7 mmol (2.7m in THF), 2.0 equiv) was added
and the crude yellow mixture stirred for 3.5 h. The reaction was
quenched by addition of sat. NH4Cl (50 mL) and the layers separat-
ed. The aqueous layer was extracted with MTBE (3ꢂ100 mL). The
recombined organic layers were dried over Na2SO4, filtered, and
concentrated in vacuum. The crude product was subjected to
a silica gel column and eluted with MTBE/Hex 1:3 to give a colorless
oil: 1.69 g (88%); Rf =0.2 (MTBE/Hex 1:1); [a]2D4 = +10.9 (c=0.36 in
EtOH); 1H NMR (300 MHz, CDCl3): d=4.26 (d, J=9.5 Hz, 1H), 4.11
(q, J=7.0 Hz, 2H), 3.62–3.41 (m, 1H), 2.46 (t, J=7.0 Hz, 2H), 2.41
(q, J=7.5 Hz, 2H), 2.30 (td, J=7.5, 2.5 Hz, 2H), 1.90–1.45 (m, 6H),
1.42 (s, 9H), 1.24 (t, J=7.0 Hz, 3H), 1.04 ppm (t, J=7.5 Hz, 3H);
13C{1H} NMR(100 MHz, CDCl3): d=211.5, 173.5, 155.9, 79.25, 60.40,
porting Information). Yield: 96%; Rf =0.33 (MTBE/Hex 1:5); [a]D24
=
1
+8.27 (c=1.09 in EtOH); H NMR (300 MHz, [D6]DMSO, 908C): d=
4.05 (q, J=7.0 Hz, 2H), 3.75–3.58 (m, 2H), 2.27 (t, J=7.0 Hz, 2H),
1.99–1.79 (m, 2H), 1.73–1.47 (m, 6H), 1.39 (s, 9H), 1.35–1.22 (m,
6H), 1.18 (t, J=7.0 Hz, 3H), 0.87 ppm (t, J=7.0 Hz, 3H);
13C{1H} NMR(75 MHz, [D6]DMSO, 908C) d=173.3, 154.8, 78.73,
60.16, 58.67, 58.32, 35.79, 35.66, 34.38, 29.84, 29.82, 28.90, 28.63,
22.67, 22.13, 14.71, 14.38 ppm; IR (film): n˜ =3450, 3369, 2960, 2932,
2872, 1736, 1691, 1548, 1478, 1455, 1389, 1365, 1321, 1250, 1174,
1104, 1030, 939, 907, 858, 773, 745, 709, 700, 513, 460 cmꢀ1; HRMS
(ESI): m/z: calcd for C19H35NO4: 364.24583 [M+Na]+; found:
364.24559; calcd for C38H70N2O8: 705.50244 [2M+Na]+; found:
705.50190.
Compound 18: Diisopropylamine (350 mL, 2.48 mmol, 1.50 equiv)
was dissolved in dry THF (8 mL) in a 25 mL round-bottomed flask
Chem. Eur. J. 2014, 20, 1964 – 1979
www.chemeurj.org
1975
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
was and cooled to 08C. nBuLi (1.03 mL, 2.5m in THF, 1.55 equiv)
was added. The reaction mixture was then allowed to stir for 1 h at
08C, cooled to ꢀ788C, and treated with 14d (253 mg, 1.65 mmol,
1.00 equiv). After 1.5 h, the reaction mixture was treated with
PhSeBr (546 mg, 2.32 mmol, 1.40 equiv), stirred for 3 h, and subse-
quently quenched by addition of sat. sodium bicarbonate solution
(6 mL). The crude suspension was warmed to room temperature
and extracted with EtOAc (3ꢂ40 mL). The recombined organic
layers were washed with brine (2ꢂ40 mL), dried over Na2SO4, fil-
tered, and concentrated in vacuum. The crude product was dis-
solved in CH2Cl2 (10 mL), cooled to 08C, and treated with an excess
of hydrogen peroxide (2.50 mL, 28.3 mmol, 17.1 equiv). After 1 h
the reaction mixture was subsequently quenched by addition of
distilled water (10 mL). Layers were separated and the aqueous
layer extracted with CH2Cl2 (3ꢂ20 mL). The recombined organic
