Diastereoselective synthesis of 4,5′-bis-proline compounds via reductive dimerization of N-acyloxyiminium ions

Article abstract of DOI:10.1021/jo062406l

A short, practical synthesis of novel, unsymmetrical 4,5′-bis-proline compounds has been achieved, highlighted by the application of an unprecedented samarium diiodide-driven regio- and diastereocontrolled reductive dimerization of N-acyloxyiminium ions generated from readily available 2-methoxy-5- silyloxymethyl-N-Boc pyrrolidines. The title proline dimers proved to be pertinent metal-free catalysts in aldol and Mannich reactions.

Full text of DOI:10.1021/jo062406l

Diastereoselective Synthesis of 4,5′-Bis-proline
Compounds via Reductive Dimerization of
N-Acyloxyiminium Ions
Franca Zanardi,*,† Andrea Sartori,† Claudio Curti,†
Lucia Battistini,† Gloria Rassu,‡ Giuseppe Nicastro,§ and
Giovanni Casiraghi*,†
Dipartimento Farmaceutico, UniVersita` degli Studi di Parma,
Viale G.P. Usberti 27A, I-43100 Parma, Italy, Istituto di
Chimica Biomolecolare del CNR, TraVersa La Crucca 3,
I-07040 Li Punti, Sassari, Italy, and Centro Interdipartimentale
Misure “Giuseppe Casnati”, Viale G.P. Usberti 23A, I-43100
Parma, Italy
FIGURE 1. Representative members of the carbon-carbon-linked bis-
proline family. Atom numbering refers to proline nucleus.
gioVanni.casiraghi@unipr.it
ReceiVed NoVember 22, 2006
However, in spite of the intriguing nature of this compound
class and the considerable promise offered by them, it is quite
surprising that the synthesis and use of these entities have been
substantially neglected.
Herein, we define a streamlined route to unsymmetrical bis-
proline structures of type 1 by exploiting a samarium diiodide-
driven regio- and diastereocontrolled reductive dimerization of
N-acyloxyiminium ions.3
In order to join the two pyrrolidine nuclei of our targets with
a robust carbon-carbon bond, we were inspired by the notorious
enamine-iminium ion coupling reaction that Nature exploits
to forge diverse bicyclic and polycyclic alkaloidal architectures.4
We set about this project with protected 5(S)-configured
hemiaminal 6, whose access from L-glutamic acid-derived
hydroxymethylpyrrolidinone 5 is illustrated in Scheme 1 (85%
yield over four steps).
A short, practical synthesis of novel, unsymmetrical 4,5′-
bis-proline compounds has been achieved, highlighted by
the application of an unprecedented samarium diiodide-driven
regio- and diastereocontrolled reductive dimerization of
N-acyloxyiminium ions generated from readily available
2-methoxy-5-silyloxymethyl-N-Boc pyrrolidines. The title
proline dimers proved to be pertinent metal-free catalysts in
aldol and Mannich reactions.
We surmised that treatment of an hemiaminal structure of
type I with a Lewis acid promoter would generate a transient
N-acyloxyiminium species II that rapidly equilibrates to ene-
carbamate III via deprotonation (Scheme 2). If conditions were
found for the donor and acceptor partners II and III to couple
