Addition of organometallic reagents to chiral N-methoxylactams: Enantioselective syntheses of pyrrolidines and piperidines

Article abstract of DOI:10.1002/chem.201302735

Enantioselective iridium-catalyzed allylic substitutions were used to prepare N-allyl hydroxamic acid derivatives that were suitable for ring-closing metathesis, giving N-methoxylactams. Reactions of these derivatives with Grignard or organolithium compou

Full text of DOI:10.1002/chem.201302735

DOI: 10.1002/chem.201302735
Addition of Organometallic Reagents to Chiral N-Methoxylactams:
Enantioselective Syntheses of Pyrrolidines and Piperidines
Mascha Jꢀkel, Jianping Qu, Tobias Schnitzer, and Gꢁnter Helmchen*[a]
Abstract: Enantioselective iridium-cat-
alyzed allylic substitutions were used to
prepare N-allyl hydroxamic acid deriv-
atives that were suitable for ring-clos-
ing metathesis, giving N-methoxylac-
tams. Reactions of these derivatives
with Grignard or organolithium com-
pounds gave hemiaminals, which could
be reduced diastereoselectively via
acyliminium intermediates to give cis-
piperidines or cis-pyrrolidines with sub-
stituents in the 2,6- or 2,5-positions, re-
spectively. In addition, compounds with
a quaternary carbon center could be
synthesized by corresponding reactions
with potassium cyanide/AcOH. The
procedures were applied in the synthe-
ses of alkaloids (ꢀ)-209D and (+)-pro-
sophylline.
AHCTUNGTRENNUNG
Keywords: alkaloids · allylic com-
pounds · enantioselectivity · iridi-
um · lactams
Introduction
We have recently developed an asymmetric Ir-catalyzed al-
lylic amination procedure by using N-alkoxy amides as nu-
cleophiles that allows chiral N-allylated hydroxylamines A
to be prepared efficiently with high enantiomeric purity and
broad scope with respect to substituents R1–R3
(Scheme 1).[1] Being interested in applications of allylic
Scheme 2. Preparation of a,a’-disubstituted pyrrolidines and piperidines
from allylic amines.
Scheme 1. Ir-catalyzed allylic substitution with hydroxamic acid deriva-
tives.
amines in the synthesis of pyrrolidine and piperidine alka-
loids,[2] we have also successfully probed a nucleophile con-
taining an olefinic moiety, R3 =CH2CH=CH2, yielding
a product suitable for ring-closing metathesis (RCM) to give
a piperidine derivative B (Scheme 2). Subsequently, we have
extended this approach and are now able to report enantio-
and diastereoselective syntheses of a variety of five- and six-
membered cyclic hydroxamic acid derivatives of type B with
enantiomeric excess of more than 90%.
Furthermore, as most of the aforementioned alkaloids
contain substituents at both a-positions of the azacycle, we
have investigated reactions of compounds B with organo-
lithium and Grignard compounds that would open a route
to hemiaminals of type C and subsequently iminium salts
and/or enamines with their vast synthetic potential
(Scheme 2). It should be noted that targets D can be gener-
ated with cis- as well as trans-configuration by first reduc-
tion and then addition of a metal organyl, respectively.
At the outset we could build on experience with Weinreb
amides RCONACTHNUTRGNEUNG
(OMe)Me[3] and the pioneering work of the
[a] M. Jꢀkel, Dr. J. Qu, T. Schnitzer,+ Prof. Dr. G. Helmchen
Organisch-Chemisches Institut
Kibayashi group[4] on alkaloid syntheses with bicyclic N-
acyl-hydroxylamines prepared by intramolecular cycloaddi-
tion of nitroso compounds. While our work was in progress,
Kouklovsky, Vincent et al. published further work with bicy-
clic N-alkoxylactams, generated by a cycloaddition approach
with nitroso compounds that differed from those used by
the Kibayashi group.[5] Finally, Chida, Sato et al. reported
Ruprecht-Karls-Universitꢀt Heidelberg
Im Neuenheimer Feld 270, 69120 Heidelberg (Germany)
Fax : (+49)6221-544205
E-mail: g.helmchen@oci.uni-heidelberg.de
[+] This author carried out a preliminary synthesis of (ꢀ)-209D.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201302735.
