Enantioselective syntheses of 2,5-disubstituted pyrrolidines based on iridium-catalyzed allylic aminations-total syntheses of alkaloids from amphibian skins

Article abstract of DOI:10.1002/chem.201100649

A broadly applicable route to trans-2,5-disubstituted pyrrolidines has been developed. Key steps are an asymmetric iridium-catalyzed allylic amination, a Suzuki-Miyaura coupling, and an intramolecular aza-Michael addition. Enantiomeric excesses in the range of 93-99 % ee have been achieved. Total syntheses of the alkaloids (-)-225 C, (+)- and (-)-223 H (xenovenine), (+)-223 AB, (+)-195 B, and (+)-223 R have been carried out as applications. Copyright

Full text of DOI:10.1002/chem.201100649

FULL PAPER
DOI: 10.1002/chem.201100649
Enantioselective Syntheses of 2,5-Disubstituted Pyrrolidines Based on
Iridium-Catalyzed Allylic Aminations—Total Syntheses of Alkaloids from
Amphibian Skins
Martin Gꢀrtner, Robert Weihofen, and Gꢁnter Helmchen*[a]
Dedicated to Professor Dieter Enders on the occasion of his 65th birthday
Abstract: A broadly applicable route to trans-2,5-disubstituted pyrrolidines has
been developed. Key steps are an asymmetric iridium-catalyzed allylic amination,
Keywords: indolizidines · iridium ·
a Suzuki–Miyaura coupling, and an intramolecular aza-Michael addition. Enantio-
pyrrolidines · pyrrolizidines · total
meric excesses in the range of 93–99% ee have been achieved. Total syntheses of
synthesis
the alkaloids (À)-225C, (+)- and (À)-223H (xenovenine), (+)-223AB, (+)-195B,
and (+)-223R have been carried out as applications.
Introduction
Many alkaloids containing a pyrrolidine moiety with sub-
stituents in positions 2 and 5 display interesting biological
activity. For example, (À)-epibatidine, isolated from skin ex-
tracts of Epipedobates tricolor, shows strong analgetic activi-
ty.[1] Some pyrrolidines, indolizidines, and pyrrolizidines, iso-
lated in trace amounts from amphibian skins[2] are noncom-
petitive blockers of nicotinic acetylcholine receptors.[3]
Due to the scarcity of occurrence of these alkaloids, their
stereoselective synthesis remains a field of great interest in
organic chemistry. Syntheses of 2,5-disubstituted pyrroli-
dines[4] were based on reduction of pyrroles,[5] nucleophilic
addition to cyclic N-acyliminium salts[6] and aminals,[7] cyclo-
addition,[8] ring-closing metathesis (RCM),[9] intramolecular
amidomercuration,[3a,10] Mannich reactions,[11] Cu-[12] or Os-
promoted[13] aminoxygenation, nucleophilic substitution,[14]
hydroamination,[15] or reductive amination[16] and related re-
ductions.[17]
Scheme 1. Retrosynthetic concept (S: protecting group).
allel work, the intermediary a,b-unsaturated esters and re-
lated carbonyl compounds were generated by a domino hy-
droformylation/Wittig olefination process.[18]
Our procedure was applied in the syntheses of the 2,5-di-
substituted pyrrolidine (À)-225C, both enantiomers of xeno-
venine (pyrrolizidine 223H), and the indolizidines (+)-
223AB, (+)-195B, and (+)-223R.
Induced by our interest in the Ir-catalyzed allylic substitu-
tion, we have developed the approach to trans-2,5-disubsti-
tuted pyrrolidines that is schematically described in
Scheme 1. The following key steps are combined: 1) Syn-
thesis of a protected allylamine by Ir-catalyzed allylic amina-
tion with a N,N-diacylamine as pronucleophile. 2) Hydrobo-
ration of the allylic double bond and Suzuki–Miyaura cou-
pling to give an a,b-unsaturated ester. 3) Ring closure by
base-promoted intramolecular aza-Michael addition. In par-
[a] M. Gꢀrtner, Dr. R. Weihofen, Prof. Dr. G. Helmchen
Organisch-Chemisches Institut der Universitꢀt Heidelberg
Im Neuenheimer Feld 270
69120 Heidelberg (Germany)
Fax : (+49)6221-544205
Results and Discussion
E-mail: g.helmchen@oci.uni-heidelberg.de
Iridium-catalyzed allylic substitution: The Iridium-catalyzed
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201100649.
allylic substitution was introduced in 1997.[19] Today, a varie-
Chem. Eur. J. 2011, 17, 7605 – 7622
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7605

ty of carbon-, nitrogen-, oxygen-, and sulfur-nucleophiles
can be applied, and enantioselectivities in the range of
>90% ee (ee=enantiomeric excess) can be achieved rou-
tinely.[20] The commonly used catalysts are obtained by reac-
ents R1 generally proceeded with good yields and high enan-
tioselectivities. However, regioselectivities were variable. In
the case of carbonate 1b, the highest regioselectivity was ob-
tained with NH
entries 4, 5); slightly lower regioselectivities were found
with the pronucleophiles NH(CHO)Cbz (entries 6, 7) and
ACHTUNGTRENN(UNG CHO)Boc as the pronucleophile (Table 1,
tion of [IrACHTUNGTRENNUNG(cod)Cl]2 (cod=1,5-cyclooctadiene), a chiral phos-
À
phoramidite ligand, and a base that effects C H activa-
tion.[21] The phosphoramidites used in this work were intro-
duced by Feringa (L1)[22] and Alexakis (L2 and L3).[23] Both
enantiomers of these ligands are readily available.
ACHTUNGTRENNUNG
NaNBoc2 (entries 1–3). Significantly worse results were ob-
tained with the acceptor-substituted carbonates 1c–f, as was
previously observed for other allylic alkylations and amina-
tions with these carbonates.[24] Concerning the preparatively
interesting pronucleophiles NH
ACHTUNGTREN(NGNU CHO)Boc and NH-
AHCTUNGTREG(NNNU CHO)Cbz, generally superior results were obtained with
the former (cf. entries 4, 5 vs. 6, 7 and 10, 11 vs. 12–14).
N-Formyl deprotection was carried out with a catalytic
amount of KOH in methanol. Selective cleavage of one of
the Boc groups from 2a and 2c was accomplished with tri-
fluoroacetic acid (TFA)/CH2Cl2 (Table 2). All the N-allyl-
amides, 4a–i, were obtained in excellent yields.[29]
As substrates the carbonates 1a–f were used, which were
prepared by standard procedures (Table 1).[24] The N,N-diac-
ylamines NH
NH
N
Suzuki–Miyaura coupling: Initially, the N,N-diacylallyla-
mines 2a and 2b were probed as reactants for hydrobora-
tion with 9-borabicycloACTHUNGETRNNU[G 3.3.1]nonane (9-BBN); conversion
was low according to TLC analysis. Considering the steric
bulk of the N-protecting groups, the mono-N-acyl amines 4
ACHTUNGTRENNUNG
Unless
stated
otherwise,
2 mol% of [IrACHTUNGTRENNUNG
(cod)Cl]2 and
Table 1. Iridium-catalyzed allylic aminations.
4 mol% of the phosphoramidite
ligand were employed. Catalyst
activation was carried out with
the base 1,5,7-triazabicyclo-
ACHTUNGTRENNUNG[4.4.0]dec-5-ene (TBD). Regio-
selectivities were determined by
1H NMR spectroscopy of the
crude products; enantiomeric
excesses were determined by
HPLC on a Daicel column or
GC analysis on a Chrompack
Entry Substrate Nucleophile
Products
L*
(S,S,aS)-L1
(S,S,aS)-L2
(S,S,aS)-L3
(S,S,aS)-L2
(R,R,aR)-L3
(R,R,aR)-L2
(S,S,aS)-L3
(R,R,aR)-L2
(S,S,aS)-L3
t [h] Yield 2+3 [%][a] 2/3[b]
ee [%][c]
column,
occasionally
after
1
2
3
4
5
6
7
8
1b
1b
1b
1b
1b
1b
1b
1c
1c
1d
1d
1d
1d
1d
1e
1e
1 f
1 f
1 f
NaNBoc2
NaNBoc2
NaNBoc2
2c+3c
2c+3c
2c+3c
G
72
21
20
22
6
81
82
84
84
91
87
96
85
93
85
86
79
85
82
84
97
74
93
77
91:9
86:14 96
93:7
95:5
95:5
93
cleavage of a protecting group.
Absolute configurations were
assigned on the basis of a rule
that has been found to hold
without exception so far.[28] Val-
idation was possible for 2c–e
and 2i–k in this work by corre-
lation with the target alkaloids.
The results obtained for the al-
lylic aminations are described
in Table 1.
E
N
95
98
98.5
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
G
R
E
N
N
T
2
2
1
90:10 97.5
88:12 95.5
78:22 93
R
N
N
R
9
R
A
1
76:24 95
10[d]
11[d]
12
13[d]
14[d]
15
16
17[e]
18[d,e]
19[e]
R
G
77:23 97
R
N
82:18 96.5
65:35 97
N
R
16
18
G
N
71:29 96.5
68:32 95.5
79:21 96.5
80:20 95.5
82:18 90.5
86:14 93.5
86:14 92.5
R
ACHTUNGTRENNUNG
Previously,[9b] excellent enan-
tio- and regioselectivity had
been obtained for the reaction
of methyl cinnamyl carbonate
(1a) with N,N-diacylamines.
The reactions of the carbonates
G
ACHTUNGTRENNUNG
G
G
3
2
2.5
G
ACHTUNGTRENNUNG
G
N
A
E
2
[a] Combined isolated yields of 2 and 3. [b] Determined by 1H NMR spectroscopy of the crude product.
[c] Determined by HPLC analysis on a chiral column. [d] The reaction was carried out with 1 mol% of
1b–f with sp3-bound substitu- [IrCl(cod)]2, 2 mol% of L*, and 4 mol% of TBD. [e] The reaction was carried out at 508C.
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Enantioselective Syntheses of 2,5-Disubstituted Pyrrolidines
Table 2. Selective deprotection.
FULL PAPER
sis was not feasible because of spots of 9-BBN and numer-
ous impurities derived from 9-BBN. For purification, oxida-
tion of residual boron compounds with H2O2/NaOH was ad-
vantageous;[34] this procedure can cause decomposition of
the Suzuki–Miyaura coupling products and has to be applied
with care. To diminish separation problems, in situ generat-
ed Cy2BH (Cy=cyclohexyl) was used for hydroboration of
ent-4a.[35] Although a good result was obtained initially
(Table 3, entry 1), the procedure suffered from poor repro-
ducibility.
(Z)-3-Iodoacrylates were also probed as coupling part-
ners. Hydroboration of ent-4a with 9-BBN followed by
Suzuki–Miyaura coupling with commercially available ethyl
(Z)-3-iodoacrylate furnished ent-6b in a yield of 87%
(Table 4). The corresponding methyl ester ent-6a was ob-
tained, albeit in a lower yield with methyl (Z)-3-iodoacry-
4
R1
R2
Method
Yield [%]
a
a
b
b
c
d
e
f
Ph
Ph
nC7H15
nC7H15
Boc
Boc
Boc
Boc
Cbz
Boc
Cbz
Boc
Cbz
Cbz
Cbz
A
B
A
B
A
A
A
A
A
A
A
93[a]
96
95
88
91
nC7H15
CH2OCPh3
CH2OCPh3
CH2OTBDPS[b]
CH2OTBDPS[b]
CH2OTBDMS[b]
CH2CH2OCPh3
100[24]
88[a]
94[a]
93
g
h
i
97[a]
98[a]
late[36] applying [PdCl
catalyst system.
2ACTHUGNTREN(UNGN dppf)]/Ph3As/DMF/Cs2CO3 as the
[a] The reaction was carried out with ent-2. [b] TBDPS= tert-butyldiphe-
nylsilyl; TBDMS=tert-butyldimethylsilyl.
Table 4. Suzuki–Miyaura coupling with (Z)-3-iodoacrylates.
were next investigated. With
these compounds complete hy-
droboration was generally ach-
ieved with 9-BBN at 508C.[30]
The
Miyaura coupling[31] was carried
out with [PdCl2A(dppf)]/Ph3As/
DMF/Cs2CO3 as the catalyst
system (dppf=1,1’-bis(diphe-
nylphosphino)ferrocene),[32]
subsequent
Suzuki–
R
Hydroboration conditions
Conditions of the Suzuki–Miyaura coupling
[PdCl2A(dppf)], Ph3As, Cs2CO3, DMF/H2O, 2 h, 50 8C
[Pd(PPh3)4], K3PO4, dioxane/H2O, overnight, RT
Yield [%]
CH3
C2H5
4 h, 508C
4 h, RT
N
G
56
87
ACHTUNGTRENNUNG
CHTUNGTRENNUNG
Intramolecular aza-Michael addition: The combination of a
Suzuki coupling and an aza-Michael cyclization appears as
an interesting strategy for the synthesis of pyrrolidines.
While this combination has only been applied in a single
case,[37] the intramolecular aza-Michael addition has been
used often for the synthesis of 2,5-disubstituted pyrroli-
dines,[38] usually as a one-pot combination with a Wads-
worth–Emmons olefination.[38b,f,i] Under these conditions,
thermodynamic control is operative and trans/cis selectivities
vary; nevertheless, a value as high as 95:5 has been
reached.[39] Very high selectivity has recently been obtained
by Enkisch and Schneider in a careful study of a Mannich/
aza-Michael combination furnishing 2,3,5-trisubstituted pyr-
rolidines.[40]
mostly with methyl (2E)-3-iodo-acrylate[33] as an alkenyl
halide (Table 3). The yields of enoates 5 were good to excel-
lent, although optimization of reaction times by TLC analy-
Table 3. Suzuki–Miyaura coupling ent-4a with methyl (2E)-3-iodoacry-
late.
In our case, the aza-Michael cyclization proceeded with
low diastereoselectivity under thermodynamically controlled
conditions. Thus, upon treatment of the ethyl ester ent-6b
(Table 5) with either Cs2CO3/tBuOH at 40–708C or KOtBu/
THF at À608C mixtures of cis- and trans-2,5-disubstituted
pyrrolidines 7 were formed. Further investigation revealed
that the trans isomer, ent-trans-(7), was formed exclusively
when the reaction was carried out with KOtBu/THF at
À788C;[41] a reaction time of less than approximately 1 h suf-
ficed to get full conversion. Essentially the same result was
obtained with the methyl ester ent-6a (Scheme 2). In this
case the relative configuration of the product ent-8a was de-
termined by X-ray crystal structure analysis (Figure 1),[42]
Entry
4, 5
a[b,c]
R1
R2
t [h][a]
Yield [%]
62[d]
80
1
2
3
4
5
6
7
8
9
Ph
nC7H15
nC7H15
CH2OCPh3
CH2OCPh3
CH2OTBDPS
CH2OTBDPS
CH2OTBDMS
CH2CH2OCPh3
Boc
Boc
Cbz
Boc
Cbz
Boc
Cbz
Cbz
Cbz
2
3
3
5
3
3
2.5
4
2
b
c
d
e
f
g
h
i
80[d]
89[d]
84[d]
84[d]
87[d]
66[d]
74[d]
[a] Reaction time for hydroboration. [b] Suzuki coupling was carried out
with methyl (2E)-3-bromoacrylate at 358C for 3 h. [c] In situ generated
Cy2BH (1.1 equiv) was used for hydroboration at RT. [d] The reaction
was carried out with ent-4.
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G. Helmchen et al.
Table 5. Intramolecular aza-Michael addition of ent-6b.
Table 6. Results of the intramolecular aza-Michael addition under opti-
mized conditions.
Entry
5, 8
R1
R2
t [min]
Yield [%]
1
2
3
4
5
6
7
a
b
Ph
nC7H15
nC7H15
CH2OCPh3
CH2OTBDPS
CH2OTBDMS
CH2CH2OCPh3
Boc
Boc
Cbz
Cbz
Cbz
Cbz
Cbz
20[18]
20[18]
30
80[18]
97[18]
86
Entry
Base (equiv)
Solvent
T [8C]
t [h]
trans/cis[a]
1
2
3
4
Cs2CO3 (5)
Cs2CO3 (5)
KOtBu (0.85)
KOtBu (0.85)
tBuOH
tBuOH
THF
70
40
3
8
0.25
0.5
69:31
75:25
84:16
100:0[b]
c
e[a]
g
70[b]
40
57
97
À60
h[a]
i[a]
50+40[c]
35
76[d]
77
THF
À78
[a] Determined by GCMS analysis. [b] 93% Isolated yield.
[a] The reaction was carried out with the enantiomer. [b] Additional
KOtBu (0.2 equiv) was added after 40 min. [c] Incomplete conversion;
the procedure was repeated with the mixed fractions after purification.
[d] A trans/cis ratio of 85:15 (1H NMR spectroscopy) was obtained.
Scheme 2. Intramolecular aza-Michael addition of ent-6a.
Scheme 3. Total synthesis of alkaloid (À)-225C.
ethylidene triphenylphosphorane under Li+-free conditions
afforded exclusively the (Z)-olefin 10 in good yield. After
hydrogenation of 10 to the corresponding saturated com-
pound 11 (formula not shown) by using Pd/C and deprotec-
tion by treatment with HCl, the alkaloid 225C was obtained.
Its spectral properties completely matched literature data.
The enantiomeric excess was determined (GC analysis) to
be 97.5% ee, the same as that of the starting material, that
is, the reaction sequence had proceeded without racemiza-
tion.
Figure 1. X-ray structure of 8a (cf. Scheme 2).
and the relative configurations of the esters ent-7 could be
assigned with confidence by comparison with the NMR
spectroscopic data of this compound.
Cyclizations of the substrates 5 with an E configuration
were carried out under the conditions optimized for (Z)-ent-
6b and, except in the case of 5h, also gave essentially pure
trans isomers[43] (Table 6), that is, the configuration of the
double bond of the enoate is of no consequence for the cyc-
lization, which is in accordance with earlier studies on the
formation of corresponding piperidines.[39c] In a control ex-
periment, the cyclization of ent-5a was carried out with
KOtBu at À458C for 3 h. As expected, a mixture of trans-
and cis-2,5-disubstituted pyrrolidines (ratio 55:45) was ob-
tained. Similarly, cyclization of 5 f at room temperature gave
a trans/cis selectivity of 72:28.
Total synthesis of (+)- and (À)-xenovenine: Pyrrolizidines
and indolizidines[47,48] are often available from monocyclic
pyrrolidines by reductive amination. In the present case, this
required a carbonyl group in the g-position of the side chain
at C2 and preferably an N-protecting group, Cbz, which
would be cleaved in the same step. The aldehyde 13, pre-
pared by reduction of ent-8c (Scheme 4), was subjected to a
Wittig reaction with the ylide derived from the commercial-
ly available phosphonium salt 14. The resultant mixture of
E/Z isomeric enol ethers was transformed into the aldehyde
15 by treatment with TFA.
Total synthesis of pyrrolidine (À)-225C: Our synthesis of
the alkaloid 225C[44,45] from 8b required four steps
(Scheme 3). First, reduction with precooled[46] diisobutylalu-
minium hydride (DIBAL-H) at À908C cleanly gave the un-
stable aldehyde 9. Wittig reaction of this compound with
The aldehyde ent-15 is an intermediate in Lhommetꢂs
total synthesis of (À)-xenovenine.[6c] This synthesis requires
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Enantioselective Syntheses of 2,5-Disubstituted Pyrrolidines
FULL PAPER
Scheme 4. Formal synthesis of (+)-xenovenine.
three further transformations: addition of methylmagnesium
chloride, Swern oxidation to the corresponding ketone ent-
17, and hydrogenolytic deprotection with concomitant re-
ductive amination. The synthesis could be significantly
shortened by introducing the methyl group with the Wittig
reagent (Scheme 5). The requisite phosphonium salt 16 was
prepared in two steps from methanol, acetaldehyde, HCl,
and PPh3 on a multigram scale.[49,50] Treatment of aldehyde
13 with the phosphorane derived from 16 gave a mixture of
E/Z isomeric enol ethers, which was directly converted to
the methyl ketone 17 in 80% yield. Finally, reductive amina-
tion was carried out by using Lhommetꢂs procedure (Pd/
BaSO4, 0.1 MPa).[6c] This was improved by employment of
Pearlmanꢂs catalyst at a slightly increased pressure of
0.5 MPa. In contrast to the prior result,[6c] the reductive ami-
nation proceeded with complete diastereoselectivity. Spec-
troscopic properties of the synthetic (+)-xenovenine (18)
completely matched literature data.[6c] Its enantiomeric
excess was determined (GC analysis) and found to be identi-
cal to that of the starting material (94.5% ee), that is, the se-
quence proceeded without racemization.
Scheme 6. Total synthesis of (À)-xenovenine.
sized from 8g in six steps as follows. Reduction of 8g with
DIBAL-H gave the unstable aldehyde 19, which was sub-
jected to a Wittig olefination with pentylidene triphenyl-
phosphorane yielding exclusively the (Z)-olefin 20. Treat-
ment with tetrabutylammonium fluoride (TBAF) effected
O-deprotection in excellent yield. The resultant alcohol 21
was oxidized to the aldehyde 22 by using the Swern method.
A subsequent Wittig reaction with commercially available 1-
(triphenylphosphoranylidene)acetone gave (E)-23 in excel-
lent yield. This compound was exposed to hydrogen
(0.5 MPa) in the presence of Pearlmanꢂs catalyst. This ef-
fected hydrogenation of the double bonds, deprotection, and
reductive amination in one pot. (À)-Xenovenine (ent-18)
was obtained diastereomerically pure (GCMS, NMR spec-
troscopy). The enantiomeric excess of 96% is proof of ab-
sence of significant racemization also for this route.
Total synthesis of indolizidine (+)-223AB: The strategy de-
scribed above was also applied to a total synthesis of indoli-
zidine 223AB[51,52] (Scheme 7). The pyrrolidine ent-8h (con-
taining 15% of the cis epimer) was chosen as the starting
material. Diastereoisomers resulting from the cis epimer
were removed at a later stage. Reduction with DIBAL-H
gave the aldehyde 24. Subsequent Wittig reaction provided
the a,b-unsaturated Weinreb amide[53] 25 as an 85:15 mix-
ture of E and Z isomers, which were separable by column
chromatography. Catalytic hydrogenation of 25 by using
Adamꢂs catalyst under carefully controlled conditions effect-
Scheme 5. Final steps of a total synthesis of (+)-xenovenine.
Considering that many natural pyrrolidines and pyrrolizi-
dines are homologues, it is desirable to devise syntheses via
a common intermediate. The pyrrolidine 8g is a suitable
relay compound (Scheme 6) as its protected hydroxymethyl
group can be transformed into a wide variety of substituents.
As example for this approach, (À)-xenovenine was synthe-
À
ed reduction of the double bond, accompanied by N O re-
ductive cleavage to give the corresponding N-methylamide
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G. Helmchen et al.
Scheme 7. Total synthesis of indolizidine (+)-223AB.
26 (see the Experimental Section) to a small extent (11%
from (E)-25). Treatment of the Weinreb amide 27 with pro-
pylmagnesium chloride gave the ketone 28 in excellent
yield. At that stage, impurities derived from the cis epimer
of ent-8h could be removed by preparative HPLC. Silyl de-
protection was carried out with TBAF, providing alcohol 29.
Swern oxidation of 29 gave an excellent yield of aldehyde
30, which was subjected to Wittig olefination by using pro-
pylidene triphenylphosphorane. The olefin 31, obtained in
good yield, was subjected to reductive amination by using a
mixture of Pd(OH)2/C and Rh/C as the catalyst[54] at a hy-
drogen pressure of 2 MPa. Indolizidine (+)-223AB (32) was
obtained with a small amount of the C-5 epimer (6%,
GCMS), which could not be removed.
formed diastereoselectively in excellent yield. Deprotection
was effected with dilute acetic acid to give alcohol 35.
The Swern oxidation of 35 gave the corresponding alde-
hyde in good yield; however, the subsequent Wittig olefina-
tion proceeded in very poor yield. Therefore, hydrogenation
of 35 by using Adamꢂs catalyst was carried out. This fur-
nished 36 in a somewhat low yield of 65% because of com-
peting cleavage of the Cbz group. Swern oxidation of 36
gave the aldehyde 37 in excellent yield.
Starting from 37, the syntheses of indolizidines (+)-195B
and (+)-223R required two further steps. Wittig olefination
afforded the (Z)-olefin 38 (Scheme 9) and reductive amina-
tion, by using the conditions that were employed before in
the synthesis of (+)-223AB, furnished indolizidine (+)-
195B (39) together with 5% of the C-5 epimer (GCMS
analysis). Indolizidine (+)-223R (41), containing 8% of the
C-5 epimer (GCMS analysis), was obtained in a similar way.
Total syntheses of indolizidines (+)-195B and (+)-223R:
For the syntheses of indolizidines (+)-195B[55] and (+)-
223R,[55a] which both are bearing a methyl group at C-5 and
differ in the side chain at C-3, introduction of the latter at a
late stage appeared desirable. Aldehyde 37 was used as a
key intermediate; it was prepared in five steps from ent-8i
(Scheme 8). Reduction with DIBAL-H afforded the alde-
hyde 33, which was subjected to Wittig olefination with 1-
(triphenylphosphoranylidene)acetone. (E)-Enone 34 was
Conclusion
We have developed flexible syntheses of trans-2,5-disubsti-
tuted pyrrolidines based on iridium-catalyzed allylic amina-
tion, Suzuki–Miyaura coupling, and intramolecular aza-Mi-
Scheme 8. Synthesis of intermediate 37.
7610
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ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 7605 – 7622