each other, rapid access to bis-pyrrolidine systems of type IV
would be at hand. However, to stop the reaction cascade at the
level of the bicyclic adducts, a reductant would have to be added
to the reaction system prior to hydrolytic quenching, which
irreversibly traps the binuclear iminium educt IV, eventually
producing neutral 2,3′-linked bis-pyrrolidines of type V.
Carbon-carbon-linked bis-proline compounds exemplified by
the formulas 1-4 in Figure 1 may be of interest for several
reasons. Their dual array of secondary amine and carboxylic
functionalities embodied onto a flexible bis-pyrrolidine scaffold
holds the prospect of binding to functional molecules and metal
ions provided that proper alignment of the donor and acceptor
sites is attainable. Also, should an orthogonal protection of the
amino and carboxyl termini be realized, grafting such dimeric
diamino diacid units onto specific peptide sequences would alter
the regular folding patterns of the biomolecule eliciting unpre-
dictable yet useful levels of structural and operational complex-
ity.1 Furthermore, coexistence within a single structure of two
stereochemically defined proline subunits which are pertinent
to recognition and catalysis could illuminate the important theme
of molecular synergism and co-operativity.2
Although the first attempts to put into practice this subtle
operation proved elusive (Table 1, entries 1-3), optimal
conditions were finally established (entry 8) consisting of
adopting a short silyl triflate-initiated equilibrium period which
(2) (a) Wright, D.; Usher, L. Curr. Org. Chem. 2001, 5, 1107-1131.
(b) Gianneschi, N. C.; Masar, M. S., III; Mirkin, C. A. Acc. Chem. Res.
2005, 38, 825-837.
(3) Few examples of enamine-iminium ion dimerization reactions have
been reported: (a) Kobayashi, S.; Gustafsson, T.; Shimizu, Y.; Kiyohara,
H.; Matsubara, R. Org. Lett. 2006, 8, 4923-4925. (b) Hong, B.-C.; Wu,
M. F.; Tseng, H.-C.; Liao, J.-H. Org. Lett. 2006, 8, 2217-2220. (c) Kuehne,
M. E.; Shannon, P. J. J. Org. Chem. 1977, 42, 2082-2087. See also:
Maryanoff, B. E.; Zhang, H. C.; Cohen, J. H.; Turchi, I. J.; Maryanoff, C.
A. Chem. ReV. 2004, 104, 1431-1628.
(4) (a) Dewick, P. M. Medicinal Natural Products: A Biosynthetic
Approach; J. Wiley & Sons: Chichester, 1997; Chapter 6. (b) Wei, X.;
Sumithran, S. P.; Deaciuc, A. G.; Burton, H. R.; Bush, L. P.; Dwoskin, L.
P.; Crooks, P. A. Life Sci. 2005, 78, 495-505.
† Dipartimento Farmaceutico.
‡ Istituto di Chimica Biomolecolare.
§ Centro Interdipartimentale Misure.
(1) For excellent reviews on peptidomimetic chemistry, see: (a) AdVances
in Amino Acid Mimetics and Peptidomimetics; Abell, A., Ed.; JAI Press:
Stamford, CT, 1999; Vol. 2. (b) Synthesis of Peptides and Peptidomimetics.
In Houben-Weyl, Methods of Organic Chemistry, 4th ed.; Goodman, M.,
Felix, A., Moroder, L., Toniolo, C., Eds.; Georg Thieme Verlag: Stuttgart,
2003; Vol. E22c.
10.1021/jo062406l CCC: $37.00 © 2007 American Chemical Society
Published on Web 01/31/2007
1814
J. Org. Chem. 2007, 72, 1814-1817