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FULL PAPER
bottom-up studies that recently also included achiral and
a few racemic monocyclic N-alkoxy-lactams.[6] These authors
have very recently studied route B ! trans-D, which we
have not pursued.[6a] The steric course of the addition reac-
tions depicted in Scheme 2 is in accordance with general
rules concerning additions to iminium ions,[6a, 7] that is, pre-
ferred axial attack of the nucleophile at the iminum ion in
the half-chair conformation.
The approach sketched out above is not without prob-
ꢀ
lems. Thus, lability of the N O bond makes it vulnerable to
reductive cleavage,[8] which would limit reactions with re-
agents of the type MR4 (R4 =H). Reducing agents, however,
ꢀ
are quite selective. For example, the N O bond is cleaved
upon catalytic hydrogenation with Raney nickel as catalyst
whereas it is unaffected with Pd/C. Experience with Weinreb
amides has revealed that elimination reactions giving either
imines or formaldehyde, are fairly common.[9]
Figure 1. Pronucleophiles, (p-allyl)Ir complexes and achiral ancillary li-
We want to point out that our objective can, in principle,
also be reached by direct addition of metal organyls to
amides followed by reduction. The limits of this approach
are, however, well-known. Nevertheless, some examples for
the diastereoselective addition of Grignard reagents to bi-
gands used.
Table 1. Ir-catalyzed allylic substitution with pronucleophile Nu1.
ACHTUNGTRENNUNG
cyclic amides followed by reduction have been reported.[10]
Reductive alkylations of monocyclic lactams are even less
common.[11] In general, amides require preactivation prior to
nucleophilic addition.[12] General used strategies are trans-
formation into the corresponding thioamides,[13,14] lactim
ethers,[15] or iminium triflates.[16] The latter method was re-
cently extended to include pyrrolidines and piperidines and
applied in alkaloid synthesis.[16d]
A widely adopted method is the conversion of N-acyl de-
rivatives into N-acyliminium ions, which readily react with
various types of nucleophiles.[17] In this case, the route to
a,a’-disubstituted pyrrolidines or piperidines almost exclu-
sively involves first reduction, then addition of acid to gener-
ate the acyliminium ion, which is then alkylated. The reverse
sequence, in analogy to Scheme 2, is uncommon, likely be-
cause of ring opening at the hemiaminal stage.[18]
Substrate Catalyst Base
t [h] Yield [%][a] 2/3[b]
ee [%][c]
96:4 98
98:2 94
1
2
3
4
1a
1c
1d
1d
C2
C4
C4
C3
TBD 1.5
59
90
71
77
DBU
DBU
DBU
2
1
3
90:10 88
93:7 93
[a] Combined yield of 2+3. [b] Determined by 1H NMR spectroscopic
analysis of the crude product. [c] Determined by HPLC analysis.
were particularly high for the reaction of substrate 1a cata-
lyzed by C2 (Table 1, entry 1). Complex C4, with dbcot
(dbcot=dibenzocyclooctatetraene) as an ancillary ligand,
was used for substrates 1c and d (Table 1, entries 2 and 3).
For 1d, further improvement was possible by using C3, de-
rived from ligand L1, as catalyst (Table 1, entry 4).
Following our general concept, the use of pronucleophile
Nu2 was probed (Table 2). This compound was readily pre-
pared from ethyl crotonate and O-methylhydroxylamine hy-
drochloride by using a procedure developed by Gissot
et al.[22] The Ir-catalyzed allylic amination of carbonate 1a
with Nu2 proceeded smoothly to give 4a with excellent
regio- and enantioselectivity.
Next, reactions with the more demanding pronucleophile
Nu3 were investigated (Scheme 3). This pronucleophile, as
well as the substitution products 6, can rearrange under
basic reaction conditions to the corresponding crotonamides
Nu2 and 4, respectively. Indeed, reaction of the allylic car-
bonates gave mixtures of the branched products 6 and 4
with modest enantioselectivity. Therefore, we decided to
Results and Discussion
Ir-catalyzed allylic amination: The Ir-catalyzed allylic substi-
tution is a reliable method for the synthesis of branched al-
lylic compounds with a high degree of regio- and enantiose-
lectivity.[19] Monosubstituted carbonates are normally used
as substrates. Recently, stable (p-allyl)Ir-complexes have
become readily accessible and, therefore, can be used as
single-species catalysts.[20] As pointed out above, hydroxamic
acid derivatives are suitable N-nucleophiles that give N-ally-
lated hydroxylamines. In the present work, the three pronu-
cleophiles Nu1–Nu3 were employed in conjunction with
“salt-free”[21] reaction conditions (Figure 1).
