Diastereoselective access to enantiomerically pure cis-2,3-disubstituted pyrrolidines

Article abstract of DOI:10.1002/ejoc.201000255

A straightforward access to enantiomerically pure 2,3-disubstituted pyrrolidines is reported that involves diastereoselective allylation of (R)-phenylglycinol-derived imines and a sequential hydrozirconation-cyclization. A number of pyrrolidine derivatives bearing aryl, heteroaryl, alkyl and alkenyl groups have been prepared in this way. Such compounds are useful building blocks in the synthesis of molecules of biological interest, as illustrated by the syntheses of proline derivatives and the naturally occurring alkaloid (-)-isoretronecanol.

Full text of DOI:10.1002/ejoc.201000255

FULL PAPER
DOI: 10.1002/ejoc.201000255
Diastereoselective Access to Enantiomerically Pure cis-2,3-Disubstituted
Pyrrolidines
Pierre-Olivier Delaye,[a] Tarun K. Pradhan,[a] Émilie Lambert,[a] Jean-Luc Vasse,*[a] and
Jan Szymoniak*[a]
Keywords: Diastereoselectivity / Allylation / Alkaloids / Heterocycles / Imines
A straightforward access to enantiomerically pure 2,3-disub-
stituted pyrrolidines is reported that involves diastereoselec-
tive allylation of (R)-phenylglycinol-derived imines and a se-
quential hydrozirconation–cyclization. A number of pyrrol-
idine derivatives bearing aryl, heteroaryl, alkyl and alkenyl
groups have been prepared in this way. Such compounds are
useful building blocks in the synthesis of molecules of bio-
logical interest, as illustrated by the syntheses of proline de-
rivatives and the naturally occurring alkaloid (–)-isoretrone-
canol.
the presence of a secondary amino group; the one-pot se-
quence in pathway (ii) involves the hydrozirconation–iodin-
ation of homoallylic amines.[6b]
Introduction
The pyrrolidine ring system is common to a number of
naturally occurring[1] and medicinally important com-
pounds.[2] Furthermore, optically pure pyrrolidines are
widely used as chiral inductors and organocatalysts in
asymmetric synthesis.[3] Although numerous syntheses of
substituted pyrrolidines have been reported,[4] there is a
continued need for simple and efficient methods that pro-
vide a stereocontrolled access to optically pure compounds.
Of the pyrrolidines synthesized, cis-2,3-disubstituted pyr-
rolidines are valuable building blocks for the preparation of
numerous bioactive molecules that possess pyrrolidine rings
and are thus attractive synthetic targets. Surprisingly, there
is a lack of general synthetic methods available for synthe- Scheme 1. Zirconium-mediated synthesis of 2-substituted pyrrol-
idines.
sizing 2,3-disubstituted pyrrolidines and a simple asymmet-
ric access to such compounds would be of significant inter-
We assumed that 2,3-disubstituted pyrrolidines could be
est.[5]
synthesized according to pathway (ii).[7] In this case, the
We recently reported a hydrozirconation-based method-
stereochemistry would be controlled by diastereoselective
ology for the asymmetric construction of five- and six-
allylation of phenylglycinol-derived imines, as shown in
membered N-heterocycles.[6] Among the reactions de-
Scheme 2.
scribed, a selective preparation of both enantiomeric 2-sub-
stituted pyrrolidines was achieved by using the same start-
ing materials (allyl bromide and an aldehyde) and (R)-phen-
ylglycinol as the chiral inductor (Scheme 1). The sequence
in pathway (i) proceeds via N-allyloxazolidines and involves
hydrozirconation–Lewis acid mediated cyclization. The
Scheme 2. Retrosynthetic approach to 2,3-disubstituted pyrrol-
idines.
preparation of the second enantiomer was based on our
finding that alkene hydrozirconation can be performed in
Although the addition of allylic organometallic com-
pounds to chiral imines is well known,[8] such reactions are
[a] Institut de Chimie Moléculaire de Reims, CNRS-UMR 6229,
Université de Reims Champagne-Ardenne,
often capricious in terms of yield and selectivity and much
BP 1039, 51687 Reims Cedex 2, France
more difficult to control in comparison with those involving
aldehydes. For example, only a few methods are applicable
to enolizable aldimines. There is still a need to increase sub-
strate scope, particularly in the organometallic part, which
Fax: +33-3-26913166
E-mail: jean-luc.vasse@univ-reims.fr
jan.szymoniak@univ-reims.fr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000255.
Eur. J. Org. Chem. 2010, 3395–3406
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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P.-O. Delaye, T. K. Pradhan, É. Lambert, J.-L. Vasse, J. Szymoniak
FULL PAPER
would provide wider access to optically active amines.
By applying Method A or B, homoallylic amines bearing
Among the metals known to promote the allylation of chi- aromatic, heteroaromatic, alkyl or alkenyl groups were ob-
ral imines, zinc and indium have emerged as attractive can- tained, most of them being isolated in diastereomerically
didates: (i) branched regioisomeric homoallylic amines typi- pure form after purification by column chromatography
cally predominate over linear amines with these metals and (Table 1). Different combinations of substituents, that is,
(ii) the required syn stereoselectivity and good diastereofa- two aryls or heteroaryls (entries 1 and 2), 2-aryl or 2-het-
cial selectivity may be achieved.[9] Herein we demonstrate eroaryl and 3-alkyl (entries 3 and 4), alkenyl and alkyl (en-
that the Barbier-type allylation of optically active phenyl- tries 5 and 6) or two alkyls (entries 8–15), were achieved.
glycinol-derived aldimines proceeded with high regio- and The method also allows the incorporation of structural
stereoselectivity.
fragments including variously protected alcohols (entries 3–
15) or amines (in this case, the low isolated yield originates
from the problematic isomeric separation, entry 15). Inter-
estingly, homoallylic amines 1j and 1k bearing reversed
Results and Discussion
Two different Barbier-type protocols were selected for alcohol protection (OTBS and OBn) can be prepared (en-
the preparation of the desired unsaturated amines. First, a tries 10 and 11). The only limitation was observed in the
mixture of imine and bromide was added to a suspension case of 2-alkyl and 3-aryl (entry 7) for which low selectivity
of zinc in the presence of a catalytic amount of CeCl3·7H2O and yield were obtained by methods A and B. Branched
in THF following the procedure of Umano-Ronchi and co- regioisomers were solely obtained irrespective of the pro-
workers.[10] This method was successfully applied to imines cedure employed. Only syn stereoisomers were formed in
derived from aromatic aldehydes to afford good yields and typically high diastereomeric ratios. The reaction proceeded
stereoselectivities (Table 1, Method A). With substrates de- with unvarying and high stereoselectivity regardless of the
rived from aliphatic aldehydes, however, the N-alkyl prod- C=C double bond configuration in the alkenyl bromide (en-
uct was competitively formed. This side-reaction possibly tries 11 and 12). The disubstituted homoallylic amine 1k
originates from the preferential formation of oxazolines in- was obtained in good yield and stereoselectivity, according
stead of imines when condensing phenylglycinol and ali- to the NMR spectrum of the crude product, and isolated
phatic aldehydes. Whereas the zinc-based protocol appears as a single isomer. The preferential formation of syn rather
to be limited to aromatic or α,β-unsaturated imines, the use than anti stereoisomers presumably arises from a Traxler–
of indium in MeOH to generate the allylmetal species[9b] Zimmermann-type transition state in which the metal is co-
allowed this side-reaction to be overcome, leading to the ordinated to both the N and the O atoms of the imine.
expected amines in good-to-moderate yields (Method B).
In this case, the imine substituents adopt a pseudo-axial
Table 1. Indium- and zinc-mediated diastereoselective allylation of phenylglycinol-derived imines.
Entry
R
RЈ
Alkene/Method[a]
Compound, dr (% yield)[b]
1
2
3
4
5
6
7
8
2-furyl
3-pyridyl
2-furyl
Ph
Ph
E/A
E/A
Z/A
Z/A
Z/B
Z/B
Z/B
Z/B
Z/B
Z/B
Z/B
E/B
Z/B
Z/B
Z/B
1a, 11:1 (86)
1b, 9.7:1 (91)[c]
1c, 10.7:1 (75)
1d, 9.2:1(85)[d]
1e, 14:1 (64)
1f, 13:1 (83)
1g, 2:1 (37)
TBSOCH2
TBSOCH2
BnOCH2
TBSOCH2
Ph
n-C5H11
BnOCH2
TBSOCH2
BnOCH2
BnOCH2
TBSOCH2
BnOCH2
BnOCH2
Ph
cinnamyl
cinnamyl
BnOCH2
BnOCH2
iBu
BnO(CH2)3
TBSO(CH2)3
TBSO(CH2)3
n-C6H13
CH3
1h, 5:1 (74)
9
1i, 11:1(54)[e]
1j, 10:1(49)
1k, 8:1 (71)
1k, 9:1 (75)
1l, 17:1 (70)
1m, 7.6:1 (55)[f]
1n, 3:1 (30)
10
11
12
13
14
15
BocNBn(CH2)2
[a] Reagents and conditions: Method A: imine (1 mmol), bromide (2.5 mmol), Zn (2.5 mmol) and CeCl3·7H2O (0.1 mmol) in THF
(10 mL), room temp., 4 h; method B: imine (1 mmol.), bromide (1.2 mmol) and In (1 mmol) in MeOH (5 mL), room temp., 4 h. [b]
Isolated yield of the major diastereomer in diastereomerically pure form. [c] Isolated as a 20:1 mixture of diastereomers. [d] Inseparable
mixture of diastereoisomers. [e] Isolated as a 25:1 mixture of diastereomers. [f] Isolated as a 11:1 mixture of diastereomers.
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Enantiomerically Pure 2,3-Disubstituted Pyrrolidines
position, which, associated with the equatorial orientation by Pd(OH)2-catalysed hydrogenolysis [Equations (1)–(5) of
of the allylmetal substituent, preferentially give the syn ad- Scheme 4]. Interestingly, depending upon the hydro-
duct. The generally high level of facial diastereoselectivity genolysis conditions applied, those pyrrolidines with an ad-
observed can be explained by assuming an efficient dis- ditional benzyloxy group can undergo selective deben-
crimination between the two diastereoisomeric pseudo- zylation at the nitrogen [Equations (2)–(4)] or both benzylic
chair-like transition states (Scheme 3).
units can be removed [Equation (5)].
Scheme 3. Stereochemical outcome of the allylation reaction.
With the aforementioned substrates in hand, the pyrrol-
idine ring was next constructed through the one-pot hydro-
zirconation–iodination sequence (Table 2). These reactions
were carried out in CH2Cl2 at room temperature according
to the previously described protocol.[6] In the present case,
however, 3 (and not 2) equiv. of the Schwartz reagent were
required to achieve the complete hydrozirconation of the
alkene. Several 2,3-disubstitued pyrrolidines were prepared
on the gram scale and isolated in good yields as a single
stereoisomer (Table 2). The method appeared to be quite
general, that is, pyrrolidines bearing an aryl and an het-
eroaryl (entry 1), a combination of alkyl and aryl or het-
eroaryl (entries 2 and 3) or two alkyl (entries 4–10) groups
were prepared. Protected alcohol or amine functions could
also be incorporated.
Scheme 4. Removal of the chiral auxiliary.
With pyrrolidines bearing an aromatic fragment at the 2-
position, the hydrogenolysis deprotection conditions proved
to be prohibited. In these cases, the chiral auxiliary was
removed prior to cyclization under oxidative conditions by
treating the allylation adduct with Pb(OAc)4 followed by
hydroxylamine transimination.[9b] The resulting primary
amine was Boc-protected and next subjected to the hydro-
zirconation–halogenation sequence. Cyclization of the re-
sulting iodocarbamate was promoted by the addition of
NaHMDS[11] to give the Boc-protected 2,3-disubstituted
pyrrolidines 5b–f (Table 3).
According to this modified strategy, 2,3-disubstituted N-
Boc-protected pyrrolidines containing aryl (entries 1 and 3),
heteroaryl (entries 1 and 2) or even an alkenyl fragment (en-
tries 4 and 5) at the 2-position were obtained in good yields.
cis-2,3-Disubstituted pyrrolidines can be considered as
useful building blocks for the synthesis of a broad range of
bioactive molecules. As examples, 3-substituted proline 6f
and 2-substituted β-prolines 6d and 6l were easily prepared
by RuCl3-catalysed oxidation of hydroxymethyl or styryl
groups (Scheme 5). Compound 6f is an orthogonally pro-
tected homoserine-constrained analogue.
Table 2. Synthesis of 2,3-disubstituted pyrrolidines.
Entry
R
RЈ
Product
% Yield
1
2
3
4
5
6
7
8
9
10
2-furyl
2-furyl
Ph
TBSOCH2
Ph
2a
2c
2g
2h
2i
75
75
77
BnOCH2
BnOCH2
iBu
BnO(CH2)3
TBSO(CH2)3
n-C6H13
CH3
C5H11
67
BnOCH2
TBSOCH2
BnOCH2
TBSOCH2
BnOCH2
BnOCH2
71[a]
47
2j
2k
2l
2m
2n
64
63
66[b]
58
BocNBn(CH2)2
[a] Isolated in diastereomerically pure form starting from a 25:1
mixture of diastereomers. [b] Isolated as a 13:1 mixture of dia-
stereomers in diastereomerically pure form starting from a 9:1 mix-
ture of diastereomers.
To obtain valuable pyrrolidine building blocks, we next
To illustrate the potential of the method in the field of
focused our attention on the removal of the chiral auxiliary. alkaloid synthesis, short stereoselective syntheses of (–)-iso-
In the case of pyrrolidines bearing an alkyl moiety at the 2- retronecanol[12] and an indolizidine, a homologue of plat-
position, the phenylglycinol residue can be easily removed enicyne, were carried out. In the first case, the pyrrolidine
Eur. J. Org. Chem. 2010, 3395–3406
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FULL PAPER
Table 3. Synthesis of Boc-protected 2,3-dusbstituted pyrrolidines Further hydrogenolysis under acidic conditions provided
the target compound 10[15] in 19% overall yield starting
with 2-aryl or 2-alkenyl groups.
from 5e. Note that two successive hydrozirconation steps
were involved in the synthesis of 10 when considering the
homoallylic amine 4e as the precursor.