layers were dried over Na2SO4, filtered, concentrated in vacuum,
and subjected to a silica gel column. Elution with CH2Cl2 and
MeOH (99:1!98:2) yielded the product as colorless oil: 160 mg
(64%); Rf =0.14 (CH2Cl2/MeOH=98:2); [a]2D5 = ꢀ29.78 (c=1.01 in
EtOH); 1H NMR (400 MHz, CDCl3): d=6.22 (dd, J=10.0, 1.5, 1H),
5.88 (dd, J=10.0, 3.0, 1H), 3.64 (mc, 1H), 3.44 (mc, 1H), 3.29 (mc,
1H), 2.34 (mc, 1H), 2.22 (mc, 1H), 2.00 (mc, 1H), 1.75 (mc, 1H), 1.57
(mc, 1H), 1.11 ppm (d, J=7.0, 3H); 13C{1H} NMR (100 MHz, CDCl3):
d=163.5, 145.2, 125.3, 63.20, 44.39, 36.60, 32.62, 22.79, 17.06 ppm;
IR (film): n˜ =3464, 2966, 2933, 2877, 2359, 2341, 1724, 1660, 1597,
1459, 1386, 1371, 1351, 1324, 1286, 1267, 1206, 1160, 1135, 819,
756, 744, 680, 604, 505, 436 cmꢀ1; HRMS (ESI): m/z: calcd for
C9H13NO: 175.08894 [M+Na]+; found: 175.08909; calcd for
C18H26N2O2: 325.18865 [2M+Na]+; found.: 325.18839; GCMS
CD3OD): d=ꢀ77.36 ppm; IR (film): n˜ =3445, 2954, 2932, 2852,
2728, 1771, 1732, 1683, 1458, 1420, 1383, 1260, 1201, 1181, 1131,
1081, 1035, 833, 800, 720, 706, 638, 596, 487, 447 cmꢀ1; HRMS (ESI):
m/z: calcd for C20H36N2O2F3: 393.27234 [2M+TFA]+; found:
393.27243; GCMS (DB50S of the free amine): 4.30 min (124, 96,
139).
Compound 1c: According to general procedure A 139 mg (65%)
were obtained. Rf =0.30 (Et2O/Hex 1:20 on AlOx-TLC, free amine);
Rf =0.30 (Et2O/Hex 1:20 on AlOx-TLC, free amine), [a]2D2 = +18.5
(c=0.54 in EtOH), 1H NMR (300 MHz, CD3OD): d=7.62–7.36 (m,
5H), 4.22–4.06 (m, 1H), 3.41–3.29 (m, 1H), 3.08–2.88 (m, 2H), 2.35–
2.19 (m, 2H), 2.16–1.68 ppm (m, 8H); 13C{1H} NMR (100 MHz,
CD3OD): d=135.8, 129.7, 129.3, 127.6, 68.97, 68.44, 51.40, 31.38,
28.38, 27.64, 23.11, 18.68 ppm; 19F NMR (280 MHz, CD3OD): d=
ꢀ77.69 ppm; IR (film): n˜ =3430, 3009, 2951, 2871, 2726, 2666,
2612, 2565, 2526, 1778, 1734, 1671, 1499, 1487, 1457, 1434, 1384,
1200, 1132, 1081, 1064, 1026, 1015, 831, 799, 758, 719, 702, 616,
594, 541 cmꢀ1; HRMS (ESI): m/z: calcd for C14H19N: 202.15903 [M]+;
found: 202.15906.
Compound 2a: According to general procedure A 150 mg (95%)
were obtained. Rf =0.24 (MTBE/Hex 1:10 on AlOx-DC, free amine);
[a]2D0 =ꢀ71.7 (c=1.08 in EtOH); 1H NMR (400 MHz, CD3OD): d=
3.59–3.47 (m, 1H), 3.31–3.25 (m, 1H), 3.21–3.08 (m, 1H), 2.32–2.18
(m, 1H), 2.16–2.03 (m, 2H), 1.99–1.87 (m, 3H), 1.84–1.73 (m, 2H),
1.71–1.56 (m, 4H), 1.42 (d, J=6.5 Hz, 3H), 1.41–1.29 (m, 4H), 1.03–
0.83 ppm (m, 3H); 13C{1H} NMR(100 MHz, CD3OD): d=71.19, 67.01,
63.73, 35.60, 33.50, 30.00, 29.62, 29.14, 28.32, 23.80, 23.34, 19.90,
14.19 ppm; 19F NMR (376 MHz, CDCl3): d=ꢀ77.70 ppm; IR (film):
n˜ =3438, 2961, 2938, 2875, 2696, 1780, 1739, 1670, 1457, 1428,
1384, 1312, 1202, 1173, 1079, 1036, 1015, 966, 829, 811, 798, 719,
705, 605, 595, 518, 487, 472 cmꢀ1; HRMS (ESI): m/z: calcd for
C13H26N: 196.20598 [M+H]+; found: 196.20607.
(DB50S): 5.83 min m/z: 151.1 [M]·+
.