Allylic substitution with Nu1 constitutes the most general
access to the requisite allylic hydroxylamines (Table 1). Sub-
stitution reactions were remarkably fast with all the allylic
substrates of type 1 probed. Regio- and enantioselectivity
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G. Helmchen et al.
Table 2. Ir-catalyzed allylic substitution with the pronucleophile Nu2.
reduce crude 7 directly. The enantiomeric excess of 9a was
found to be identical to that of the starting material 4a.
Hexa- and heptacyclic hydroxamic acid derivatives were
obtained from the branched allylic substitution products 2
as depicted in Scheme 5. Boc deprotection with trifluoroace-
tic acid (TFA) or hydrochloric acid followed by Steglich acy-
Substrate Catalyst Base
t [h] Yield [%][a] 4/5[b]
ee [%][c]
1
2
3
4
1a
1b
1b
1e
C2
C2
TBD
1
92
76
80
64
97:3 96
DBU 17
93:7 96
92:8 95
80:20 92
ent-C1[d] DBU 17
ent-C1[d] DBU
7
[a] Isolated yield of branched isomer. [b] Determined by 1H NMR spec-
troscopic analysis of the crude product. [c] Determined by HPLC analy-
sis. [d] 8 mol% catalyst was used.
Scheme 5. Synthesis of hexa- and heptacyclic hydroxamic acid deriva-
tives.
lation[25] with vinylacetic acid or allylacetic acid gave dienes
6 and 10, respectively, which were subjected to RCM to give
olefins 11 and 12, respectively. Hydrogenation of the double
Scheme 3. Ir-catalyzed amination with Nu3.
ꢀ
bond without cleavage of the N O bond was carried out
with Pd/C as catalyst and gave the hydroxamic acid deriva-
carry out the Ir-catalyzed amination with the Boc-protected
pronucleophile Nu1 and to install the enoyl group after-
wards.
tives 13 and 14 in good overall yields.
Alkylation/reduction of hydroxamic acid derivatives; Opti-
mization of reaction conditions and mechanistic aspects: N-
Methoxylactam 13a was chosen as test substrate for identifi-
cation of suitable conditions for the nucleophilic addition
and subsequent reduction to 2,6-disubstituted piperidines
(cf. Scheme 2). The reaction of phenylmagnesium bromide
with 13a in tetrahydrofuran (THF) proceeded smoothly at
room temperature with full conversion after one hour.
Work-up by addition of water, extraction with ethyl acetate,
and concentration of the extract in vacuo gave the crude
Cyclic hydroxamic acid derivatives: Pyrrolidinones
9
(Scheme 4) were prepared in good yields from substitution
products 4 by ring-closing metathesis (RCM) in toluene as
solvent and subsequent reduction with sodium borohydride/
nickel chloride.[23] This seemingly simple route required
a considerable amount of optimization because of a marked
tendency of the primarily formed conjugated N-methoxylac-
tam 7 to rearrange to enamine 8.[24] This rearrangement oc-
curred upon contact with silica or alumina. Chromatograph-
ic purification of 7 turned out to be possible with solvents
containing acetic acid; however, it was advantageous to
1
product, which was analyzed by H and 13C NMR spectros-
copy. The spectra were consistent with a mixture of diaste-
reomers of the expected N,O-hemiaminal (cf. C; R1, R3 =
Ph, R2 =OMe, Scheme 2).
The crude material was subjected to catalytic hydrogena-
tion (1 bar) with transition-metal catalysts to yield known
2,6-diphenylpiperidine (15)[26] (Table 3). Under all condi-
tions tried, only cis-15 was formed, the trans-diastereomer
1
was not detected by H or 13C NMR spectroscopic analysis.
With palladium on charcoal and Pearlmanꢂs catalyst, the re-
ꢀ
action times were long and the isolated yields low, the N O
bond was cleaved during hydrogenation (Table 3, entries 1
and 3). Acidification with acetic acid led to acceleration of
the reduction, and product 15 was isolated in an improved
yield of 55% (Table 3, entry 2). The use of platinum on
charcoal and platinum derived from PtO2 led to mixtures of
Scheme 4. Synthesis of N-methoxypyrrolidones.