Entry
R
RЈ
% Yield of 4
% Yield of 5
1
2
3
4
5
3-pyridyl Ph
4b (58)[a]
4c (65)
4d (73)
4e (72)
4f (86)
5b (48)[a]
5c (52)
2-furyl
Ph
TBSOCH2
TBSOCH2
5d (68)[b]
5e (77)
cinnamyl BnOCH2
cinnamyl TBSOCH2
5f (90)
[a] Obtained starting from a 20:1 mixture of diastereomers, ee =
90%. [b] Obtained starting from a 9.2:1 mixture of diastereomers,
ee = 80%.
Scheme 7. Synthesis of (–)-indolizidine 10.
Conclusions
We have reported a convenient stereoselective access to
2,3-disubstituted pyrrolidines based on chiral imine dia-
stereoselective allylation and sequential hydrozirconation–
cyclization, most of the products being isolated in an enan-
tiomerically pure form. The methodology can be applied
to the synthesis of a broad range of compounds bearing a
combination of aryl, heteroaryl, alkyl and alkenyl groups.
It offers a straightforward asymmetric entry to bioactive
molecules possessing a pyrrolidine ring, as exemplified with
a short synthesis of α- and β-proline derivatives as well as
the naturally occurring (–)-isoretronecanol.
Scheme 5. Access to substituted proline and β-proline analogues.
3k was subjected to TBAF desilylation to give the corre-
sponding amino alcohol. Subsequent conversion of the hy-
droxy group to the bromide promoted a spontaneous cycli-
zation to afford the bicyclic 3Јk, which, after OBn deprotec-
tion, provided the optically pure (–)-isoretronecanol in 43%
overall yield starting from 3k (Scheme 6).
Experimental Section
General: All reactions were conducted under argon. Prior to use,
THF and Et2O were distilled under argon from sodium benzophe-
none ketyl, and Et3N and CH2Cl2 were distilled under argon from
CaH2. Cp2Zr(H)Cl was prepared according to a known pro-
cedure.[16] 1H and 13C NMR spectra were recorded at 25 °C in
CDCl3, unless specified otherwise.
General Procedure for the Preparation of Homoallylic Amines
(Method A): A solution of imine (1 mmol) and bromide (2.5 mmol)
in THF (5 mL) was added dropwise to a suspension of Zn (158 mg,
2.5 mmol) and CeCl3·7H2O (37 mg, 0.1 mmol) in THF (5 mL) at
room temp. The reaction mixture was stirred at room temp. for
4 h and then quenched with H2O (10 mL). The aqueous layer was
extracted with Et2O (3ϫ10 mL). The organic phases were com-
bined, dried with MgSO4, filtered and concentrated under reduced
pressure. The residue was purified by flash chromatography on sil-
ica gel eluting with a mixture of PE/AcOEt to give the correspond-
ing amine.
Scheme 6. Synthesis of (–)-isoretronecanol.
The indolizidine skeleton can also be constructed, as il-
lustrated by the synthesis of the six-membered homologue
of platynecine. The synthesis started from the pyrrolidine
5e bearing a masked aldehyde function at the 2-position
and a protected 3-hydroxymethyl chain (Scheme 7). Gener-
ation of the prolinecarbaldehyde skeleton was achieved by
OsO4-catalysed oxidation of the styryl moiety. The crude
aldehyde underwent indium-mediated allylation to give 7
in 64% yield over two steps as a separable 8:1 mixture of
diastereomers.[13,14] The alcohol function was then pro-
tected as a benzyloxy group. The hydrozirconation–iodin-
ation sequence was applied to the major isomer 8 to afford
the intermediate iodopyrrolidine, which, after removal of
(2R)-2-{[(1R,2R)-1-(2-Furyl)-2-phenylbut-3-en-1-yl]amino}-2-
phenylethanol (1a): Obtained as an 11:1 mixture of diastereomers
and isolated in pure diastereomerically pure form as a yellow oil
(286 mg, 86%). [α]2D0 = –31.8 (c = 1, CH2Cl2). 1H NMR (250 MHz,
CDCl3): δ = 1.75 (br. s, 1 H, NH), 2.20 (br. s, 1 H, OH), 3.36 (dd,
3
2JH,H = 12.1, JH,H = 8.1 Hz, 1 H, CHAHBOH), 3.54–3.62 (m, 2
H, CHAHBOH, CHCH=CH2), 3.74 (t, J = 8.5 Hz, 1 H, PhCHNH),
the Boc group, spontaneously cyclized to give the bicycle 9. 3.96 (d, 3JH,H = 8.5 Hz, 1 H, FurCHNH), 4.97 (d, 3JH,H = 17.9 Hz,
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Enantiomerically Pure 2,3-Disubstituted Pyrrolidines
3
1 H, CH=CHAHB), 4.99 (d, JH,H = 9.9 Hz, 1 H, CH=CHAHB), under reduced pressure. The residue was purified by flash
3
5.88–6.02 (m, 2 H, CH=CH2, furyl 3-H), 6.14 (dd, JH,H = 3.1,
chromatography on silica gel eluting with a mixture of PE/AcOEt
(9:1) to give the corresponding amine.
3
4
1.8 Hz, 1 H, furyl 4-H), 7.04 (dd, JH,H = 7.6, JH,H = 1.9 Hz, 2
H), 7.15–7.53 (m, 9 H) ppm. 13C NMR (62.5 MHz, CDCl3): δ =
55.5, 59.7, 62.7, 65.5, 108.4, 110.1, 117.2, 127.2, 127.3, 127.6, 128.5,
128.7, 129.0, 138.3, 141.5, 141.8, 142.1 ppm. HRMS (ESI): calcd.
for C22H23NO2Na [M + Na]+ 356.1626; found 356.1633.
(R)-2-[(3S,4S,E)-4-(Benzyloxymethyl)-1-phenylhexa-1,5-dien-3-yl-
amino]-2-phenylethanol (1e): Obtained as a 14:1 mixture of dia-
stereomers and isolated in pure diastereomerically pure form as a
yellow oil (264 mg, 64%). [α]2D0 = –13.2 (c = 1, CH2Cl2). H NMR
1
(250 MHz, CDCl3): δ = 2.75 (m, 1 H, CH–CH=CH2), 3.41–3.58
(m, 4 H, CHAHBOH, CH2OBn, Ph–CH=CH–CHNH), 3.69 (dd,
(2R)-2-Phenyl-2-{[(1R,2R)-2-phenyl-1-pyridin-3-ylbut-3-en-1-yl]-
amino}ethanol (1b): Obtained as a 9.7:1 mixture of diastereomers
and isolated as a 20:1 mixture of diastereomers as a yellow oil
(313 mg, 91%). Major diastereomer: 1H NMR (250 MHz, CDCl3):
3
2JH,H = 10.6, J H,H = 4.5 Hz, 1 H, CHAHBOH), 3.86 (dd, 3JH,H
=
2
7.1, 4.6 Hz, 1 H, NHCH–CH2OH), 4.42 (d, JH,H = 12.0 Hz, 1 H,
CHAHBPh), 4.50 (d, JH,H = 12.0 Hz, 1 H, CHAHBPh), 5.17–5.26
(m, 2 H, CH=CH2), 5.74 (m, 1 H, CH=CH2), 5.83 (dd, JH,H
2
3
δ = 3.41 [dd, 2J(H,H) = 10.3, JH,H = 7.3 Hz, 1 H, CHAHBOH],
3
=
3.52–3.66 (m, 2 H, CHAHBOH, CHCH=CH2), 3.95 (d, J = 8.0 Hz,
15.8, 8.7 Hz, 1 H, Ph–CH=CH), 6.33 (d, 3JH,H = 15.8 Hz, 1 H, Ph–
CH=CH), 7.13–7.28 (m, 15 H, Ar-H) ppm. 13C NMR (62.5 MHz,
CDCl3): δ = 48.2, 59.0, 61.1, 65.8, 70.9, 72.9, 118.4, 126.2, 127.2,
127.25, 127.4, 1247.5, 127.7, 128.2, 128.3, 128.4, 129.8, 131.7,
135.6, 136.7, 138.1, 141.8 ppm.
3
1 H, Pyr–CHNH), 4.87 (d, JH,H = 17.0 Hz, 1 H, CH=CHAHB),
3
4.94 (d, JH,H = 10.1 Hz, 1 H, CH=CHAHB), 5.79 (ddd, J = 17.0,
10.1, 8.7 Hz, 1 H, CH=CH2), 6.98–7.33 (m, 12 H, Ar-H), 8.25
3
4
(4JH,H = 1.5 Hz, 1 H, pyridyl 2-H), 8.36 (dd, JH,H = 4.8, JH,H
=
1.5 Hz, 1 H, pyridyl 6-H) ppm. 13C NMR (62.5 MHz, CDCl3): δ =
57.2, 63.9, 64.3, 66.2, 118.0, 123.3, 127.4, 127.6, 127.8, 128.6, 128.7,
129.2, 136.2, 137.8, 138.2, 141.3, 141.4, 148.4, 150.1 ppm. HRMS
(ESI): calcd. for C23H25N2O [M + H]+ 345.1967; found 345.1974.
(R)-2-[(3S,4S,E)-4-[(tert-Butyldimethylsilyloxy)methyl]-1-phenyl-
hexa-1,5-dien-3-ylamino]-2-phenylethanol (1f): Obtained as a 13:1
mixture of diastereomers and isolated in pure diastereomerically
pure form as a yellow oil (363 mg, 83%). [α]2D0 = +1.2 (c = 1,
CH2Cl2). 1H NMR (250 MHz, CDCl3): δ = 0.00 [s, 6 H, (CH3)2Si],
0.84 [s, 9 H, (CH3)3C], 2.58 (m, 1 H, CH–CH=CH2), 3.46–3.71 (m,
5 H, CH2OSi, NHCHCH2OH), 3.87 (dd, 3JH,H = 7.1, 4.5 Hz, 1 H,
(2R)-2-{[(1R,2R)-1-(2-Furyl)-2-[(tert-butyldimethylsilyloxy)methyl]-
but-3-en-1-yl]amino}-2-phenylethanol (1c): Obtained as a 10.7:1
mixture of diastereomers and isolated in diastereomerically pure
form as an orange oil (301 mg, 75%). [α]2D0 = –6.4 (c = 1, CH2Cl2).
1H NMR (250 MHz, CDCl3): δ = –0.07 (s, 3 H, CH3SiCH3), 0.00
(s, 3 H, CH3SiCH3), 0.85 [s, 9 H, (CH3)3C], 1.94 (br. s, 1 H, NH),
3
Ph–CH=CH–CH), 5.13–5.23 (m, 2 H, CH=CH2), 5.68 (dt, JH,H
3
= 17.3, 8.7 Hz, 1 H, CH=CH2), 5.87 (dd, JH,H = 15.8, 8.7 Hz, 1
3
3
H, Ph–CH=CH), 6.38 (d, JH,H = 15.8 Hz, 1 H, Ph–CH=CH),
2.64 (m, 1 H, CHCH=CH2), 2.97 (br. s, 1 H, OH), 3.45 (dd, JH,H
7.14–7.25 (m, 10 H) ppm. 13C NMR (62.5 MHz, CDCl3): δ = –5.5,
–5.4, 18.1, 25.8, 50.4, 58.2, 61.1, 63.6, 65.9, 118.3, 126.1, 127.2 (3
C), 128.30, 128.35, 129.7, 131.7, 135.6, 136.8, 141.8 ppm. HRMS
(ESI): calcd. for C27H40NO2Si [M + H]+ 438.2828; found 438.2820.
= 10.0, 6.7 Hz, 1 H, NHCHCH2OH), 3.51 (dd, 2JH,H = 11.7, 3JH,H
= 7.5 Hz, 1 H, CHACHBOH), 3.66–3.76 (m, 3 H, CHACHBOH,
CH2OSi), 4.03 (d, J = 6.2 Hz, 1 H, FurCHNH), 5.02–5.12 (m, 2
H, CH=CH2), 5.64 (dt, J = 17.2, 10.0 Hz, 1 H, CH=CH2), 6.01 (d,
3JH,H = 3.0 Hz, 1 H, furyl 3-H), 6.17 (dd, 3JH,H = 3.0, 2.0 Hz, 1 H,
furyl 4-H), 7.14–7.25 (m, 6 H, Ar-H) ppm. 13C NMR (62.5 MHz,
CDCl3): δ = –5.5, –5.4, 18.2, 25.8, 50.6, 53.9, 61.4, 63.7, 65.5, 107.7,
109.6, 117.9, 127.1, 127.2, 128.3, 136.0, 141.3, 141.4, 154.7 ppm.
HRMS (ESI): calcd. for C23H36NO3Si [M + H]+ 402.2464; found
402.2466.