General procedure (A) for the functionalization of indolizidi-
nones: R3MgX (3–5 equiv) was added to an ice-cold stirred solution
of indolizidinone (1 equiv) in THF (0.06m) and the resulting mixture
was subsequently allowed to warm to room temperature. Sodium
borohydride (2–3 equiv) and acetic acid (excess) were added at
ꢀ10 or 08C and the resulting suspension stirred for 1 h at ambient
temperatures. The resulting mixture was basified by addition of
2m NaOH (5 mL) and extracted with CH2Cl2 (5ꢂ10 mL), dried over
Na2SO4, filtered, and concentrated in vacuum (400 mbar, 258C) to
get a crude oil. Workup procedures and further details are given
for each individual IBA in the Supporting Information.
Compound 2b: According to general procedure A 568 mg (87%)
were obtained. Rf =0.60 (Et2O/Pentan 1:5 on AlOx-DC (free amine));
1
[a]2D2 =ꢀ32.5 (c=0.06 in EtOH), H NMR (300 MHz, [D6]DMSO): d=
2.69 (m, 1H), 2.43–2.23 (m, 2H), 1.59–0.58 (m, 14H), 0.22 (t, J=
7.5 Hz, 3H), 0.20 ppm (t, J=7.5 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3): d=67.67, 66.91, 63.88, 32.79, 31.34, 31.14, 30.63, 29.44,
28.48, 25.03, 11.33, 10.89 ppm; 19F NMR (282 MHz, [D6]DMSO): d=
ꢀ78.51 ppm; IR (film): n˜ =3408, 2955, 2921, 2872, 2850, 2660,
1714, 1659, 1651, 1461, 1434, 1383, 1261, 1203, 1178, 1106, 1049,
1012, 988, 969, 803, 727, 719, 637, 613, 552, 536, 520, 507, 496,
483, 470, 458, 451, 420, 406 cmꢀ1; HRMS (ESI): m/z: calcd for
C12H24N: 182.19033 [M+H]+; found: 182.19038.
Compound 1a: According to general procedure A 72.6 mg (80%)
were obtained. Rf =0.15 (Et2O/Hex 1/10 on AlOx-TLC, free amine);
[a]2D2 = +59.6 (c=0.24 in EtOH); 1H NMR (300 MHz, CD3OD): d=
3.84–3.60 (m, 1H), 3.21–3.08 (m, 2H), 3.09–2.87 (m, 1H), 2.41–2.23
(m, 1H), 2.25–1.80 (m, 6H), 1.80–1.31 (m, 8H), 0.99 ppm (t, J=
7.0 Hz, 3H); 13C{1H} NMR(100 MHz, [D6]DMSO) d=66.59, 63.02,
49.76, 33.34, 28.16, 27.99, 27.27, 22.20, 18.84, 17.88, 13.71 ppm;
19F NMR(280 MHz, CDCl3): d=ꢀ76.16 ppm; IR (film): n˜ =3668, 3448,
3004, 2955, 2939, 2871, 2675, 2652, 2620, 2584, 2541, 2502, 2407,
1680, 1472, 1455, 1433, 1423, 1385, 1204, 1181, 1132, 1085, 1075,
1061, 1028, 1010, 987, 836, 802, 722, 708, 596, 517 cmꢀ1; HRMS
(ESI): m/z: calcd for C11H22N: 168.1747 [M+H]+; found: 168.1748;
calcd for C24H44N2O2F3: 449.3349 [2M+TFA]+; found: 449.3351;
calcd for C22H44N2Cl: 371.3188 [2M+Cl]+; found: 371.3188; GCMS
(DB50S-Slowramp/of the free amine): 6.61 min (124, 96, 70).
Compound 3a: According to general procedure A 74 mg (81%)
were obtained. Rf =0.10 (Hex/Et2O=10:1, ALOx, free amine);
[a]2D4 = +39.58 (c=0.81 in MeOH, d.r.>99:1, >99% ee); 1H NMR
(400 MHz, CD3OD): d=3.74 (ddd, J=12.0, 9.0, 3.5 Hz, 1H); 3.05 (mc,
1H); 2.96 (mc, 1H); 2.83 (td, J=11.5 Hz, J=6.5 Hz, 1H); 2.36 (mc,
1H); 2.19–1.87 (m, 5H); 1.77–1.61 (m, 2H); 1.61–1.38 (m, 2H);
1.37–1.22 (m, 2H); 1.03 (d, J=6.5 Hz, 3H); 1.01 ppm (t, J=7.5 Hz,
3H); 13C{1H} NMR (100 MHz, CD3OD): d=73.69, 66.60, 52.04, 35.93,
32.55, 29.50, 28.29, 26.02, 20.07, 18.34, 9.715 ppm; 19F NMR
(282 MHz, CD3OD): d=ꢀ77.45 ppm; IR (film): n˜ =3437, 2971, 2940,
2887, 2771, 2721, 2676, 2623, 2572, 1778, 1732, 1672, 1462, 1436,
1385, 1202, 1143, 1086, 1073, 1053, 1006, 834, 799, 721, 707,
596 cmꢀ1; GCMS (DB50S): m/z: 167.1 [M]·+, 138.1 [MꢀC2H5]·+, 96.0
Compound 1b: According to general procedure A 64 mg (80%)
were obtained. Rf =0.20 (Et2O/pentan 1:6 on AlOx-TLC (free
amine)); 1H NMR (300 MHz, CD3OD): d=3.80–3.60 (m, 1H), 3.20–
3.09 (m, 2H), 3.10–2.93 (m, 1H), 2.29 (dddd, J=12.5, 9.5, 6.5,
3.0 Hz, 1H), 2.21–1.85 (m, 5H), 1.73–1.43 (m, 4H), 1.37 ppm (d, J=
6.5 Hz, 3H); 13C{1H} NMR (100 MHz, CD3OD): d=67.31, 60.47, 50.53,
31.62, 28.48, 27.83, 22.53, 18.78, 17.41 ppm; 19F NMR (280 MHz,
[MꢀC5H11]·+
;
HRMS (ESI): calcd for C13H22F3NO2: 168.17468
[MꢀTFA]+; found: 168.17488; calcd for C24H44F3N2O2: 449.33494
[2MꢀTFA]+; found: 449.33454.