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Syntheses of Pyrrolidines and Piperidines
FULL PAPER
Table 3. Alkylation/reduction starting from 13a.
had to be immediately reduced. Reduction with H2/
Pd(OH)2/C (Pearlman catalyst) in ethanol furnished
a mixture of pyrrolidine 20 and the N-methyl deriv-
ative 21 (Table 4, entry 1). With Raney nickel as
catalyst, N-methylation also occurred in the sol-
vents methanol and isopropanol (Table 4, entries 2–
4), which indicates that the N-methyl group was de-
rived from the N-OCH3 moiety. N-Methylation was
almost completely avoided with a THF/water mix-
ture as solvent (Table 4, entry 5); under these con-
ditions, cis-2,5-diphenylpyrrolidine (20) was isolated
in 76% yield and the trans isomer was not detected.
Compounds 20[30] and 21[30] have been reported in
the literature and were characterized by 1H and
13C NMR spectroscopy.
Reduction conditions
Procedure[a] t [h] 15/16[b] Yield [%][c]
1
2
3
4
5
6
7
8
9
H2, Pd/C, EtOH
A
A
A
A
A
A
A
B
42
5
>99:1 28
92:8 55
96:4 17
H2, Pd/C, MeOH/AcOH (9:1)
H2, Pd(OH)2/C, MeOH
H2, Rh/C, MeOH
H2, Pt/C, MeOH
H2, PtO2, MeOH
H2, Raney nickel, MeOH
NaBH3CN, AcOH
NaBH4, AcOH
48
48
48
48
18
1.5
1.5
2
100:0 38
75:25 n.d.
37:63 n.d.
>99:1 88
<1:99 87
<1:99 80
<1:99 86
<1:99 80
B
10 NaB
N
B
11 NaBH3CN, Sc
N
B
2
To verify that the N-methyl group originated
from the O-methyl group and to gain insight into
the mechanism of formation of 21, control experi-
ments with the O-CD3 analogue of 9a were carried
out under the developed conditions (Table 4, en-
tries 4 and 5; Scheme 7). These reaction conditions
[a] Procedure A: A suspension of crude hemiaminal and catalyst (20 wt%) in the
stated solvent was stirred under hydrogen atmosphere (1 bar) at RT; Procedure B:
After the reaction with the Grignard reagent, AcOH (excess) and then the complex
metal hydride (5 equiv) were added. [b] Determined by GC-MS analysis or 1H NMR
spectroscopic analysis of the crude product. [c] Isolated yield, only one diastereomer
found.
the piperidine and N-methoxypiperidine (Table 3, entries 5
and 6). Finally, Raney nickel turned out to be the catalyst of
choice. Thus, cis-2,6-diphenylpiperidine (15) was obtained as
a single product in 88% yield over two steps (Table 3,
entry 7).
Clear drawbacks of catalytic hydrogenation are restriction
to substrates with saturated side chains and cleavage of the
ꢀ
N O bond. Therefore, application of acid-stable complex
hydrides, NaBH3CN,[27] NaBH4/AcOH,[28] and NaB
(OAc)3H/
AcOH were examined as reducing agents. The reactions
were carried out as follows. A solution of N-methoxylactam
13a in THF was treated with the organometallic reagent;
after complete consumption of the starting material, an
excess of acetic acid and then the reducing agent were
added. The three reductants gave similar results (Table 3,
Scheme 6. Alkylation/reduction of N-methoxylactam 9a.
entries 8–10). An additional experiment with ScACTHUNRGTNEUNG(OTf)3 in-
stead of acetic acid required aqueous work-up after the ad-
dition of the Grignard reagent but also gave acceptable re-
sults (Table 3, entry 11). All these reductions proceeded in
good yields and with perfect cis-diastereoselectivity accord-
Table 4. Alkylation/catalytic hydrogenation of 9a according to Scheme 6.
Catalyst
Solvent
t [h]
20/21[a]
Yield of 20 [%][b]
1
2
3
4
5
Pd(OH)2/C
EtOH
MeOH
EtOH
iPrOH
THF/H2O
20
48
120
96
33:67
66:34
73:27
73:27
98:2
n.d.
n.d.
n.d.
n.d.