(R)-2-[(2R,3R)-1-Benzyloxy-3-phenylpent-4-en-2-ylamino]-2-phenyl-
ethanol (1g): Obtained as a 2:1 mixture of diastereomers and iso-
lated in pure diastereomerically pure form as a yellow oil (143 mg,
37%). [α]2D0 = –47.7 (c = 1, CH2Cl2). 1H NMR (250 MHz, CDCl3):
δ = 2.10 (br. s, 2 H, NH, OH), 2.98 (m, 1 H, CH–CH=CH2), 3.17–
3.26 (m, 2 H, CH2OBn), 3.43 (m, 2 H), 3.53–3.63 (m, 2 H), 4.21
3
(s, 2 H, OCH2Ph), 5.06–5.16 (m, 2 H, CH=CH2), 6.05 (dt, JH,H
=
(2R)-2-{[(1R,2R)-2-[(tert-Butyldimethylsilyloxy)methyl]-1-phenyl-
but-3-en-1-yl]amino}-2-phenylethanol (1d): Obtained as an 9.2:1
mixture of diastereomers and isolated in pure diastereomerically
pure form as a pale-yellow oil (349 mg, 85%). [α]2D0 = –23.3 (c = 1,
CH2Cl2). 1H NMR (250 MHz, CDCl3 ): δ = 0.00 (s, 6 H,
CH3SiCH3), 0.85 [s, 9 H, (CH3)3C], 2.60 (m, 1 H, CHCH=CH2),
2.99 (br. s, 1 H, OH), 3.36 (dd, J = 9.7, 7.2 Hz, 1 H), 3.49 (dd, J
= 11.5, 7.5 Hz, 1 H), 3.61 (dd, J = 10.0, 4.7 Hz, 1 H), 3.73 (m, 2
H), 4.04 (d, J = 5.0 Hz, 1 H, CH–CH–CH=CH2), 5.05 (d, J =
9.7 Hz, 1 H, CH=CHA HB ), 5.07 (d, J = 17. 5 Hz, 1 H,
CH=CHAHB), 5.52 (dt, J = 17.5, 9.7 Hz, 1 H, CH=CH2), 7.14–
7.23 (m, 10 H, Ar-H) ppm. 13C NMR (62.5 MHz, CDCl3): δ =
–5.5, –5.4, 18.1, 25.8, 51.1, 59.4, 60.6, 63.6, 65.0, 117.8, 126.9,
127.1, 127.3, 127.8, 128.0, 128.4, 136.0, 140.9, 141.7 ppm. HRMS
(ESI): calcd. for C25H38NO2Si [M + H]+ 412.2672; found 412.2674.
16.7, 9.7 Hz, 1 H CH=CH2), 7.16–7.34 (m, 15 Ar-H) ppm. 13C
NMR (62.5 MHz, CDCl3): δ = 52.8, 60.2, 63.4, 66.5, 69.7, 72.9,
116.8, 126.4, 126.9, 127.3, 127.50, 127.55, 128.0, 128.2, 128.4,
128.5, 138.1, 138.4, 141.6, 142.5 ppm. HRMS (ESI): calcd. for
C26H30NO2 [M + H]+ 388.2277; found 388.2274.
(R)-2-[(2R,3S)-1-Benzyloxy-3-vinyloctan-2-ylamino]-2-phenyl-
ethanol (1h): Obtained as a 5:1 mixture of diastereomers and iso-
lated in pure diastereomerically pure form as a yellow oil (282,
74%). [α]2D0 = –40.2 (c = 1, CH2Cl2). 1H NMR (250 MHz, CDCl3):
3
δ = 0.85 (t, JH,H = 6.4 Hz, 3 H CH3), 1.08–1.43 [m, 8 H CH3-
3
(CH2)4], 1.99 (br. s, 1 H, NH), 2.28 (app. sept, JH,H = 4.3 Hz, 1
H , C H – C H = C H 2 ) , 2 . 7 3 ( d t , J = 6 . 7 , 4 . 3 H z , 1 H ,
BnOCH2CHNH), 3.18 (br. s, 1 H, OH), 3.32–3.44 (m, 3 H,
2
3
CH2OBn, CHAHBOH), 3.64 (dd, JH,H = 10.5, JH,H = 4.5 Hz, 1
H, CHAHBOH), 3.88 (dd, 3JH,H = 9.2, 4.5 Hz, 1 H, CH–CH2OH),
4.32 (s, 2 H, OCH2Ph), 5.02–5.11 (m, 2 H, CH=CH2), 5.62 (dt,
3JH,H = 16.5, 10.5 Hz, 1 H, CH=CH2), 7.23–7.36 (m, 10 Ar-
H) ppm. 13C NMR (62.5 MHz, CDCl3): δ = 14.0, 22.5, 27.3, 30.9,
31.8, 45.3, 57.8, 61.7, 66.8, 70.2, 72.8, 116.6, 126.9, 127.0, 127.2,
127.4, 128.3, 128.5, 128.2, 139.2, 141.2 ppm. HRMS (ESI): calcd.
for C25H36NO2 [M + H]+ 382.2746; found 382.2737.
General Procedure for the Preparation of Homoallylic Amines
(Method B): Small pieces of In (113 mg, 1 mmol) were added to
a solution of imine (or oxazolidine) (1 mmol) and allyl bromide
(1.2 mmol) in MeOH (5 mL) at room temp. The reaction mixture
was stirred at room temp. for 6 h and then a saturated aqueous
solution of NaHCO3 (5 mL) was added. The resulting mixture was
filtered and the filtrate was concentrated under reduced pressure.
The residue was dissolved in AcOEt (30 mL), washed with H2O
(10 mL), dried with MgSO4, filtered and the solvent was removed
(R)-2-[(3S,4S)-3-(Benzyloxymethyl)-5-methylhept-1-en-4-ylamino]-
2-phenylethanol (1i): Obtained as a 11:1 mixture of diastereomers
Eur. J. Org. Chem. 2010, 3395–3406
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3399

P.-O. Delaye, T. K. Pradhan, É. Lambert, J.-L. Vasse, J. Szymoniak
FULL PAPER
and isolated in pure diastereomerically pure form as a pale-yellow
3JH,H = 6.5 Hz, 3 H, CH3), 2.20 (br. s, 1 H, NH), 2.61 (m, 1 H, CH–
CH=CH2), 2.86 (m, 1 H, CH–CH3), 3.38–3.57 (m, 3 H, CH2OBn,
oil (198 mg, 54%). [α]2D0 = –104.9 (c = 1, CH2Cl2). 1H NMR
3
2
3
(250 MHz, CDCl3): δ = 0.46 (d, JH,H = 6.5 Hz, 3 H, CH3–CH– CHAHBOH), 3.64 (dd, JH,H = 10.7, JH,H = 4.5 Hz, 1 H,
3
3
CH3), 0.81 (d, JH,H = 6.8 Hz, 3 H, CH3–CH–CH3), 0.97–1.18 (m,
CHAHBOH), 3.88 (dd, JH,H = 8.2, 4.2 Hz, 1 H, PhCHNH), 4.44
2
2
2 H, CH2-iPr), 1.58 (m, 1 H, CH3–CH–CH3), 2.67–2.82 (m, 2 H,
(d, JH,H = 12.2 Hz, 1 H, PhCHAHBO), 4.48 (d, JH,H = 12.2 Hz,
CH–CH=CH2, CH–CH2-iPr), 3.37 (dd, J = 9.0, 6.8 Hz, 1 H, 1 H, PhCHAHBO), 5.17–5.28 (m, 2 H, CH=CH2), 5.77 (m, 1 H,
CHAHBOBn), 3.47–3.53 (m, 2 H, CHAHBOBn, CHAHBOH), 3.65
CH=CH2), 7.26–7.34 (m, 10 H, Ar-H) ppm. 13C NMR (62.5 MHz,
(dd, J = 10.5, 4.7 Hz, 1 H, CHAHBOH), 3.89 (dd, J = 8.5, 4.7 Hz, CDCl3): δ = 17.9, 47.6, 50.7, 61.7, 66.8, 71.3, 72.9, 117.9, 127.1,
1 H, NHCHPh), 4.41 (d, J = 12.0 Hz, 1 H, CHAHBPh), 4.47 (d, J
127.40, 127.45, 127.50, 128.2, 128.5, 136.2, 138, 2, 141.5 ppm.
= 12.0 Hz, 1 H, CHAHBPh), 5.17–5.23 (m, 2 H, CH=CH2), 5.77 HRMS (ESI): calcd. for C21H28NO2 [M + H]+ 326.2120; found
(m, 1 H, CH=CH2), 7.21–7.34 (m, 10 H, Ar-H) ppm. 13C NMR 326.2133.
(62.5 MHz, CDCl3): δ = 21.1, 24.0, 24.3, 40.5, 45.6, 52.1, 61.3, 66.8,
tert-Butyl Benzyl{(4S,5S)-5-(benzyloxymethyl)-4-[(R)-2-hydroxy-1-
71.1, 72.8, 127.4, 127.5, 127.6, 128.2, 128.4, 136.4, 138.3,
phenylethylamino]hept-6-enyl}carbamate (1n): Obtained as a 3:1
141.1 ppm. HRMS (ESI): calcd. for C24H34NO2 [M + H]+
mixture of diastereomers and isolated in pure diastereomerically
368.2590; found 368.2592.
pure form as a pale-orange oil (163 mg, 30%). [α]2D0 = –38.3 (c = 1,
(R)-2-{(3S,4S)-7-Benzyloxy-3-[(tert-butyldimethylsilyloxy)methyl]- CH2Cl2). 1H NMR (250 MHz, CDCl3): δ = 1.41 [br. s, 9 H,
hept-1-en-4-ylamino}-2-phenylethanol (1j): Obtained as a 10:1 mix-
ture of diastereomers and isolated in pure diastereomerically pure
form as a pale-yellow oil (237 mg, 49%). [α]2D0 = –50.8 (c = 1,
(CH3)3C], 1.52 (br. m, 2 H), 1.86 (br. s, 1 H, NH), 2.40–3.00 (br.
2
3
m, 4 H), 3.10–3.64 (br. m, 4 H), 3.60 (dd, JH,H = 10.6, JH,H
=
4.3 Hz, 1 H, CHAHBOH), 3.85 (br. s, 1 H, NHCHCH2OH), 4.15–
2
CH2Cl2). 1H NMR (250 MHz, CDCl3 ): δ = 0.00 (s, 3 H, 4.30 (br. m, 2 H, PhCH2N), 4.38 (d, JH,H = 12.6 Hz, 1 H,
2
CH3SiCH3), 0.01 (s, 3 H, CH3SiCH3), 0.83 [s, 9 H, (CH3)3Si], 1.14–
CHAHBOBn), 4.43 (d, JH,H = 12.6 Hz, 1 H, CHAHBOBn), 5.13–
5.21 (m, 2 H, CH=CH2), 5.69 (m, 1 H, CH=CH2) 7.10–7.35 (m,
1.80 [m, 5 H, CH-(CH2)2–CH2OSi, NH], 2.52–2.72 (m, 2 H,
3
NHCH–CH–CH=CH2), 3.31 (t, JH,H = 6.4 Hz, 2 H, CH2-OBn), 15 H, Ar-H) ppm. 13C NMR (62.5 MHz, CDCl3): δ = 28.4, 29.9
3.49–3.58 (m, 2 H, CH2O), 3.64–3.73 (m, 2 H, CH2O), 3.90 (dd,
(br.), 44.6, 45.5, 50.3 (br), 52.9, 61.5, 67.2, 71.2, 72.8, 79.5, 118.1,
3JH,H = 8.5, 4.5 Hz, 1 H, NHCH–CH2OH), 4.44 (s, 2 H, OCH2Ph), 127.0, 127.40, 127.45, 127.6, 128.2, 128.3, 128.4, 136.1, 138.4 (br),
5.15–5.22 (m, 2 H, CH=CH2), 5.73 (m, 1 H, CH=CH2), 7.30–7.36 141.0, 155.6 ppm. HRMS (ESI): calcd. for C34H45N2O4 [M + H]+
(m, 10 Ar-H) ppm. 13C NMR (62.5 MHz, CDCl3): δ = –5.0, –4.9, 545.3379; found 545.3381.
18.6, 26.3, 26.9, 27.6, 48.8, 54.3, 61.9, 6.4, 67.6, 70.9, 73.2, 118.3,
General Procedure for the Preparation of Pyrrolidines 2 (Method C):
127.9, 128.1 (3 C), 128.8, 128.9, 136.9, 139.0, 141.8 ppm.
Cp2Zr(H)Cl (772 mg, 3 mmol) was added in one portion to a solu-
(R)-2-{(3S,4S)-3-(Benzyloxymethyl)-7-[(tert-butyldimethylsilyl-
oxy)methyl]hept-1-en-4-ylamino}-2-phenylethanol (1k): Obtained
as a 9:1 mixture of diastereomers and isolated in pure dia-
stereomerically pure form as a pale-yellow oil (362 mg, 75%). [α]D
= –87.5 (c = 1, CH2Cl2). 1H NMR (250 MHz, CDCl3): δ = 0.00 (s,
3 H, CH3SiCH3), 0.01 (s, 3 H, CH3SiCH3), 0.88 [s, 9 H, (CH3)3Si],
1.10–1.63 [m, 4 H, CH-(CH2)2–CH2OBn], 2.61–2.76 (m, 2 H,
tion of homoallylic amine 1 (1 mmol) in CH2Cl2 (3 mL) under ar-
gon and the resulting mixture was stirred until complete dissol-
ution. Then I2 (254 mg, 1 mmol) was added and the reaction mix-
ture was stirred for 2 h. CH2Cl2 (10 mL) was added and the organic
phase was washed with HCl (1 , 2ϫ3 mL) and Na2CO3 (10%,
2ϫ3 mL), dried with MgSO4, filtered and the solvent was removed
under reduced pressure. The residue was purified by flash
NHCH–CH–CH=CH2), 3.39–3.67 (m, 6 H, CH2OH, CH2OSi, chromatography on silica gel eluting with a mixture of PE/AcOEt
3
CH2OBn), 3.88 (dd, JH,H = 8.4, 4.4 Hz, 1 H, NHCH–CH2OH), to give the corresponding pyrrolidine 2.
2
2
4.43 (d, JH,H = 12.1 Hz, 1 H), 4.49 (d, JH,H = 11.1 Hz, 1 H),
5.17–5.23 (m, 2 H, CH=CH2), 5.79 (m, 1 H, CH=CH2), 7.25–7.35
(m, 10 H, Ar-H) ppm. 13C NMR (62.5 MHz, CDCl3): δ = –5.4,
18.2, 25.9, 27.2, 29.2, 46.1, 54.7, 61.6, 62.9, 66.9, 71.3, 72.8, 117.6,
126.8, 127.4, 127.5, 128.2, 128.4, 136.7, 138.2, 141.2 ppm.