Enantioselective Syntheses of 2,5-Disubstituted Pyrrolidines
FULL PAPER
tert-butyl {(1S)-1-[(trityloxy)methyl]prop-2-enyl}carbamate (4d),[24] (+)-
tert-butyl (2S,5S)-2-(2-methoxy-2-oxoethyl)-5-phenylpyrrolidine-1-carbox-
ylate (ent-8a),[18] and (À)-1,1-dimethylethyl (2R,5S)-2-heptyl-5-[2-(meth-
yloxy)-2-oxoethyl]pyrrolidine-1-carboxylate (8b).[18]
General procedure 1 (GP1, Ir-catalyzed allylic amination): For the suc-
cess of the following procedure it is important to use well-dried TBD
(see above), which is hygroscopic, and to weigh it fast! A solution of
[IrClACTHUNTRGEN(UGN cod)]2 (2 mol%), TBD (8 mol%), and L1, L2, or L3 (4 mol%) in
dry THF (content of water <30 mgmLÀ1, Karl-Fischer titration) was
stirred under an atmosphere of argon for 90 (L1), 5 (L2), or 30 min (L3)
at RT. Then, allylic carbonate 1 (1 equiv) and nucleophile (1.0–1.2 equiv)
were added and the mixture was stirred for the time stated in Table 1;
conversion was monitored by TLC or GCMS analysis. After complete
conversion had been reached, the solution was filtered through a pad of
Celite and the solvent was removed in vacuo. The crude product was ana-
lyzed with respect to the ratio of branched and linear products by
1H NMR spectroscopy. The branched products 2 and the linear products
3 were separated by flash chromatography (silica, petroleum ether/ethyl
acetate).
Scheme 9. Total syntheses of indolizidines (+)-195B and (+)-223R.
(+)-Di-tert-butyl [(1R)-1-phenylprop-2-en-1-yl]imidodi-carbonate (ent-
2a) and di-tert-butyl [(2E)-3-phenylprop-2-en-1-yl]imidodicarbonate
(3a): GP1 was carried out with [IrClACHTUNRGTNEUNG(cod)]2 (134.1 mg, 200 mmol),
(R,R,aR)-L3 (227 mg, 399 mmol), TBD (112 mg, 805 mmol), 1a (1.97 g,
10.25 mmol), NaNBoc2 (2.79 g, 11.7 mmol), and dry THF (15 mL). Com-
plete conversion was reached after 18 h at RT (monitored by TLC analy-
chael addition. This strategy was successfully applied in syn-
theses of the alkaloids (À)-225C and both enantiomers of
xenovenine. Our route was extended to 3,5-disubstituted in-
dolizidines, exemplified by the syntheses of (+)-223AB and
indolizidines (+)-195B and (+)-223R.
sis, RfACHTNUTRGNEUNG(1a)=0.37, petroleum ether/ethyl acetate 4:1). The ratio of ent-2a/
3a was determined by 1H NMR spectroscopy of the crude product (ent-
2a/3a 99:1). The crude product was subjected to flash chromatography
on silica (petroleum ether/ethyl acetate 4:1) to yield ent-2a and 3a
Experimental Section
(2.90 g, 85%) as an inseparable mixture (colorless oil). R
fA(3a)=0.53, petroleum ether/ethyl acetate 4:1
fACHTUNGTREN(NUNG ent-2a)=0.53,
R CHTUNGTRENNUNG
General: 1H NMR spectra were recorded on
a Bruker AC 300
Product ent-2a: [a]D =49.1 (c=1.16 in CHCl3, 99% ee (HPLC)); HPLC
(Chiralcel OJ-H, n-hexane/iPrOH 99.5:0.5, flow: 0.5 mLminÀ1, RT, l=
220 nm): tR((À)-2a)=13.1, tR((+)-2a)=11.3 min; 1H NMR (300 MHz,
CDCl3, RT): d=1.29 (s, 18H; tBu), 5.22–5.32 (m, 2H; 3-H), 5.84 (d, J=
8.1 Hz, 1H; 1-H), 6.31 (ddd, J=17.1, 10.3, 7.9 Hz, 1H; 2-H), 7.10–
7.27 ppm (m, 5H; Ph); 13C NMR (75 MHz, CDCl3, RT): d=28.01 (q, C-
(300 MHz) or a Bruker Avance 500 (500 MHz) spectrometer at RT in
CDCl3 or at 908C in [D8]toluene. Chemical shifts are reported in d units
relative to CHCl3 (dH =7.26 ppm), TMS (dH =0.00 ppm), or toluene
(dH =2.11 ppm (central line of the quintet)). 13C NMR spectra were re-
corded on
a Bruker AC 300 (75 MHz) or a Bruker Avance 500
(125 MHz) spectrometer at RT in CDCl3 or at 908C in [D8]toluene.
Chemical shifts are reported in d units relative to CDCl3 (dC =77.16 ppm
(central line of the triplet)) or toluene (dC =21.10 ppm (central line of
the septet)). The following abbreviations were used throughout: s=sin-
glet, d=doublet, t=triplet, q=quartet, qui=quintet, m=multiplet, brs=
broad signal. The assignment of signals for compounds 2–43 was con-
firmed by 1H,1H-COSY, 1H,13C-COSY, and DEPT spectra. Optical rota-
tions were measured with a Perkin–Elmer 341 Polarimeter in a 1 dm
thermostated cuvette by using a mercury lamp. Concentration c is given
in g per 100 mL. HRMS were recorded on a JEOL JMS-700 instrument
(EI and FAB) or a Bruker ApexQe instrument (ESI). Elemental analyses
were carried out at the Organisch-Chemisches Institut, Universitꢀt Hei-
delberg. Enantiomeric excesses were determined by chiral GC analysis
on a HP 5890 instrument or by chiral HPLC on a HP 1090 or HP 1100
instrument. For HPLC the following columns from Daicel were used:
Chiralpak AD-H (250ꢃ4.6 mm, 5 mm) with guard cartridge AD-H (10ꢃ
4 mm, 5 mm), Chiralpak AS-H (250ꢃ4.6 mm, 5 mm) with guard cartridge
AS-H (10ꢃ4 mm, 5 mm), Chiralcel OD-H (250ꢃ4.6 mm, 5 mm) with
guard cartridge OD-H (10ꢃ4 mm, 5 mm), and Chiralcel OJ-H (250ꢃ
4.6 mm, 5 mm) with guard cartridge OJ-H (10ꢃ4 mm, 5 mm). For GC
analysis a Permethyl b-Cyclodextrin column from Chrompack (WCOT
fused silica, Cp-Cyclodextrin-B-236m-19, 25 m ꢃ 0.25 mm) was used. For
preparative HPLC a Gilson-305 pump coupled with a Knauer UV detec-
tor 2600 and a silica column (Latek, 5m, 21ꢃ250 mm) were used.
ACHUNTGRENUN(G CH3)3), 62.02 (d, C-1), 82.55 (s, CAHCTUNGTERN(NUGN CH3)3), 119.41 (t, C-3), 126.66 (d, Ph),
127.07 (d, Ph), 128.31 (d, Ph), 135.69 (d, C-2), 140.53 (s, Ph), 152.60 ppm
(s, NCOO); elemental analysis calcd (%) for C19H27NO4: C 68.44, H 8.13,
N 4.20; found: C 68.72, H 8.16, N 4.35.
1
Product 3a: H NMR (300 MHz, CDCl3, RT): d=1.50 (s, 18H; tBu), 4.31
(dd, J=6.2, 1.3 Hz, 2H; 1-H), 6.20 (dt, J=15.9, 6.2 Hz, 1H; 2-H), 6.52
(d, J=15.9 Hz, 1H; 3-H), 7.17–7.38 ppm (m, 5H; Ph); 13C NMR
(75 MHz, CDCl3, RT): d=28.22 (q, C
ACHTUGNTERN(NUNG CH3)3), 48.27 (t, C-1), 82.49 (s, C-
AHCTUNGTRENNG(NU CH3)3), 125.25 (d, C-2), 126.49 (d, Ph), 127.68 (d, Ph), 128.64 (d, Ph),
132.42 (d, C-3), 136.94 (s, Ph), 152.49 ppm (s, NCOO); elemental analysis
calcd (%) for C19H27NO4: C 68.44, H 8.13, N 4.20; found: C 68.45, H
8.02, N 4.11.
(+)-tert-Butyl formyl[(1R)-1-phenylprop-2-en-1-yl]carbamate (ent-2b)
and tert-butyl formyl[(2E)-3-phenylprop-2-en-1-yl]carbamate (3b): GP1
was carried out with [Ir
(24 mg, 40 mmol), TBD (11 mg, 80 mmol), 1a (200 mg, 1.04 mmol), NH-
(CHO)Boc (174 mg, 1.20 mmol), and dry THF (0.5 mL). Complete con-
version was reached after 0.7 h at RT (monitoring by TLC analysis, Rf-
ACHTUNGTRNEN(UNG cod)Cl]2 (13.6 mg, 20.3 mmol), (R,R,aR)-L2
AHCTUNGTRENNUNG
AHCTUNGERTG(NNUN 1a)=0.37, petroleum ether/ethyl acetate 4:1). The ratio ent-2b/3b was
determined by 1H NMR spectroscopy of the crude product (ent-2b/3b
98:2). The crude product was subjected to flash chromatography on silica
(petroleum ether/ethyl acetate 4:1) to yield ent-2b and 3b (260 mg, 96%)
as an inseparable mixture (colorless oil). RfACHTNUTRGENNUG(ent-2b)=0.46, RfAHCTUNGTRENN(GUN 3b)=0.46,
petroleum ether/ethyl acetate 4:1.
THF was dried over sodium benzophenone ketyl and the water content
was determined by Karl-Fischer titration. TBD, a hygroscopic compound,
was stored in a desiccator over KOH. IUPAC names were generated
with the program ACD/Lab 6.0 from Advanced Chemistry Develop-
ment.
Product ent-2b: [a]D =62.2 (c=1.00 in CHCl3, 97.5% ee (HPLC));
HPLC (Chiralcel OJ-H, n-hexane/iPrOH 95:5, flow: 0.5 mLminÀ1, RT,
l=220 nm):
tR((À)-2b)=12.5,
tR((+)-2b)=28.2 min;
1H NMR
(300 MHz, CDCl3, RT): d=1.30 (s, 9H; tBu), 5.30–5.40 (m, 2H; 3-H),
6.14 (d, J=7.9 Hz, 1H; 1-H), 6.38 (ddd, J=16.2, 10.7, 7.9 Hz, 1H; 2-H),
7.19–7.34 (m, 5H; Ph), 9.32 ppm (s, 1H; CHO); 13C NMR (75 MHz,
The following compounds were prepared according to published proce-
dures: tert-butyl formyl{(1S)-1-[(trityloxy)methyl]prop-2-enyl}carbamate
(2 f),[24] tert-butyl formyl[(2E)-4-(trityloxy)but-2-enyl]carbamate (3 f),[24]
CDCl3, RT): d=27.95 (q, CACHTUNGTRENN(UG CH3)3), 56.61 (d, C-1), 84.41 (s, CACHTUNGTRENNUNG(CH3)3),
Chem. Eur. J. 2011, 17, 7605 – 7622
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7611