76
Raney nickel
Raney nickel
Raney nickel
Raney nickel
1
ing to H and 13C NMR spectroscopic analysis. The N-alkoxy
group can either be utilized as a protecting group in further
transformations, or easily cleaved with Zn/AcOH or SmI2.[8]
The optimal conditions were then applied to butyrolactam
9a (Scheme 6). NMR spectroscopic analysis of the crude
product obtained after addition of PhMgBr and aqueous
work-up revealed a mixture of the N,O-hemiaminal 17 and
acyclic ketone 18, which were both unstable, but were char-
72
[a] Determined by GC-MS analysis of the crude products. [b] Isolated
yield.
indeed furnished the N-CHD2-amine [D2]-21 as expected for
a pathway involving elimination of water to give an enam-
ine, elimination of formaldehyde, imine reduction, and re-
ductive amination. In addition to [D2]-21, compound [D3]-21
was detected by HRMS analysis of the hydrogenation prod-
ucts; according to the NMR assignment, this species con-
tained an N-CHD2 group and one D at C-3 of the pyrroli-
dine moiety, albeit only to the extent of 15–20%. Control
1
acterized by H and 13C NMR spectroscopic analysis. After
a few hours storage, a further compound was detected that
turned out to be imine 19.[29] The formation of 19 could be
accelerated by addition of an acid or silica gel, to the extent
that is was obtained as the main product. Accordingly, the
crude product from the addition of the Grignard reagent
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G. Helmchen et al.
with diisobutylaluminum hydride (DIBAL-H) and subse-
quent addition of phenylmagnesium bromide, by using a pro-
cedure developed by the Chida group[6a] (see the Supporting
Information). In addition, cis- and trans-22 were reduced to
pyrrolidines 20. Whereas the diastereoselectivity was modest
with NaBH4 or NaBACTHNUGTRNE(NUG OAc)3H (Table 5, entries 1 and 2), it
was excellent with NaBH3CN, especially when acetic acid
was replaced by a Lewis acid (Table 5, entries 3 and 4).
However, in the latter case, the yield of 22 was low and
imine 19 was formed as by-product.
Experiments with the seven-membered ring analogue re-
vealed some limits of the procedure, with ring-opened prod-
ucts being obtained almost exclusively (Scheme 8). Thus, re-
Scheme 8. Alkylation/metal hydride reduction of 14a.
Scheme 7. Alkylation/hydrogenation of deuterium labeled [D3]-9a.
action of 14a with phenylmagnesium bromide followed by
hydrogenation over Raney nickel in methanol gave a mixture
of products, from which the expected 2,7-diphenylazepane
was isolated in less than 5% yield (not shown). Reduction
with NaBH3CN/AcOH (cf. Scheme 8) gave acyclic alcohol
23 as mixture of diastereomers in 68% yield. Clearly, open-
ing of the hemiacetal intermediate is the dominating reac-
tion in this case.
experiments (Scheme 7, entries 2 and 3) with THF/H2O and
THF/D2O as solvents revealed that H/D exchange at C-3
occurs to a considerable degree during the reaction se-
quence.
The above observations are compatible with, at least in
part, an intramolecular retro-ene type fragmentation trans-
ferring one D to C-3 and yielding D2C=O (cf. Scheme 7). As
pointed out above, fragmentation reactions under strongly
basic as well as acidic conditions are well-known.[9] A cyclic
retro-ene reaction of this type has been proposed but not
verified so far.[9a,31]
Alkylation of butyrolactam 9a followed by reduction with
complex metal hydrides in acetic acid was straightforward
(Table 5). N-Methoxypyrrolidine 22 was formed in good
yield, however, with varying degrees of diastereoselectivity
in favor of the cis-isomer. For an unambiguous configura-
tional assignment, trans-22 was prepared by reduction of 9a
Scope of the alkylation/reduction procedure to give a,a’-di-
AHCTUNGTREGsNNNU ubstituted pyrrolidines and piperidines: The scope of the
addition/reduction sequence was then probed. Addition of
Grignard reagents to the five-membered N-methoxy-lactam
9a, and subsequent catalytic hydrogenation with Raney
nickel under the optimized conditions, furnished cis-2,5-di<-
substituted pyrrolidines in moderate to good yields and with
high diastereoselectivity (Scheme 9, products 24–26); the
13C NMR spectra of all products displayed only one set of
signals. The relative cis configuration of 24 was established
by comparison with the reported NMR data for cis- as well
as trans-24.[32] By analogy, assumption of the cis-configura-
tion for 25 and 26 appears warranted.