(2R)-2-[(2R,3R)-2-(2-Furyl)-3-phenylpyrrolidin-1-yl]-2-phenyl-
ethanol (2a): Pale-yellow oil (250 mg, 75%). [α]2D0 = –35.6 (c = 1,
CH2Cl2). H NMR (250 MHz, CDCl3): δ = 2.03–2.54 (m, 3 H, 4-
1
H, 4-H pyrrolidine, OH), 3.03 (m, 1 H, 5-H pyrrolidine), 3.19 (m,
1 H, 5Ј-H pyrrolidine), 3.43 (m, 1 H, 3-H pyrrolidine), 3.70–3.82
(m, 3 H, NCHPh–CH2OH), 4.38 (d, J = 7.9 Hz, 1 H, 2-H pyrrol-
idine), 5.84 (m, 1 H, 3-H furyl), 6.10 (m, 1 H, 4-H furyl), 6.91–7.37
(m, 11 H, 5-H furyl, Ph-H) ppm. 13C NMR (62.5 MHz, CDCl3): δ
= 28.9, 49.9, 51.5, 61.5, 64.0, 67.4, 108.5, 110.3, 126.6, 128.1, 128.4,
128.7, 129.2, 138.7, 139.9, 141.7, 155.4 ppm. HRMS (ESI): calcd.
for C22H24NO2 [M + H]+ 334.1807; found 334.1822.
(2R)-2-{[(1S,2S)-2-[(tert-Butyldimethylsilyloxy)methyl]-1-hexylbut-
3-en-1-yl]amino}-2-phenylethanol (1l): Obtained as a 17:1 mixture
of diastereomers and isolated in pure diastereomerically pure form
as a colourless oil (293 mg, 70%). [α]2D0 = –83.2 (c = 1, CH2Cl2).
1H NMR (250 MHz, CDCl3): δ = –0.01 (CH3SiCH3), 0.00 (s, 3 H,
CH3SiCH3), 0.82 [m, 12 H, (CH3)3Si, CH3–CH2], 1.07–1.34 [m, 11
H, CH3-(CH2)5–CH, NH], 2.51–2.73 (m, 3 H, NHCH–CH, OH),
3.48–3.56 (m, 2 H, CH2-O), 3.63–3.71 (m, 2 H, CH2-O), 3.86 (dd,
3JH,H = 8.5, 4.5 Hz, 1 H, NHCH–CH2OH), 5.11–5.18 (m, 2 H,
CH=CH2), 5.72 (m, 1 H, CH=CH2), 7.28–7.30 (m, 5 H, Ar-
H) ppm. 13C NMR (62.5 MHz, CDCl3): δ = –5.5, –5.4, 14.0, 18.2,
22.6, 25.8, 26.0, 29.2, 30.5, 31.8, 48.4, 53.8, 61.5, 63.8, 66.9, 117.5,
127.4, 127.5, 128.4, 136.6, 141.4 ppm. HRMS (ESI): calcd. for
C25H46NO2Si [M + H]+ 420.3298; found 420.3305.
(2R)-2-[(2R,3R)-3-[(tert-Butyldimethylsilyloxy)methyl]-2-(2-furyl)-
pyrrolidin-1-yl]-2-phenylethanol (2c): Yellow oil (301 mg, 75 %).
[α]2D0 = –6.1 (c = 1, CH2Cl2). 1H NMR (250 MHz, CDCl3): δ =
–0.02 (s, 3 H, CH3SiCH3), 0.00 (s, 3 H, CH3SiCH3), 0.91 [s, 9 H,
2
3
(CH3)3-C], 1.79 (tt, JH,H = 12.1, JH,H = 8.7 Hz, 1 H, 4-H pyrrol-
idine), 2.03 (m, 1 H, 4Ј-H pyrrolidine), 2.43 (br. s, 1 H, OH), 2.54
3
3
(dt, JH,H = 11.0, 7.5 Hz, 1 H, 3-H pyrrolidine), 2.93 (q, JH,H
=
3
8.0 Hz, 1 H, 5-H pyrrolidine), 3.07 (td, JH,H = 8.7, 3.0 Hz, 1 H,
5Ј-H pyrrolidine), 3.29 (dd, JH,H = 10.1, JH,H = 2.5 Hz, 1 H,
CHAHBOSi), 3.32 (dd, JH,H = 10.1, JH,H = 2.7 Hz, 1 H,
CHAHBOSi), 3.76 (m, 3 H, NCH–CH2OH), 4.29 (d, JH,H
2
3
(2R)-2-{[(1S,2S)-2-[(tert-Butyldimethylsilyloxy)methyl]-1-methyl-
but-3-en-1-yl]amino}-2-phenylethanol (1m): Obtained as a 7.6:1 mix-
ture of diastereomers and isolated as an 11:1 mixture of dia-
2
3
3
=
stereomers in pure form as a colourless oil (179 mg, 55%). [α]2D0
–71.3 (c = 1, CH2Cl2). H NMR (250 MHz, CDCl3): δ = 0.90 (d,
=
8.0 Hz, 1 H, 2-H pyrrolidine), 6.16 (d, J = 3.0 Hz, 1 H, 3-H furyl),
1
3
6.39 (dd, JH,H = 3.0, 2.0 Hz, 1 H, 4-H furyl), 7.28–7.42 (m, 6 H,
3400
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 3395–3406

Enantiomerically Pure 2,3-Disubstituted Pyrrolidines
5-H furyl, Ph-H) ppm. 13C NMR: δ = –5.6, –5.5, 25.8, 46.1, 50.7,
57.7, 63.5, 63.6, 66.6, 108.0, 110.0, 127.5, 128.2, 128.7, 138.4, 141.5,
155.2 ppm.
25.9, 26.7, 27.1, 44.1, 50.3, 60.6, 62.9, 63.4, 67.6, 70.6, 72.7, 127.5,
128.2, 128.7, 138.6, 139.6 ppm.
(2R)-2-{(2S,3S)-3-(Benzyloxymethyl)-2-[3-(tert-butyldimethylsilyl-
oxy)propyl]pyrrolidin-1-yl}-2-phenylethanol (2k): Pale-yellow oil
(2R)-2-[(2R,3R)-2-(Benzyloxymethyl)-3-phenylpyrrolidin-1-yl]-2-
phenylethanol (2g): Pale-yellow oil (298 mg, 77%). [α]2D0 = +4.2 (c
1
(309 mg, 64%). [α]2D0 = –3.7 (c = 1, CH2Cl2). H NMR (250 MHz,
1
CDCl3): δ = 0.05 [s, 6 H, (CH3)2Si], 0.91 [s, 9 H, (CH3)3C], 1.16–
1.63 [m, 5 H, OCH2-(CH2)2, 4-H pyrrolidine], 1.88 (m, 1 H, 4Ј-H
pyrrolidine), 2.26 (m, 1 H, 3-H pyrrolidine), 2.60 (br. s, 1 H, OH),
2.81 (dt, J = 9.6, 7.9 Hz, 1 H, 5-H pyrrolidine), 2.93–3.13 (m, 2 H,
= 1, CH2Cl2). H NMR: δ = 1.92 (m, 1 H, 4-H pyrrolidine), 2.21
2
3
(m, 1 H, 4Ј-H pyrrolidine), 2.88 (dt, JH,H = 12.0, JH,H = 7.4 Hz,
1 H, 5-H pyrrolidine), 2.95–3.12 (m, 3 H, CH2OBn, 2-H pyrrol-
3
idine), 3.29 (t, JH,H = 7.9 Hz, 1 H, 5Ј-H pyrrolidine), 3.59 (m, 1
2
3
2
3
2-H, 5Ј-H pyrrolidine), 3.39 (dd, JH,H = 9.0, JH,H = 7.3 Hz, 1 H,
CHAHBOSi), 3.46–3.53 [m, 4 H, OCH2-(CH2)2, CH2OBn], 3.72–
H, 3-H pyrrolidine), 3.73 (dd, JH,H = 10.1, JH,H = 4.0 Hz, 1 H,
CHAHBOH), 3.90–4.06 (m, 2 H, NCH–CHAHBOH), 4.22 (s, 2 H,
CH2OBn), 7.10–7.36 (m, 15 H, Ph-H) ppm. 13C NMR (62.5 MHz,
CDCl3): δ = 28.4, 46.8, 51.1, 60.5, 63.2, 67.6, 67.6, 71.6, 73.2, 126.2,
127.5, 127.6, 128.10, 128.15, 128.20, 128.4, 128.7, 137.8, 138.5,
139.9 ppm. HRMS (ESI): calcd. for C26H30NO2 [M + H]+
388.2277; found 388.2280.
2
3.91 (m, 3 H, NCH–CH2OH), 4.42 (d, JH,H = 12.1 Hz, 1 H,
2
PhCHAHBO), 4.48 (d, JH,H = 12.1 Hz, 1 H, PhCHAHBO), 7.28–
7.33 (m, 10 H) ppm. 13C NMR (62.5 MHz, CDCl3): δ = –5.8, 25.2,
25.5, 26.7, 29.7, 41.0, 49.8, 60.3, 62.8, 63.1, 67.1, 70.0, 72.5, 127.0,
127.10, 127.15, 127.80, 127.85, 128.2 ppm (quaternary C atoms are
missing).
(2R)-2-[(2R,3S)-2-(Benzyloxymethyl)-3-pentylpyrrolidin-1-yl]-2-
(2R)-2-[(2S,3S)-2-[(tert-Butyldimethylsilyloxy)methyl]-2-hexyl-
pyrrolidin-1-yl]-2-phenylethanol (2l): Colourless oil (264 mg, 63%).
[α]2D0 = –5.3 (c = 1, CH2Cl2). 1H NMR (250 MHz, CDCl3): δ =
0.00 [s, 6 H, (CH3)2Si], 0.85–0.87 [m, 12 H, CH3–CH2, (CH3)3C],
1.18–1.27 [m, 10 H, (CH2)5], 1.50 (m, 1 H, 4-H pyrrolidine), 1.79
(dtd, J = 12.2, 8.1, 3.9 Hz, 1 H, 4Ј-H pyrrolidine), 2.01 (sext, J =
phenylethanol (2h): Pale-yellow oil (255 mg, 67%). [α]2D0 = –7.0 (c =
3
0.2, CH2Cl2). 1H NMR (250 MHz, CDCl3): δ = 0.84 (t, JH,H
=
6.4 Hz, 3 H, CH3), 1.08–1.34 [m, 8 H, (CH2)4], 1.39–1.60 (m, 2 H,
4-H pyrrolidine), 1.74 (m, 1 H, 3-H pyrrolidine), 2.79 (td, JH,H
=
3
9.0, 6.7 Hz, 1 H, 5Ј-H pyrrolidine), 3.11 (t, JH,H = 7.6 Hz, 1 H,
5Ј-H pyrrolidine), 3.23–3.39 (m, 3 H, CH2OBn, 2-H pyrrolidine),
3.55 (dd, 2JH,H = 10.5, 3JH,H = 4.5 Hz, 1 H, CHAHBOH), 3.84 (dd,
3
7.7 Hz, 1 H, 3-H pyrrolidine), 2.82 (q, JH,H = 8.1 Hz, 1 H, 5-H
pyrrolidine), 2.89 (m, 1 H, 2-H pyrrolidine), 3.03 (m, 1 H, 5-H
2
3JH,H = 8.5, 4.5 Hz, 1 H, NCH–CH2OH), 3.97 (dd, JH,H = 10.2,
2
3
pyrrolidine), 3.49 (dd, JH,H = 10.2, JH,H = 7.5 Hz, 1 H,
2
3JH,H = 8.8 Hz, 1 H, CHAHBOH), 4.45 (d, JH,H = 12.2 Hz, 1 H,
2
3
CHAHBOSi), 3.59 (dd, JH,H = 10.2, JH,H = 7.2 Hz, 1 H,
2
OCHAHBPh), 4.46 (d, JH,H = 12.2 Hz, 1 H, OCHAHBPh), 7.30–
CHAHBOSi), 3.75 (t, 3JH,H = 6.5 Hz, 1 H, NCHPh), 3.80 (dd, 2JH,H
7.39 (m, 10 H, Ph-H) ppm. 13C NMR (62.5 MHz, CDCl3): δ =
14.0, 22.5, 28.4, 29.6, 30.4, 32.0, 41.9, 51.2, 58.6, 63.4, 67.9, 71.2,
73.3, 127.50, 127.55, 127.7, 128.2, 128.3, 128.7, 138.0, 138.9 ppm.
3
2
= 10.4, JH,H = 6.5 Hz, 1 H, CHAHBOH), 3.87 (dd, JH,H = 10.4,
3JH,H = 6.5 Hz, 1 H, CHAHBOH), 7.29–7.33 (m, 5 H, Ph-H) ppm.
13C NMR (62.5 MHz, CDCl3): δ = –5.2, 14.2, 18.3, 22.8, 26.0, 26.8,
27.1, 29.5, 29.9, 32.0, 44.3, 50.6, 61.0, 63.1, 63.5, 67.7, 127.7, 128.5,
128.9, 139.7 ppm. HRMS (ESI): calcd. for C25H46NO2Si [M + H]+
420.3298; found 420.3302.