G. Helmchen et al.
1
110.10 (d, C-3), 126.62 (d, Ph), 127.30 (d, Ph), 128.52 (d, Ph), 134.50 (d,
C-2), 139.54 (s, Ph), 152.46 (s, NCOO), 163.23 ppm (d, CHO); elemental
analysis calcd (%) for C15H19NO3: C 68.94, H 7.33, N 5.36; found: C
68.95, H 7.30, N 5.38.
Product 3d: H NMR (300 MHz, CDCl3, RT): d=0.86 (t, J=6.7 Hz, 3H;
10-H), 1.20–1.37 (m, 10H; 5-H, 6-H, 7-H, 8-H, 9-H), 1.53 (s, 9H; tBu),
1.98 (dt, J=7.4, J=7.0 Hz, 2H; 4-H), 4.11 (dd, J=6.2, 1.0 Hz, 2H; 1-H),
5.37 (dtt, J=15.4, 6.4, 1.4 Hz, 1H; 2-H), 5.63 (dtt, J=14.6, 6.7, 1.0 Hz,
1H; 3-H), 9.17 ppm (s, 1H; CHO); 13C NMR (75 MHz, CDCl3, RT): d=
Product 3b: 1H NMR (300 MHz, CDCl3, RT): d=1.57 (s, 9H; tBu), 4.37
(dd, J=6.4, 1.3 Hz, 2H; 1-H), 6.17 (dt, J=15.8, 6.4 Hz, 1H; 2-H), 6.59
(d, J=15.8 Hz, 1H; 3-H), 7.21–7.41 (m, 5H; Ph), 9.25 ppm (s, 1H;
14.21 (q, C-10), 22.77 (t, C-9), 28.17 (q, C
29.24 (t), 31.95 (t), 32.28 (t, C-4), 42.31 (t, C-1), 83.90 (s, C
(d, C-2), 135.02 (d, C-3), 152.62 (s, NCOO), 162.86 ppm (d, CHO);
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
CHO); 13C NMR (75 MHz, CDCl3, RT): d=28.63 (q, C
C-1), 84.67 (s, C
ACHTUNGTRENNUNG
+
HRMS (ESI): m/z: calcd for C16H29NNaO3
: 306.20396; found:
ACHTUNGTRENNUNG
306.20448 [M+Na]+; elemental analysis calcd (%) for C16H29NO3: C
129.13 (d, Ph), 133.97 (d, C-2), 137.04 (s, Ph), 152.89 (s, NCOO),
163.26 ppm (d, CHO); elemental analysis calcd (%) for C15H19NO3: C
68.94, H 7.33, N 5.36; found: C 68.78, H 7.31, N 5.31.
67.81, H 10.31, N 4.94; found: C 67.56, H 10.28, N 4.84.
(+)-Phenylmethyl formyl [(1R)-1-heptylprop-2-en-1-yl]carbamate (2e)
and phenylmethyl (2E)-dec-2-en-1-yl
carried out with [Ir(cod)Cl]2 (13.2 mg, 20.0 mmol), (S,S,aS)-L3 (23.2 mg,
40.7 mmol), TBD (12.5 mg, 89.8 mmol), 1b (209.1 mg, 975.7 mmol), NH-
(CHO)Cbz (200.1 mg, 1.069 mmol), and dry THF (2 mL). Complete con-
version was reached after 2 h at RT (monitored by TLC, RfA(1b)=0.35,
ACHTUNGTRNE(NUNG formyl)carbamate (3e): GP1 was
(À)-Di-tert-butyl [(1R)-1-heptylprop-2-en-1-yl]imidodicarbonate (2c)
and 2-decen-1-yl-di-tert-butylimidodicarbonate (3c): GP1 was carried out
with [IrACHTUNGTRENNUNG(cod)Cl]2 (134 mg, 200 mmol), (S,S,aS)-L3 (228 mg, 400 mmol),
TBD (112 mg, 805 mmol), 1b (2.196 g, 10.25 mmol), NaNBoc2 (2.557 g,
10.69 mmol), and dry THF (15 mL). Complete conversion was reached
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
CTHUNGTRENNUNG
petroleum ether/ethyl acetate 20:1). The ratio 2e/3e=88:12 was deter-
after 20 h at RT (monitoring by TLC, RfACTHUNTGRNEUNG(1b)=0.70, petroleum ether/
1
mined by H NMR spectroscopy of the crude product, which was subject-
ethyl acetate 20:1). The ratio 2c/3c=93:7 was determined by 1H NMR
spectroscopy of the crude product. The crude product was subjected to
flash chromatography on silica (petroleum ether/ethyl acetate 50:1) to
ed to flash chromatography on silica (petroleum ether/ethyl acetate 20:1)
to yield 2e (273.8 mg, 88%) and 3e (23.8 mg, 7%) as colorless oils. Rf-
ACHUTNRGENUN(G 2e)=0.28, RfACHTUNGTREN(NUNG 3e)=0.21, petroleum ether/ethyl acetate 20:1.
yield 2c (2.931 g, 80%) and 3c (134 mg, 4%) as colorless oils. R
0.23, RfA(3c)=0.19, petroleum ether/ethyl acetate 50:1.
fACHTUNGTNER(NUNG 2c)=
Product (S)-2e: [a]D =À11.9 (c=1.13 in CHCl3, 95% ee (HPLC));
CHTUNGTRENNUNG
HPLC (Chiralpak AS-H, n-hexane/iPrOH 98:2, flow: 0.5 mLminÀ1, RT,
Product 2c: [a]D =À1.3 (c=1.11 in CHCl3); 1H NMR (300 MHz, CDCl3,
RT): d=0.87 (t, J=6.7 Hz, 3H; 7’-H), 1.22–1.33 (m, 10H; 2’-H, 3’-H, 4’-
H, 5’-H, 6’-H), 1.49 (s, 18H; tBu), 1.60–1.76 (m, 1H; 1’-H), 1.76–1.90 (m,
1H; 1’-H), 4.56–4.66 (m, 1H; 1-H), 5.09 (ddd, J=10.3, 1.3, 1.3 Hz, 1H; 3-
H), 5.15 (ddd, J=17.3, 1.4, 1.4 Hz, 1H; 3-H), 6.00 ppm (ddd, J=17.2,
10.3, 6.7 Hz, 1H; 2-H); 13C NMR (75 MHz, CDCl3, RT): d=14.23 (q, C-
1
l=210 nm): tR((À)-2e)=12.1, tR((+)-2e)=13.4 min; H NMR (300 MHz,
CDCl3, RT): d=0.87 (t, J=6.8 Hz, 3H; 7’-H), 1.09–1.34 (m, 10H; 2’-H,
3’-H, 4’-H, 5’-H, 6’-H), 1.70–1.94 (m, 2H; 1’-H), 4.91 (ddddd, J=8.3, 7.3,
7.3, 1.0, 1.0 Hz, 1H; 1-H), 5.12 (ddd, J=10.2, 1.2, 1.2 Hz, 1H; 3-H), 5.16
(ddd, J=17.2, 1.2, 1.2 Hz, 1H; 3-H), 5.26 (d, J=12.1 Hz, 1H; CH2Ph),
5.31 (d, J=12.1 Hz, 1H; CH2Ph), 6.05 (ddd, J=17.3, 10.2, 7.2 Hz, 1H; 2-
H), 7.32–7.44 (m, 5H; Ph), 9.26 ppm (s, 1H; CHO); 13C NMR (75 MHz,
CDCl3, RT): d=14.20 (q, C-7’), 22.75 (t, C-6’), 26.47 (t), 29.25 (t), 29.26
(t), 31.87 (t), 31.91 (t), 55.35 (d, C-1), 68.90 (t, CH2Ph), 117.58 (t, C-3),
128.55 (d, Ph), 128.88 (d, Ph), 128.94 (d, Ph), 134.83 (s, Ph), 136.65 (d, C-
2), 153.99 (s, NCOO), 163.10 ppm (d, CHO); HRMS (ESI): m/z: calcd
for C19H27NNaO3+: 340.18831; found: 340.18837 [M+Na]+; elemental
analysis calcd (%) for C19H27NO3: C 71.89, H 8.57, N 4.41; found: C
71.85, H 8.59, N 4.42.
7’), 22.79 (t, C-6’), 26.54 (t), 28.20 (q, C
ACHTUNGTRENNUNG
(t), 32.65 (t, C-1’), 59.38 (d, C-1), 82.16 (s, CACHTUNGTRENNUNG
138.20 (d, C-2), 153.25 ppm (s, NCOO); HRMS (FAB): m/z: calcd for
C20H38NO4+: 356.2801; found: 356.2820 [M+Na]+; elemental analysis
calcd (%) for C20H37NO4: C 67.57, H 10.49, N 3.94; found: C 67.49, H
10.44, N 4.09.
Product 3c: 1H NMR (300 MHz, CDCl3, RT): d=0.87 (t, J=6.8 Hz, 3H;
10-H), 1.20–1.38 (m, 10H; 5-H, 6-H, 7-H, 8-H, 9-H), 1.49 (s, 18H; tBu),
2.00 (td, J=6.8, 6.8 Hz, 2H; 4-H), 4.09 (dd, J=6.0, 0.8 Hz, 2H; 1-H),
5.39–5.50 (m, 1H; CH=CH), 5.54–5.66 ppm (m, 1H; CH=CH); 13C NMR
(75 MHz, CDCl3, RT): d=14.24 (q, C-10), 22.80 (t, C-9), 28.23 (q, C-
Product 3e: 1H NMR (300 MHz, CDCl3, RT): d=0.88 (t, J=6.8 Hz, 3H;
10-H), 1.17–1.36 (m, 10H; 9-H, 8-H, 7-H, 6-H, 5-H), 1.97 (dt, J=6.7,
6.7 Hz, 2H; 4-H), 4.18 (ddt, J=6.5, 1.1, 1.1 Hz, 2H; 1-H), 5.30 (s, 2H;
CH2Ph), 5.39 (dtt, J=15.3, 6.3, 1.3 Hz, 1H; 2-H), 5.64 (dtt, J=15.3, 6.6,
1.0 Hz, 1H; 3-H), 7.32–7.45 (m, 5H; Ph), 9.24 ppm (s, 1H; CHO);
13C NMR (75 MHz, CDCl3, RT): d=14.23 (q, C-10), 22.79 (t, C-9), 29.04
(t), 29.22 (t), 29.24 (t), 31.94 (t), 32.27 (t), 42.60 (t, C-1), 68.91 (d,
CH2Ph), 123.27 (d, C-3), 128.53 (d, Ph), 128.88 (d, Ph), 128.94 (d, Ph),
134.89 (s, Ph), 135.65 (d, C-2), 154.11 (s, NCOO), 162.55 ppm (d, CHO);
HRMS (ESI): m/z: calcd for C19H27NNaO3+: 340.18831; found: 340.18818
[M+Na]+; elemental analysis calcd (%) for C19H27NO3: C 71.89, H 8.57,
N 4.41; found: C 71.66, H 8.65, N 4.44.
ACHTUNGTRENNUNG
CACHTUNGTRENNUNG
152.56 ppm (s, NCOO); elemental analysis calcd (%) for C20H37NO4: C
67.57, H 10.49, N 3.94; found: C 67.63, H 10.54, N 3.95.
(+)-1,1-Dimethylethyl formyl [(1R)-1-heptylprop-2-en-1-yl]carbamate
(2d) and 1,1-dimethylethyl (2E)-dec-2-en-1-yl
GP1 was carried out with [Ir(cod)Cl]2 (34.7 mg, 51.7 mmol), (S,S,aS)-L3
(56.0 mg, 98.3 mmol), TBD (28.4 mg, 204 mmol), 1b (1.100 g, 5.131 mmol),
NH(CHO)Boc (786 mg, 5.41 mmol), and dry THF (3 mL). Complete
ACHTUNGERTN(NUNG formyl)carbamate (3d):
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
conversion was reached after 18 h at RT (GCMS analysis). The ratio 2d/
3d=95:5 was determined by H NMR spectroscopy of the crude product,
which was subjected to flash chromatography on silica (petroleum ether/
ethyl acetate 50:1) to yield 2d (1.174 g, 81%) and 3d (45.7 mg, 3%) as
(+)-Phenylmethyl formyl ((1S)-1-{[(triphenylmethyl)oxy]methyl}prop-2-
en-1-yl)carbamate (2g) and phenylmethyl formyl{(2E)-4-[(triphenylme-
thyl)oxy]but-2-en-1-yl}carbamate (3g): GP1 was carried out with [Ir-
1
AHCTUNGTRENNUNG
colorless oils. RfACHTUNGTRENNUNG(2d)=0.31, RfCAHUTNGTREN(NUNG 3d)=0.24, petroleum ether/ethyl acetate
ACHTUNGTRENNUNG
20:1.
Product (S)-2d: [a]D =À14.3 (c=1.03 in CHCl3); 1H NMR (300 MHz,
CDCl3, RT): d=0.87 (t, J=6.7 Hz, 3H; 7’-H), 1.15–1.35 (m, 10H; 2’-H,
3’-H, 4’-H, 5’-H, 6’-H), 1.53 (s, 9H; tBu), 1.70–1.94 (m, 2H; 1’-H), 4.88
(ddddd, J=8.3, 7.0, 7.0, 1.2, 1.2 Hz, 1H; 1-H), 5.12 (ddd, J=10.2, 1.2,
1.2 Hz, 1H; 3-H), 5.16 (ddd, J=17.1, 1.3, 1.3 Hz, 1H; 3-H), 6.03 (ddd,
J=17.2, 10.3, 7.0 Hz, 1H; 2-H), 9.21 ppm (s, 1H; CHO); 13C NMR
(75 MHz, CDCl3, RT): d=14.21 (q, C-7’), 22.77 (t, C-6’), 26.45 (t), 28.23
CTHUNGTRENNUNG
ether/ethyl acetate 5:1). The ratio 2g/3g=76:24 was determined by
1H NMR spectroscopy of the crude product, which was subjected to flash
chromatography on silica (petroleum ether/ethyl acetate 20:1) to yield 2g
(358.8 mg, 72%) and 3g (100.8 mg, 20%) as colorless oils. TLC: R
0.41, RfA(3g)=0.37, petroleum ether/ethyl acetate 5:1.
Product (R)-2g: [a]D =À33.0 (c=1.01 in CHCl3, 93% ee (HPLC); HPLC
fACHTUNGTRENNUNG(2g)=
CTHUNGTRENNUNG
(Chiralcel OD-H, n-hexane/iPrOH 99:1, flow: 0.5 mLminÀ1
, RT, l=
(q, C
(s,
ACHTUNGTRENNUNG
205 nm): tR((+)-2g)=34.4, tR((À)-2g)=38.8 min; 1H NMR (300 MHz,
CDCl3, RT): d=3.35 (dd, J=9.3, 5.6 Hz, 1H; 1’-H), 3.51 (t, J=9.3 Hz,
1H; 1’-H), 5.07–5.23 (m, 4H; 3-H, CH2Ph), 5.25–5.35 (m, 1H; 1-H), 5.88
(ddd, J=17.4, 10.4, 7.0 Hz, 1H; 2-H), 7.17–7.29 (m, 12H; Ph), 7.29–7.38
C
G
+
163.53 ppm (d, CHO); HRMS (FAB): m/z: calcd for C16H30NO3
:
284.2257; found: 284.2240 [M+H]+; elemental analysis calcd (%) for
C16H29NO3: C 67.81, H 10.31, N 4.94; found: C 67.77, H 10.51, N 5.13.
7612
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ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 7605 – 7622

Enantioselective Syntheses of 2,5-Disubstituted Pyrrolidines
FULL PAPER
(m, 8H; Ph), 9.31 ppm (s, 1H; CHO); 13C NMR (75 MHz, CDCl3, RT):
d=54.95 (d, C-1), 63.05 (t, C-1’), 68.89 (t, CH2Ph), 86.74 (s, CPh3), 118.93
(t, C-3), 127.16 (d, Ph), 127.94 (d, Ph), 128.45 (d, Ph), 128.74 (d, Ph),
128.83 (d, Ph), 133.27 (d, C-2), 134.65 (s, Ph), 143.90 (s, Ph), 153.89 (s,
NCOO), 163.04 ppm (d, CHO); HRMS (ESI): m/z: calcd for
C32H29NNaO4+: 514.19888; found: 514.19964 [M+Na]+; elemental analy-
sis calcd (%) for C32H29NO4: C 78.19, H 5.95, N 2.85; found: C 78.14, H
6.02, N 2.69.
Product 3g: 1H NMR (300 MHz, CDCl3, RT): d=3.53–3.58 (m, 2H; 4-
H), 4.23–4.28 (m, 2H; 1-H), 5.29 (s, 2H; CH2Ph), 5.66–5.83 (m, 2H; 2-H,
3-H), 7.18–7.44 (m, 20H; Ph), 9.24 ppm (s, 1H; CHO); 13C NMR
(75 MHz, CDCl3, RT): d=42.21 (t, C-1), 64.00 (t, C-4), 69.03 (t, CH2Ph),
87.01 (s, CPh3), 124.48 (d, CH=CH), 127.13 (d, Ph), 127.95 (d, Ph), 128.55
(d, Ph), 128.72 (d, Ph), 128.89 (d, Ph), 128.95 (d, Ph), 131.29 (d, CH=
CH), 134.77 (s, Ph), 144.17 (s, Ph), 154.00 (s, NCOO), 162.49 ppm (d,
CHO); HRMS (ESI): m/z: calcd for C32H29NNaO4+: 514.19888; found:
514.19957 [M+Na]+.
Product 2i: [a]D =13.7 (c=0.89 in CHCl3, 97% ee (HPLC)); HPLC
(Chiralcel OD-H, n-hexane/iPrOH 99.5:0.5, flow: 0.5 mLminÀ1, RT, l=
205 nm): tR((À)-2i)=29.1, tR((+)-2i)=31.9 min; 1H NMR (300 MHz,
CDCl3, RT): d=1.00 (s, 9H; tBu), 3.79 (dd, J=10.1, 6.0 Hz, 1H; 1’-H),
4.12 (t, J=9.8 Hz, 1H; 1’-H), 5.12–5.29 (m, 5H; 1-H, 3-H, CH2Ph), 5.95
(ddd, J=17.4, 10.4, 7.1 Hz, 1H; 2-H), 7.30–7.46 (m, 11H; Ph), 7.57–7.67
(m, 4H; Ph), 9.33 ppm (s, 1H; CHO); 13C NMR (75 MHz, CDCl3, RT):
d=19.26 (s, SiCACHTNURTGENNUG(CH3)3), 26.82 (q, SiCACHTUNGTREN(NUGN CH3)3), 55.79 (d, C-1), 62.94 (t, C-
1’), 68.95 (t, CH2Ph), 119.07 (t, C-3), 127.85 (d, Ph), 128.54 (d, Ph),
128.87 (d, Ph), 128.90 (d, Ph), 129.87 (d, Ph), 129.89 (d, Ph), 132.88 (d, C-
2), 133.32 (s, Ph), 133.36 (s, Ph), 134.70 (s, Ph), 135.68 (d, Ph), 135.69 (d,
Ph), 153.96 (s, NCOO), 163.14 ppm (d, CHO); HRMS (ESI): m/z: calcd
for C29H33NNaO4Si+: 510.20711; found: 510.20742 [M+Na]+; elemental
analysis calcd (%) for C29H33NO4Si: C 71.42, H 6.82, N 2.87; found: C
71.28, H 6.85, N 2.80.
1
Product 3i: H NMR (300 MHz, CDCl3, RT): d=1.06 (s, 9H; tBu), 4.14–
4.18 (m, 2H; 4-H), 4.23–4.28 (m, 2H; 1-H), 5.30 (s, 2H; CH2Ph), 5.66–
5.80 (m, 2H; 2-H, 3-H), 7.34–7.44 (m, 11H; Ph), 7.63–7.69 (m, 4H; Ph),
9.27 ppm (s, 1H; CHO); 13C NMR (75 MHz, CDCl3, RT): d=19.34 (s,
(À)-1,1-Dimethylethyl [(1R)-1-({[(1,1-dimethylethyl)
methyl)prop-2-en-1-yl]formylcarbamate (ent-2h) and 1,1-dimethylethyl
((2E)-4-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}but-2-en-1-yl)formylcar-
bamate (3h): GP1 was carried out with [Ir(cod)Cl]2 (67.0 mg, 99.8 mmol),
(R,R,aR)-L3 (114.1 mg, 200.3 mmol), TBD (55.6 mg, 399.4 mmol), 1d
(3.764 g, 9.788 mmol), NH(CHO)Boc (1.491 g, 10.27 mmol), and dry
THF (5 mL). Complete conversion was reached after 67 h at RT (moni-
toring by TLC, RfA
ACHTUNGERTN(NUNG diphenyl)silyl]oxy}-
SiCACTHUNRTGENNUG(CH3)3), 26.95 (q, SiCACHUTGNTERN(NUGN CH3)3), 42.04 (t, C-1), 63.64 (t, C-4), 68.99 (t,
AHCTUNGTRENNUNG
CH2Ph), 123.33 (d, CH=CH), 127.79 (d, Ph), 128.54 (d, Ph), 128.88 (d,
Ph), 128.95 (d, Ph), 129.80 (d, Ph), 133.20 (d, CH=CH), 133.65 (s, Ph),
134.78 (s, Ph), 135.64 (d, Ph), 154.02 (s, NCOO), 162.44 ppm (d, CHO);
HRMS (ESI): m/z: calcd for C29H33NNaO4Si+: 510.20711; found:
510.20750 [M+Na]+; elemental analysis calcd (%) for C29H33NO4Si: C
71.42, H 6.82, N 2.87; found: C 71.13, H 6.98, N 2.83.
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
CHTUNGTRENNUNG(1d)=0.22, petroleum ether/ethyl acetate 20:1). The
ratio ent-2h/3h was determined by 1H NMR spectroscopy of the crude
product (ent-2h/3h 82:18). The crude material was subjected to flash
chromatography on silica (petroleum ether/ethyl acetate 20:1) to yield
ent-2h (3.138 g, 71%) as white needles (m.p. 39–408C) and 3h (695 mg,
(À)-Phenylmethyl
methyl)prop-2-en-1-yl]formylcarbamate (ent-2j) and phenylmethyl
((2E)-4-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}but-2-en-1-yl)formylcar-
bamate (3j): GP1 was carried out with [Ir(cod)Cl]2 (67.1 mg, 100 mmol),
(R,R,aR)-L3 (114.4 mg, 200.8 mmol), TBD (57.9 mg, 416 mmol), 1e
(2.603 g, 9.994 mmol), NH(CHO)Cbz (1.999 g, 11.16 mmol), and dry
[(1R)-1-({[(1,1-dimethylethyl)ACHTGNUTERNNU(G dimethyl)silyl]oxy}-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
16%) as a colorless oil. RfACTHNUTRGENN(UG ent-2h)=0.23, RfACHUTNGTREN(NGUN 3h)=0.16, petroleum ether/
ethyl acetate 20:1.
AHCTUNGTRENNUNG
Product ent-2h: [a]D =À9.8 (c=1.52 in CHCl3, 97% ee (HPLC)); HPLC
(Chiralcel OD-H, n-hexane/iPrOH 99.5:0.5, flow: 0.5 mLminÀ1, RT, l=
205 nm): tR((+)-2h)=10.3, tR((À)-2h)=11.5 min; 1H NMR (300 MHz,
CDCl3, RT): d=1.02 (s, 9H; SitBu), 1.50 (s, 9H; OtBu), 3.78 (dd, J=9.9,
6.2 Hz, 1H; 1’-H), 4.10 (t, J=9.6 Hz, 1H; 1’-H), 5.11–5.24 (m, 3H; 1-H,
3-H), 5.95 (ddd, J=17.3, 10.5, 6.8 Hz, 1H; 2-H), 7.34–7.46 (m, 6H; Ph),
7.61–7.68 (m, 4H; Ph), 9.27 ppm (s, 1H; HCO); 13C NMR (75 MHz,
THF (10 mL). Complete conversion was reached after 3 h at RT (moni-
toring by GCMS analysis). The ratio ent-2j/3j was determined by
1H NMR spectroscopy of the crude product (ent-2j/3j 80:20). The crude
mixture was subjected to flash chromatography on silica (petroleum
ether/ethyl acetate 20:1) to yield ent-2j (2.664 g, 73%) and 3j (617 mg,
17%) as colorless oils. RfACTHNUTRGENN(UG ent-2j)=0.46, RfACHUTNGTREN(NGUN 3j)=0.29, petroleum ether/
ethyl acetate 10:1.
CDCl3, RT): d=19.31 (s, SiCCAHTUNGTREN(GUN CH3)3), 26.84 (q, SiCACHTUGNTRENNNUG
Product (S)-2j: [a]D =6.9 (c=1.06 in CHCl3, 95.5% ee (HPLC)); HPLC
(Chiralpak AS-H, n-hexane/iPrOH 98:2, flow: 0.5 mLminÀ1, RT, l=
205 nm): tR((À)-2j)=10.0, tR((+)-2j)=9.2 min; 1H NMR (300 MHz,
CDCl3, RT): d=À0.03 (s, 3H; SiCH3), À0.01 (s, 3H; SiCH3), 0.82 (s, 9H;
tBu), 3.75 (dd, J=10.1, 6.3 Hz, 1H; 1’-H), 4.02 (dd, J=9.9, 9.4 Hz, 1H;
1’-H), 5.05–5.14 (m, 1H; 1-H), 5.19 (ddd, J=10.4, 1.2, 1.2 Hz, 1H; 3-H),
5.23 (ddd, J=17.3, 1.3, 1.3 Hz, 1H; 3-H), 5.28 (s, 2H; CH2Ph), 6.01 (ddd,
J=17.4, 10.4, 7.1 Hz, 1H; 2-H), 7.33–7.43 (m, 5H; Ph), 9.29 ppm (s, 1H;
CHO); 13C NMR (75 MHz, CDCl3, RT): d=À5.44 (q, SiCH3), À5.32 (q,
G
3), 127.84 (d, Ph), 129.85 (d, Ph), 129.88 (d, Ph), 133.41 (s, Ph), 133.45 (d,
C-2), 133.50 (s, Ph), 135.67 (d, Ph), 135.73 (d, Ph), 152.55 (s, NCOO),
163.54 ppm (d, CHO); HRMS (ESI): m/z: calcd for C26H35NNaO4Si+:
476.22276; found: 476.22359 [M+Na]+; elemental analysis calcd (%) for
C26H35NO4Si: C 68.84, H 7.78, N 3.09; found: C 68.88, H 7.77, N 2.92.
Product 3h: 1H NMR (300 MHz, CDCl3, RT): d=1.06 (s, 9H; SitBu),
1.54 (s, 9H; OtBu), 4.12–4.24 (m, 4H; 1-H, 4-H), 5.65–5.81 (m, 2H; 2-H,
3-H), 7.34–7.44 (m, 6H; Ph), 7.63–7.70 (m, 4H; Ph), 9.20 ppm (s, 1H;
SiCH3), 18.21 (s, SiCACHTUNGTRENNUG(CH3)3), 25.85 (q, SiCCAHUTNGTRENN(UGN CH3)3), 57.06 (d, C-1), 62.26
CHO); 13C NMR (75 MHz, CDCl3, RT): d=19.36 (s, SiC
(q, SiC(CH3)3), 28.16 (q, OC
(s, OC(CH3)3), 123.96 (d, CH=CH), 127.80 (d, Ph), 129.80 (d, Ph), 132.70
ACHTUNGTRENNUNG
(t, C-1’), 68.96 (t, CH2Ph), 118.97 (t, C-3), 128.60 (d, Ph), 128.90 (d, Ph),
128.95 (d, Ph), 133.07 (d, C-2), 134.78 (s, Ph), 153.93 (s, NCOO),
163.14 ppm (d, CHO); HRMS (ESI): m/z: calcd for C19H29NNaO4Si+:
386.17581; found: 386.17594 [M+Na]+; elemental analysis calcd (%) for
C19H29NO4Si: C 62.78, H 8.04, N 3.85; found: C 62.62, H 8.12, N 3.88.
G
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
(d, CH=CH), 133.69 (s, Ph), 135.64 (d, Ph), 152.59 (s, NCOO),
162.76 ppm (d, CHO); HRMS (ESI): m/z: calcd for C26H35NNaO4Si+:
476.22276; found: 476.22260 [M+Na]+.
Product 3j: 1H NMR (300 MHz, CDCl3, RT): d=0.04 (s, 6H; Si
ACHTUNGTRENNUNG(CH3)2),
0.89 (s, 9H; tBu), 4.09–4.14 (m, 2H; 4-H), 4.22–4.27 (m, 2H; 1-H), 5.29
(s, 2H; CH2Ph), 5.59–5.78 (m, 2H; 2-H, 3-H), 7.34–7.43 (m, 5H; Ph),
9.24 ppm (s, 1H; CHO); 13C NMR (75 MHz, CDCl3, RT): d=À5.12 (q,
(+)-Phenylmethyl
methyl)prop-2-en-1-yl]formylcarbamate (2i) and phenylmethyl ((2E)-4-
{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}but-2-en-1-yl)formylcarbamate
(3i): GP1 was carried out with [Ir(cod)Cl]2 (67.2 mg, 100 mmol), (S,S,aS)-
L2 (120 mg, 200 mmol), TBD (57.3 mg, 412 mmol), 1d (3.891 g,
10.12 mmol), NH(CHO)Cbz (1.957 g, 10.92 mmol), and dry THF
(10 mL). Complete conversion was reached after 18 h at RT (monitoring
fA
3i was determined by 1H NMR spectroscopy of the crude product (2i/3i
71:29). The crude mixture was subjected to flash chromatography on
silica (petroleum ether/ethyl acetate 20:1) to yield 2i (2.935 g, 59%), 3i
[(1S)-1-({[(1,1-dimethylethyl)ACHTGNUTERNNU(G diphenyl)silyl]oxy}-
ACHTUNGTRENNUNG
SiCAHTGNUERTN(NNUG CH3)2), 18.52 (s, SiCACHUTNTRGENUN(GN CH3)3), 26.06 (q, SiCACHTNUGRTNE(NUGN CH3)3), 42.04 (t, C-1), 62.99
AHCTUNGTRENNUNG
(t, C-4), 69.02 (t, CH2Ph), 123.27 (d, CH=CH), 128.58 (d, Ph), 128.90 (d,
Ph), 128.97 (d, Ph), 133.79 (d, CH=CH), 134.81 (s, Ph), 154.02 (s,
NCOO), 162.47 ppm (d, CHO); HRMS (ESI): m/z: calcd for
C19H29NNaO4Si+: 386.17581; found: 386.17588 [M+Na]+; elemental anal-
ysis calcd (%) for C19H29NO4Si: C 62.78, H 8.04, N 3.85; found: C 62.50,
H 7.89, N 3.95.
ACHTUNGTRENNUNG
by TLC, R CHTUNGTRENNUNG(1d)=0.49, petroleum ether/ethyl acetate 10:1). The ratio 2i/
(À)-Phenylmethyl formyl ((1S)-1-{2-[(triphenylmethyl)oxy]ethyl}prop-2-
en-1-yl)carbamate (ent-2k) and phenylmethyl formyl {(2E)-5-[(triphenyl-
methyl)oxy]pent-2-en-1-yl}carbamate (3k): GP1 was carried out with [Ir-
(1.109 g, 22%), and 4g (187 mg, 4%) as colorless oils. R
(3i)=0.33, petroleum ether/ethyl acetate 10:1.
fACHTUNGTRENUN(NG 2i)=0.52, Rf-
ACHTUNGTRENNUNG
Chem. Eur. J. 2011, 17, 7605 – 7622
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7613