Table 5. Alkylation/complex hydride reduction of 9a.
The reactions of the six-membered N-methoxy-lactams
likewise gave cis-2,6-disubstituted piperidines in good to ex-
cellent yield with high diastereoselectivity (Scheme 9, prod-
ucts 15 and 27–35). Alkyl, aryl as well as functionalized
alkyl groups were probed as substituents. The 1,3-dioxan-2-
yl ethyl group allows preparation of bicyclic compounds
through subsequent reductive amination, as will be de-
scribed later. In the addition step, organolithium reagents
react at ꢀ788C, whereas Grignard reagents require room
temperature. In all cases, cis isomers were obtained with ex-
cellent diastereoselectivity (more than 10:1). The configura-
tional assignment was based on comparison with literature
Reducing agent
NaBH4
d.r.[a]
5:1
6:1
15:1
Yield of 22 [%][b]
1
2
3
4
77
80
85
42
NaB
N
NaBH3CN
NaBH3CN, Sc
N
>20:1
[a] Determined by GC-MS analysis of the crude products. [b] Isolated
yield.
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Syntheses of Pyrrolidines and Piperidines
FULL PAPER
Scheme 9. Alkylation/catalytic hydrogenation of N-methoxylactams. In
the product formulas, the substituent R is presented at the left. Diaste-
reomeric ratios were determined by GC-MS analysis or on the basis of
1H NMR spectroscopic analysis of the crude products. See the Supporting
Information for a more detailed table. [a] The reaction was carried out at
ꢀ788C. [b] In addition, 35% of benzyl-deprotected product was isolated.
[c] A mixture of Raney nickel and Pd/C was used as catalyst.
Scheme 10. Alkylation/complex metal hydride reduction of N-methoxy-
lactams. In the product formulas, the substituent R is presented at the
left. See the Supporting Information for a more detailed table. Diastereo-
meric ratio was determined by GC-MS analysis or on the basis of
1H NMR spectroscopic analysis of the crude products. [a] The reaction
was carried out at ꢀ788C.
data (15,[26] 27,[33] 29,[33a] and 31[34]); the axial disposition of
both 2-H and 6-H was apparent from vicinal coupling con-
stants (J=10.4–10.8 and 2.2–2.5 Hz) for all products. For
a few selected examples the cis-configuration was further
verified by NOESY experiments (see the Supporting Infor-
mation).
The scope of the alkylation/metal hydride reduction se-
quence is summarized in Scheme 10. With N-methoxy-
butyroACHTUNGTRENNUNGlactams, moderate to good diastereoselectivities in
products derived from 9b. The stereochemical assignments
were made as follows. For 39, the diastereoisomers were
separated and individually characterized by NMR spectro-
scopic analysis, including NOESY experiments. Further-
more, as an empirical correlation, it was found that coupling
constants of the protons NCH(Ph) were 9–10 Hz for the
major cis-isomers and 7.0–7.6 Hz for the minor trans-iso-
mers.
favor of the cis-products were obtained (Scheme 10, 36–40).
The introduction of unsaturated side chains, for example
allyl- (37) and 2-trimethylsilylethinyl (38) groups, was possi-
ble with this sequence. As reducing agents, NaBH3CN,
NaBH4,
The six-membered N-methoxy-lactams gave cis-2,6-disub-
stituted piperidines in high yield (Scheme 10, 41–46). Reduc-
tions of hemiaminals derived from phenyl-substituted
lactam 13a were best carried out with NaBH3CN/AcOH,
whereas NaBH4 was better suited for hemiaminals derived
from the alkyl-substituted starting materials 13c and 13d.
The addition of allylmagnesium bromide to 13a gave a hemi-
aminal with a prop-1-enyl group (NMR analysis), and subse-
quent reduction produced 42 with an internal double bond.
The corresponding isomerization did not occur in the case
of the five-membered N-methoxy-lactam (Scheme 10, 37).
NaBACHTUNGTRENNUNG(OAc)3H and DIBAL-H were investigated (see the
Supporting Information for a detailed table). Diastereose-
lectivities (5:1 to 8:1) of reductions with compounds derived
from phenyl-substituted 9a were optimal with NaBH3CN/
AcOH, whereas NaBH4/AcOH gave significantly superior
yield and diastereoselectivity in the case of butyl-substituted
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G. Helmchen et al.