Compound 3b: According to general procedure A 98 mg (98%)
were obtained. Rf =0.16 (Hex/Et2O=6:1, ALOx, free amine); [a]D24
=
+42.08 (c=1.00 in MeOH); 1H NMR (300 MHz, CD3OD): d=3.75
Chem. Eur. J. 2014, 20, 1964 – 1979
www.chemeurj.org
1976 ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
(ddd, J=12.0, 8.5, 3.5 Hz, 1H), 3.04 (m, 2H), 2.83 (td, J=11.5,
6.0 Hz, 1H), 2.36 (mc, 1H), 2.18–1.80 (m, 5H), 1.77–1.62 (m, 2H),
1.59–1.21 (m, 5H), 1.03 (d, J=6.5 Hz, 3H), 0.98 ppm (t, J=7.0, 3H);
13C{1H}-NMR (100 MHz, CD3OD): d=73.60, 65.28, 52.09, 35.90, 35.12,
32.55, 30.08, 28.32, 20.05, 19.45, 18.35, 14.08 ppm; 19F NMR
(282 MHz, CD3OD): d=ꢀ77.24 ppm; IR (KBr): n˜ =3435, 2962, 2934,
2878, 2644, 2601, 2548, 1671, 1459, 1418, 1387, 1200, 1175, 1128,
1085, 1051, 997, 830, 798, 720 cmꢀ1; HRMS (ESI): m/z: calcd for
C14H24F3NO2: 182.19033 [MꢀTFA]+; found: 182.19035; GCMS
(282 MHz, CD3OD): d=ꢀ77.63 ppm; IR (film): n˜ =3431, 2958, 2934,
2864, 2696, 2591, 1779, 1740, 1671, 1460, 1384, 1200, 1181, 1140,
1050, 832, 798, 720, 707, 595 cmꢀ1; HRMS (ESI): m/z: calcd for
C19H34F3NO2: 252.26858 [MꢀTFA]+; found: 252.26832; GCMS
(DB50S/of the free amine): 6.54 min m/z: 251.2 [M]·+
, 180.1
[MꢀC5H11]·+
.
Compound 3g: According to general procedure A 103 mg (98%)
were obtained. Rf =0.39 (Hex/Et2O=6:1, ALOx, free amine), [a]D25
=
+47.98 (c=1.00 in MeOH), 1H NMR (300 MHz, CD3OD): d=3.75
(ddd, J=12.0, 9.0, 4.0 Hz, 1H), 3.11–2.97 (m, 2H), 2.91 (td, J=11.5,
6.5 Hz, 1H), 2.38 (dddd, J=13.0, 9.5, 6.5, 3.0 Hz, 1H), 2.23–1.84 (m,
5H), 1.77–1.14 (m, 20H), 0.99–0.87 ppm (m, 6H), 13C{1H} NMR
(75 MHz, CD3OD): d=72.79, 65.47, 52.06, 40.66, 33.14, 33.08, 32.73,
30.15, 30.06, 29.52, 29.20, 28.44, 26.12, 23.78, 23.58, 20.11, 14.35,
14.24 ppm, 19F NMR (282 MHz, CD3OD): d=ꢀ77.64 ppm; IR (film):
n˜ =3444, 2958, 2934, 2863, 1779, 1741, 1671, 1457, 1436, 1384,
1201, 1176, 798, 720, 706, 638, 591, 447 cmꢀ1, HRMS (ESI): m/z:
calcd for C20H36F3NO2 [MꢀTFA]+: 266.28423; found: 266.28398;
GCMS (DB50S/of the free amine): 6.78 min m/z: 265.3 [M]·+, 180.1
(DB50S/of the free amine): 5.11 min m/z: 181.1 [M]·+
, 138.1
[MꢀC3H7]·+, 96.0 [MꢀC6H13]·+
.