(2R)-2-[(2S,3S)-3-(Benzyloxymethyl)-2-isobutylpyrrolidin-1-yl]-2-
phenylethanol (2i): Isolated in pure diastereomerically pure form as
a pale-yellow oil (71 %) starting from a 25:1 mixture of dia-
stereomers. [α]2D0 = –4.0 (c = 1, CH2Cl2). 1H NMR (250 MHz,
CDCl3): δ = 0.73 (d, 3JH,H = 6.5 Hz, 3 H, CH3–CH–CH3), 0.74 (d,
(2R)-2-[(2S,3S)-3-(Benzyloxymethyl)-2-methylpyrrolidin-1-yl]-2-
phenylethanol (2m): Isolated as a 13:1 mixture of diastereomers in
pure diastereomerically pure form starting from a 9:1 mixture of
3
3JH,H = 6.3 Hz, 3 H, CH3–CH–CH3), 1.09 (t, JH,H = 6.5 Hz, 2 H,
CH2-iPr), 1.48–1.60 (m, 2 H, 4-H pyrrolidine), 1.85 (m, 1 H, CH3–
CH–CH3), 2.19 (hex., 3JH,H = 7.5 Hz, 1 H, 3-H pyrrolidine), 2.74–
2.85 (m, 2 H, 5-H pyrrolidine, OH), 2.93–3.02 (m, 2 H, 2-H pyrrol-
idine, 5Ј-H pyrrolidine), 3.34 (dd, 2JH,H = 9.0, 3JH,H = 7.5 Hz, 1 H,
CHAHBOBn), 3.42 (dd, JH,H = 9.0, JH,H = 7.3 Hz, 1 H,
CHAHBOBn), 3.69–3.88 (m, 3 H, NCH–CH2OH), 4.42 (s, 2 H,
PhCH2O), 7.21–7.32 (m, 10 H, Ph-H) ppm. 13C NMR (62.5 MHz,
CDCl3): δ = 22.6, 23.2, 24.8, 26.9, 38.5, 41.2, 49.9, 58.8, 63.2, 67.2,
70.4, 72.9, 127.4, 127.50, 127.55, 128.20, 128.25, 128.7, 138.2,
139.6 ppm. HRMS (ESI): calcd. for C24H34NO2 [M + H]+
368.2590; found 368.2585.
diastereomers as a pale-yellow oil (208 mg, 64 %). Major dia-
3
stereomer: 1H NMR (250 MHz, CDCl3): δ = 1.00 (d, JH,H
=
6.8 Hz, 3 H, CH3), 1.59 (m, 1 H, 4-H pyrrolidine), 1.92 (m, 1 H,
2
4Ј-H pyrrolidine), 2.50 (m, 1 H, 3-H pyrrolidine), 2.96 (dd, JH,H
2
3
3
= 12.7, JH,H = 8.0 Hz, 1 H), 3.20 (m, 1 H, 5-H pyrrolidine), 3.35–
3
3.57 (m, 3 H, CH2OBn, 2-H pyrrolidine), 3.90 (q, JH,H = 8.6 Hz,
1 H, CH–CH2OH), 4.05 (m, 2 H, CH2OH), 4.44 (br. s, 1 H, OH),
4.46 (s, 2 H, PhCH2O), 7.20–7.36 (m, 10 H, Ph-H) ppm. 13C NMR
(62.5 MHz, CDCl3): δ = 12.8, 25.7, 41.5, 51.1, 58.5, 63.0, 68.0, 69.9,
73.2, 127.7, 127.8, 128.4, 128.5, 128.7, 129.0, 136.7, 137.8 ppm.
HRMS (ESI): calcd. for C21H28NO2 [M + H]+ 326.2120; found
326.2109.
(2R)-2-{(2S,3S)-2-[3-(Benzyloxy)propyl]-3-[(tert-butyldimethyl-
silyloxy)methyl]pyrrolidin-1-yl}-2-phenylethanol (2j): Pale-yellow oil
tert-Butyl Benzyl(3-{(2S,3S)-3-(benzyloxymethyl)-1-[(R)-2-hydroxy-
1
(227 mg, 47%). [α]2D0 = –8.5 (c = 1, CH2Cl2). H NMR (250 MHz,
1-phenylethyl]pyrrolidin-2-yl}propyl)carbamate (2n): Yellow oil
1
CDCl3): δ = 0.00 [s, 6 H, (CH3)2Si], 0.86 [s, 9 H, (CH3)3C], 1.24– (316 mg, 58%). [α]2D0 = –5.3 (c = 1, CH2Cl2). H NMR (250 MHz,
1.66 [m, 5 H, OCH2-(CH2)2, 4-H pyrrolidine], 1.81 (m, 1 H, 4-H
pyrrolidine), 2.03 (m, 1 H, 3-H pyrrolidine), 2.69 (br. s, 1 H, OH),
CDCl3): δ = 1.44 [m, 12 H, (CH3)3-C, 4-H pyrrolidine, NBoc–CH2–
CH2], 1.81 (m, 1 H, 4Ј-H pyrrolidine), 2.20 (m, 1 H, 3-H pyrrol-
idine), 2.62 (br. s, 1 H, OH), 2.74 (q, J = 8.2 Hz, 1 H, 5-H pyrrol-
idine), 2.86–3.18 (m, 3 H, 2-H, 5Ј-H pyrrolidine), 3.30–3.50 (m, 3
H), 3.60–3.82 (m, 3 H), 4.24–4.41 (m, 4 H, NCH2Ph, OCH2Ph),
7.14–7.34 (m, 15 H, Ph-H) ppm. 13C NMR (62.5 MHz, CDCl3): δ
= 27.0, 27.8, 28.4, 41.4, 44.8, 49.8, 50.6, 59.0, 63.7, 67.6, 70.2, 72.9,
79.5, 126.9, 127.4, 127.5 (2 C), 128.2, 128.3 (2 C), 128.6 (2 C),
2
3
2.82 (dt, JH,H = 9.7, JH,H = 7.9 Hz, 1 H, 5-H pyrrolidine), 2.93
3
2
(q, JH,H = 6.3 Hz, 1 H, 2-H pyrrolidine), 3.02 (td, JH,H = 9.7,
3JH,H = 6.0 Hz, 1 H, 5Ј-H pyrrolidine), 3.37 [t, JH,H = 6.5 Hz,
3
2
3
2 H, OCH2-(CH2)2], 3.52 (dd, JH,H = 9.9, JH,H = 7.5 Hz, 1 H,
CHAHBOSi), 3.61 (dd, JH,H = 10.1, JH,H = 7.4 Hz, 1 H,
CHAHBOSi), 3.74 (t, JH,H = 6.1 Hz, 1 H, NCH–CH2OH), 3.81–
2
3
3
3.90 (m, 2 H, CH2OH), 4.47 (s, 2 H, PhCH2O), 7.28–7.34 (m, 10 138.2, 138.6, 139.7, 155.7 ppm. HRMS (ESI): calcd. for
H, Ph-H) ppm. 13C NMR (62.5 MHz, CDCl3): δ = –5.4, 18.1, 25.8,
C34H45N2O4 [M + H]+ 545.3379; found 545.3390.
Eur. J. Org. Chem. 2010, 3395–3406
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3401

P.-O. Delaye, T. K. Pradhan, É. Lambert, J.-L. Vasse, J. Szymoniak
FULL PAPER
General Procedure for the Preparation of Pyrrolidines 3 (Method D):
A mixture of homoallylic amine 2 (1 mmol) and Pd(OH)2/C (20%,
60 mg) in MeOH (5 mL) under hydrogen was stirred overnight at
room temp. The crude mixture was filtered through a pad of Celite
and concentrated under vacuum. The residue was purified by flash
chromatography on silica gel using Et2O/Et2NH gradient elution
(100:0Ǟ98:2) to give the corresponding amine.
Celite and concentrated under reduced pressure. The residue was
diluted in CH2Cl2 (20 mL) then Et3N (0.46 mL) and Boc2O
(785 mg, 3.6 mmol) were added and the reaction mixture was
stirred for 6 h at room temp. Then the solvent was removed under
vacuum. The residue was diluted into THF (15 mL) and a solution
of TBAF (1  in THF, 9 mL) was added dropwise. After 2 h of
stirring, the solvent was removed under vacuum and the residue
was purified by flash chromatography on silica gel eluting with a
mixture of PE/AcOEt (1:1) to give 3l as a pale-yellow oil (996 mg,
(2R,3R)-2-(Benzyloxymethyl)-3-phenylpyrrolidine (3g): Colourless
oil (214 mg, 80%). [α]2D0 = –46 (c = 1, CH2Cl2). 1H NMR
(250 MHz, CDCl3): δ = 2.05 (m, 1 H, 4-H pyrrolidine), 2.21 (dtd,
1
83%). [α]2D0 = –3.6 (c = 1, CH2Cl2). H NMR (250 MHz, CDCl3):
3
δ = 0.82 (t, JH,H = 6.6 Hz, 3 H, CH3), 1.22 [br. s, 9 H, (CH3)3-C],
3
2JH,H = 16.6, JH,H = 8.2, 3.8 Hz, 1 H, 4Ј-H pyrrolidine), 2.35 (br.
1.37–1.44 [m, 10 H, (CH2)5], 1.58 (m, 1 H, 4-H pyrrolidine), 1.90
s, 1 H, NH), 2.98–3.12 (m, 3 H, 5-H pyrrolidine, CH2OBn), 3.28
(m, 1 H, 4-H pyrrolidine), 2.32 (m, 1 H, 3-H pyrrolidine), 2.69 (br.
3
(ddd, J = 10.1, 8.8, 3.8 Hz, 1 H, 5Ј-H pyrrolidine), 3.40 (q, JH,H
3
s, 1 H, OH), 3.31 (br. d, JH,H = 8.0 Hz, 2 H, CH2OH), 3.60 (m, 2
= 7.5 Hz, 1 H, 2-H pyrrolidine), 3.53 (td, 3JH,H = 7.4, 4.9 Hz, 1 H,
3-H pyrrolidine), 4.27 (s, 2 H, PhCH2O), 7.17–7.33 (m, 10 H, Ph-
H) ppm. 13C NMR (62.5 MHz, CDCl3): δ = 31.7, 45.4, 46.2, 61.6,
71.7, 73.1, 126.1, 127.4, 127.5, 128.0, 128.2, 128.3, 138.2,
141.6 ppm. HRMS (ES+): calcd. for C18H22NO [M + H]+
268.1701; found 268.1696.
H, 5-H, 2-H pyrrolidine), 3.91 (m, 1 H, 5Ј-H pyrrolidine) ppm. 13
C
NMR (62.5 MHz, CDCl3): δ = 14.0, 22.5, 25.5, 26.6, 28.4, 29.7,
29.9, 31.8, 44.5, 45.0, 57.9, 61.9, 79.1, 155.0 ppm. HRMS (ESI):
calcd. for C16H31NNaO3 [M + Na]+ 308.2202; found 308.2216.
General Procedure for the Preparation of Boc-Protected Pyrrolidines
4 (Method E): Pb(OAc)4 (2.18 g, 4.9 mmol) was added in one por-
tion to a solution of homoallylic amine 1 (4.5 mmol) in a 1:1 mix-
ture of CH2Cl2/MeOH (50 mL) at 0 °C. The resulting mixture was
stirred at 0 °C for 30 min and then NH2OH·HCl (3.2 g, 45 mmol)
was added and the stirring was continued for 30 min at 0 °C. The
solvent was then removed under reduced pressure. The residue was
taken up with CH2Cl2 (50 mL) and the solid was filtered off. Et3N
(1.25 mL) and Boc2O (1.07 g, 4.9 mmol) were added to the filtrate
and the resulting mixture was stirred at room temp. for 2 h. H2O
(20 mL) was added and the organic layer was washed with HCl
(1 , 10 mL) and Na2CO3 (10%, 10 mL), dried with MgSO4, fil-
tered and the solvent was removed under reduced pressure. The
residue was purified on silica gel eluting with a mixture of PE/
AcOEt to give compound 4.
(2S,3S)-3-(Benzyloxymethyl)-2-isobutylpyrrolidine (3i): Colourless
oil (185 mg, 75%). [α]2D0 = +37.3 (c = 2, CH2Cl2). 1H NMR
3
(250 MHz, CDCl3): δ = 0.89 (d, JH,H = 6.8 Hz, 3 H, CH3–CH–
3
CH3), 0.92 (d, JH,H = 6.5 Hz, 3 H, CH3–CH–CH3), 1.29 (m, 2 H,
CH2-iPr), 1.60–1.78 (m, 3 H, 4-H, 4Ј-H pyrrolidine, NH), 1.94 [dtd,
J = 12.7, 8.8, 4.8 Hz, 1 H, CH-(CH3)2], 2.27 (m, 1 H, 3-H pyrrol-
idine), 2.80 (ddd, J = 10.7, 8.7, 7.2 Hz, 1 H, 5-H pyrrolidine), 3.00–
2
3
3.12 (m, 2 H, 2-H, 5Ј-H pyrrolidine), 3.37 (dd, JH,H = 9.0, JH,H
= 6.7 Hz, 1 H, CHAHBOSi), 3.47 (dd, 2JH,H = 9.0, JH,H = 6.0 Hz,
3
1 H, CHAHBOSi), 4.48 (s, 2 H, PhCH2O), 7.33 (m, 5 H, Ph-
H) ppm. 13C NMR (62.5 MHz, CDCl3): δ = 22.0, 23.7, 25.9, 29.5,
39.3, 41.2, 45.1, 58.8, 70.8, 73.2, 127.5, 127.6, 128.3, 138.4 ppm.
HRMS (ES+): calcd. for C16H26NO [M + H]+ 248.2017; found
248.2023.
tert-Butyl (2R,3R)-[2-Phenyl-1-(3-pyridyl)but-3-enyl]carbamate
(4b): Obtained starting from a 20:1 mixture of diastereomers as a
white solid (845 mg, 58%); m.p. 176 °C, ee = 90%. [α]2D0 = –48 (c
= 1, CH2Cl2). 1H NMR (250 MHz, CDCl3): δ = 1.31 [s, 9 H,
(CH3)3-C], 3.68 (m, 1 H, CH–CH=CH2), 5.07 (m, 4 H, CHNHBoc,
CH=CH2), 5.90 (m, 1 H, CH=CH2), 7.06–7.37 (m, 7 H, Ar-H),
(2S,3S)-3-(Benzyloxymethyl)-2-[3-(tert-butyldimethylsilyloxy)-
propyl]pyrrolidine (3k): Colourless oil (290 mg, 80%). [α]2D0 = +12.3
(c = 1, CH2Cl2). 1H NMR (250 MHz, CDCl3): δ = 0.05 [s, 6 H,
CH-(CH3)2], 0.91 [s, 9 H, C-(CH3)3], 1.36–1.71 [m, 5 H, SiOCH2-
(CH2)2, 4-H pyrrolidine], 1.91 (m, 1 H, 4-H pyrrolidine), 2.04 (br.