Configurations of the major cis-products were assigned on
1
the basis of the H NMR coupling constants of the axial 2-H
and 6-H (J=10.4–11.9 Hz and 2.3–3.1 Hz). In the case of 44
1
and 45, H and 13C NMR spectral assignment was possible
for the cis- as well as the trans- diastereomer.
Trisubstituted pyrrolidines and piperidines: Build-up of qua-
ternary centers is of continuing interest in organic synthesis.
Chida et al.[6a] have explored reactions of N-benzyloxylac-
tams with organolithium reagents and subsequent addition
of trimethylsilyl cyanide (3 equiv) and SnCl4 (1.3 equiv). Al-
though the use of various six-membered lactams gave rise to
pure diastereomers, only one example of a five-membered
lactam was investigated, which displayed low diastereoselec-
tivity of 1.3:1. Application of this procedure to 9a mainly
furnished imines, that is, elimination products. Similarly, the
addition of a Grignard reagent to 9a followed by Lewis acid
promoted allylation (Scheme 11) gave rise to imine 19 and
the ring-opened allylation product 53, although the yield
and reproducibility of these reactions were low. According
to a control experiment with [D3]-9a, [D5]-53 is formed by
elimination to give formaldehyde, imine formation and addi-
Scheme 12. Alkylation/cyanide addition of N-methoxylactams. A more
detailed table is included in the Supporting Information. Diastereomer
ratios were determined by 1H NMR spectroscopic analysis of the crude
products.
steric course of the reduction
and cyanation are very similar,
that is, axial approach of the
nucleophile to the iminium
ion.[6a]
Syntheses of alkaloids (ꢀ)-
209D and (+)-prosophylline:
Piperidines and pyrrolidines are
structural motifs of numerous
biologically active compounds,
in particular alkaloids,[35] and
are often used as probes for
new
synthetic
procedures.
Scheme 11. Attempted addition of Grignard reagent followed by allylation.
Widely occurring among alka-
loids are cis-2,6-disubstituted
tion of the allyltin reagent. Clearly, N-methoxylactams are
less stable to Lewis acids than N-benzyloxylactams.
piperidines, in particular compounds with an additional 3-
OH group, and cis-2,5-disubstituted pyrrolidines. More com-
plex bicyclic structures, for example indolizidines, are often
derived from the monocyclic heterocycles by an additional
reductive amination step (Figure 2). Many methods for the
stereoselective synthesis of all these alkaloids have been de-
veloped.[36,37] However, the number of methods based on
asymmetric catalysis is still quite small.[38] To broaden the
repertoire of such syntheses and to test the applicability of
the procedures described above, we synthesized indolizidine
(ꢀ)-209D and 3-hydroxypiperidine alkaloid (+)-prosophyl-
line. So far only one enantioselective synthesis of (+)-proso-
phylline has been reported.[39]
Fortunately, we found that the simple procedure described
above for reductions with complex hydrides was also suita-
ble for addition of cyanide (Scheme 12). Thus, reaction of
the N-methoxylactam with a Grignard reagent followed by
addition of KCN and acetic acid furnished amino nitriles
47–52 in good to high yield. Diastereoselectivity was very
high (more than 20:1) for the six-membered ring and moder-
ate (ca. 4:1) for the five-membered ring compounds. For the
preparation of 49, methyl magnesium bromide was not suit-
able, whereas methyl lithium furnished a yield of 35% and
diastereomeric ratio of 4:1. The configuration of 47 was de-
termined by an X-ray crystal structure analysis (see the Sup-
porting Information). The configurations of 48 and 50 were
corroborated by the close resemblance of their NMR data
to those of the analogous N-benzyloxylactams. Clearly, the
The synthesis of the indolizidine alkaloid (ꢀ)-209D is de-
tailed in Scheme 13. Reaction of (1,3-dioxan-2-ylethyl)-mag-
nesium bromide with 13c, prepared from 2c (94% ee), and
subsequent catalytic hydrogenation with Raney nickel as
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Chem. Eur. J. 2013, 19, 16746 – 16755

Syntheses of Pyrrolidines and Piperidines
FULL PAPER
Starting material for the synthesis of (+)-prosophylline
was N-methoxylactam 55 (Scheme 14), which was obtained
from 2d (93% ee) in 48% yield in four steps using a route
reported by us.[1a] Standard protection gave O-benzyl deriva-
tive 56, which was suitable for addition of Grignard reagent
57. However, subsequent reduction required some optimiza-
tion; eventually, 58 was obtained in 64% yield by using
a mixture of palladium on charcoal and Raney nickel in
methanol as catalyst. Simultaneous removal of the benzyl
protection groups in the reduction step was not accom-
plished. This was achieved with Pearlmans catalyst under
10 bar hydrogen pressure after a reaction time of three days.