Compound 3c: According to general procedure A 57 mg (71%)
were obtained. Rf =0.18 (Hex/Et2O=6:1, ALOx, free amine); [a]D25
=
+37.98 (c=1.00 in MeOH); 1H NMR (300 MHz, CD3OD): d=3.75
(ddd, J=12.0, 9.0, 3.5 Hz, 1H), 3.12–2.96 (m, 2H), 2.83 (td, J=11.5,
6.5 Hz, 1H), 2.37 (mc, 1H), 2.21–1.83 (m, 5H), 1.77–1.61 (m, 2H),
1.61–1.19 (m, 7H), 1.03 (d, J=6.5 Hz, 3H), 0.96 ppm (t, J=7.0 Hz,
3H); 13C{1H} NMR (100 MHz, CD3OD): d=73.62, 65.46, 52.08, 35.93,
32.79, 32.56, 30.14, 28.32, 28.28, 23.50, 20.05, 18.35, 14.13 ppm;
19F NMR (282 MHz, CD3OD): d=ꢀ77.37 ppm; IR (film): n˜ =3423,
2961, 2936, 2875, 2587, 2543, 1771, 1732, 1682, 1671, 1460, 1440,
[MꢀC6H13]·+
.
Compound 3h: According to general procedure A 76 mg (76%)
1417, 1385, 1200, 1179, 1133, 1051, 829, 798, 719, 708, 597 cmꢀ1
;
were obtained. Rf =0.45 (Hex/Et2O=6:1, ALOx, free amine); [a]D25
=
HRMS (ESI): m/z: calcd for C15H26F3NO2: 196.20598 [MꢀTFA]+;
+41.78 (c=1.01 in MeOH); 1H NMR (300 MHz, CD3OD): d=5.81
(dddd, J=16.5, 10.0, 8.0, 6.5 Hz, 1H), 5.32–5.18 (m, 2H), 3.77 (ddd,
J=11.5, 9.0, 4.0 Hz, 1H), 3.19–2.99 (m, 2H), 2.93 (td, J=11.5, 6.5 Hz,
1H), 2.79–2.60 (mc, 1H), 2.46–2.25 (m, 2H), 2.18–1.93 (m, 4H), 1.82–
1.14 (m, 11H), 0.93 ppm (t, J=7.0 Hz, 3H); 13C{1H} NMR (100 MHz,
CD3OD): d=162.0 (d, J=35.5 Hz), 133.0, 120.2, 117.8 (d, J=
291.0 Hz), 73.08, 64.77, 52.26, 40.55, 37.66, 33.12, 30.17, 29.47,
29.20, 28.28, 23.77, 20.17, 14.24 ppm; 19F NMR (282 MHz, CD3OD):
d=ꢀ77.67 ppm, IR (film): n˜ =3445, 2959, 2935, 2864, 2753, 2699,
2591, 1780, 1747, 1671, 1457, 1444, 1436, 1384, 1202, 1177, 995,
925, 834, 798, 720, 706, 641, 597, 454 cmꢀ1; HRMS (ESI): m/z: calcd
for C17H28F3NO2: 222.22163 [MꢀTFA]+; found: 222.22155; GCMS
found: 196.20595; GCMS (DB50S/of the free amine): 5.43 min m/z:
195.1 [M]·+, 138.1 [MꢀC4H9]·+, 96.0 [MꢀC7H15]·+
.
Compound 3d: According to general procedure A 72 mg (75%)
were obtained. Rf =0.10 (Hex/Et2O=6:1, ALOx, free amine); [a]D25
=
+47.18 (c=0.68 in MeOH); 1H NMR (300 MHz, CD3OD): d=5.82
(ddt, J=17.0, 10.0, 6.5 Hz, 1H), 5.13–4.95 (m, 2H), 3.74 (ddd, J=
12.0, 8.5, 3.5, 1H), 3.13–2.97 (m, 2H), 2.84 (td, J=11.5, 6.5 Hz, 1H),
2.35 (mc, 1H), 2.21 ꢀ1.85 (m, 7H), 1.77–1.21 (m, 7H), 1.03 ppm (d,
J=6.5, 3H); 13C{1H} NMR (100 MHz, CD3OD): d=138.95, 115.84,
73.64, 65.32, 52.11, 35.89, 34.31, 32.54, 32.42, 30.13, 28.31, 25.40,
20.05, 18.35 ppm; 19F NMR (282 MHz, CD3OD): d=ꢀ77.69 ppm; IR
(film): n˜ =3077, 2963, 2932, 1773, 1737, 1685, 1669, 1460, 1445,
1414, 1386, 1261, 1198, 1119, 1054, 914, 705, 662, 406 cmꢀ1; HRMS
(ESI): m/z: calcd for C16H26F3NO2: 208.20598 [MꢀTFA]+; found:
208.20596; GCMS (DB50S/of the free amine): 5.67 min m/z: 207.1
(DB50S/of the free amine): 5.96 min m/z: 221.2 [M]·+
, 180.1
[MꢀC3H5]·+
.