TABLE 1. Optimizing the Reductive Dimerization of
Hemiaminal 6
SCHEME 1. Preparation of Hemiaminal 6
SCHEME 2. Access to Carbon-Carbon-Linked
Bis-pyrrolidine Systems via Reductive Dimerization of
Pyrrolidinium Species
yielda
(%)
dr
Lewis acid
reductant
7 + 8:
9:10
entry
1
(conditions)
(conditions)
7
8
TBSOTf, 1.0 equiv
NaBH4, 2.0 equiv
10b
(THF, -15 ˚C, 20 min) (-15 ˚C, 60 min)
BF3‚OEt2, 1.0 equiv NaBH4, 2.0 equiv
(THF, -15 ˚C, 20 min) (-15 ˚C, 60 min)
TBSOTf, 1.0 equiv H2, Pd/C
(THF, -15 ˚C, 20 min) (-10 ˚C, 120 min)
TBSOTf, 1.0 equiv
SmI2, 2.0 equivd
(THF, -15 ˚C, 20 min) (-15 ˚C, 120 min)
TBSOTf, 1.0 equiv
SmI2, 2.0 equivd
2
3
4
5
3c
19b
30
6:1.5:1
b,c
(THF, -80 ˚C, 20 min) (-80 to -30 ˚C,
90 min)
was followed by in situ reductive blockage with samarium
diiodide in THF and final quenching.5,6
6
7
8
TBSOTf, 1.0 equiv
(THF, rt, 10 min)
TBSOTf, 1.0 equiv
(THF, -15 ˚C, 1 min)
TBSOTf, 1.5 equiv
(THF, -15 ˚C, 5 min)
SmI2, 2.0 equivd
(rt, 30 min)
40b
5
SmI2, 2.0 equivd
(-15 ˚C, 5 min)
SmI2, 1.5 equivd
(-15 ˚C, 5 min)
50b,c
55
6:1.6:1
20:2:1
In the event, we were pleased to find that by strictly adhering
to this protocol, the reductive dimerization of hemiaminal 6
occurred with high margins of regio- and diastereocontrol to
produce (2R,3′R,5S,5′S)-2,3′-bipyrrolidine 7 predominantly (55%
isolated yield), accompanied by minor amounts of partially
deprotected counterpart 8 (15%), which could nicely converted
to 7 by simple reprotection (Boc2O, Et3N, 95%). Marginal
amounts of two other diastereoisomers were also recovered, to
which stereostructures 9 and 10 were attributed as shown.
Inspection of the results in Table 1 reveals that balancing of
reaction time and temperature is critical for the success of the
reaction. In particular, the reaction gave the best results using
a 5 min iminium ion equilibrium period at -15 °C before
addition of the reducing samarium reagent in order for unsatur-
ated dimers or saturated monomeric byproducts to be minimized
(entries 4-7 vs 8).
The structural assignment of the N-Boc-protected binuclear
pyrrolidines 7 and 8 by NMR analyses proved troublesome due
to the occurrence of multiple backbone rotamers; therefore,
removal of the carbamoyl fragments was planned. Gratifyingly,
the N,N-deprotected counterpart, which quantitatively derived
from 7 and 8 by TFA treatment, furnished readable 1D- and
2D-NMR spectra from which a firm stereostructural assignment
was secured (Figure S1, Supporting Information).7
15
a Isolated yields. b Mixtures of dimeric unsaturated compounds (m/z )
875.5) were also detected, whose identification was not pursued. c Significant
amounts of (S)-1-(tert-butoxycarbonyl)-2-(tert-butyldiphenylsilanyloxym-
ethyl)pyrrolidine formed. d Quenching procedure: aq Na2S2O3 was added
to the reaction mixture, and the aqueous phase was extracted with EtOAc.
See the Experimental Section for details.
transition-state models in Figure 2, for the donor ene-carbamate
component a simple 1,3-asymmetric induction operates to favor
the attack on the re face, whereas in the acceptor component a
1,2-induction is favored probably arising from the transmittal
of the stereodirecting information of the stereogenic center onto
the proximal carbamate protecting group (si face attack pre-
ferred).8 In addition, in the preferred model, one can envision
a favorable antiperiplanar attack of the enecarbamate moiety to
the iminium ion which would allow good orbital overlap.
With the preparation of bis-pyrrolidine 7 secured, advance-
ment to bis-proline 14 only required minimal structural modi-
fication, that is oxidation of the two primary carbinol ends to
carboxylic functions and dismantling of the two pyrrolidine
N-Boc protective groups. Thus, as depicted in Scheme 3, dimer
7 was almost quantitatively desilylated to diol 11, which was
subjected to conventional Swern oxidation.9 Stable bis-aldehyde
12 was formed (91% isolated yield) that was further oxidized
to protected diacid 13 (NaClO2, NaH2PO4; 90% yield). Finally,
acidic treatment (6 N aq HCl, dioxane) quantitatively converted
13 into the targeted bis-proline 14, which was isolated as its
water-soluble bis-hydrochloride salt. Preparation of the free
Apparently, during the crucial carbon-carbon coupling
reaction, both the ene-carbamate component and the N-
acyloxyiminium ion approached each other in a facially selective
manner to avoid repulsive interactions with the bulky sily-
loxymethyl and carbamoyl substituents. Consistent with open
(5) While various Lewis acids may be successfully employed to generate
iminium ions in situ from N,O-acetals (e.g., TBSOTf, TMSOTf, BF3‚OEt2),
the choice of the reducing agent (SmI2) proved to be critical, as shown in
Table 1.
(6) Unsatisfactory results were obtained when other solvents mixtures
with coordinating additives were employed (e.g., THF/HMPA, THF/
DMPU).
(7) Similarly, the stereostructures of minor isomers 9 and 10 were
ascertained by 1D- and 2D-NMR analysis of the corresponding N,N-
deprotected compounds. See the Supporting Information.
(8) For a description of the chiral relay principle, see: (a) Bull, S. D.;
Davies, S. G.; Fox, D. J.; Garner, A. C.; Sellers, T. G. R. Pure Appl. Chem.
1998, 70, 1501-1506. (b) Hopman, J. C. P.; van den Berg, E.; Ollero Ollero,
L.; Hiemstra, H.; Speckamp, W. N. Tetrahedron Lett. 1995, 36, 4315-
4318. (c) Clayden, J.; Lund, A.; Vellverdu`, L.; Helliwell, M. Nature 2004,
431, 966-971.
(9) Mancuso, A. J.; Swern, D. Synthesis 1981, 165-185.
J. Org. Chem, Vol. 72, No. 5, 2007 1815