G. Helmchen et al.
A
RT until TLC monitoring showed complete conversion (RfACTHUNGTERNNU(G ent-2c)=0.61,
G
petroleum ether/ethyl acetate 20:1). NaOH (2n, 20 mL) was added and
the aqueous layer was separated and extracted with CH2Cl2 (30 mL). The
combined organic layers were dried over MgSO4 and concentrated in
vacuo. Purification by flash chromatography (silica, petroleum ether/
ethyl acetate 20:1, RfACTHNUTRGNE(UNG ent-4b)=0.21) yielded ent-4b (155.1 mg, 88%) as a
colorless oil.
CTHUNGTRENNUNG
Starting from 2d: GP2 was carried out with 2d (1.174 g, 4.142 mmol),
KOH (195 mg, 3.48 mmol), and methanol (50 mL). Complete conversion
was reached after 90 min (RfACHTNUTRGNE(NUG 2d)=0.24, petroleum ether/ethyl acetate
ethyl acetate 10:1.
20:1). The crude product was subjected to flash chromatography on silica
(petroleum ether/ethyl acetate 20:1) to yield 4b (1.007 g, 95%) as a col-
orless oil.
Product (R)-2k: [a]D =6.2 (c=0.90 in CHCl3, 94.5% ee (HPLC)); HPLC
(Chiralpak AD-H, n-hexane/iPrOH 95:5, flow: 0.5 mLminÀ1, RT, l=
205 nm): tR((À)-2k)=15.6, tR((+)-2k)=18.7 min; 1H NMR (300 MHz,
CDCl3, RT): d=2.06–2.16 (m, 1H; 1’-H), 2.17–2.29 (m, 1H; 1’-H), 2.99–
3.07 (m, 2H; 2’-H), 5.04–5.27 (m, 5H; 1-H, 3-H, CH2Ph), 5.99 (ddd, J=
17.3, 10.2, 7.1 Hz, 1H; 2-H), 7.16–7.32 (m, 11H; Ph), 7.32–7.42 (m, 9H;
Ph), 9.14 ppm (s, 1H; CHO); 13C NMR (75 MHz, CDCl3, RT): d=32.32
(t, C-1’), 52.87 (d, C-1), 60.44 (t, C-2’), 68.87 (t, CH2Ph), 86.75 (s, CPh3),
117.76 (t, C-3), 127.05 (d, Ph), 127.86 (d, Ph), 128.49 (d, Ph), 128.78 (d,
Ph), 128.87 (d, Ph), 134.76 (s, Ph), 135.98 (d, C-2), 144.18 (s, Ph), 153.83
(s, NCOO), 162.93 ppm (d, CHO); HRMS (ESI): m/z: calcd for
C33H31NNaO4+: 528.21453; found: 528.21482 [M+Na]+; elemental analy-
sis calcd (%) for C33H31NO4: C 78.39, H 6.18, N 2.77; found: C 78.26, H
6.25, N 2.76.
Product (R)-4b: [a]D =À13.0 (c=0.57 in CHCl3, 96% ee (GC)); GC (b-
CD, 1258C isothermal): tR((+)-4b)=56.7, tR((À)-4b)=58.0 min;
1H NMR (300 MHz, CDCl3, RT): d=0.87 (t, J=6.7 Hz, 3H; 7’-H), 1.22–
1.35 (brs, 10H; 2’-H, 3’-H, 4’-H, 5’-H, 6’-H), 1.39–1.55 (m, 2H; 1’-H),
1.44 (s, 9H; tBu), 3.98–4.13 (brs, 1H; 1-H), 4.35–4.50 (brs, 1H; NH),
5.07 (dt, J=10.4, 1.3 Hz, 1H; 3-H), 5.14 (dt, J=17.2, 1.3 Hz, 1H; 3-H),
5.74 ppm (ddd, J=16.7, 10.4, 5.6 Hz, 1H; 2-H); 13C NMR (75 MHz,
CDCl3, RT): d=14.23 (q, C-7’), 22.79 (t, C-6’), 25.84 (t), 28.56 (q, C-
AHCTUNRTGEG(NUNN CH3)), 29.36 (t), 29.54 (t), 31.93 (t), 35.40 (t, C-1’), 52.94 (d, C-1), 79.39
(s, CACTHUNGTRNEUNG(CH3)3), 114.31 (t, C-3), 139.37 (d, C-2), 155.56 ppm (s, NCOO);
HRMS (FAB): m/z: calcd for C15H30NO2+: 256.2276; found: 256.2228
[M+H]+; elemental analysis calcd (%) for C15H29NO2: C 70.54, H 11.45,
N 5.48; found: C 70.34, H 11.30, N 5.74.
1
Product 3k: H NMR (300 MHz, CDCl3, RT): d=2.30 (td, J=6.8, 6.7 Hz,
2H; 4-H), 3.07 (t, J=6.7 Hz, 2H; 5-H), 4.18 (d, J=6.2 Hz, 2H; 1-H),
5.23 (s, 2H; CH2Ph), 5.48 (dt, J=15.4, 6.2 Hz, 1H; 2-H), 5.68 (dt, J=
15.0, 6.8 Hz, 1H; 3-H), 7.17–7.35 (m, 14H; Ph), 7.37–7.45 (m, 6H; Ph),
9.23 ppm (s, 1H; CHO); 13C NMR (75 MHz, CDCl3, RT): d=33.12 (t, C-
4), 42.45 (t, C-1), 62.98 (t, C-5), 68.93 (t, CH2Ph), 86.56 (s, OCPh3),
125.45 (d, C-3), 127.02 (d, Ph), 127.87 (d, Ph), 128.50 (d, Ph), 128.79 (d,
Ph), 128.85 (d, Ph), 128.91 (d, Ph), 131.91 (d, C-2), 134.80 (s, Ph), 144.39
(s, Ph), 153.98 (s, NCOO), 162.44 ppm (d, CHO); HRMS (ESI): m/z:
calcd for C33H31NNaO4+: 528.21453; found: 528.21461 [M+Na]+; elemen-
tal analysis calcd (%) for C33H31NO4: C 78.39, H 6.18, N 2.77; found: C
78.64, H 6.30, N 2.66.
(À)-Phenylmethyl [(1R)-1-heptylprop-2-en-1-yl]carbamate (4c): GP2
was carried out with 2e (267 mg, 841 mmol), KOH (3.5 mg, 62 mmol), and
methanol (10 mL). Complete conversion was reached after 16 h (Rf-
AHCTUNGERTG(NNUN 2e)=0.40, petroleum ether/ethyl acetate 10:1). The crude product was
subjected to flash chromatography on silica (petroleum ether/ethyl ace-
tate 10:1) to yield 4c (221 mg, 91%) as white needles (m.p. 52–548C). Rf-
AHCTUNGTREGUN(NN 4c)=0.23, petroleum ether/ethyl acetate 10:1.
Product (S)-4c: [a]D =12.1 (c=1.00 in CHCl3); 1H NMR (300 MHz,
CDCl3, RT): d=0.88 (t, J=6.6 Hz, 3H; 7’-H), 1.16–1.40 (m, 10H; 2’-H,
3’-H, 4’-H, 5’-H, 6’-H), 1.41–1.56 (m, 2H; 1’-H), 4.09–4.22 (m, 1H; 1-H),
4.55–4.75 (brs, 1H; NH), 5.06–5.20 (m, 4H; 3-H, CH2Ph), 5.76 (ddd, J=
17.1, 10.6, 5.7 Hz, 1H; 2-H), 7.27–7.43 ppm (m, 5H; Ph); 13C NMR
(75 MHz, CDCl3, RT): d=14.21 (q, C-7’), 22.77 (t, C-6’), 25.76 (t), 29.31
(t), 29.49 (t), 31.91 (t), 35.29 (t), 55.35 (d, C-1), 66.82 (t, CH2Ph), 114.73
(t, C-3), 128.23 (d, Ph), 128.65 (d, Ph), 128.94 (d, Ph), 136.75 (s, Ph),
138.94 (d, C-2), 155.96 ppm (s, NCOO); HRMS (ESI): m/z: calcd for
C18H27NNaO2+: 312.19340; found: 312.19306 [M+Na]+; elemental analy-
sis calcd (%) for C18H27NO2: C 74.70, H 9.40, N 4.84; found: C 75.00, H
9.44, N 4.75.
General procedure 2 (GP2, N-formyl deprotection): A solution of 2 in
methanol was treated with KOH (0.2 equiv). The resulting mixture was
stirred at RT until TLC monitoring showed complete conversion. The sol-
vent was removed in vacuo and the residue was purified by flash chroma-
tography (silica, petroleum ether/ethyl acetate) or recrystallization to
yield 4.
(+)-tert-Butyl [(1R)-1-phenylprop-2-en-1-yl]imidocarbonate (ent-4a)
Starting from 2a: A solution of 2a (1.00 g, 3.00 mmol) in CH2Cl2 (20 mL)
was treated with TFA (500 mg, 4.42 mmol) and stirred overnight at RT
until TLC monitoring showed complete conversion (RfACTHNUTRGNE(NUG 2a)=0.65, petro-
leum ether/diethyl ether 4:1). Aqueous NaOH (10%, 4 mL) and brine
(5 mL) were added and the organic layer was separated, dried over
Na2SO4, and concentrated in vacuo. Purification by flash chromatography
(+)-Phenylmethyl
((1R)-1-{[(triphenylmethyl)oxy]methyl}prop-2-en-1-
yl)carbamate (ent-4e): GP2 was carried out with ent-2g (2.781 g,
5.657 mmol), KOH (0.10 g, 1.78 mmol), and methanol (50 mL). Complete
conversion was reached after 1 h (R
fACHTUNGTNER(NUNG ent-2g)=0.20, petroleum ether/
ethyl acetate 10:1). The crude product was recrystallized from methanol
(silica, petroleum ether/ethyl acetate 9:1,
RfACTHNGUETRNNU(G 4a)=0.53) yielded 4a
to yield ent-4e (2.299 g, 88%) as white needles (m.p. 140–1428C). R
4e)=0.14, petroleum ether/ethyl acetate 10:1.
fACHTUNGTRENNUNG(ent-
(671 mg, 96%) as colorless square crystals (m.p. 54–558C).
Starting from 2b: GP2 was carried out with ent-2b (302 mg, 1.16 mmol),
KOH (12 mg, 210 mmol), and methanol (5 mL). Complete conversion was
reached after 1.5 h (RfACHTUNGTRENNUNG(ent-2b)=0.46, petroleum ether/diethyl ether 4:1).
The crude product was subjected to flash chromatography on silica (pen-
tane/diethyl ether 4:1) to yield ent-4a (250 mg, 93%).
Product ent-4a: [a]D =62.2 (c=1.00 in CHCl3); 1H NMR (300 MHz,
CDCl3, RT): d=1.42 (s, 9H; tBu), 4.70–5.00 (brs, 1H; 1-H), 5.13–5.36
(m, 3H; 3-H, NH), 6.16 (ddd, J=17.2, 10.2, 5.5 Hz, 1H; 2-H), 7.20–
7.37 ppm (m, 5H; Ph); 13C NMR (75 MHz, CDCl3, RT): d=28.54 (q, C-
Product (S)-4e: [a]D =À21.0 (c=1.14 in CHCl3); 1H NMR (300 MHz,
CDCl3, RT): d=3.23 (d, J=4.4 Hz, 2H; 1’-H), 4.34–4.46 (brs, 1H; 1-H),
5.01–5.13 (brs, 1H; NH), 5.10 (d, J=12.3 Hz, 1H; CH2Ph), 5.15 (d, J=
12.3 Hz, 1H; CH2Ph), 5.19–5.31 (m, 2H; 3-H), 5.92 (ddd, J=17.2, 10.4,
5.4 Hz, 1H; 2-H), 7.24–7.45 ppm (m, 20H; Ph); 13C NMR (75 MHz,
CDCl3, RT): d=53.58 (d, C-1), 65.60 (t, C-1’), 66.94 (t, CH2Ph), 86.75 (s,
CPh3), 116.01 (t, C-3), 127.26 (d, Ph), 128.01 (d, Ph), 128.27 (d, Ph),
128.68 (d, Ph), 128.79 (d, Ph), 136.45 (d, C-2), 143.82 (s, Ph), 156.01 ppm
(s, NCOO); HRMS (ESI): m/z: calcd for C31H29NNaO3+: 486.20396;
found: 486.20418 [M+Na]+; elemental analysis calcd (%) for C31H29NO3:
C 80.32, H 6.31, N 3.02; found: C 80.18, H 6.22, N 2.98.
ACHTUNGTRENNUNG(CH3)3), 56.79 (d, C-1), 79.85 (s, CCAHTUNGTRNEN(UGN CH3)3), 115.61 (t, C-3), 127.19 (d, Ph),
127.66 (d, Ph), 128.82 (d, Ph), 138.17 (d, C-2), 141.26 (s, Ph), 155.20 ppm
(s, NCOO); elemental analysis calcd (%) for C15H19NO3: C 72.07, H 8.21,
N 6.00; found: C 71.85, H 8.21, N 5.95.
(+)-1,1-Dimethylethyl [(1R)-1-({[(1,1-dimethylethyl)ACHTNUTRGNEUNG(diphenyl)silyl]oxy}-
methyl)prop-2-en-1-yl]carbamate (ent-4 f): GP2 was carried out with ent-
2h (3.138 g, 6.917 mmol), KOH (80 mg, 1.4 mmol), and methanol
(À)-1,1-Dimethylethyl [(1R)-1-heptylprop-2-en-1-yl]carbamate (4b)
Starting from 2c: A solution of ent-2c (245.6 mg, 690.8 mmol) in CH2Cl2
(40 mL). Complete conversion was reached after 1 h (R
fACHTUNGTREN(NUNG ent-2h)=0.23,
(6 mL) was treated with TFA (0.07 mL, 0.9 mmol) and stirred for 1 h at
petroleum ether/ethyl acetate 20:1). The crude product was subjected to
7614
www.chemeurj.org
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 7605 – 7622