Compound 4: Predried CeCl3 (380 mg, 1.55 mmol, 5.00 equiv) was
heated in vacuum to 1608C for 2 h. Dry THF (4.9 mL) was added at
room temperature and the resulting yellow suspension subjected
to an ultrasonic bath for 2 h. The reaction mixture was cooled to
ꢀ788C, treated with propyl magnesium chloride (775 mL, 2.0m in
Et2O, 5.00 equiv) and stirred for 2.5 h. Compound 18 (47 mg,
0.31 mmol, 1.00 equiv) in THF (0.8 mL) was added by syringe and
the resulting mixture warmed to room temperature. After 17 h, the
crude mixture was cooled to ꢀ108C and treated with sodium bor-
ohydride (35 mg, 923 mmol, 3.00 equiv) and glacial acetic acid
(2 mL). The resulting suspension was stirred for 1 h at ambient
temperatures. The mixture was basified by addition of 2m NaOH
(10 mL) and extracted with CH2Cl2 (4ꢂ50 mL), dried over Na2SO4,
filtered, and concentrated in a vacuum (400 mbar, 258C) to give
a crude oil. The crude product was subjected to an AlOx-column
and eluted with Hex/Et2O (15:1). Collected fractions were directly
treated with an excess of TFA prior to concentrating the purified
product in vacuum. The product was obtained as colorless oil:
47 mg (52%); Rf =0.63 (Hex/Et2O=6:1, ALOx, free amine); [a]2D5 = +
68.68 (c=1.31 in MeOH), 1H NMR (400 MHz, CD3OD) d=5.84 (mc,
1H), 5.77 (mc, 1H), 5.77 (dt, J=10.3, 1.8, 1H), 3.93–3.79 (m, 2H),
3.24–3.06 (m, 2H), 2.59–2.43 (m, 2H), 2.22–2.01 (m, 2H), 1.90 (mc,
1H), 1.76 (mc, 1H), 1.68–1.51 (m, 2H), 1.45 (mc, 1H), 1.14 (d, J=7.0,
3H), 1.02 ppm (t, J=7.0, 3H); 13C{1H} NMR (75 MHz, CD3OD): d=
133.7, 124.9, 70.51, 64.08, 52.93, 36.07, 34.39, 28.72, 20.98, 19.21,
17.82, 14.07 ppm, 19F NMR (282 MHz, CD3OD) d=ꢀ77.60 ppm; IR
(film): n˜ =3437, 2969, 2939, 2880, 2667, 2537, 1777, 1677, 1460,
[M]·+, 138.1 [MꢀC5H9]·+, 96.0 [MꢀC8H15]·+
.
Compound 3e: According to general procedure A 99 mg (99%)
were obtained. Rf =0.33 (Hex/Et2O=6:1, ALOx, free amine); [a]D24
=
+48.68 (c=0.99 in MeOH); 1H NMR (300 MHz, CD3OD): d=3.75
(ddd, J=11.5, 9.0, 4.0 Hz, 1H), 3.11–2.98 (m, 2H), 2.91 (td, J=11.5,
6.5 Hz, 1H), 2.38 (dddd, J=13.0, 9.5, 6.5, 3.0 Hz, 1H), 2.22–1.95 (m,
4H), 1.87 (mc, 1H), 1.77–1.15 (m, 14H), 0.99 (t, J=7.0 Hz, 3H),
0.93 ppm (t, J=7.0, 3H); 13C{1H} NMR (100 MHz, CD3OD): d=161.5
(d, J=37.0 Hz), 117.5 (d, J=290.0 Hz), 72.79, 65.28, 52.07, 40.69,
35.14, 33.14, 30.05, 29.51, 29.21, 28.45, 23.78, 20.11, 19.45, 14.24,
14.09 ppm; 19F NMR (282 MHz, CD3OD): d=ꢀ77.74 ppm; IR (film):
n˜ =3439, 2963, 2937, 2876, 2749, 2698, 2566, 1779, 1739, 1692,
1668, 1456, 1384, 1202, 1051, 993, 923, 832, 798, 720, 707, 594,
457 cmꢀ1
; HRMS (ESI): m/z: calcd for C17H30F3NO2: 224.23728
[MꢀTFA]+; found: 224.23719; GCMS (DB50S/of the free amine):
5.97 min m/z: 223.2 [M]·+, 180.1 [MꢀC3H7]·+
.