2
s, 1 H, NH), 2.27 (m, 1 H, 3-H pyrrolidine), 2.78 (ddd, JH,H
=
3
3
8.35 (s, 1 H, 2-H pyridine), 8.47 (d, JH,H = 3.7 Hz, 1 H, 6-H pyr-
9.2, JH,H = 8.7, 7.3 Hz, 1 H, 5-H pyrrolidine), 2.92–3.06 (m, 2 H,
2-H, 5Ј-H pyrrolidine), 3.36 (d, JH,H = 9.0, JH,H = 6.7 Hz, 1 H,
idine) ppm. 13C NMR (62.5 MHz, CDCl3): δ = 28.6, 55.9, 57.2,
80.3, 118.8, 123.3, 127.6, 128.7, 129.1, 135.2, 136.8, 139.7, 148.9,
149.3, 155.2 ppm (1 C is missing). HRMS (ES+): calcd. for
C20H25N2O2 [M + H]+ 325.1916; found 325.1919.
2
3
2
3
CHAHBOBn), 3.46 (dd, JH,H = 9.0, JH,H = 6.0 Hz, 1 H,
CHAHBOBn), 3.56–3.64 (m, 2 H, CH2OSi), 4.45 (s, 2 H, PhCH2O),
7.25–7.30 (m, 5 H, Ph-H) ppm. 13C NMR (62.5 MHz, CDCl3): δ
= –5.4, 18.2, 25.9, 26.7, 29.4, 31.1, 41.0, 45.1, 61.1, 63.2, 70.7, 73.1,
127.4, 127.5, 128.2, 138.0 ppm. HRMS (ES+): calcd. for
C21H38NO2Si [M + H]+ 364.2672; found 364.2674.
tert-Butyl (2R,3R)-[2-[(tert-Butyldimethylsilyloxy)methyl]-1-(2-fur-
yl)but-3-enyl]carbamate (4c): Colourless oil (1.14 g, 65%). [α]2D0
=
1
+24 (c = 1, CH2Cl2). H NMR (250 MHz, CDCl3): δ = –0.01 (s, 3
H, CH3Si–CH3), 0.00 (s, 3 H, CH3Si–CH3), 0.88 [s, 9 H,
(CH3)3CSi], 1.9 [s, 9 H, (CH3)3C-O], 2.63 (m, 1 H, CH–CH=CH2),
(2S,3S)-[2-(3-Methylbutyl)pyrrolidin-3-yl]methanol Hydrochloride
(3Јi): Colourless oil (186 mg, 96%). [α]2D0 = +14.4 (c = 2, MeOH).
3
3
3
1H NMR (250 MHz, CD3OD): δ = 0.79 [d, JH,H = 5.6 Hz, 6 H,
3.56 (d, JH,H = 3.8 Hz, 2 H, CH2OSi), 4.94 (dd, JH,H = 7.7,
5.2 Hz, 1 H, CH-NHBoc), 5.11–5.21 (m, 2 H, CH=CH2), 5.78 (m,
1 H, CH=CH2), 5.88 (m, 1 H, NH), 6.14 (s, 1 H, furyl-H), 6.27 (s,
1 H, furyl-H), 7.29 (s, 1 H, furyl-H) ppm. 13C NMR (62.5 MHz,
CDCl3): δ = –5.8, –5.7, 18.0, 25.8, 28.3, 48.1, 51.1, 63.8, 79.0, 106.5,
110.0, 117.7, 135.8, 141.4, 154.3, 155.3 ppm. HRMS (ES+): calcd.
for C20H35NNaO4Si [M + Na]+ 404.2233; found 404.2243.
(CH3)2–CH], 1.49 (m, 3 H, CH2-iPr, 4-H pyrrolidine), 1.85–2.21
[m, 3 H, (CH3)2–CH, 3-H, 4-H pyrrolidine], 3.09 (m, 1 H, 5-H
3
pyrrolidine), 3.21 (dt, 2JH,H = 11.0, JH,H = 8.6 Hz, 1 H, 5Ј-H pyr-
rolidine), 3.41 (m, 2 H, 2-H pyrrolidine, CHAHBOH), 3.51 (dd,
3
2JH,H = 10.8, JH,H = 4.3 Hz, 1 H, CHAHBOH) ppm. 13C NMR
(62.5 MHz, CD3OD): δ = 22.4, 23.4, 26.6, 28.5, 37.2, 42.6, 44.9,
61.4, 61.7 ppm. HRMS (ES+): calcd. for C9H20NO [M – Cl]+
158.1545; found 158.1542.
tert-Butyl (2R,3R)-[2-[(tert-Butyldimethylsilyloxy)methyl]-1-phen-
ylbut-3-enyl]carbamate (4d): Obtained starting from a 9.2:1 mixture
of diastereoisomers as a colourless oil (1.28 g, 73%). ee = 80%.
[α]2D0 = +0.4 (c = 1, CH2Cl2). 1H NMR (250 MHz, CDCl3): δ =
0.00 [s, 6 H, (CH3)2Si], 0.91 [s, 9 H, (CH3)3CSi], 1.49 [s, 9 H,
(CH3)3C-O], 2.41 (m, 1 H, CH–CH=CH2), 3.49 (m, 2 H, CH2OSi),
tert-Butyl (2R,3S)-3-(Hydroxymethyl)-2-hexylpyrrolidine-1-carb-
oxylate (3l): A mixture of 2l (1.26 g, 3 mmol) and Pd(OH)2/C (20%,
300 mg) in MeOH (15 mL) under hydrogen was stirred overnight
at room temp. The crude mixture was filtered through a pad of
3402
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 3395–3406

Enantiomerically Pure 2,3-Disubstituted Pyrrolidines
3
4.87 (m, 1 H, CHNHBoc), 5.13 (d, JH,H = 10.0 Hz, 1 H, 7.11 (m, 5 H, Ar-H), 7.98 (s, 0.62 H, 2-H pyridine minor), 8.08 (s,
3
CH=CHAHB), 5.16 (d, JH,H = 17.5 Hz, 1 H, CH=CHAHB), 5.84
0.38 H, 2-H pyridine minor), 8.32 (m, 1 H, 6-H pyridine) ppm. 13
C
NMR (62.5 MHz, CDCl3): δ = 26.3 (major), 26.9 (minor), 28.1
3
(m, 1 H, CH=CH2), 6.35 (br. d, JH,H = 6.0 Hz, 1 H, NH), 7.20–
7.28 (m, 5 H, Ph-H) ppm. 13C NMR (62.5 MHz, CDCl3): δ = –5.7, (major), 28.4 (minor), 45.9 (major), 46.4 (minor), 49.0 (minor), 49.7
18.0, 25.8, 27.4, 28.4, 49.6, 57.2, 63.3, 117.2, 126.5, 126.8, 128.1,
136.7, 141.6, 155.4 ppm. HRMS (ESI): calcd. for C22H38NO3Si [M
+ H]+ 392.2621; found 392.2612.
(major), 63.0 (minor), 63.3 (major), 79.7 (major), 79.9 (minor),
122.4 (minor + major), 127.1 (minor + major), 128.1 (minor +
major), 128.3 (minor + major, 2 C), 134.1 (major), 134.8 (minor),
136.0 (minor), 136.9 (major), 147.9 (major + minor), 148.3 (major
+ minor), 154.0 (major), 154.2 (minor) ppm. HRMS (ESI): calcd.
for C20H25N2O2 [M + H]+ 325.1916; found 325.1911.
tert-Butyl [(2R,3R,E)-2-(Benzyloxymethyl)-1-styrylbut-3-enyl]-
carbamate (4e): White solid (1.27 g, 72%); m.p. 76 °C. [α]2D0 = +35.3
(c = 1, CH2Cl2). 1H NMR (250 MHz, CDCl3): δ = 1.39 [s, 9 H,
(CH3)3C-O], 2.55 (m, 1 H, CH–CH=CH2), 3.46 (m, 2 H, tert-Butyl (2R,3R)-3-[(tert-Butyldimethylsilyloxy)methyl]-2-(2-
2
CH2OBn), 4.37 (d, JH,H = 12.0 Hz, 1 H, OCHAHBPh), 4.39 (d,
furyl)pyrrolidine-1-carboxylate (5c): Yellow oil (198 mg, 52%).
2JH,H = 12.0 Hz, 1 H, OCHAHBPh), 4.45 (br. s, 1 H, NH), 5.12 (d, [α]2D0 = –6.7 (c = 1, CH2Cl2). 1.8:1 mixture of rotamers. H NMR
1
3JH,H = 10.2 Hz, 1 H, CH=CHAHB), 5.14 (d, JH,H = 17.8 Hz, 1 (250 MHz, CDCl3): δ = –0.01 [s, 2.1 H, (CH3)2Si minor], 0.00 [s,
3
3
H, CH=CHAHB), 5.24 (br. d, JH,H = 8.0 Hz, 1 H, NHCH), 5.70
(dt, J = 17.8, 10.2 Hz, 1 H, CH=CH2), 5.99 (dd, JH,H = 15.9,
3.9 H, (CH3)2Si minor], 0.90 [s, 9 H, (CH3)3CSi], 1.34 [s, 5.85 H,
(CH3)3CO, major], 1.48 [s, 3.15 H, (CH3)3CO minor], 1.86–2.09
(m, 2 H, 4-H pyrrolidine), 2.62 (m, 1 H, 3-H pyrrolidine), 3.03–
3.49 (m, 3 H, 5-H pyrrolidine, CH2OSi), 3.63–3.80 (m, 1 H, 5Ј-H
3
3
6.3 Hz, 1 H, Ph–CH=CH), 6.44 (d, JH,H = 15.9 Hz, 1 H, Ph–
CH=CH), 7.14–7.24 (m, 10 H, Ph-H) ppm. 13C NMR (62.5 MHz,
CDCl3): δ = 27.6, 28.2, 53.4, 70.5, 73.0, 78.9, 118.3, 126.2, 127.2,
3
pyrrolidine), 4.91 (d, JH,H = 7.5 Hz, 0.65 H, 2-H pyrrolidine
3
127.4, 127.7, 127.9, 128.15, 128.25, 130.8, 135.4, 136.6, 137.8, major), 4.91 (d, JH,H = 7.3 Hz, 0.35 H, 2-H pyrrolidine major),
155.0 ppm. HRMS (ESI): calcd. for C25H31NO3Na [M + Na]+ 6.11 (s, 0.65 H, furyl-H major), 6.21 (m, 0.35 H, furyl-H major),
416.2202; found 416.2205.
6.33 (m, 1 H, furyl-H), 7.34 (m, 1 H, 5-H furyl major) ppm. 13C
NMR (62.5 MHz, CDCl3): δ = –5.7 (major), –5.6 (minor), 25.8,
26.0 (major), 26.9 (minor), 28.2 (major), 28.4 (minor), 45.2 (major),
45.8 (minor), 45.9 (minor), 46.6 (major), 55.9 (minor), 56.4 (major),
62.7, 79.2, 106.9, 107.4, 109.8 (major), 110.0 (minor), 141.0
(major), 141.2 (minor), 154.0 (major), 154.2 (minor) ppm. HRMS
(ESI): calcd. for C20H35NO4SiNa [M + Na]+ 404.2233; found
404.2239.
tert-Butyl [(2R,3R,E)-2-[(tert-Butyldimethylsilyloxy)methyl]-1-styr-
ylbut-3-enyl]carbamate (4f): Colourless oil (1.22 g, 72%). [α]2D0
=
1
+38.2 (c = 1, CH2Cl2). H NMR (250 MHz, CDCl3): δ = 0.06 [s,
6 H, (CH3)2Si], 0.93 [s, 9 H, (CH3)3CSi], 1.45 [s, 9 H, (CH3)3C-O],
2.45 (m, 1 H, CH–CH=CH2), 3.67 (m, 1 H, CHAHBOSi), 3.80 (m,
1 H, CHAHBOSi), 4.53 (m, 1 H, CHNHBoc), 5.22 (d, JH,H
18.5 Hz, 1 H, CH=CHAHB), 5.24 (d, JH,H = 9.0 Hz, 1 H,
3
=
3
CH=CHAHB), 5.60 (br. d, J = 6.8 Hz, 1 H, NH), 5.83 (m, 1 H, tert-Butyl (2R,3R)-3-[(tert-Butyldimethylsilyloxy)methyl]-2-phenyl-
3
CH=CH2), 6.14 (dd, JH,H = 15.8, 6.0 Hz, 1 H, PhCH=CH), 6.55
pyrrolidine-1-carboxylate (5d): Pale-yellow oil (266 mg, 68%). ee =
(d, JH,H = 15.8 Hz, 1 H, PhCH=CH), 7.18–7.38 (m, 5 H, Ph- 80%. [α]2D0 = –19.8 (c = 1, CH2Cl2). 2:1 mixture of rotamers. 1H
3
H) ppm. 13C NMR (62.5 MHz, CDCl3): δ = –5.7, –5.6, 18.1, 25.8,
28.4, 49.3, 54.1, 63.8, 78.9, 117.9, 126.4, 127.3, 128.4, 128.6, 130.6,
136.1, 137.0, 155.3 ppm. HRMS (ESI): [M + Na]+ calcd. for
C24H39NO3SiNa 400.2597; found 400.2592.
NMR (250 MHz, CDCl3): δ = –0.08 [s, 6 H, (CH3)2Si], 0.86 [s, 9
H, (CH3)3CSi], 1.15 [s, 6 H, (CH3)3C-O, major], 1.43 [s, 3 H,
(CH3)3C-O, minor], 1.70 (m, 1 H, 4-H pyrrolidine), 1.93 (m, 1 H,
4-H pyrrolidine), 2.63 (m, 1 H, 3-H pyrrolidine), 2.98–3.15 (m, 2
3
H, CH2OSi), 3.43–3.85 (m, 2 H, 5-H pyrrolidine), 4.88 (d, JH,H
=
General Procedure for the Preparation of Boc-Protected Pyrrolidines
5 (Method F): Cp2Zr(H)Cl (772 mg, 3 mmol) was added in one por-
tion to a solution of 4 (1 mmol) in CH2Cl2 (3 mL) under argon
and the resulting mixture was stirred until complete dissolution.