Enantioselective Syntheses of 2,5-Disubstituted Pyrrolidines
flash chromatography on silica (petroleum ether/ethyl acetate 10:1) to
yield ent-4 f (2.599 g, 88%) as a colorless oil. RfACTHNUTRGNE(UNG ent-4 f)=0.33, petroleum
ether/ethyl acetate 10:1.
FULL PAPER
toring showed complete conversion (R
ethyl acetate 9:1). According to GP3, Suzuki coupling was carried out
with [PdCl2A(dppf)] (117.5 mg, 160 mmol), Ph3As (53 mg, 170 mmol),
fACHTUNGTNER(NUNG ent-4a)=0.53, petroleum ether/
CHTUNGTRENNUNG
Product (S)-4 f: [a]D =À27.1 (c=1.69 in CHCl3) (lit.:[29d] [a]D =À27.7
(c=1.02 in CHCl3)). NMR spectroscopic data matched those repor-
ted.[29d]
Cs2CO3 (1.76 g, 5.40 mmol), methyl (2E)-3-bromoacrylate (0.54 g,
3.3 mmol), and DMF/H2O 15:1 (12 mL) at 358C. Flash chromatography
on silica (petroleum ether/ethyl acetate 4:1, RfACTHNUTRGNE(UNG ent-5a)=0.48) yielded
ent-5a (598 mg, 62%) as colorless square crystals (m.p. 79–808C). NMR
(À)-Phenylmethyl
[(1S)-1-({[(1,1-dimethylethyl)ACHTGNUTERNNU(G diphenyl)silyl]oxy}-
spectroscopic data matched those reported.[18]
methyl)prop-2-en-1-yl]carbamate (4g): GP2 was carried out with 2i
(+)-Methyl (2E,6R)-6-({[(1,1-dimethylethyl)oxy]carbonyl}amino)tridec-
2-enoate (5b): According to GP3, hydroboration was carried out with 4b
(1.008 g, 3.939 mmol), 9-BBN (965 mg, 7.91 mmol), and dry THF
(2.934 g, 6.016 mmol), KOH (100 mg, 1.78 mmol), and methanol (60 mL).
Complete conversion was reached after 45 min (RfACTHNUTRGNEUNG(2i)=0.52, petroleum
ether/ethyl acetate 10:1). The crude product was subjected to flash chro-
matography on silica (petroleum ether/ethyl acetate 10:1) to yield 4g
(15 mL). Complete conversion was reached after 3 h (R
troleum ether/ethyl acetate 3:1). According to GP3, Suzuki coupling was
carried out with [PdCl2A(dppf)] (145 mg, 198 mmol), Ph3As (121 mg,
fACHTUNGTREN(NUNG 4b)=0.89, pe-
(2.580 g, 93%) as a colorless oil. RfACTHNUTRGNE(UNG 4g)=0.44, petroleum ether/ethyl ace-
tate 10:1. [a]D =À21.9 (c=1.08 in CHCl3) (lit.:[29f] [a]D =À22.8 (c=1.0 in
CTHUNGTRENNUNG
CHCl3)); NMR spectroscopic data matched those reported.[29f]
396 mmol), Cs2CO3 (2.314 g, 7.102 mmol), methyl (2E)-3-iodoacrylate
(930 mg, 4.35 mmol), and DMF/H2O 15:1 (10 mL). Oxidation followed
by purification by flash chromatography on silica (petroleum ether/ethyl
(+)-Phenylmethyl
[(1R)-1-({[(1,1-dimethylethyl)ACHTGNUTERNNU(G dimethyl)silyl]oxy}-
methyl)prop-2-en-1-yl]carbamate (ent-4h): GP2 was carried out with ent-
2j (94.5 mg, 260 mmol), KOH (15 mg, 0.27 mmol), and methanol (5 mL).
Complete conversion was reached after 1 h (RfACTHNUTRGNE(UNG ent-2j)=0.47, petroleum
acetate 10:1) yielded 5b (1.076 g, 80%) as a colorless oil. RfACTHUNRTGNE(GNU 5b)=0.46,
petroleum ether/ethyl acetate 3:1; NMR spectroscopic data matched
those reported.[18]
ether/ethyl acetate 10:1). The crude product was subjected to flash chro-
(À)-Methyl
(2E,6S)-6-({[(phenylmethyl)oxy]carbonyl}amino)tridec-2-
enoate (ent-5c): According to GP3, hydroboration was carried out with
ent-4c (1.756 g, 6.066 mmol), 9-BBN (1.259 g, 10.31 mmol), and dry THF
matography on silica (petroleum ether/ethyl acetate 10:1) to yield ent-4h
(84.4 mg, 97%) as a colorless oil. RfACTHNUTRGNE(UNG ent-4h)=0.33, petroleum ether/ethyl
acetate 10:1; [a]D =35.7 (c=1.04 in CHCl3); NMR spectroscopic data
matched those reported.[16h]
(20 mL). Complete conversion was reached after 3 h (R
petroleum ether/ethyl acetate 5:1). According to GP3, Suzuki coupling
was carried out with [PdCl2A(dppf)] (224 mg, 304 mmol), Ph3As (186 mg,
608 mmol), Cs2CO3 (3.557 g, 10.52 mmol), methyl (2E)-3-iodoacrylate
(1.430 g, 6.682 mmol), and DMF/H2O 15:1 (20 mL). Purification of the
crude product by flash chromatography on silica (petroleum ether/ethyl
acetate 5:1) yielded ent-5c (1.816 g, 80%) as white needles (m.p. 52–
fACHTUNGTREN(NUNG ent-4c)=0.47,
(+)-Phenylmethyl ((1S)-1-{2-[(triphenylmethyl)oxy]ethyl}prop-2-en-1-yl)-
carbamate (ent-4i): GP2 was carried out with ent-2k (8.571 g,
16.95 mmol), KOH (200 mg, 3.56 mmol), and methanol (200 mL). Com-
plete conversion was reached after 2 h (RfACTHNUTRGNE(NUG ent-2k)=0.63, petroleum
ether/ethyl acetate 5:1). The crude product was subjected to flash chro-
CTHUNGTRENNUNG
matography on silica (petroleum ether/ethyl acetate 5:1) to yield ent-4i
(7.832 g, 97%) as a white solid. RfACTHNUTRGNE(NUG ent-4i)=0.50, petroleum ether/ethyl
548C). RfACTHNUTRGNE(UNG ent-5c)=0.27, petroleum ether/ethyl acetate 5:1.
Product (R)-5c: [a]D =1.0 (c=1.03 in CHCl3); 1H NMR (300 MHz,
CDCl3, RT): d=0.87 (t, J=6.7 Hz, 3H; 13-H), 1.15–1.40 (m, 10H; 8-H,
9-H, 10-H, 11-H, 12-H), 1.40–1.54 (m, 2H; 7-H), 1.54–1.73 (m, 2H; 5-H),
2.13–2.35 (m, 2H; 4-H), 3.55–3.67 (brs, 1H; 6-H), 3.71 (s, 3H; OCH3),
4.50 (d, J=9.3 Hz, 1H; NH), 5.09 (s, 2H; CH2Ph), 5.83 (d, J=15.7 Hz,
1H; 2-H), 6.95 (ddd, J=15.6, 7.5, 6.9 Hz, 1H; 3-H), 7.27–7.43 ppm (m,
5H; Ph); 13C NMR (75 MHz, CDCl3, RT): d=14.07 (q, C-13), 22.62 (t,
C-12), 25.79 (t), 28.79 (t, C-4), 29.18 (t), 29.44 (t), 31.75 (t), 34.00 (t),
35.45 (t), 51.07 (d, C-6), 51.40 (q, OCH3), 66.64 (t, CH2Ph), 121.22 (d, C-
2), 128.04 (d, Ph), 128.10 (d, Ph), 128.52 (d, Ph), 136.61 (s, Ph), 148.61 (d,
C-3), 156.09 (s, NCOO), 166.98 ppm (s, C-1); HRMS (ESI): m/z: calcd
for C22H33NNaO4+: 398.23018; found: 398.23016 [M+Na]+; elemental
analysis calcd (%) for C22H33NO4: C 70.37, H 8.86, N 3.73; found: C
70.16, H 8.86, N 3.65.
acetate 5:1.
Product (R)-4i: [a]D =À10.9 (c=1.23 in CHCl3); 1H NMR (300 MHz,
CDCl3, RT): d=1.66–1.78 (m, 1H; 1’-H), 1.88–2.03 (m, 1H; 1’-H), 3.15–
3.22 (m, 2H; 2’-H), 4.38–4.44 (m, 1H; 1-H), 4.97–5.14 (m, 2H; 3-H), 5.06
(d, J=12.3 Hz, 1H; CH2Ph), 5.12 (d, J=12.3 Hz, 1H; CH2Ph), 5.50 (brd,
J=6.6 Hz, 1H; NH), 5.65 (ddd, J=17.1, 10.4, 5.4 Hz, 1H; 2-H), 7.17–7.29
(m, 9H; Ph), 7.29–7.36 (m, 5H; Ph), 7.36–7.53 ppm (m, 6H; Ph);
13C NMR (75 MHz, CDCl3, RT): d=34.29 (t, C-1’), 51. 67 (d, C-1), 60.44
(t, C-2’), 66.51 (t, CH2Ph), 87.10 (s, CPh3), 114.82 (t, C-3), 126.98 (d, Ph),
127.81 (d, Ph), 127.94 (d, Ph), 127.99 (d, Ph), 128.44 (d, Ph), 128.55 (d,
Ph), 136.67 (s, Ph), 137.83 (d, C-2), 143.89 (s, Ph), 155.72 ppm (s,
NCOO); HRMS (ESI): m/z: calcd for C32H31NNaO3+: 500.21961; found:
500.21932 [M+Na]+; elemental analysis calcd (%) for C32H31NO3: C
80.47, H 6.54, N 2.93; found: C 80.34, H 6.57, N 2.95.
(+)-Methyl (2E,6R)-6-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-7-[(tri-
phenylmethyl)oxy]hept-2-enoate (ent-5d): According to GP3, hydrobora-
tion was carried out with ent-4d (2.952 g, 6.872 mmol), 9-BBN (1.676 g,
13.74 mmol), and dry THF (15 mL). Complete conversion was reached
General procedure 3 (GP3, Suzuki–Miyaura coupling): Under an atmos-
phere of argon, a solution of 4 (1 equiv) in dry THF was treated with 9-
BBN (2 equiv). The mixture was heated at 508C until TLC monitoring
showed complete conversion (solution A). In a separate flask, a suspen-
after 5 h (R
(ent-4d)=0.43, petroleum ether/ethyl acetate 5:1). According
2A(dppf)] (262 mg,
sion of [PdCl2ACHTUNGTRENNUNG(dppf)] (5 mol%), Ph3As (10 mol%), Cs2CO3 (1.8 equiv),
to GP3, Suzuki coupling was carried out with [PdCl CTHUNGTRENNUNG
and methyl (2E)-3-iodoacrylate (1.1 equiv) in DMF/H2O 15:1 (degassed
with helium) was vigorously stirred for 15 min under an atmosphere of
argon. At RT, solution A was added and the resulting mixture was stirred
overnight. Then, water was added, and the solution was extracted with
diethyl ether, dried over MgSO4, and concentrated in vacuo. The residue
was subjected to flash chromatography (silica, petroleum ether/ethyl ace-
tate) to yield the crude product. A solution of the crude product in THF
(15 mL per mmol) was treated with NaOH (1m solution, 5 mL per
mmol) and 30% H2O2 (1 mL per mmol) at 08C. After 10 min, saturated
NaHCO3 solution was added. The solution was extracted with diethyl
ether, dried over MgSO4, and concentrated in vacuo. Purification by flash
chromatography (silica, petroleum ether/ethyl acetate) yielded the cou-
pling product.
321 mmol), Ph3As (197 mg, 643 mmol), Cs2CO3 (3.765 g, 11.56 mmol),
methyl (2E)-3-iodoacrylate (1.610 g, 7.523 mmol), and DMF/H2O 15:1
(16 mL). Purification of the crude product by flash chromatography on
silica (petroleum ether/ethyl acetate 10:1) yielded ent-5d (3.160 g, 89%)
as a white glass. RfACHTNUTGRNEUNG(ent-5d)=0.24, petroleum ether/ethyl acetate 10:1;
m.p. 96–978C; NMR spectroscopic data matched those reported.[18]
(+)-Methyl (2E,6R)-6-({[(phenylmethyl)oxy]carbonyl}amino)-7-[(triphe-
nylmethyl)oxy]hept-2-enoate (ent-5e): According to GP3, hydroboration
was carried out with ent-4e (1.925 g, 4.152 mmol), 9-BBN (1.013 g,
8.302 mmol), and dry THF (15 mL). Complete conversion was reached
after 3 h (R
(ent-4e)=0.29, petroleum ether/ethyl acetate 5:1). According
2A(dppf)] (152 mg,
to GP3, Suzuki coupling was carried out with [PdCl CTHUNGTRENNUNG
207 mmol), Ph3As (128 mg, 417 mmol), Cs2CO3 (2.431 g, 7.461 mmol),
methyl (2E)-3-iodoacrylate (978 mg, 4.57 mmol), and DMF/H2O 15:1
(10 mL). Purification of the crude product by flash chromatography on
silica (petroleum ether/ethyl acetate 5:1) yielded ent-5e (1.926 g, 84%)
(+)-Methyl
(2E,6R)-6-[(tert-butoxycarbonyl)amino]-6-phenylhex-2-
enoate (ent-5a): A solution of BH3 in THF (1m, 3.4 mL, 3.4 mmol) was
treated with cyclohexene (570 mg, 6.9 mmol) at RT to give a milklike sus-
pension. Then ent-4a (0.71 g, 3.0 mmol) was added and the resulting solu-
tion (solution A) was stirred for 2 h at RT, after which time TLC moni-
as white needles (m.p. 94–968C). RfACTHNUTRGNE(UNG ent-5e)=0.16, petroleum ether/ethyl
Chem. Eur. J. 2011, 17, 7605 – 7622
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7615

G. Helmchen et al.
acetate 5:1. [a]D =10.0 (c=1.25 in CHCl3); 1H NMR (300 MHz, CDCl3,
RT): d=1.72 (q, J=7.5 Hz, 2H; 5-H), 2.07–2.24 (m, 2H; 4-H), 3.09
(brdd, J=9.3, 3.6 Hz, 1H; 7-H), 3.21 (brdd, J=9.1, 3.3 Hz, 1H; 7-H),
3.70 (s, 3H; OCH3), 3.72–3.84 (brs, 1H; 6-H), 4.92 (brd, J=8.8 Hz, 1H;
NH), 5.08 (s, 2H; CH2Ph), 5.76 (d, J=15.7 Hz, 1H; 2-H), 6.90 (dt, J=
15.5, 6.7 Hz, 1H; 3-H), 7.18–7.42 ppm (m, 20H; Ph); 13C NMR (75 MHz,
CDCl3, RT): d=28.92 (t, C-4), 31.03 (t, C-5), 51.12 (d, C-6), 51.57 (q,
OCH3), 64.87 (t, C-7), 66.90 (t, CH2Ph), 86.69 (s, CPh3), 121.53 (d, C-2),
127.29 (d, Ph), 128.03 (d, Ph), 128.25 (d, Ph), 128.29 (d, Ph), 128.70 (d,
Ph), 128.73 (d, Ph), 136.63 (s, Ph), 143.77 (s, Ph), 148.44 (d, C-3), 156.12
(s, NCOO), 167.08 ppm (s, C-1); HRMS (ESI): m/z: calcd for
C35H35NNaO5+: 572.24074; found: 572.24158 [M+Na]+; elemental analy-
sis calcd (%) for C35H35NO5: C 76.48, H 6.42, N 2.55; found: C 76.65, H
6.41, N 2.54.
18.41 (s, SiCACTHNGUTREN(NUG CH3)3), 26.00 (q, SiCCAHTUNGRTNEN(UNG CH3)3), 28.99 (t, C-4), 30.49 (t, C-5),
51.52 (q, OCH3), 52.21 (d, C-6), 64.87 (t, C-7), 66.86 (t, CH2Ph), 121.49
(d, C-2), 128.23 (d, Ph), 128.26 (d, Ph), 128.67 (d, Ph), 136.71 (s, Ph),
148.58 (d, C-3), 156.17 (s, NCOO), 167.09 ppm (s, C-1); HRMS (ESI): m/
z: calcd for C22H35NNaO5Si+: 444.21767; found: 444.21823 [M+Na]+; ele-
mental analysis calcd (%) for C22H35NO5Si: C 62.67, H 8.37, N 3.32;
found: C 62.53, H 8.31, N 3.30.
(+)-Methyl (2E,6R)-6-({[(phenylmethyl)oxy]carbonyl}amino)-8-[(triphe-
nylmethyl)oxy]oct-2-enoate (ent-5i): According to GP3, hydroboration
was carried out with ent-4i (156.0 mg, 322.6 mmol), 9-BBN (79.7 mg,
653.2 mmol), and dry THF (5 mL). Complete conversion was reached
after 2 h (R
(ent-4i)=0.34, petroleum ether/ethyl acetate 3:1). According
2A(dppf)] (12.0 mg,
to GP3, Suzuki coupling was carried out with [PdCl CTHUNGTRENNUNG
16.4 mmol), Ph3As (10.0 mg, 32.7 mmol), Cs2CO3 (192 mg, 588 mmol),
methyl (2E)-3-iodoacrylate (76.9 mg, 359 mmol), and DMF/H2O 15:1
(1 mL). Purification by flash chromatography on silica (petroleum ether/
ethyl acetate 5:1) yielded ent-5i (133.8 mg, 74%) as white needles (m.p.
(+)-Methyl (2E,6R)-7-{[(1,1-dimethylethyl)ACTHNUGRTENUNG(diphenyl)silyl]oxy}-6-({[(1,1-
dimethylethyl)oxy]carbonyl}amino)hept-2-enoate (ent-5 f): According to
GP3, hydroboration was carried out with ent-4 f (2.483 g, 5.833 mmol), 9-
BBN (1.424 g, 11.67 mmol), and dry THF (15 mL). Complete conversion
85–868C). RfACHTNUTRGNENG(U ent-5i)=0.21, petroleum ether/ethyl acetate 3:1. [a]D =2.8
was reached after 3 h (R
5:1). According to GP3, Suzuki coupling was carried out with [PdCl2-
(dppf)] (237 mg, 290 mmol), Ph3As (178 mg, 581 mmol), Cs2CO3 (3.415 g,
10.48 mmol), methyl (2E)-3-iodoacrylate (1.373 g, 6.416 mmol), and
DMF/H2O 15:1 (14 mL). Purification by flash chromatography on silica
(petroleum ether/ethyl acetate 5:1) yielded ent-5 f (2.508 g, 84%) as a
(ent-4 f)=0.54, petroleum ether/ethyl acetate
(c=1.25 in CHCl3); 1H NMR (300 MHz, CDCl3, RT): d=1.41–1.54 (m,
2H; 5-H), 1.59–1.71 (m, 1H; 7-H), 1.82–1.98 (m, 1H; 7-H), 2.10–2.29 (m,
2H; 4-H), 3.11–3.26 (m, 2H; 8-H), 3.70 (s, 3H; OCH3), 3.75–3.88 (m,
1H; 6-H), 5.01–5.12 (m, 2H; CH2Ph), 5.15 (d, J=8.7 Hz, 1H; NH), 5.77
(d, J=15.6 Hz, 1H; 2-H), 6.89 (dt, J=15.6, 6.9 Hz, 1H; 3-H), 7.16–
7.45 ppm (m, 20H; Ph); 13C NMR (75 MHz, CDCl3, RT): d=28.73 (t, C-
4), 32.98 (t, C-5), 34.18 (t, C-7), 49.09 (d, C-6), 51.38 (q, OCH3), 60.33 (t,
C-8), 66.51 (t, CH2Ph), 87.07 (s, OCPh3), 121.12 (d, C-2), 127.01 (d, Ph),
127.84 (d, Ph), 127.98 (d, Ph), 128.46 (d, Ph), 128.51 (d, Ph), 136.59 (s,
ACHTUNGTRENNUNG
colorless oil. R
spectroscopic data matched those reported.[18]
(+)-Methyl (2E,6R)-7-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-6-({[(phe-
fACHTUNGTRENNUNG(ent-5 f)=0.37, petroleum ether/ethyl acetate 5:1; NMR
AHCTUNGTRENNUNG
Ph), 143.86 (s, Ph), 148.53 (d, C-3), 155.92 (s, NCOO), 166.97 ppm (s, C-
nylmethyl)oxy]carbonyl}amino)hept-2-enoate (ent-5g): According to
GP3, hydroboration was carried out with ent-4g (1.379 g, 3.001 mmol), 9-
BBN (733 mg, 6.00 mmol), and dry THF (6 mL). Complete conversion
+
1); HRMS (ESI): m/z: calcd for C36H31NNaO5
: 586.25639; found:
586.25616 [M+Na]+; elemental analysis calcd (%) for C36H31NO5: C
76.71, H 6.62, N 2.48; found: C 76.49, H 6.57, N 2.41.
was reached after 2.5 h (R
5:1). According to GP3, Suzuki coupling was carried out with [PdCl2-
(dppf)] (110 mg, 150 mmol), Ph3As (92 mg, 0.30 mmol), Cs2CO3 (1.760 g,
fACHTUNGTRENUN(NG ent-4g)=0.44, petroleum ether/ethyl acetate
(+)-Methyl
(2Z,6R)-6-[(tert-butoxycarbonyl)amino]-6-phenylhex-2-
G
enoate (ent-6a): According to GP3, hydroboration was carried out with
ent-4a (172 mg, 737 mmol), 9-BBN (296 mg, 2.43 mmol), and dry THF
(1 mL). Complete conversion was reached after 4 h (monitored by
GCMS). According to GP3, Suzuki coupling was carried out with [PdCl2-
5.402 mmol), methyl (2E)-3-iodoacrylate (708 mg, 3.31 mmol), and DMF/
H2O 15:1 (7 mL). Purification by flash chromatography on silica (petro-
leum ether/ethyl acetate 5:1) yielded ent-5g (1.423 g, 87%) as white nee-
dles (m.p. 86–878C). R
G
ACHTNUGTNER(NGNU dppf)] (27.0 mg, 36.8 mmol), Ph3As (22.6 mg, 73.8 mmol), Cs2CO3
1
[a]D =14.1 (c=1.01 in CHCl3); H NMR (300 MHz, CDCl3, RT): d=1.06
(s, 9H; tBu), 1.64–1.74 (m, 2H; 5-H), 2.09–2.31 (m, 2H; 4-H), 3.66–3.80
(m, 3H; 6-H, 7-H), 3.73 (s, 3H; OCH3), 4.93 (brd, J=8.3 Hz, 1H; NH),
5.10 (s, 2H; CH2Ph), 5.80 (brd, J=15.7 Hz, 1H; 2-H), 6.93 (dt, J=15.6,
6.8 Hz, 1H; 3-H), 7.29–7.47 (m, 11H; Ph), 7.58–7.66 ppm (m, 4H; Ph);
(432 mg, 1.33 mmol), methyl (2Z)-3-iodoacrylate (187 mg, 882 mmol), and
DMF/H2O 15:1 (2 mL). Purification by flash chromatography on silica
(petroleum ether/ethyl acetate 4:1) yielded ent-6a (131 mg, 56%) as
white plates (m.p. 47–498C). RfACTHNUGRTENUNG(ent-6a)=0.25, petroleum ether/ethyl ace-
1
tate 4:1. [a]D =26.7 (c=1.13 in CHCl3); H NMR (300 MHz, CDCl3, RT):
d=1.41 (s, 9H; tBu), 1.79–1.99 (m, 2H; 5-H), 2.51–2.78 (m, 2H; 4-H),
3.67 (s, 3H; OCH3), 4.50–4.75 (brs, 1H; 6-H), 4.95 (d, J=5.8 Hz, 1H;
NH), 5.77 (ddd, J=11.5, 1.5, 1.5 Hz, 1H; 2-H), 6.23 (ddd, J=11.4, 7.6,
7.6 Hz, 1H; 3-H), 7.20–7.36 ppm (m, 5H; Ph); 13C NMR (75 MHz,
13C NMR (75 MHz, CDCl3, RT): d=19.44 (s, SiC
(CH3)3), 28.91 (t, C-4), 30.52 (t, C-5), 51.58 (q, OCH3), 52.29 (d, C-6),
ACHTUNGTRENNUNG
65.59 (t, C-7), 66.87 (t, CH2Ph), 121.46 (d, C-2), 127.94 (d, Ph), 127.96 (d,
Ph), 128.23 (d, Ph), 128.27 (d, Ph), 128.68 (d, Ph), 130.00 (d, Ph), 130.05
(d, Ph), 133.13 (s, Ph), 133.18 (s, Ph), 135.67 (d, Ph), 135.71 (d, Ph),
136.68 (s, Ph), 148.52 (d, C-3), 156.15 (s, NCOO), 167.11 ppm (s, C-1);
HRMS (ESI): m/z: calcd for C32H39NNaO5Si+: 568.24897; found:
568.24959 [M+Na]+; elemental analysis calcd (%) for C32H39NO5Si: C
70.43, H 7.20, N 2.57; found: C 70.34, H 7.34, N 2.63.
CDCl3, RT): d=25.94 (t, C-4), 28.49 (q, C
(q, OCH3), 54.72 (d, C-6), 79.53 (s, C(CH3)3), 120.18 (d, C-2), 126.44 (d,
Ph), 127.40 (d, Ph), 128.72 (d, Ph), 149.11 (d, C-3), 155.39 (s, NCOO),
ACHTUNGTREN(NNUG CH3)3), 36.16 (t, C-5), 51.17
AHCTUNGTRENNUNG
+
166.73 ppm (s, C-1); HRMS (FAB): m/z: calcd for C18H26NO4
320.1862; found: 320.1875 [M+H]+.
:
(+)-Methyl (2E,6R)-7-{[(1,1-dimethylethyl)
(dimethyl)silyl]oxy}-6-({[(phe-
(+)-Ethyl (2Z,6R)-6-[(tert-butoxycarbonyl)amino]-6-phenylhex-2-enoate
(ent-6b): Under an atmosphere of argon, a solution of ent-4a (100 mg,
429 mmol) in dry THF (1 mL) was treated with 9-BBN (80 mg,
0.65 mmol) and stirred for 4 h at RT, until GCMS monitoring showed
complete conversion. The solvent was removed in vacuo and the residue
nylmethyl)oxy]carbonyl}amino)hept-2-enoate (ent-5h): According to
GP3, hydroboration was carried out with ent-4h (2.149 g, 6.405 mmol), 9-
BBN (1.566 g, 12.83 mmol), and dry THF (10 mL). Complete conversion
was reached after 4 h (R
5:1). According to GP3, Suzuki coupling was carried out with [PdCl2-
(dppf)] (235 mg, 320 mmol), Ph3As (196 mg, 640 mmol), Cs2CO3 (3.758 g,
fACHTUNGTRENUN(NG ent-4h)=0.50, petroleum ether/ethyl acetate
was treated with
a solution of ethyl (2Z)-3-iodoacrylate (0.06 mL,
N
0.49 mmol), [Pd(PPh3)4] (28 mg, 24 mmol), and K3PO4 (3m in degassed
ACHTUNGTRENNUNG
11.53 mmol), methyl (2E)-3-iodoacrylate (1.518 g, 7.094 mmol), and
DMF/H2O 15:1 (16 mL). Purification by flash chromatography on silica
(petroleum ether/ethyl acetate 5:1) yielded ent-5h (1.789 g, 66%) as a
water, 0.28 mL, 0.84 mmol) in degassed dioxane (2 mL). The mixture was
stirred overnight at RT until GCMS showed no further conversion. Satu-
rated NaHCO3 solution was added and the solution was extracted with
diethyl ether. The combined organic layers werde dried over Na2SO4 and
concentrated in vacuo. The residue was subjected to flash chromatogra-
colorless oil. R
19.0 (c=0.97 in CHCl3); 1H NMR (300 MHz, CDCl3, RT): d=0.04 (s,
6H; Si(CH3)2), 0.88 (s, 9H; tBu), 1.61–1.72 (m, 2H; 5-H), 2.20–2.32 (m,
fACHTUNGTRENNUNG(ent-5h)=0.31, petroleum ether/ethyl acetate 5:1. [a]D =
G
phy on silica (petroleum ether/diethyl ether 4:1, RfACTHNGUTERN(UNG ent-6b)=0.14) to
2H; 4-H), 3.56–3.75 (m, 3H; 6-H, 7-H), 3.72 (s, 3H; OCH3), 4.92 (d, J=
8.3 Hz, 1H; NH), 5.10 (s, 2H; CH2Ph), 5.84 (d, J=15.7 Hz, 1H; 2-H),
6.96 (dt, J=15.3, 6.8 Hz, 1H; 3-H), 7.28–7.40 ppm (m, 5H; Ph);
13C NMR (75 MHz, CDCl3, RT): d=À5.38 (q, SiCH3), À5.36 (q, SiCH3),
yield ent-6b (124 mg, 87%) as a colorless solid (m.p. 62–638C). [a]D =
33.8 (c=1.05 in CHCl3); H NMR (300 MHz, CDCl3, RT): d=1.25 (t, J=
7.1 Hz, 3H; CH2CH3), 1.40 (s, 9H; tBu), 1.79–1.98 (m, 2H; 5-H), 2.50–
2.78 (m, 2H; 4-H), 4.13 (q, J=7.1 Hz, 2H; CH2CH3), 4.52–4.74 (brs, 1H;
1
7616
www.chemeurj.org
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 7605 – 7622