Compound 3 f: According to general procedure A 78 mg (75%)
were obtained. Rf =0.48 (Hex/Et2O=6:1, ALOx, free amine); [a]D25
=
+52.78 (c=1.02 in MeOH); 1H NMR (300 MHz, CD3OD): d=3.75
(ddd, J=11.5, 9.0, 4.0 Hz, 1H), 3.14–2.97 (m, 2H), 2.91 (td, J=11.5,
6.5 Hz, 1H), 2.38 (dddd, J=13.0, 9.5, 6.5, 3.0 Hz, 1H), 2.23–1.82 (m,
5H), 1.78–1.14 (m, 18H), 1.04–0.82 ppm (m, 6H); 13C{1H} NMR
(75 MHz, CD3OD): d=161.7 (d, J=36.5 Hz), 117.6 (d, J=290.0 Hz),
72.79, 65.46, 52.05, 40.64, 33.14, 33.02, 32.64, 30.04, 29.52, 29.20,
28.43, 25.82, 23.77, 23.46, 20.11, 14.25, 14.25 ppm; 19F NMR
Chem. Eur. J. 2014, 20, 1964 – 1979
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1977
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
1429, 1385, 1203, 1137, 1052, 836, 800, 769, 721, 708, 597,
14.40 ppm; 19F NMR (282 MHz, CD3OD): d=ꢀ77.73 ppm; IR (film):
n˜ =2969, 2938, 2881, 2788, 2701, 2549, 1780, 1742, 1671, 1461,
1431, 1385, 1202, 1173, 833, 812, 798, 720, 706, 596 cmꢀ1; HRMS
(ESI): m/z: calcd for C16H26F3NO2: 196.20598 [MꢀTFA]+; found:
196.20597; calcd for C30H52F6N2O4: 505.39754 [2MꢀTFA]+; found:
505.39770; GCMS (DB50S/of the free amine): 5.34 min m/z: 152.1
518 cmꢀ1
, HRMS (ESI): m/z: calcd for C17H28F3NO2: 180.17468
[MꢀTFA]+; found: 180.17474; GCMS (DB50S/of the free amine):
5.05 min m/z: 179.2 [M]·+, 136.1 [MꢀC3H7]·+
.
Compound 20a: Diisopropylamine (165 mL, 1.16 mmol, 1.50 equiv)
was dissolved in dry THF (5 mL) and cooled to 08C. nBuLi (480 mL,
2.5m in THF, 1.55 equiv) was added. The reaction mixture was then
allowed to stir for 1 h at 08C, cooled to ꢀ788C, and treated with X
(98 mg, 0.77 mmol, 1.00 equiv). After 1.5 h, the reaction mixture
was treated with methyl iodide (72 mL, 1.16 mmol, 1.50 equiv),
stirred for 2.5 h at ꢀ788C, and subsequently warmed to room tem-
perature. The reaction mixture was quenched by addition of dist.
water (5 mL) and extracted with EtOAc (3ꢂ20 mL). The recom-
bined organic layers were dried over Na2SO4, filtered, and concen-
trated in vacuum. The crude product (d.r.=2:1) was subjected to
a silica gel column and eluted with CH2Cl2/MeOH (98:2) to give
12% (13 mg) of the major diastereomer and 88% (96 mg) of the
diastereomeric mixture; Rf =0.50 (CH2Cl2/MeOH=98:2); 1H NMR
(400 MHz, CDCl3): d=3.18 (mc, 1H); 2.93 (mc, 1H); 2.89 (s, 3H); 2.34
(mc, 1H); 2.00 (mc, 1H); 1.88 (mc, 1H); 1.25 (mc, 1H); 1.20 (d, J=
7.0 Hz, 3H); 0.97 ppm (d, J=6.5 Hz, 3H); 13C{1H} NMR (75 MHz,
CDCl3): d=173.1, 57.67, 39.08, 36.70, 29.04, 19.05, 17.78 ppm.
[MꢀC3H7]·+, 110.0 [MꢀC6H13]·+
.