Then I2 (254 mg, 1 mmol) was added and the reaction mixture was
stirred for 2 h. CH2Cl2 (10 mL) was added and the organic phase
was washed with HCl (1 , 2 ϫ 3 mL) and Na2CO3 (10 %,
2ϫ3 mL), dried with MgSO4, filtered and the solvent was removed
under reduced pressure. The crude material was dissolved in THF
(10 mL) and NaHMDS (1  in THF, 1.5 mL) was added dropwise
3
8.0 Hz, 0.67 H, 2-H pyrrolidine major), 5.05 (d, JH,H = 7.5 Hz,
0.33 H, 2-H pyrrolidine minor), 7.10–7.28 (m, 5 H, Ph-H) ppm.
Major rotamer: 13C NMR (62.5 MHz, CDCl3): δ = –5.2, –5.0, 18.6,
25.7, 28.5, 46.2, 47.1, 63.2, 63.3, 79.4, 127.1, 127.5, 128.1, 141.4,
154.8 ppm. HRMS (ESI): calcd. for C22H38NO3Si [M + H]+
392.2621; found 392.2619.
tert-Butyl (2R,3R)-3-(Benzyloxymethyl)-2-styrylpyrrolidine-1-carb-
oxylate (5e): Yellow oil (303 mg, 77%). [α]2D0 = +0.7 (c = 1, CH2Cl2).
1H NMR (250 MHz, CDCl3): δ = 1.39 [s, 9 H, (CH3)3CO], 1.64
at 0 °C. The resulting mixture was stirred for 2 h at room temp. (m, 1 H, 4-H pyrrolidine), 1.93 (m, 1 H 4Ј-H pyrrolidine), 2.62 (m,
Then Et2O (10 mL) and H2O (10 mL) were added. The aqueous
layer was extracted with Et2O (2ϫ5 mL). The combined organic
layers were washed with HCl (1 , 5 mL) and Na2CO3 (10 %,
5 mL), dried with MgSO4, filtered and the solvent was removed
under reduced pressure. The residue was purified by flash
chromatography on silica gel eluting with a mixture of PE/AcOEt
to give compound 5.
1 H, 3-H pyrrolidine), 3.33–3.45 (m, 3 H, CH2OBn, 5-H pyrrol-
idine), 3.59 (app. t, JH,H = 9.7 Hz, 1 H, 5Ј-H pyrrolidine), 4.42 (d,
2JH,H = 12.0 Hz, 1 H, PhCHAHBO), 4.51 (d, 2JH,H = 12.0 Hz, 1 H,
3
PhCHAHBO), 4.61 (m, 1 H, 2-H pyrrolidine), 6.01 (dd, JH,H
=
3
15.5, 6.7 Hz, 1 H, PhCH=CH), 6.40 (d, JH,H = 15.5 Hz, 1 H,
PhCH=CH), 7.27–7.29 (m, 10 H, Ph-H) ppm. 13 C NMR
(62.5 MHz, CDCl3): δ = 25.2, 28.3, 43.5, 45.0, 60.5, 69.7, 73.2, 79.0,
126.2 (2 C), 127.2, 127.5, 127.6, 128.2, 128.4, 131.1, 136.8, 137.9,
154.4 ppm. HRMS (ESI): calcd. for C25H31NO3Na [M + Na]+
416.2202; found 416.2204.
tert-Butyl (2R,3R)-3-Phenyl-2-(3-pyridyl)pyrrolidine-1-carboxylate
(5b): Yellow oil (1.55 mg, 48%). ee = 90%. [α]2D0 = –168 (c = 0.35,
1
CH2Cl2). 1.6:1 mixture of rotamers. H NMR (250 MHz, CDCl3):
δ = 1.20 [s, 5.54 H, (CH3)3C-O, major], 1.48 [s, 3.46 H, (CH3)3C- tert-Butyl (2R,3R)-3-[(tert-Butyldimethylsilyloxy)methyl]-2-styryl-
O minor], 2.10–2.19 (m, 1 H, 4-H pyrrolidine), 2.27–2.46 (m, 1 H,
4Ј-H pyrrolidine), 3.59–4.02 (m, 3 H, 5-H, 3-H pyrrolidine), 5.01
(d, J = 7.8 Hz, 0.62 H, 2-H pyrrolidine major), 5.08 (d, J = 7.8 Hz,
0.38 H, 2-H pyrrolidine minor), 6.80 (m, 2 H, pyridine-H), 6.95–
pyrrolidine-1-carboxylate (5f): Yellow oil (339 mg, 90%). [α]2D0
=
–1.2 (c = 1, CH2Cl2). 1.8:1 mixture of rotamers. Major rotamer:
1H NMR (250 MHz, CDCl3): δ = 0.03 [s, 6 H, (CH3)2Si], 0.90 [s,
9 H, (CH3)3CSi], 1.40 [s, 9 H, (CH3)3C-O], 1.64 (app. quint, JH,H
Eur. J. Org. Chem. 2010, 3395–3406
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3403

P.-O. Delaye, T. K. Pradhan, É. Lambert, J.-L. Vasse, J. Szymoniak
FULL PAPER
= 10.2 Hz, 1 H, 4-H pyrrolidine), 1.91 (m, 1 H, 4Ј-H pyrrolidine),
purified by flash chromatography on silica gel eluting with a mix-
2.51 (m, 1 H, 3-H pyrrolidine), 3.40 (m, 1 H, 5-H pyrrolidine), 3.58
ture of PE/AcOEt to give 6f as a yellow oil (239 mg, 64%). [α]2D0
=
3
(m, 3 H, 5Ј-H pyrrolidine CH2OSi), 4.48 (t, JH,H = 6.8 Hz, 1 H,
–4.2 (c = 1, CH2Cl2). 1.4:1 mixture of rotamers. 1H NMR
(250 MHz, CDCl3): δ = 0.00 [s, 6 H, (CH3)2Si], 0.86 [s, 9 H,
(CH3)3CSi], 1.38 [s, 5.3 H, (CH3)3C-O, major], 1.43 [s, 3.7 H,
2-H pyrrolidine), 6.06 (dd, 3JH,H = 15.5, 6.9 Hz, 1 H, Ph–CH=CH),
3
6.39 (d, JH,H = 15.5 Hz, 1 H, Ph–CH=CH), 7.20–7.38 (m, 5 H,
Ph-H) ppm. Major rotamer: 13C NMR (62.5 MHz, CDCl3): δ = (CH3)3C-O, minor], 1.80–1.98 (m, 2 H, 4-H pyrrolidine), 2.55 (m,
–5.5, 18.1, 25.4, 25.8, 28.4, 45.2, 46.1, 60.6, 62.6, 79.1, 126.2, 128.4, 1 H, 3-H pyrrolidine), 3.33 (m, 1 H, 5-H pyrrolidine), 3.47 (dd,
3
131.1, 137.0, 154.5 ppm (2 C are missing). HRMS (ESI): calcd. for
2JH,H = 10.1, JH,H = 6.8 Hz, 1 H, CHAHBOSi), 3.62 (m, 2 H, 5Ј-
3
C24H39NNaO3Si [M + Na]+ 400.2597; found 400.2590.
H pyrrolidine, CHAHBOSi), 3.66 (s, 3 H, OCH3), 4.23 (d, JH,H
=
3
8.5 Hz, 0.6 H, 2-H pyrrolidine major), 4.32 (d, JH,H = 8.4 Hz, 0.4
H, 2-H pyrrolidine minor) ppm. Major rotamer: 13C NMR
(62.5 MHz, CDCl3): δ = –5.5, 18.2, 25.8, 26.4, 28.2, 45.2, 45.5, 51.5,
60.7, 61.9, 62.0, 79.8, 153.7, 172.0 ppm. HRMS (ESI): calcd. for
C18H35NO5SiNa [M + Na]+ 396.2182; found 396.2172.
General Procedure for the Preparation of β-Proline Analogues 6d
and 6l (Method G): A solution of TBAF (1  in THF, 1.5 mL) was
added to a solution of 5d (391 mg, 1 mmol) in THF (5 mL) at room
temp. The resulting mixture was stirred for 2 h and then the solvent
was removed under reduced pressure. The residue was dissolved in
CH2Cl2 (20 mL), washed with water (3 ϫ 10 mL), dried with
MgSO4, filtered and concentrated under reduced pressure to give
quantitatively 5Јd.
(1S,7aS)-1-(Benzyloxymethyl)hexahydro-1H-pyrrolizine (3Јk):
TBAF (1  in THF, 1.8 mL) was added dropwise to a solution of
3k (440 mg, 1.2 mmol) in THF (12 mL) at 0 °C under argon. The
reaction mixture was stirred for 6 h at room temp. and the solvent
was removed under reduced pressure. The residue (240 mg) was
diluted in CH2Cl2 (6 mL) and then Et3N (3 mL), PPh3 (300 mg,
1.5 mmol) and CBr4 (280 mg, 1.5 mmol) were successively added
at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. CH2Cl2
(10 mL) was added and the reaction mixture was washed with an
aqueous solution of NaOH (2 , 5 mL). The organic layer was
dried with MgSO4, filtered and concentrated under vacuum. The
residue was purified by flash chromatography on silica gel using
Et2O/Et2NH gradient elution (100:0 Ǟ80:20) to give the corre-
RuCl3·H2O (6.2 mg, 0.1 mmol) was added to a solution of 5Јd or
3l (1 mmol) in a 2:2:3 mixture of CCl4/CH3CN/H2O (14 mL) and
the resulting black mixture was stirred for 10 min. Then NaIO4
(1.28 g, 6 mmol) was added in one portion and the stirring was
continued for 2 h. Water (5 mL) and CH2Cl2 (5 mL) were added.
The aqueous layer was extracted with CH2Cl2 (3ϫ5 mL), the or-
ganic phases were combined, dried with NaSO4, filtered and con-
centrated under reduced pressure. The residue was filtered through
a pad of silica eluting with AcOEt to give the corresponding acid.
(2R,3S)-1-(tert-Butoxycarbonyl)-2-phenylpyrrolidine-3-carboxylic
Acid (6d): Yellow oil (250 mg, 86%). [α]2D0 = –3.7 (c = 1, CH2Cl2).
2.75:1 mixture of rotamers/ 1H NMR (250 MHz, CDCl3): δ = 1.12
[s, 6.6 H, (CH3)3C-O, major], 1.40 [s, 2.4 H, (CH3)3C-O, minor],
1.99 (m, 1 H, 4-H pyrrolidine), 2.31 (app. quint, J = 10.9 Hz, 1 H,
4Ј-H pyrrolidine), 3.29–3.48 (m, 2 H, 5-H pyrrolidine), 3.77 (t,
3JH,H = 9.4 Hz, 1 H, 3-H pyrrolidine), 5.04 (d, 3JH,H = 8.4 Hz, 0.63
sponding amine (139 mg, 50%). [α]2D0 = –54.8 (c = 1, MeOH). H
NMR (250 MHz, CDCl3): δ = 1.33 (m, 1 H), 1.52 (m, 1 H), 1.60–
1.87 (m, 4 H), 2.45 (dt, JH,H = 9.5, JH,H = 6.5 Hz, 1 H), 2.51–
2.62 (m, 2 H), 2.99 (ddd, JH,H = 10.9, JH,H = 9.1, 6.3 Hz, 1 H),
3.13 (ddd, JH,H = 10.2, JH,H = 7.1, 3.3 Hz, 1 H), 3.44–3.57 (m, 3
H, CH2OBn, 2-H pyrrolidine), 4.51 (s, 2 H, PhCH2O), 7.29–7.35
(m, 5 H) ppm. 13C NMR (62.5 MHz, CDCl3): δ = 26.1, 26.5, 27.5,
41.4, 54.0, 55.7, 66.2, 71.2, 73.1, 127.4, 127.5, 128.2, 138.3 ppm.
HRMS (ESI): calcd. for C15H22NO [M + Na]+ 232.1696; found
232.1701.
1
2
3
2
3
2
3
3
H, 2-H pyrrolidine minor), 5.19 (d, JH,H = 7.5 Hz, 0.37 H, 2-H
pyrrolidine minor), 7.06–7.24 (m, 5 H, Ph-H), 9.03 (br. s, 1 H,
CO2H) ppm. Major rotamer: 13C NMR (62.5 MHz, CDCl3): δ =
24.0, 28.0, 45.5, 49.4, 62.2, 79.9, 126.7, 127.3, 127.8, 139.8, 154.2,
174.6 ppm. HRMS (ESI): calcd. for C16H20NO4 [M – H]+
290.1392; found 290.1398.
[(1S,7aS)-Hexahydro-1H-pyrrolizin-1-yl]methanol Hydrochloride
[(–)-Isoretronecanol]: A mixture of 3Јk (82 mg, 0.29 mmol) and
Pd(OH)2/C (20%, 35 mg) in a mixture of MeOH (5 mL) and HCl
(6 , 50 µL) under hydrogen was stirred overnight at room temp.
The crude mixture was filtered through a pad of Celite and concen-
trated under reduced pressure to give the title compound (45 mg,
87%). [α]2D0 = –38.5 (c = 1, MeOH). 1H NMR (250 MHz, CD3OD):
δ = 1.75–1.89 (m, 3 H), 1.94–2.14 (m, 3 H), 2.52 (m, 1 H), 2.92
(app. td, JH,H = 10.9, 5.9 Hz, 1 H), 3.21 (m, 2 H), 3.36 (app. td,
JH,H = 11.7, 5.3 Hz, 1 H, CHAHBN), 3.52–3.71 (m, 3 H, CH2OH,
(2R,3S)-1-(tert-Butoxycarbonyl)-2-hexylpyrrolidine-3-carboxylic
Acid (6l): Yellow oil (67%). [α]2D0 = +3.7 (c = 1, CH2Cl2). 1H NMR
(250 MHz, CDCl3): δ = 0.85 (m, 3 H, CH3), 1.23 [m, 10 H, (CH2)5],
1.44 [s, 9 H, (CH3)3C-O], 2.05 (m, 1 H, 4-H pyrrolidine), 2.35 (m,
3
1 H, 4Ј-H pyrrolidine), 3.09 (dt, JH,H = 11.8, 7.1 Hz, 1 H, 3-H
pyrrolidine), 3.40 (br. m, 2 H, 5-H pyrrolidine), 4.18 (br. m, 1 H, 2-
H pyrrolidine), 9.27 (br. s, 1 H, CO2H) ppm. 13C NMR (62.5 MHz,
CDCl3): δ = 14.0, 22.4, 24.4, 26.4, 28.4, 29.4, 31.2, 21.7, 44.2, 47.2,
58.0, 79.9, 154.6, 176.5 ppm. HRMS (ESI): calcd. for
C16H28NNaO4 [M – H]+ 298.2018; found 298.2005.