Enantioselective Syntheses of 2,5-Disubstituted Pyrrolidines
FULL PAPER
6-H), 4.96 (d, J=5.7 Hz, 1H; NH), 5.76 (dt, J=11.5, 1.5 Hz, 1H; 2-H),
6.21 (dt, J=11.5, 7.6 Hz, 1H; 3-H), 7.20–7.35 ppm (m, 5H; Ph);
13C NMR (75 MHz, CDCl3, RT): d=14.36 (q, CH2CH3), 25.93 (t, C-4),
0.695 mmol) was added. Complete conversion was reached after 70 min
(R
flash chromatography on silica (petroleum ether/ethyl acetate 5:1) yield-
ed ent-8e (1.093 g, 57%) as a colorless oil. RfA(ent-8e)=0.19, petroleum
fACHTUNGRTEN(NUNG ent-6e)=0.17, petroleum ether/ethyl acetate 5:1). Purification by
28.48 (q, C
ACHTUNGTRENNUNG(CH3)3), 36.18 (t, C-5), 54.68 (d, C-6), 59.98 (t, CH2CH3), 79.56
CTHUNGTRENNUNG
ether/ethyl acetate 5:1. [a]D =57.3 (c=1.36 in CHCl3); 1H NMR
(500 MHz, toluene, 908C): d=1.58 (dd, J=12.7, 7.0 Hz, 1H; 3-H), 1.71–
1.79 (m, 1H; 4-H), 1.79–1.86 (m, 1H; 4-H), 1.99–2.08 (m, 1H; 3-H), 2.22
(dd, J=14.4, 9.5 Hz, 1H; 1’’-H), 2.76–3.04 (m, 1H; 1’’-H), 3.14–3.29 (m,
1H; 1’-H), 3.34 (s, 3H; OCH3), 3.36–3.46 (m, 1H; 1’-H), 3.91–4.03 (m,
1H; 5-H), 4.28 (ddd, J=8.7, 8.7, 3.3 Hz, 1H; 2-H), 4.93–5.03 (m, 2H;
CH2Ph), 6.97–7.17 (m, 14H; Ph), 7.41–7.47 ppm (m, 6H; Ph); 13C NMR
(125 MHz, toluene, 908C): d=27.28 (t, C-4), 29.84 (t, C-3), 38.96 (t, C-
1’), 51.54 (q, OCH3), 56.54 (d, C-2), 59.07 (d, C-5), 65.49 (t, C-1’’), 67.66
(t, CH2Ph), 88.40 (s, CPh3), 128.07 (d, Ph), 128.74 (d, Ph), 128.85 (d, Ph),
129.23 (d, Ph), 129.39 (d, Ph), 130.12 (d, Ph), 138.62 (s, Ph), 145.78 (s,
Ph), 154.90 (s, NCOO), 172.04 ppm (s, C-2’); HRMS (ESI): m/z: calcd
for C35H35NNaO5+: 572.24074; found: 572.24106 [M+Na]+.
(s, C(CH3)3), 120.62 (d, C-2), 126.42 (d, Ph), 127.37 (d, Ph), 128.69 (d,
ACHTUNGTRENNUNG
Ph), 142.67 (s, Ph), 148.71 (d, C-3), 155.37 (s, NCOO), 166.32 ppm (s,
CO2Et); MS (FAB+): m/z: 334.2 [M+H]+; elemental analysis calcd (%)
for C19H27NO4: C 68.44, H 8.16, N 4.20; found: C 68.30, H 8.10, N 4.20.
General procedure 4 (GP4, intramolecular Michael addition): Under an
atmosphere of argon, a solution of 5 or 6 (1 equiv) in dry THF was treat-
ed with KOtBu (0.8 equiv) at À788C. The yellow solution was stirred at
À788C until TLC monitoring showed complete conversion. Then, water
was added and the solution was allowed to warm to RT. The aqueous
layer was separated and extracted with diethyl ether. The combined or-
ganic layers were dried over MgSO4 and concentrated in vacuo. The resi-
due was subjected to flash chromatography (silica, petroleum ether/ethyl
acetate) to yield the trans-2,5-disubstituted pyrrolidine.
(À)-tert-Butyl
(2R,5R)-2-(2-ethoxy-2-oxoethyl)-5-phenylpyrrolidine-1-
carboxylate (7): GP4 was carried out with 5b (80 mg, 0.24 mmol), KOtBu
(À)-Phenylmethyl
(2S,5S)-2-({[(1,1-dimethylethyl)ACTHNGUTERNNU(G diphenyl)silyl]oxy}-
methyl)-5-[2-(methyloxy)-2-oxoethyl]pyrrolidine-1-carboxylate (8g): GP4
was carried out with 6g (2.389 g, 4.377 mmol), KOtBu (394 mg,
3.51 mmol), and dry THF (40 mL). Complete conversion was reached
(20 mg, 0.18 mmol), and dry THF (1.5 mL). Complete conversion was
reached after 30 min (RfACTHNUTRGNE(UNG 5b)=0.32, petroleum ether/ethyl acetate 4:1).
Purification by flash chromatography on silica (petroleum ether/ethyl
acetate 4:1, Rf(7)=0.35) yielded 7 (74 mg, 93%) as a colorless oil. [a]D =
À80.6 (c=0.96 in CHCl3); 1H NMR (300 MHz, toluene, 908C): d=1.06
(t, J=7.1 Hz, 3H; CH2CH3), 1.22 (s, 9H; tBu), 1.46 (dd, J=10.9, 5.6 Hz,
1H; 4-H), 1.61 (dd, J=11.5, 5.6 Hz, 1H; 3-H), 1.92–2.17 (m, 2H; 3-H, 4-
H), 2.34 (dd, J=14.9, 9.4 Hz, 1H; 1’-H), 3.10 (d, J=14.8 Hz, 1H; 1’-H),
3.94–4.04 (m, 2H; CH2CH3), 4.52 (t, J=6.5 Hz, 1H; 2-H), 4.74 (d, J=
7.1 Hz, 1H; 5-H), 6.94–7.05 (m, 3H; Ph), 7.05–7.14 ppm (m, 2H; Ph);
13C NMR (75 MHz, toluene, 908C): d=15.10 (q, CH2CH3), 28.95 (t, C-3),
after 40 min (R
tion by flash chromatography on silica (petroleum ether/ethyl acetate
5:1) yielded 8g (2.318 g, 97%) as a colorless oil. RfACTHNUTRGNEUNG(8g)=0.32, petroleum
fACHTUNGTREN(NUGN 6g)=0.29, petroleum ether/ethyl acetate 5:1). Purifica-
ether/ethyl acetate 5:1.
1
Product (2R,5R)-8g: [a]D =25.0 (c=0.90 in CHCl3); H NMR (300 MHz,
toluene, 908C): d=1.11 (s, 9H; tBu), 1.59 (dd, J=12.3, 7.0 Hz, 1H; 4-H),
1.71–1.87 (m, 1H; 3-H), 1.88–1.98 (m, 1H; 3-H), 1.98–2.09 (m, 1H; 4-H),
2.23 (dd, J=14.9, 9.4 Hz, 1H; 1’’-H), 2.76–3.04 (m, 1H; 1’’-H), 3.35 (s,
3H; OCH3), 3.61–3.78 (m, 1H; 1’-H), 3.80–3.97 (m, 2H; 2-H, 1’-H), 4.29
(ddd, J=8.7, 8.7, 3.3 Hz, 1H; 5-H), 4.99 (s, 2H; CH2Ph), 7.02–7.25 (m,
11H; Ph), 7.64–7.72 ppm (m, 4H; Ph); 13C NMR (75 MHz, toluene,
29.20 (q, C
ACHTUNGTRENNUNG
CH2CH3), 63.22 (d, C-5), 79.95 (s, CAHCUTNGTRENNUNG
Ph), 129.27 (d, Ph), 171.84 ppm (s, C-2’); HRMS (ESI): m/z: calcd for
C19H27NNaO4+: 356.18323; found: 356.18331 [M+Na]+; elemental analy-
sis calcd (%) for C19H27NO4: C 68.44, H 8.16, N 4.20; found: C 68.48, H
7.98, N 4.02.
908C): d=20.41 (s, SiCACHTNURTGENNUG(CH3)3), 27.03 (t, C-3), 28.17 (q, SiCAHCTUNGTREN(NUGN CH3)3), 29.83
(t, C-4), 39.20 (t, C-1’’), 51.54 (q, OCH3), 56.71 (d, C-5), 60.50 (d, C-2),
65.68 (t, C-1’), 67.60 (t, CH2Ph), 128.77 (d, Ph), 128.89 (d, Ph), 129.20 (d,
Ph), 129.41 (d, Ph), 130.79 (d, Ph), 135.35 (s, Ph), 135.37 (s, Ph), 136.86
(d, Ph), 138.65 (s, Ph), 154.96 (s, NCOO), 172.04 ppm (s, C-2’’); HRMS
(ESI): m/z: calcd for C32H39NNaO5Si+: 568.24897; found: 568.24955
[M+Na]+; elemental analysis calcd (%) for C32H39NO5Si: C 70.43, H
7.20, N 2.57; found: C 70.20, H 7.23, N 2.50.
(+)-tert-Butyl (2S,5S)-2-(2-methoxy-2-oxoethyl)-5-phenylpyrrolidine-1-
carboxylate (ent-8a): GP4 was carried out with ent-5a (26 mg, 81 mmol),
KOtBu (7.3 mg, 65 mmol), and dry THF (0.5 mL). Complete conversion
was reached after 30 min (RfACHTUNGTREN(NUNG ent-5a)=0.25, petroleum ether/ethyl acetate
4:1). Purification by flash chromatography on silica (petroleum ether/di-
(+)-Phenylmethyl (2R,5R)-2-({[(1,1-dimethylethyl)ACHTNUTRGNE(NUG dimethyl)silyl]oxy}-
ethyl ether 8:1, RfACHTUNGTRENNUNG(ent-8a)=0.21) yielded ent-8a (20 mg, 77%) as color-
less square crystals; NMR spectroscopic data matched those reported.[18]
methyl)-5-[2-(methyloxy)-2-oxoethyl]pyrrolidine-1-carboxylate (ent-8h):
GP4 was carried out with ent-6h (1.789 g, 4.243 mmol), KOtBu (381 mg,
3.40 mmol), and dry THF (17 mL). Due to incomplete conversion after
50 min, GP4 was repeated with the mixed fractions obtained after
workup and purification, KOtBu (371 mg, 3.31 mmol), and dry THF
(À)-Phenylmethyl (2R,5S)-2-heptyl-5-[2-(methyloxy)-2-oxoethyl]pyrroli-
dine-1-carboxylate (8c): GP4 was carried out with 6c (181.2 mg,
482.5 mmol), KOtBu (43.3 mg, 386 mmol), and dry THF (5 mL). Complete
conversion was reached after 30 min (RfACTHNUGRTNEUNG(6c)=0.27, petroleum ether/ethyl
acetate 5:1). Purification by flash chromatography on silica (petroleum
(17 mL). Complete conversion was reached after 40 min (RfACHTUNGTRENNUNG(ent-6h)=
0.31, petroleum ether/ethyl acetate 5:1). Purification by flash chromatog-
raphy on silica (petroleum ether/ethyl acetate 5:1) yielded ent-8h
(1.354 g, 76%) as a colorless oil containing 15% (1H NMR spectra, see
ether/ethyl acetate 5:1) yielded 8c (156.3 mg, 86%) as a colorless oil. Rf-
A
CHCl3); 1H NMR (300 MHz, toluene, 908C): d=0.89 (t, J=6.7 Hz, 3H;
7’-H), 1.09–1.33 (m, 11H; 1’-H, 2’-H, 3’-H, 4’-H, 5’-H, 6’-H), 1.39 (dd, J=
12.2, 6.9 Hz, 1H; 3-H), 1.59 (dd, J=11.9, 6.6 Hz, 1H; 4-H), 1.63–1.96 (m,
3H; 3-H, 4-H, 1’-H), 2.19 (dd, J=15.0, 9.5 Hz, 1H; 1’’-H), 2.94 (d, J=
13.7 Hz, 1H; 1’’-H), 3.37 (s, 3H; OCH3), 3.75 (t, J=7.6 Hz, 1H; 2-H),
4.22–4.32 (m, 1H; 5-H), 5.04 (d, J=12.5 Hz, 1H; CH2Ph), 5.13 (d, J=
12.5 Hz, 1H; CH2Ph), 7.04–7.29 ppm (m, 5H; Ph); 13C NMR (75 MHz,
toluene, 908C): d=14.87 (q, C-7’), 23.78 (t, C-6’), 27.69 (t), 28.44 (t, C-3),
29.67 (t, C-4), 30.44 (t), 30.76 (t), 33.07 (t), 35.01 (t, C-1’), 39.26 (t, C-1’’),
51.54 (q, OCH3), 56.00 (d, C-5), 59.53 (d, C-2), 67.62 (t, CH2Ph), 128.79
below) of the C-5 epimer. RfACTHNUTRGNE(NUG ent-8h)=0.39, petroleum ether/ethyl ace-
tate 5:1. [a]D =47.1 (c=1.09 in CHCl3, containing 15% C-5 epimer);
1H NMR (300 MHz, toluene, 908C): d=À0.01 (s, 6H; Si
ACHTUGNTREN(UNNG CH3)2), 0.90 (s,
9H; tBu), 1.58 (dd, J=12.4, 6.6 Hz, 1H; 4-H), 1.69–1.89 (m, 2H; 3-H),
2.02 (dd, J=12.4, 7.6 Hz, 1H; 4-H), 2.22 (dd, J=14.6, 9.7 Hz, 1H; 1’’-H),
2.76–3.06 (m, 1H; 1’’-H), 3.36 (s, 3H; OCH3), 3.46–3.72 (m, 2H; 1’-H),
3.77–3.88 (m, 1H; 2-H), 4.21–4.34 (m, 1H; 5-H), 5.02 (d, J=12.5 Hz, 1H;
CH2Ph), 5.12 (d, J=12.4 Hz, 1H; CH2Ph), 7.02–7.16 (m, 3H; Ph), 7.21–
7.28 ppm (m, 2H; Ph); the C-5-epimer displays a s at d=0.91 ppm, which
was used for its quantification; 13C NMR (75 MHz, toluene, 908C): d=
(d, Ph), 129.25 (d, Ph), 129.41 (d, Ph), 138.88 (s, Ph), 154.97 (s, NCOO),
+
172.13 ppm (s, C-2’’); HRMS (ESI): m/z: calcd for C22H33NNaO4
:
À4.46 (q, Si
ACHTGNUERTN(NUGN CH3)2), 19.29 (s, SiCACHTNURGTENNG(UN CH3)3), 26.96 (q, SiCCAHTNUGTREN(NUGN CH3)3), 27.04 (t,
398.23018; found: 398.23046 [M+Na]+; elemental analysis calcd (%) for
C-3), 31.05 (t, C-4), 39.32 (t, C-1’’), 51.54 (q, OCH3), 56.68 (d, C-5), 60.64
(d, C-2), 64.66 (t, C-1’), 67.74 (t, CH2Ph), 128.88 (d, Ph), 129.34 (d, Ph),
129.45 (d, Ph), 138.66 (s, Ph), 154.97 (s, NCOO), 172.04 ppm (s, C-2’’);
HRMS (ESI): m/z: calcd for C22H35NNaO5Si+: 444.21767; found:
444.21768 [M+Na]+; elemental analysis calcd (%) for C22H35NO5Si: C
62.67, H 8.37, N 3.32; found: C 62.44, H 8.30, N 3.31.
C22H33NO4: C 70.37, H 8.86, N 3.73; found: C 70.27, H 8.78, N 3.76.
(+)-Phenylmethyl (2R,5R)-2-[2-(methyloxy)-2-oxoethyl]-5-{[(triphenyl-
methyl)oxy]methyl}pyrrolidine-1-carboxylate (ent-8e): GP4 was carried
out with ent-6e (1.923 g, 3.498 mmol), KOtBu (314.5 mg, 2.803 mmol),
and dry THF (25 mL). After 40 min additional KOtBu (78.0 mg,
Chem. Eur. J. 2011, 17, 7605 – 7622
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7617