Compound 5: According to general procedure A 32 mg (96%)
were obtained. Rf =0.42 (Hex/Et2O=6:1, ALOx, free amine);
1H NMR (300 MHz, CD3OD): d=3.70 (mc, 1H), 3.18 (dt, J=11.5,
4.0 Hz, 1H), 3.05 (mc, 1H), 2.81 (mc, 1H), 2.32 (mc, 1H), 2.14–1.97
(m, 2H), 1.90–1.26 (m, 9H), 1.05 (d, J=7.5 Hz, 3H), 1.03–0.98 ppm
(m, 6H); 13C{1H} NMR (100 MHz, CD3OD): d=74.52, 67.48, 52.90,
40.14, 32.02, 31.07, 30.45, 28.08, 19.89, 19.25, 18.33, 14.06,
12.21 ppm; 19F NMR (282 MHz, CD3OD): d=ꢀ77.60 ppm; HRMS
(ESI): m/z: calcd for C16H26F3NO2 [MꢀTFA]+: 196.20598; found.:
196.20597; calcd for C30H52F6N2O4 [2MꢀTFA]+: 505.39754; found:
505.39770; GCMS (DB50S/of the free amine): 5.37 min m/z: 152.1
[MꢀC3H7]·+, 110.0 [MꢀC6H13]·+
.
Acknowledgements
Compound 21a: This compound was synthesized along the lines
of the synthesis of 20a. Yield 97 mg (97%). The crude product
(d.r.=2:1) was subjected to a silica gel column and eluted with
CH2Cl2/MeOH (98:2). A second silica gel column using MTBE/Hex
(2:1)!CH2Cl2/MeOH (98:2) as the eluent yielded both diastereo-
mers as colorless oils. Rf =0.21 (MTBE); [a]2D4 = +45.48 (c=1.01 in
We are grateful to the Deutsche Forschungsgemeinschaft and
the Evonik-Stiftung (graduate fellowship to F.A.) for the gener-
ous financial support of this work. Donation of chemicals from
Evonik, Chemetall, and BASF is gratefully acknowledged. We
would like to thank E. Koch for initial work, and J. Sieler for
providing X-ray crystallographic data on compounds 12a and
12b.
1
CHCl3); H NMR (300 MHz, CDCl3): d=3.55 (mc, 1H); 3.42 (mc, 1H);
3.00 (td, J=10.5, 5.0 Hz, 1H); 2.35 (mc, 1H); 2.11 (mc, 1H); 2.01–
1.85 (m, 2H); 1.71 (mc, 1H); 1.48 (mc, 1H); 1.36 (mc, 1H); 1.22 (d,
J=7.0 Hz, 3H); 1.20 (mc, 1H); 0.99 ppm (d, J=6.5 Hz, 3H);
13C{1H} NMR (75 MHz, CDCl3): d=172.1, 65.56, 45.35, 39.46, 36.77,
35.22, 32.35, 22.38, 18.11, 18.04 ppm; IR (film): n˜ =3475, 2959,
2928, 2874, 1634, 1664, 1437, 1383, 1329, 1285, 1278, 1209, 1162,
892, 729, 637, 599, 588 cmꢀ1; GCMS (DB50S): 5.83 min m/z 167.1
Keywords: large-scale synthesis · Mannich reaction · natural
products · organocatalysis · total synthesis
+
+
[M] , 125.0 [MꢀC3H6] , 97.1 [MꢀC5H10] +; HRMS (ESI): m/z: calcd
for C10H17NO: 168.13829 [M+H]+; found: 168.13840; calcd for
C20H34N2O2: 335.26930 [2M+H]+; found.: 335.26916; calcd for
C20H34N2O2: 335.25125 [2M+Na]+; found: 357.25142.
C
C
C
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Compound 21b: This compound was synthesized along the lines
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(d.r.=2:1) was subjected to a silica gel column and eluted with
CH2Cl2/MeOH (98:2). A second silica gel column using MTBE/Hex
(2:1)!CH2Cl2/MeOH (98:2) as the eluent yielded both diastereo-
mers as colorless oils. Rf =0.17 (MTBE); 1H NMR (300 MHz, CDCl3):
d=3.60–3.38 (m, 2H); 2.97 (mc, 1H); 2.50 (mc, 1H); 2.12 (mc, 1H);
1.92 (m, 1H); 1.80–1.50 (m, 4H); 1.38 (mc, 1H); 1.22 (d, J=7.5 Hz,
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+
C
18.39 ppm; GCMS (DB50S): 5.83 min m/z: 167.1 [M]
, 125.0
[MꢀC3H6] , 97.1 [MꢀC5H10] +; HRMS (ESI): m/z calcd for C10H17NO:
168.13829 [M+H]+; found: 168.13840; calcd for C20H34N2O2:
335.26930 [2M+H]+; found: 335.26916; calcd for C20H34N2O2:
335.25125 [2M+Na]+; found: 357.25142.
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[52] CCDC-905604 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Structure parameters for 12b: C18H23NO4, M=317.37, T=130.1(10) K,
orthorhombic space group: P212121. Protons are omitted for clarity, ex-
cluding H4.
Received: October 18, 2013
Published online on January 16, 2014
Chem. Eur. J. 2014, 20, 1964 – 1979
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