CHAHBN), 4.11 (dt, JH,H = 9.1, 8.0 Hz, 1 H, CHN) ppm. 13C
NMR (62.5 MHz, CD3OD): δ = 26.4, 27.0, 27.1, 44.2, 55.1, 57.0,
61.5, 71.1 ppm. HRMS (ESI): calcd. for C8H16NO [M + H]+
142.1232; found 142.1228.
3
Methyl (2R,3S)-1-(tert-Butoxycarbonyl)-3-[(tert-butyldimethyl-
silyloxy)methyl]pyrrolidine-2-carboxylate (6f): RuCl3·H2O (22 mg,
0.1 mmol) was added to a solution of 5f (417 mg, 1 mmol) in a
2:2:3 mixture of CCl4/CH3CN/H2O (14 mL) and the resulting black
mixture was stirred for 10 min. Then NaIO4 (1.28 g, 6 mmol) was
added in one portion and the stirring was continued for 2 h. Water
(5 mL) and CH2Cl2 (5 mL) were added. The aqueous layer was
extracted with CH2Cl2 (3 ϫ5 mL) and the organic phases were
combined, dried with NaSO4, filtered and concentrated under re-
duced pressure. The residue was diluted in a 5:1 mixture of Et2O/
tert-Butyl (2R,3S)-3-(Benzyloxymethyl)-2-[(R)-1-hydroxybut-3-
enyl]-1-pyrrolidine-1-carboxylate (7): A solution of OsO4 (4% in
water, 1.6 mL) was added to a solution of 5e (1.16 g, 2.95 mmol)
in a 2:1 mixture of THF/H2O (90 mL) and the resulting mixture
was stirred for 15 min. NaIO4 (3.15 g, 14.6 mmol) was then added
in one portion and the stirring was continued for 3 h. Water
(50 mL) and CH2Cl2 (50 mL) were added. The aqueous layer was
extracted with CH2Cl2 (3ϫ50 mL) and then the combined organic
MeOH (18 mL) and a solution of TMSCHN2 (2  in Et2O, 0.6 mL) phases were washed with brine (100 mL), dried with MgSO4, fil-
was added dropwise. The stirring was continued for 30 min and
the solvent was removed under reduced pressure. The residue was
tered and concentrated under reduced pressure. The crude material
was diluted in a 1:1 mixture of THF/MeOH (15 mL) cooled to 0 °C
3404
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 3395–3406

Enantiomerically Pure 2,3-Disubstituted Pyrrolidines
and then allyl bromide (1.5 mL, 18 mmol) and In (690 mg, 6 mmol)
were added. The resulting mixture was stirred for 6 h at room temp.
and then a saturated aqueous solution of NaHCO3 (15 mL) was
added. The solid was filtered off, the aqueous layer was extracted
with AcOEt (3ϫ20 mL) and the combined organics phases were
dried with MgSO4, filtered and concentrated under vacuum. The
residue was purified by flash chromatography on silica gel using
PE/AcOEt gradient elution (95:5Ǟ80:20) to give the correspond-
ing alcohol (680 mg, 64%) as an 8:1 mixture of diastereomers.
(1S,8R,8aR)-8-Benzyloxy-1-(benzyloxymethyl)octahydroindolizine
(9): Cp2Zr(H)Cl (65 mg, 0.25 mmol) was added in one portion to
a solution of 8 (95 mg, 0.21 mmol) in CH2Cl2 (1 mL) and the reac-
tion mixture was stirred at room temp. until complete dissolution
(ca. 2 h) and then I2 (56 mg, 0.21 mmol) was added. The stirring
was continued for 1 h and then CH2Cl2 (4 mL) and HCl (1 ,
1 mL) were added. The organic layer was washed with HCl (1 ,
2ϫ1 mL), dried with MgSO4 and filtered through a pad of silica
gel. The filtrate was concentrated under reduced pressure. The resi-
due (85 mg) was diluted in CH2Cl2 (15 mL) and then TFA (1.5 mL)
was added at 0 °C and the resulting mixture was stirred for 2 h at
room temp. The solvent and the excess TFA were removed under
reduced pressure. The residue was diluted in CH2Cl2 (20 mL), solid
NaHCO3 (200 mg) was added and the mixture was stirred for 2 h
at room temp. The solid was filtered off, the filtrate was washed
with NaOH (2 , 5 mL), dried with MgSO4, filtered and concen-
trated under reduced pressure to give 9 as a yellow oil (45 mg,
The major diastereoisomer was isolated in pure form as a yellow
oil (415 mg, 39%). [α]2D0 = +26.5 (c = 2, CH2Cl2). 1H NMR
(250 MHz, CDCl3): δ = 1.46 [s, 9 H, (CH3)3C], 1.81–2.25 (m, 4
H, 3-H, 4-H pyrrolidine, CHAHB–CH=CH2), 2.37–2.58 (m, 2 H,
CHAHB–CH=CH2, OH), 3.62–3.74 (m, 4 H, CH2OBn, 5-H pyr-
rolidine), 3.63 (br. s, 1 H, CHNBoc), 3.95 (br. d, 3JH,H = 6.1 Hz, 1
H, CHOH), 4.53 (s, 2 H, PhCH2O), 5.07–5.13 (m, 2 H, CH=CH2),
5.88 (m, 1 H, CH=CH2), 7.28–7.38 (m, 5 H, Ph-H) ppm. 13C NMR
(62.5 MHz, CDCl3): δ = 26.5 (br.), 28.4, 40.1, 41.8 (br.), 46.3, 61.4,
69.1, 71.3 (br.), 73.2, 79.4 (br.), 117.2, 127.7, 128.3 (2 C), 135.7,
137.7 ppm (1 C is missing). HRMS (ESI): calcd. for C21H31NO4Na
[M + Na]+ 384.2151; found 384.2155.
61%), which was used in the next step without purification. [α]2D0
=
–26.5 (c = 1, CH2Cl2). 1H NMR: δ = 1.24 (m, 1 H, CH2–CHAHB–
CH2), 1.42 (m, 1 H, CH2–CHAHB–CH2), 1.58 (m, 1 H), 1.91–2.23
3
(m, 6 H), 2.31 (d, JH,H = 8.5 Hz, 1 H), 2.54 (m, 1 H, CHAHBN),
2
3
3.14 (m, 2 H, CHN, CHAHBN), 3.51 (t, JH,H = JH,H = 8.9 Hz, 1
2
3
H, PhCHAHBO, 3.66 (dd, JH,H = 8.9, JH,H = 6.6 Hz, 1 H,
(1R,7S,7aR)-1-Allyl-7-(benzyloxymethyl)-5,6,7,7a-tetrahydro-
pyrrolo[1,2-c]oxazol-3(1H)-one (7Ј): A solution of NaHMDS (1 
in THF, 0.25 mL) was added to a solution of 7 (82 mg, 0.23 mmol)
in THF (5 mL) at 0 °C and the resulting mixture was stirred for
2 h at room temp. Water (5 mL) was added and the organic layer
was washed with HCl (1 , 5 mL), dried with MgSO4, filtered and
concentrated under reduced pressure to give 7Ј (52 mg, 78%) after
purification by flash chromatography on silica gel eluting with a
2
CHAHBOBn), 3.78 (br. s, 1 H, CHO), 4.25 (d, JH,H = 11.4 Hz, 1
H, PhCHAHBO), 4.26 (s, 2 H, PhCH2O), 4.51 (d, 2JH,H = 11.4 Hz,
1 H, PhCHAHBO), 7.24–7.35 (m, 10 H, Ph-H) ppm. 13C NMR
(62.5 MHz, CDCl3): δ = 18.6, 26.7, 27.6, 40.2, 52.4, 53.7, 70.7,
72.75, 72.80, 72.9, 127.3, 127.4, 127.6, 128.1, 128.2, 138.1,
138.6 ppm. HRMS (ESI): calcd. for C23H30NO2 [M + H]+
352.2277; found 352.2280.
1
1:1 mixture of PE/AcOEt. H NMR (250 MHz, CDCl3): δ = 1.79
(1S,8R,8aR)-Octahydro-1-(hydroxymethyl)indolizin-8-ol (10): A
solution of 9 (60 mg, 0.17 mmol) in MeOH (3 mL) and HCl (6 ,
0.05 mL) in the presence of Pd/C (10%, 30 mg) was stirred for 10 h
under H2. The crude mixture was filtered through a pad of Celite
and concentrated under reduced pressure to give 10 (33 mg, 93%).
[α]2D0 = –3.9 (c = 1, MeOH). 1H NMR (250 MHz, CDCl3): δ =
1.34–1.52 (m, 3 H), 1.76–2.09 (m, 6 H), 2.34 (m, 1 H), 3.03–3.14
(m, 2 H), 3.55 (dd, 2JH,H = 11.8, 3JH,H = 4.2 Hz, 1 H, CHAHBOH),
(m, 1 H, 4-H pyrrolidine), 2.08 (m, 1 H, 4Ј-H pyrrolidine), 2.37–
2.60 (m, 3 H, CH2–CH=CH2, 3-H pyrrolidine), 3.10 (ddd, 2JH,H
11.2, JH,H = 8.8, 5.2 Hz, 1 H, 5-H pyrrolidine), 3.34–3.43 (m, 2
=
3
2
3
H, CH2OBn), 3.62 (dt, JH,H = 11.1, JH,H = 8.0 Hz, 1 H, 5Ј-H
3
pyrrolidine), 3.72 (dd, JH,H = 6.5, 4.1 Hz, 1 H, 2-H pyrrolidine),
4.44 (d, JH,H = 12.2 Hz, 1 H, PhCHAHBO), 4.50 (d, JH,H
12.2 Hz, 1 H, PhCHAHBO), 4.71 (dt, JH,H = 6.2, 4.1 Hz, 1 H,
CHOH), 5.16 (d, JH,H = 11.7 Hz, 1 H, CH=CHAHB), 5.17 (d, J
2
2
=
3
3
3
3.67 (d, = 11.8, JH,H = 8.2 Hz, 1 H, CHAHBOH), 3.50–3.80 (br.
s, 2 H, 2 OH), 4.22 (br. s, 1 H, CHOH) ppm. 13C NMR (62.5 MHz,
CDCl3): δ = 19.5, 24.8, 31.9, 42.1, 54.05, 54.15, 63.4, 65.8,
69.1 ppm. HRMS (ESI): calcd. for C9H18NO2 [M + H]+ 172.1338;
found 172.1335.
= 15.7 Hz, 1 H, CH=CHAHB), 5.79 (ddt, J = 15.7, 11.7, 7.0 Hz, 1
H, CH=CH2), 7.29–7.38 (m, 5 H, H Ph) ppm. 13 C NMR
(62.5 MHz, CDCl3): δ = 26.7, 30.0, 39.6, 39.7, 44.5, 65.3, 69.5, 73.4,
75.0, 119.0, 127.8, 128.40, 128.45, 129.5, 131.7 ppm (1 C is miss-
ing). HRMS (ESI): calcd. for C17H21NO3Na [M + Na]+ 310.1419;
found 310.1409.
Supporting Information (see also the footnote on the first page of
1
this article): H and 13C NMR spectra of new compounds.
tert-Butyl (2R,3S)-2-[(R)-1-Benzyloxybut-3-enyl]-3-(benzyloxy-
methyl)pyrrolidine-1-carboxylate (8): NaH (30 mg, 1.23 mmol),
BnBr (0.1 mL, 0.82 mmol) and Bu4NI (10 mg, 0.04 mol) were
added in one portion to a solution of 7 (150 mg, 0.41 mmol) in
THF (0.4 mL) at room temp. The solution was stirred for 10 h at
room temp. and then water (1 mL) was added. The aqueous layer
was extracted with Et2O (3ϫ2 mL) and the organic phases were
combined, dried with Na2SO4, filtered and concentrated under re-
duced pressure to give 8 (96 mg, 52%) as a pale-yellow oil after
purification by flash chromatography on silica gel using a 5:1 mix-
ture of PE/AcOEt as eluent. [α]2D0 = +28 (c = 1, CH2Cl2). 1H NMR
(250 MHz, CDCl3): δ = 1.46 (s, 9 H), 1.67–1.94 (m, 2 H), 2.38–
2.57 (m, 3 H), 3.04–3.60 (m, 5 H), 4.08–4.60 (m, 5 H), 5.04–5.16
(m, 2 H), 5.94 (m, 1 H), 7.14–7.32 (m, 10 H) ppm. 13C NMR
(62.5 MHz, CDCl3): δ = 26.7, 28.5, 35.7, 42.5, 45.9, 59.4, 70.9,
72.9, 73.3, 79.4, 79.7, 116.4, 127.2, 127.5, 127.6, 127.8, 128.2, 128.3,
135.9, 137.9, 138.6, 155.0 ppm. HRMS (ESI): calcd. for
C28H37NO4Na [M + Na]+ 474.2620; found 474.2628.
Acknowledgments
Financial support of this work by the Agence Nationale pour la
Recherche and the Ministère de l’Education Nationale et de la Re-
cherche is gratefully acknowledged.
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Received: February 24, 2010
[7] This has been anticipated by a preliminary result, already re-
Published Online: May 11, 2010
ported in ref.[6b]
.
3406
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Eur. J. Org. Chem. 2010, 3395–3406