G. Helmchen et al.
(+)-Phenylmethyl (2R,5R)-2-[2-(methyloxy)-2-oxoethyl]-5-{2-[(triphenyl-
methyl)oxy]ethyl}pyrrolidine-1-carboxylate (ent-8i): GP4 was carried out
with ent-6i (6.558 g, 11.64 mmol), KOtBu (1.045 g, 9.314 mmol), and dry
THF (80 mL). Complete conversion was reached after 35 min (RfACTHNUTRGNE(NUG ent-
6i)=0.38, petroleum ether/ethyl acetate 5:1). Purification by flash chro-
matography on silica (petroleum ether/ethyl acetate 5:1) yielded ent-8i
silica (petroleum ether/ethyl acetate 10:1) yielded 10 (542 mg, 77%) as a
colorless oil. [a]D =À60.5 (c=1.08 in CHCl3); 1H NMR (300 MHz, tolu-
ene, 908C): d=0.89 (t, J=6.0 Hz, 3H; 7’’-H), 1.21–1.36 (m, 11H; 1’’-H,
2’’-H, 3’’-H, 4’’-H, 5’’-H, 6’’-H), 1.39–1.54 (m, 2H; 3-H), 1.48 (s, 9H; tBu),
1.59 (d, J=6.5 Hz, 3H; 4’-H), 1.67–1.96 (m, 3H; 4-H, 1’’-H), 2.07–2.20
(m, 1H; 1’-H), 2.50–2.70 (m, 1H; 1’-H), 3.70–3.88 (m, 2H; 2-H, 5-H),
5.29–5.41 (m, 1H; 2’-H), 5.42–5.55 ppm (m, 1H; 3’-H)
(75 MHz, toluene, 908C): d=13.76 (q, C-4’), 14.86 (q, C-7’’), 23.81 (t, C-
6’’), 27.86 (t), 28.59 (t, C-4), 28.85 (t, C-3), 29.68 (q, C(CH3)3), 30.57 (t),
30.93 (t), 32.24 (t), 33.10 (t, C-1’), 35.23 (t, C-1’’), 59.00 (d, C-2), 59.37 (d,
;
13C NMR
(5.067 g, 77%) as a white powder (m.p. 95–968C). RfACTHNUTRGNEUNG(ent-8i)=0.43, petro-
leum ether/ethyl acetate 5:1. [a]D =21.4 (c=1.16 in CHCl3); 1H NMR
(300 MHz, toluene, 908C): d=1.33–1.58 (m, 3H; 3-H, 4-H, 1’’-H), 1.58–
1.71 (m, 1H; 4-H), 1.72–1.88 (m, 1H; 3-H), 2.04–2.26 (m, 2H; 1’-H, 1’’-
H), 2.80–2.99 (m, 1H; 1’-H), 3.06–3.28 (m, 2H; 2’’-H), 3.36 (s, 3H;
OCH3), 3.89–4.02 (m, 1H; 5-H), 4.14–4.26 (m, 1H; 2-H), 4.99–5.15 (m,
2H; CH2Ph), 6.97–7.32 (m, 14H; Ph), 7.40–7.52 ppm (m, 6H; Ph);
13C NMR (75 MHz, toluene, 908C): d=28.65 (t, C-4), 29.51 (t, C-3), 35.47
(t, C-1’’), 39.17 (t, C-1’), 51.54 (q, OCH3), 55.93 (d, C-2), 57.44 (d, C-5),
62.87 (t, C-2’’), 67.65 (t, CH2Ph), 88.44 (s, OCPh3), 128.03 (d, Ph), 128.83
(d, Ph), 128.89 (d, Ph), 129.19 (d, Ph), 129.46 (d, Ph), 130.13 (d, Ph),
AHCTUNGTRENNUNG
C-5), 79.34 (s, CACTHNUTRGNEUNG(CH3)3), 126.70 (d, C-3’), 128.60 (d, C-2’), 154.63 ppm (s,
NCOO); HRMS (ESI): m/z: calcd for C20H37NNaO2+: 346.27165; found:
346.27206 [M+Na]+; elemental analysis calcd (%) for C20H37NO2: C
74.25, H 11.53, N 4.33; found: C 74.12, H 11.48, N 4.23.
(À)-1,1-Dimethylethyl (2R,5R)-2-butyl-5-heptylpyrrolidine-1-carboxylate
(11): A suspension of 10 (512.9 mg, 1.585 mmol) and Pd/C (52 mg) in
methanol (10 mL) was vigorously stirred under an atmosphere of hydro-
gen (1 bar) at RT. After 3 h, TLC monitoring showed complete conver-
sion (Rf(10)=0.48, Rf(11)=0.56, petroleum ether/ethyl acetate 10:1). The
suspension was filtered through a short column with silica and concen-
trated in vacuo to yield 11 (474.2 mg, 92%) as a colorless oil. [a]D =
À61.5 (c=1.08 in CHCl3); 1H NMR (300 MHz, toluene, 908C): d=0.86–
0.93 (2t, J=7.0 Hz, 6H; 4’-H, 7’’-H), 1.16–1.39 (m, 16H), 1.39–1.51 (m,
2H), 1.47 (s, 9H; tBu), 1.67–1.97 (m, 4H), 3.66–3.83 ppm (m, 2H; 2-H, 5-
H); 13C NMR (75 MHz, toluene, 908C): d=14.86 (q), 14.91 (q), 23.81 (t),
138.81 (s, Ph), 145.97 (s, Ph), 154.90 (s, NCOO), 172.10 ppm (s, C-2’);
+
HRMS (ESI): m/z: calcd for C36H37NNaO5
: 586.25639; found:
586.25644 [M+Na]+; elemental analysis calcd (%) for C36H37NO5: C
76.71, H 6.62, N 2.48; found: C 76.57, H 6.56, N 2.55.
General procedure 5 (GP5, reduction of methyl esters with DIBAL-H):
By using our double Schlenk flask[46] under an atmosphere of argon, a so-
lution of 8 in dry CH2Cl2 was treated with DIBAL-H (1.0m in hexanes,
2 equiv, precooled) at À908C. The solution was stirred at À908C until
TLC showed complete conversion. Then, methanol (precooled) was
added and the solution was stirred for 15 min at À908C. Then saturated
sodium potassium tartrate solution and water were added and the solu-
tion was allowed to warm up to RT. The aqueous layer was separated
and extracted with CH2Cl2. The combined organic layers were dried over
MgSO4 and concentrated in vacuo. The residue was subjected to flash
chromatography (silica, petroleum ether/ethyl acetate) to yield the alde-
hyde.
23.88 (t), 27.21 (t), 27.89 (t), 28.91 (t), 29.70 (q, CCAHTUNGTRENUN(GN CH3)3), 30.08 (t), 30.58
(t), 30.94 (t), 33.11 (t), 34.77 (t), 35.15 (t), 59.07 (d), 59.11 (d), 79.17 (s, C-
AHCTUNGTREN(GNUN CH3)3), 154.63 ppm (s, NCOO); HRMS (ESI): m/z: calcd for
C20H39NNaO2+: 348.28730; found 348.28797 [M+Na]+; elemental analysis
calcd (%) for C20H39NO2: C 73.79, H 12.08, N 4.30; found: C 73.86, H
12.26, N 4.36.
(À)-(2R,5R)-2-Butyl-5-heptylpyrrolidine (12) [pyrrolidine (À)-225C]: A
solution of 11 (39.8 mg, 122 mmol) in 5% HCl in methanol (2 mL) was
heated at 608C for 2 h until TLC monitoring showed complete conver-
(À)-1,1-Dimethylethyl (2R,5S)-2-heptyl-5-(2-oxoethyl)pyrrolidine-1-car-
boxylate (9): GP5 was carried out with 8b (149.4 mg, 437.5 mmol),
DIBAL-H (1m in hexanes, 0.9 mL, 0.9 mmol), and dry CH2Cl2 (5 mL) at
sion to the hydrochloride 12·HCl (Rf(11)=0.68, RfACHTNUTRGNE(NUG 12·HCl)=0.00, petro-
leum ether/ethyl acetate 3:1). The solvent was removed in vacuo to yield
12·HCl as colorless needles in quantitative yield. A solution of 12·HCl in
aqueous NaOH (1m, 5 mL) was extracted with diethyl ether (25 mL).
The organic layer was dried over MgSO4 and the solvent was removed in
vacuo to yield 12 (24.3 mg, 88%) as a colorless oil. [a]D =À11.6 (c=0.89
in CHCl3, 97.5% ee (GC)) (lit.:[7c] for (2S,5S)-12: [a]D =10 (c=1.1 in
CHCl3)); GC (b-CD, 1158C isothermal): tR((+)-12)=50.5 min, tR((À)-
12)=50.7 min; 1H NMR (300 MHz, CDCl3, RT): d=0.88 (t, J=6.7 Hz,
3H; CH3), 0.89 (t, J=6.6 Hz, 3H; CH3), 1.19–1.38 (m, 18H), 1.38–1.52
(m, 2H), 1.52–1.65 (brs, 1H; NH), 1.85–2.00 (m, 2H), 3.02–3.17 ppm (m,
2H; 2-H, 5-H); 13C NMR (75 MHz, CDCl3, RT): d=14.22 (q), 14.22 (q),
22.79 (t), 23.01 (t), 27.49 (t), 29.45 (t), 29.69 (t), 29.92 (t), 31.98 (t), 32.68
(t), 32.68 (t), 37.11 (t), 37.42 (t), 58.15 (d), 58.17 ppm (d); HRMS (ESI):
m/z: calcd for C15H32N+: 226.25293; found: 226.25312 [M+H]+.
À908C. Complete conversion was reached after 20 min (R
troleum ether/ethyl acetate 3:1). Purification by flash chromatography on
silica (petroleum ether/ethyl acetate 3:1, Rf(9)=0.46) yielded
fACHTUNGTREN(NUNG 8b)=0.61, pe-
9
(115.8 mg, 85%) as a colorless oil, which was directly used in the next
1
step. [a]D =À47.6 (c=1.27 in CHCl3); H NMR (300 MHz, toluene, 908C,
partial decomposition during acquisition): d=0.89 (t, J=6.6 Hz, 3H; 7’-
H), 1.12–1.48 (m, 12H; 4-H, 1’-H, 2’-H, 3’-H, 4’-H, 5’-H, 6’-H), 1.43 (s,
9H; tBu), 1.54–1.96 (m, 4H; 3-H, 4-H, 1’-H), 2.08–2.14 (m, 1H; 1’’-H),
2.71 (brd, J=15.4 Hz, 1H; 1’’-H), 3.59–3.72 (m, 1H; 2-H), 4.06–4.16 (m,
1H; 5-H), 9.52 ppm (t, J=1.6 Hz, 1H; CHO); 13C NMR (75 MHz, tolu-
ene, 908C): d=14.85 (q, C-7’), 23.79 (t, C-6’), 27.76 (t), 28.70 (t, C-4),
29.54 (q, C
ACHTUNGTRENNUNG
C-1’), 49.83 (t, C-1’’), 53.93 (d, C-5), 59.19 (d, C-2), 80.09 (s, CAHCTUNTGRENNUNG
199.44 ppm (d, C-2’’); HRMS (ESI): m/z: calcd for C18H33NNaO3
334.23527; found: 334.23561 [M+Na]+.
+
:
(+)-Phenylmethyl (2S,5R)-2-heptyl-5-(2-oxoethyl)pyrrolidine-1-carboxyl-
ate (13): GP5 was carried out with ent-8c (197.3 mg, 525 mmol), DIBAL-
H (1m in hexanes, 1.05 mL, 1.05 mmol), and dry CH2Cl2 (5 mL) at
General procedure 6 (GP6, Wittig reaction with n-alkyltriphenylphos-
phonium salts): Under an atmosphere of argon, potassium hexamethyl
disilazide (KHMDS; 0.5m in toluene, 1.5 equiv) was added dropwise to a
suspension of the phosphonium salt (1.5 equiv) in dry THF at 08C. The
orange solution was stirred for 10 min at 08C. Then, a solution of the al-
dehyde (1.0 equiv) in dry THF was added and the mixture was stirred at
08C until TLC monitoring showed complete conversion. Water was
added and the solution was extracted with diethyl ether. The combined
organic layers were dried over MgSO4 and concentrated in vacuo. The
residue was purified by flash chromatography on silica (petroleum ether/
ethyl acetate) to yield the olefin.
À908C. Complete conversion was reached after 40 min (R
fACHTUNGTREN(NUNG ent-8c)=0.50,
petroleum ether/ethyl acetate 3:1). Purification by flash chromatography
on silica (petroleum ether/ethyl acetate 3:1, Rf(13)=0.38) yielded 13
(163.8 mg, 90%) as a colorless oil, which was directly used in the next
step. [a]D =45.1 (c=1.04 in CHCl3); 1H NMR (300 MHz, toluene, 908C):
d=0.89 (t, J=6.5 Hz, 3H; 7’-H), 1.09–1.35 (m, 13H; 3-H, 1’-H, 2’-H, 3’-
H, 4’-H, 5’-H, 6’-H), 1.53–1.69 (m, 1H; 3-H), 1.70–1.89 (m, 2H; 4-H),
2.04 (dd, J=16.1, 8.2 Hz, 1H; 1’’-H), 2.70 (brd, J=15.5 Hz, 1H; 1’’-H),
3.71 (brt, J=7.0 Hz, 1H; 2-H), 4.10–4.19 (m, 1H; 5-H), 5.01 (d, J=
12.4 Hz, 1H; CH2Ph), 5.10 (d, J=12.4 Hz, 1H; CH2Ph), 7.02–7.29 (m,
5H; Ph), 9.44 ppm (s, 1H; CHO); 13C NMR (75 MHz, toluene, 908C):
d=14.88 (q, C-7’), 23.77 (t, C-6’), 27.65 (t, C-3), 28.60 (t, C-4), 30.11 (t),
30.41 (t), 30.72 (t), 33.05 (t), 34.97 (t, C-1’), 49.51 (t, C-1’’), 55.89 (d, C-5),
59.39 (d, C-2), 67.63 (t, CH2Ph), 128.48 (d, Ph), 128.80 (d, Ph), 128.92 (d,
Ph), 138.42 (s, Ph), 155.00 (s, NCOO), 199.32 ppm (d, C-2’’); HRMS
(À)-1,1-Dimethylethyl
(2S,5R)-2-[(2Z)-but-2-en-1-yl]-5-heptylpyrroli-
dine-1-carboxylate (10): GP6 was carried out with 9 (675 mg, 2.17 mmol),
ethyltriphenylphosphonium bromide (1.047 g, 2.820 mmol), KHMDS
(0.5m in toluene, 5.6 mL, 2.8 mmol), and dry THF (16 mL). Complete
conversion was reached after 30 min (Rf(9)=0.46, Rf(10)=0.60, petrole-
um ether/ethyl acetate 3:1). Purification by flash chromatography on
7618
www.chemeurj.org
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 7605 – 7622