Hydrolysis of the acetal with hydrochloric acid furnished
(+)-prosophylline in a total yield of 55%. The physical and
spectral data were in accordance with those reported in the
literature {m.p. 82–838C; [a]2D0 = +8.4 (c=0.72, CHCl3);
lit.:[2d] m.p. 85.5–868C; [a]D20 = +10.3 (c=1.30, CHCl3)}.[2d,39]
Figure 2. Examples of 2,6-disubstituted piperidine alkaloids.
Conclusion
Enantioselective iridium-catalyzed allylic substitution in
combination with ring-closing metathesis constitutes a con-
venient approach for the preparation of enantiomerically
enriched N-methoxylactams. From these, cis-piperidines or
cis-pyrrolidines are available through reactions with
Grignard reagents or organolithium compounds followed by
diastereoselective reductions with Raney nickel or complex
metal hydrides/acetic acid. In addition, compounds with
a quaternary carbon can be synthesized by reaction with po-
tassium cyanide/AcOH. The procedure was applied in the
syntheses of alkaloids (ꢀ)-209D and (+)-prosophylline.
Scheme 13. Synthesis of indolizidine (ꢀ)-209D.
catalyst, furnished 33 in 82% yield over two steps. Depro-
tection of the aldehyde and reductive amination were car-
ried out in one pot by using palladium on charcoal in acidi-
fied methanol. Elevated hydrogen pressure and long reac-
tion times were required to obtain full conversion. The re-
ductive amination proceeded with perfect cis-diastereoselec-
tivity to give alkaloid (ꢀ)-209D in 75% yield; the spectral
data matched the reported data {[a]2D0 =ꢀ60.6 (c=1.14,
CHCl3); lit.:[40e] [a]D20 =ꢀ66.5 (c=1.00, CHCl3)}.[10b, 40]
Experimental Section
General procedure for alkylation/reduction with H2/Raney nickel: Under
an atmosphere of argon, Grignard reagent (1.2 equiv) was added to a so-
lution of N-methoxy-amide (1 equiv) in anhydrous THF (0.2m). The re-
action mixture was stirred at RT for 1–2 h, then water was added, and
the resultant mixture was extracted with ethyl acetate. The organic layer
was dried over MgSO4 and concentrated in vacuo. A suspension of the
crude product and Raney nickel in the stated solvent was stirred under
a hydrogen atmosphere (balloon) at RT overnight. The catalyst was re-
moved by filtration through a pad of silica and the filtrate was concen-
trated in vacuo. The residue was subjected to flash chromatography (pe-
troleum ether/triethylamine, ca. 97:3).
General procedure for alkylation/reduction with complex metal hydrides:
Under an atmosphere of argon, Grignard reagent (1.2 equiv) or organo-
lithium reagent (1.2 equiv) was added to a solution of an N-methoxy-
amide (1 equiv) in anhydrous THF (0.2m). The reaction mixture was
stirred at RT for 1–2 h, then AcOH (1 mLmmolꢀ1 of N-methoxy-amide)
was added dropwise and the mixture was stirred for 10 min before a com-
plex metal hydride (5 equiv) was added. When TLC monitoring indicated
complete conversion, aqueous NaOH (10%) was added and the mixture
was extracted with CH2Cl2. The combined organic layers were dried over
MgSO4 and the solvent was removed in vacuo. The residue was subjected
to flash chromatography (petroleum ether/ethyl acetate).
Scheme 14. Synthesis of (+)-prosophylline.
Chem. Eur. J. 2013, 19, 16746 – 16755
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www.chemeurj.org
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Acknowledgements
This work was supported by the Deutsche Forschungsgemeinschaft (SFB
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Syntheses of Pyrrolidines and Piperidines
FULL PAPER
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Received: July 13, 2013
Published online: October 21, 2013
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www.chemeurj.org
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