Enantioselective Syntheses of 2,5-Disubstituted Pyrrolidines
FULL PAPER
+
(ESI): m/z: calcd for C21H31NNaO3
[M+Na]+.
:
368.21961; found: 368.21934
(+)-(3S,5R,7aS)-3-Heptyl-5-methylhexahydro-1H-pyrrolizine (18) [(+)-
xenovenine]: A suspension of 17 (100.5 mg, 269 mmol) and Pd(OH)2/C
(12.0 mg) in methanol (3 mL) was vigorously stirred under an atmos-
phere of hydrogen (5 bar) at RT. After 16 h, TLC monitoring showed
complete conversion (Rf(17)=0.46, Rf(18)=0.00, petroleum ether/ethyl
acetate 10:1). The suspension was filtered through a short column with
silica and concentrated in vacuo. The residue was treated with water
(5 mL) and NaOH (1m, 0.1 mL) and the mixture was extracted with di-
ethyl ether (20 mL). The organic layer was dried over MgSO4 and the
solvent was removed in vacuo to give 18 (47.1 mg, 78%) as a pale-yellow
oil showing NMR spectroscopic data that matched those reported.[47]
[a]D =13.2 (c=1.04 in CHCl3, 94.5% ee (GC)) (lit.:[6c] for (3R,5S,7aR)-
18: [a]D =À11.4 (c=1.37 in CHCl3)); GC (b-CD, 1408C isothermal):
tR((+)-18)=17.8, tR((À)-18)=18.2 min; HRMS (EI): m/z: calcd for
C15H29N+: 223.2300; found: 223.2258 [M]+.
(+)-Phenylmethyl (2S,5R)-2-heptyl-5-(3-oxopropyl)pyrrolidine-1-carbox-
ylate (15): Under an atmosphere of argon, KHMDS (0.5m in toluene,
2.4 mL, 1.2 mmol) was added dropwise to a suspension of the phosphoni-
um salt 14 (417.8 mg, 1.22 mmol) in dry THF (8 mL) at 08C. The resul-
tant red solution was stirred for 10 min at 08C. Then, a solution of 13
(233.9 mg, 677 mmol) in dry THF (1 mL, precooled) was added dropwise.
The solution was stirred for 10 min at 08C until TLC monitoring showed
complete conversion into enol ethers (Rf(13)=0.05, Rf(enol ethers)=
0.25, petroleum ether/ethyl acetate 10:1). Water (0.1 mL) was added and
the solvent was removed in vacuo. The residue was purified by flash
chromatography on silica (petroleum ether/ethyl acetate 10:1) to yield a
mixture of E/Z-isomeric enol ethers. This mixture was dissolved in 50%
TFA/CHCl3 1:2 (9 mL) at 08C and the mixture stirred for 45 min until
TLC monitoring showed complete conversion (Rf(enol ethers)=0.52,
Rf(15)=0.41, petroleum ether/ethyl acetate 3:1). Saturated sodium hy-
drogencarbonate solution (10 mL) was added cautiously. The aqueous
layer was separated and extracted with CHCl3 (20 mL). The combined
organic layers were dried over MgSO4 and the solvent was removed in
vacuo. The residue was purified by flash chromatography on silica (petro-
leum ether/ethyl acetate 3:1) to yield 15 (147 mg, 60%) as a colorless oil.
[a]D =61.5 (c=1.03 in CHCl3) (lit.:[6c] for (2R,5S)-15: [a]D =À67 (c=1.00
in CHCl3)); 1H NMR (300 MHz, toluene, 908C): d=0.88 (t, J=6.4 Hz,
3H; 7’-H), 1.12–1.33 (m, 12H; 4-H, 1’-H, 2’-H, 3’-H, 4’-H, 5’-H, 6’-H),
1.33–1.41 (m, 1H; 3-H), 1.42–1.59 (m, 1H; 1’’-H), 1.60–1.84 (m, 3H; 3-H,
4-H, 1’-H), 1.84–2.00 (m, 3H; 1’’-H, 2’’-H), 3.62–3.84 (m, 2H; 2-H, 5-H),
5.01 (d, J=12.4 Hz, 1H; CH2Ph), 5.14 (d, J=12.4 Hz, 1H; CH2Ph), 6.98–
7.29 (m, 5H; Ph), 9.39 ppm (s, 1H; CHO); 13C NMR (75 MHz, toluene,
908C): d=14.88 (q, C-7’), 23.79 (t, C-6’), 27.73 (t), 27.82 (t, C-1’’), 28.83
(t, C-4), 28.97 (t), 30.46 (t, C-3), 30.77 (t), 33.08 (t), 34.93 (t, C-1’), 41.95
(t, C-2’’), 58.58 (d, C-5), 59.51 (d, C-2), 67.66 (t, CH2Ph), 128.89 (d, Ph),
(+)-Phenylmethyl (2R,5R)-2-({[(1,1-dimethylethyl)ACHTNUTRGNE(NUG diphenyl)silyl]oxy}-
methyl)-5-(2-oxoethyl)pyrrolidine-1-carboxylate (19): GP5 was carried
out with 8g (1.100 g, 2.016 mmol), DIBAL-H (1m in hexanes, 4 mL,
4 mmol), and dry CH2Cl2 (15 mL) at À788C. Complete conversion was
reached after 30 min (RfACTHNUTRGNE(UNG 8g)=0.44, petroleum ether/ethyl acetate 3:1).
Purification by flash chromatography on silica (petroleum ether/ethyl
acetate 3:1, Rf(19)=0.33) yielded 19 (909 mg, 87%) as a colorless oil,
which was directly used in the next step. [a]D =35.5 (c=1.13 in CHCl3);
1H NMR (300 MHz, toluene, 908C): d=1.11 (s, 9H; tBu), 1.30 (dd, J=
12.0, 7.3 Hz, 1H; 4-H), 1.46–1.84 (m, 2H; 3-H), 1.84–1.98 (m, 1H; 4-H),
2.03 (dd, J=13.6, 7.5 Hz, 1H; 1’’-H), 2.68 (d, J=15.3 Hz, 1H; 1’’-H),
3.54–3.74 (m, 1H; 1’-H), 3.76–3.94 (m, 2H; 2-H, 1’-H), 4.13–4.22 (m, 1H;
5-H), 4.96 (s, 2H; CH2Ph), 7.02–7.18 (m, 5H; Ph), 7.18–7.25 (m, 6H; Ph),
7.63–7.72 (m, 4H; Ph), 9.42 ppm (s, 1H; CHO); 13C NMR (75 MHz, tolu-
ene, 908C): d=20.39 (s, SiCACHTUNGTRENNU(G CH3)3), 27.19 (t, C-3), 28.16 (q, SiCACHTUNGTRENNUNG(CH3)3),
30.28 (t, C-4), 49.43 (t, C-1’’), 54.88 (d, C-5), 60.34 (d, C-2), 65.61 (t, C-
1’), 67.83 (t, CH2Ph), 128.91 (d, Ph), 129.23 (d, Ph), 129.30 (d, Ph), 129.44
(d, Ph), 129.46 (d, Ph), 130.80 (d, Ph), 130.83 (d, Ph), 135.27 (s, Ph),
135.32 (s, Ph), 136.84 (d, Ph), 138.81 (s, Ph), 154.99 (s, NCOO),
199.21 ppm (d, C-2’’); HRMS (ESI): m/z: calcd for C31H37NNaO4Si+:
538.23841; found: 538.23894 [M+Na]+.
129.40 (d, Ph), 129.45 (d, Ph), 138.44 (s, Ph), 155.24 (s, NCOO),
200.23 ppm (d, C-3’’); HRMS (ESI): m/z: calcd for C22H33NNaO3
382.23527; found: 382.23537 [M+Na]+.
+
:
(+)-Phenylmethyl (2S,5R)-2-heptyl-5-(3-oxobutyl)pyrrolidine-1-carboxyl-
ate (17): KHMDS (0.5m in toluene, 5.1 mL, 2.55 mmol) was added drop-
wise to a suspension of 16 (1.105 g, 2.54 mmol) in dry THF at À788C.
The dark-red solution was stirred for 10 min at À788C. Then, a solution
of 13 (438.7 mg, 1.27 mmol) in dry THF (5 mL, precooled) was added
quickly. The resultant solution was stirred for 30 min at À788C when
TLC monitoring showed complete conversion to the enol ethers
(Rf(13)=0.26, Rf(enol ethers)=0.70, petroleum ether/ethyl acetate 3:1).
The solution was allowed to warm to RT. Then water (0.1 mL) was
added and the solvent was removed in vacuo. The residue was subjected
to flash chromatography on silica (petroleum ether/ethyl acetate 3:1) to
yield the intermediary enol ethers as a mixture of E/Z isomers. A solu-
tion of the enol ethers in methanol (10 mL) was treated with HCl (1 mL,
5% in methanol) and water (0.2 mL) and heated at 508C. After 30 min
TLC monitoring showed complete conversion (Rf(enol ethers)=0.70,
Rf(17)=0.43, petroleum ether/ethyl acetate 3:1). The solvent was re-
moved in vacuo and the residue was subjected to flash chromatography
on silica (petroleum ether/ethyl acetate 3:1) to yield 17 (377.8 mg, 80%)
as a colorless oil. [a]D =61.0 (c=1.00 in CHCl3) (lit.:[6c] for (2R,5S)-17:
(À)-Phenylmethyl
(2S,5S)-2-({[(1,1-dimethylethyl)ACTHNGUTERNNU(G diphenyl)silyl]oxy}-
methyl)-5-[(2Z)-hept-2-en-1-yl]pyrrolidine-1-carboxylate (20): GP6 was
carried out with 19 (1.629 g, 3.159 mmol), pentyltriphenylphosphonium
bromide (1.963 g, 4.749 mmol), KHMDS (0.5m in toluene, 9.5 mL,
4.75 mmol), and dry THF (30 mL). Complete conversion was reached
after 30 min (Rf(19)=0.33, Rf(20)=0.62, petroleum ether/ethyl acetate
3:1). Purification by flash chromatography on silica (petroleum ether/
ethyl acetate 20:1) yielded 20 (1.462 g, 81%) as a colorless oil. [a]D =
À44.2 (c=0.94 in CHCl3); 1H NMR (300 MHz, toluene, 908C): d=0.87
(t, J=6.9 Hz, 3H; 7’’-H), 1.13 (s, 9H; tBu), 1.23–1.36 (m, 4H; 5’’-H, 6’’-
H), 1.47–1.61 (m, 1H; 4-H), 1.82–2.21 (m, 6H; 3-H, 4-H, 1’’-H, 4’’-H),
2.52–2.74 (brs, 1H; 1’’-H), 3.64–3.85 (brs, 1H; 1’-H), 3.85–4.06 (m, 3H;
2-H, 5-H, 1’-H), 4.97–5.09 (m, 2H; CH2Ph), 5.23–5.34 (m, 1H; 2’’-H),
5.37–5.48 (m, 1H; 3’’-H), 7.02–7.12 (m, 3H; Ph), 7.14–7.26 (m, 8H; Ph),
7.65–7.76 ppm (m, 4H; Ph); 13C NMR (75 MHz, toluene, 908C): d=14.78
(q, C-7’’), 20.42 (s, SiC
ACHTUGNTREN(UNNG CH3)3), 23.46 (t, C-6’’), 27.36 (t, C-3), 28.18 (q,
SiC(CH3)3), 28.35 (t, C-4’’), 28.66 (t, C-4), 32.48 (t, C-1’’), 33.16 (t, C-5’’),
AHCTUNGTRENNUNG
60.04 (d, C-5), 60.61 (d, C-2), 65.75 (t, C-1’), 67.58 (t, CH2Ph), 127.07 (d,
C-2’’), 128.71 (d, Ph), 128.87 (d, Ph), 129.25 (d, Ph), 129.38 (d, Ph),
130.75 (d, Ph), 133.43 (d, C-3’’), 135.43 (s, Ph), 136.87 (d, Ph), 138.84 (s,
Ph), 155.14 ppm (s, NCOO); HRMS (ESI): m/z: calcd for
C36H47NNaO3Si+: 592.32174; found: 592.32192 [M+Na]+; elemental anal-
ysis calcd (%) for C36H47NO3Si: C 75.88, H 8.31, N 2.46; found: C 75.61,
H 8.24, N 2.46.
1
[a]D =À61.4 (c=1.1 in CHCl3)); H NMR (300 MHz, toluene, 908C): d=
0.89 (t, J=6.7 Hz, 3H; 7’-H), 1.10–1.36 (m, 12H; 3-H, 1’-H, 2’-H, 3’-H,
4’-H, 5’-H, 6’-H), 1.36–1.48 (m, 1H; 4-H), 1.48–1.64 (m, 1H; 1’’-H), 1.65–
1.90 (m, 3H; 3-H, 4-H, 1’-H), 1.76 (s, 3H; 4’’-H), 1.91–2.15 (m, 3H; 1’’-H,
2’’-H), 3.69–3.81 (m, 2H; 2-H, 5-H), 5.02 (d, J=12.4 Hz, 1H; CH2Ph),
5.15 (d, J=12.4 Hz, 1H; CH2Ph), 7.04–7.30 ppm (m, 5H; Ph); 13C NMR
(75 MHz, toluene, 908C): d=14.87 (q, C-7’), 23.78 (t, C-6’), 27.75 (t),
28.89 (t, C-4), 29.07 (t, C-3), 29.64 (q, C-4’’), 29.72 (t, C-1’’), 30.46 (t),
30.78 (t), 33.08 (t), 34.98 (t, C-1’), 41.76 (t, C-2’’), 58.81 (d, C-5), 59.51 (d,
C-2), 67.58 (t, CH2Ph), 128.81 (d, Ph), 129.38 (d, Ph), 129.42 (d, Ph),
138.43 (s, Ph), 155.27 (s, NCOO), 205.89 ppm (s, C-3’’); HRMS (ESI): m/
z: calcd for C23H35NNaO3+: 396.25092; found: 396.25121 [M+Na]+; ele-
mental analysis calcd (%) for C23H35NO3: C 73.96, H 9.44, N 3.75; found:
C 74.08, H 9.60, N 3.88.
(À)-Phenylmethyl (2S,5S)-2-[(2Z)-hept-2-en-1-yl]-5-(hydroxymethyl)pyr-
rolidine-1-carboxylate (21): Under an atmosphere of argon, a solution of
20 (1.459 g, 2.560 mmol) in dry THF (12 mL) was treated with
TBAF·3H2O (988 mg, 3.13 mmol). The solution was stirred for 16 h at
RT, after which time TLC monitoring showed complete conversion
(Rf(20)=0.42, petroleum ether/ethyl acetate 10:1). Saturated NH4Cl solu-
tion (15 mL) and water (15 mL) were added and the solution was extract-
ed with diethyl ether (3ꢃ40 mL). The combined organic layers were
Chem. Eur. J. 2011, 17, 7605 – 7622
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7619

G. Helmchen et al.
dried over MgSO4 and concentrated in vacuo. Purification by flash chro-
matography on silica (petroleum ether/ethyl acetate 3:1, Rf(21)=0.18)
yielded 21 (808.8 mg, 95%) as a colorless oil. [a]D =À55.9 (c=0.87 in
CHCl3); 1H NMR (300 MHz, toluene, 908C): d=0.86 (t, J=6.8 Hz, 3H;
7’-H), 1.21–1.34 (m, 4H; 5’-H, 6’-H), 1.39–1.56 (m, 2H; 3-H, 4-H), 1.66–
1.86 (m, 2H; 3-H, 4-H), 1.90–2.14 (m, 4H; 1’-H, 4’-H, OH), 2.46–2.61 (m,
1H; 1’-H), 3.48 (dd, J=10.4, 4.4 Hz, 1H; 1’’-H), 3.60 (dd, J=10.5, 5.0 Hz,
1H; 1’’-H), 3.77–3.91 (m, 2H; 2-H, 5-H), 5.04 (d, J=12.4 Hz, 1H;
CH2Ph), 5.12 (d, J=12.4 Hz, 1H; CH2Ph), 5.22 (dt, J=10.7, 7.3 Hz, 1H;
2’-H), 5.40 (dt, J=10.6, 7.2 Hz, 1H; 3’-H), 7.02–7.16 (m, 3H; Ph), 7.22–
7.27 ppm (m, 2H; Ph); 13C NMR (75 MHz, toluene, 908C): d=14.77 (q,
C-7’), 23.44 (t, C-6’), 27.72 (t, C-4), 28.34 (t, C-4’), 28.97 (t, C-3), 32.59 (t,
C-1’), 33.11 (t, C-5’), 60.14 (d, C-2), 61.77 (d, C-5), 66.45 (t, C-1’’), 67.98
(t, CH2Ph), 126.75 (d, C-2’), 128.93 (d, Ph), 129.30 (d, Ph), 129.49 (d, Ph),
133.54 (d, C-3’), 138.60 (s, Ph), 156.39 ppm (s, NCOO); HRMS (ESI): m/
z: calcd for C20H29NNaO3+: 354.20396; found: 354.20398 [M+Na]+.
C-7’), 23.46 (t, C-6’), 27.78 (q, C-4’’), 28.35 (t, C-3), 28.35 (t, C-4’), 30.26
(t, C-4), 32.45 (t, C-1’), 33.12 (t, C-5’), 59.62 (d, C-2), 59.77 (d, C-5), 67.85
(t, CH2Ph), 126.64 (d, C-2’), 128.92 (d, Ph), 129.40 (d, Ph), 129.45 (d, Ph),
130.96 (d, C-2’’), 133.74 (d, C-3’), 138.55 (s, Ph), 146.42 (d, C-1’’), 155.03
(s, NCOO), 196.27 ppm (s, C-3’’); HRMS (ESI): m/z: calcd for
C23H31NNaO3+: 392.21961; found: 392.21980 [M+Na]+; elemental analy-
sis calcd (%) for C23H31NO3: C 74.76, H 8.46, N 3.79; found: C 75.00, H
8.51, N 3.88.
(À)-(3R,5S,7aR)-3-Heptyl-5-methylhexahydro-1H-pyrrolizine
(ent-18)
[(À)-xenovenine]:
A
suspension of 23 (105.4 mg, 285.2 mmol) and
Pd(OH)2/C (23.5 mg) in methanol (4 mL) was vigorously stirred under an
atmosphere of hydrogen (5 bar) at RT. After 22 h, TLC monitoring
showed complete conversion (Rf(23)=0.33, RfACTHNUTRGENUG(N ent-18)=0.09, petroleum
ether/ethyl acetate 3:1). The suspension was filtered through a short
column with silica and the filtrate concentrated in vacuo. The residue
was treated with NaOH (1m, 5 mL) and the mixture extracted with dieth-
yl ether (2ꢃ20 mL). The organic layer was dried over MgSO4 and the
solvent removed in vacuo to yield ent-18 (55.0 mg, 86%) as a colorless
oil. [a]D =À13.5 (c=0.72 in CHCl3, 96% ee (GC)) (lit.:[6c] [a]D =À11.4
(c=1.37 in CHCl3)).
General procedure 7 (GP7, Swern oxidation): Under an atmosphere of
argon, DMSO (8 equiv) was added dropwise to a solution of (COCl)2
(4 equiv) in dry CH2Cl2 at À788C. After 10 min at À788C, a solution of
the alcohol (1 equiv) in dry CH2Cl2 was added dropwise and the solution
was stirred for 30 min at À788C. Then NEt3 (16 equiv) was added drop-
wise and the solution was stirred at À788C until TLC monitoring showed
complete conversion. Water was added and the solution was allowed to
warm to RT. The aqueous layer was separated and extracted with
CH2Cl2. The combined organic layers were dried over MgSO4 and con-
centrated in vacuo. Purification by flash chromatography (silica, petrole-
um ether/ethyl acetate) yielded the aldehyde.
For compounds 24–41 see the Supporting Information.
Acknowledgements
We thank J. Hoecker, T. Sçhner, C. Adam, and O. Tverskoy for experi-
mental assistance, Dr. F. Rominger for the crystal structure analysis, and
Prof. Dr. K. Ditrich (BASF AG) for enantiomerically pure 1-arylethyla-
mines.
(À)-Phenylmethyl (2S,5S)-2-formyl-5-[(2Z)-hept-2-en-1-yl]pyrrolidine-1-
carboxylate (22): GP7 was carried out with 21 (655.7 mg, 1.978 mmol),
(COCl)2 (0.69 mL, 7.9 mmol), DMSO (1.10 mL, 15.5 mmol), NEt3
(4.4 mL, 32 mmol), and dry CH2Cl2 (23 mL). Complete conversion was
reached after 15 min (Rf(21)=0.18, Rf(22)=0.47, petroleum ether/ethyl
acetate 3:1). Purification by flash chromatography on silica (petroleum
ether/ethyl acetate 3:1) yielded 22 (621.7 mg, 95%) as a colorless oil.
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1
[a]D =À82.0 (c=1.07 in CHCl3); H NMR (300 MHz, toluene, 908C): d=
0.87 (t, J=6.5 Hz, 3H; 7’’-H), 1.21–1.33 (m, 4H; 5’’-H, 6’’-H), 1.33–1.44
(m, 1H; 4-H), 1.44–1.67 (m, 2H; 3-H, 4-H), 1.67–1.80 (m, 1H; 3-H),
1.87–2.19 (m, 3H; 1’’-H, 4’’-H), 2.36–2.72 (m, 1H; 1’’-H), 3.86–4.02 (m,
1H; 5-H), 4.00 (brd, J=7.3 Hz, 1H; 2-H), 4.95–5.12 (m, 2H; CH2Ph),
5.12–5.31 (m, 1H; 2’’-H), 5.31–5.51 (m, 1H; 3’’-H), 7.01–7.38 (m, 5H;
Ph), 9.29 ppm (s, 1H; CHO); 13C NMR (75 MHz, toluene, 908C): d=
14.76 (q, C-7’’), 23.45 (t, C-6’’), 26.23 (t, C-3), 28.31 (t, C-4’’), 29.11 (t, C-
4), 32.55 (t, C-1’’), 33.09 (t, C-5’’), 59.94 (d, C-5), 66.80 (d, C-2), 68.18 (t,
CH2Ph), 126.29 (d, C-2’’), 128.98 (d, Ph), 129.31 (d, Ph), 129.46 (d, Ph),
133.89 (d, C-3’’), 138.32 (s, Ph), 199.25 ppm (d, C-1’); HRMS (ESI): m/z:
calcd for C20H27NNaO3+: 352.18831; found: 352.18870 [M+Na]+.
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General procedure 8 (GP8, Wittig reaction with stabilized ylides): A so-
lution of the aldehyde (1.0 equiv) and the phosphorane (1.3 equiv) in tol-
uene was heated at reflux until TLC monitoring showed complete con-
version. After concentration in vacuo, the residue was purified by flash
chromatography (silica, petroleum ether/ethyl acetate) to yield the
alkene.
(À)-Phenylmethyl (2S,5S)-2-[(2Z)-hept-2-en-1-yl]-5-[(1E)-3-oxobut-1-en-
1-yl]pyrrolidine-1-carboxylate (23): GP8 was carried out with 22 (621 mg,
1.89 mmol), 1-(triphenylphosphoranylidene)acetone (797 mg, 2.50 mmol),
and toluene (30 mL). Complete conversion was reached after 5 h (moni-
toring by TLC, Rf(22)=0.47, Rf(23)=0.33, petroleum ether/ethyl acetate
3:1). Purification by flash chromatography on silica (petroleum ether/
ethyl acetate 3:1) yielded 23 (621 mg, 89%) as a pale-yellow oil. [a]D =
À84.6 (c=1.25 in CHCl3); 1H NMR (300 MHz, toluene, 908C): d=0.89
(t, J=6.3 Hz, 3H; 7’-H), 1.22–1.37 (m, 5H; 4-H, 5’-H, 6’-H), 1.46 (dd, J=
12.5, 6.8 Hz, 1H; 3-H), 1.57–1.74 (m, 1H; 3-H), 1.84 (s, 3H; 4’’-H), 1.85–
1.95 (m, 1H; 4-H), 1.97–2.17 (m, 3H; 1’-H, 4’-H), 2.52–2.74 (m, 1H; 1’-
H), 3.88 (t, J=7.0 Hz, 1H; 2-H), 4.28 (t, J=6.1 Hz, 1H; 5-H), 4.95 (d,
J=12.3 Hz, 1H; CH2Ph), 5.14 (d, J=12.3 Hz, 1H; CH2Ph), 5.26 (dt, J=
7.5, 7.5 Hz, 1H; 2’-H), 5.39–5.50 (m, 1H; 3’-H), 5.91 (d, J=15.7 Hz, 1H;
2’’-H), 6.42 (dd, J=16.0, 5.8 Hz, 1H; 1’’-H), 7.01–7.15 (m, 3H; Ph), 7.16–
7.24 ppm (m, 2H; Ph); 13C NMR (75 MHz, toluene, 908C): d=14.76 (q,
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Chem. Eur. J. 2011, 17, 7605 – 7622

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Received: March 1, 2011
Published online: May 24, 2011
7622
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Chem. Eur. J. 2011, 17, 7605 – 7622