FIGURE 3. Ensemble of 10 lowest energy structures of bis-proline
14. Color code: green, carbon; red, oxygen; blue, nitrogen; gray,
hydrogen.
SCHEME 4. Examples of Crossed Aldol and Mannich
Reactions Catalyzed by Bis-Proline 14
Paralleling exactly the synthesis protocol to (2S,4R,2′S,5′R)-
configured proline dimer 14, the enantiomeric (2R,4S,2′R,5S)-
counterpart ent-14 (not shown) was assembled by starting with
commercially available, D-glutamic acid-derived (5R)-hydroxym-
ethylpyrrolidin-2-one (48% overall yield for nine steps).
The ability of bis-proline compound 14 to catalyze asym-
metric crossed aldol and Mannich reactions was investigated
vis-a`-vis certain previously established proline-catalyzed pro-
cesses.11,12 Here, the question was: does proline dimer 14 also
catalyze these fundamental reactions, and if so, is its efficacy
comparable with, or does it even override the notorius organo-
catalytic ability of proline itself? To address these questions,
we evaluated the aldol addition of acetone to p-nitrobenzalde-
hyde (Scheme 4, eq 1). The reaction, catalyzed by 30 mol % of
14 in DMSO at 25 °C, afforded the corresponding cross-aldol
product in a 62% yield and in 65% ee after 12 h.13 Under similar
conditions, the use of (S)-proline as the catalyst afforded the
aldol product in comparable yield and slightly higher enanti-
oselectivity (72% ee), while maintaining the same sense of
enantioinduction (see the Supporting Information for details).12a
A quite similar behavior was observed in the aldol coupling
between cyclohexanone and p-nitrobenzaldehyde, where com-
parable yields and levels of simple diastereoselection and
enantioinduction were obtained (61% yield, 60/40 anti/syn dr,
90% and 76% ee).12b
FIGURE 2. Transition states for the ene-carbamate/iminium ion
coupling reaction leading to the corresponding stereoisomeric products.
SCHEME 3. Preparation of Bis-proline 14a
a Atom numbering refers to IUPAC nomenclature.
diamino diacid was cleanly effected by passing an aqueous
solution of the HCl salt onto a DOWEX column (H+ form)
eluting with 1.5% aqueous ammonia solution.
Confirmation of the stereostructure of 14 as well as its
conformational behavior for solutions in water (90:10 H2O/D2O)
were made on the basis of 2D NMR experiments. The three-
dimensional structure of 14 was calculated from 15 interproton
distance restraints, using the simulated annealing calculations.10
The 10 structures with the lowest energy were selected as a
representative ensemble for the structure of 14 (Figure 3). The
two proline residues were clearly found to be trans-disposed,
with H2 and H3′ located on opposite sides within the molecule
(J2,3′ ) 10.2 Hz; H2-C2-C3′-H3′ dihedral angle ) 180 (
40°).
Application of bis-proline 14 vis-a`-vis (S)-proline in a
Mannich reaction was examined using acetone and N-p-
methoxyphenyl-protected R-imino ethyl glyoxylate (Scheme 4,
eq 2). The reactions were accomplished within 12 h with a
(11) (a) Dalko, P., Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138-
5175. (b) Houk, K. N., List. B., Eds. Acc. Chem. Res. 2004, 37, 487 (special
issue on organocatalysis). (c) Koc´ovsky´, P., Malkov, A. V., Eds. Tetrahedron
Symposia-in-Print No. 116: Organocatalysis in Organic Synthesis 2006,
62, 243-502.
(12) (a) List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc.
2000, 122, 2395-2396. (b) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F.,
III. J. Am. Chem. Soc. 2001, 123, 5260-5267. (c) Cordova, A.; Notz, W.;
Zhong, G.; Betancort, J. M.; Barbas, C. F., III. J. Am. Chem. Soc. 2002,
124, 1842-1843.
(10) Casiraghi, G.; Rassu, G.; Auzzas, L.; Burreddu, P.; Gaetani, E.;
Battistini, L.; Zanardi, F.; Curti, C.; Nicastro, G.; Belvisi, L.; Motto, I.;
Castorina, M.; Giannini, G.; Pisano, C. J. Med. Chem. 2005, 48, 7675-
7687.
(13) Lowering the catalyst loading to 10 mol % resulted in a prolonged
reaction time and diminished enantioselectivity.
1816 J. Org. Chem., Vol. 72, No. 5, 2007

(C4), 26.9 (3CH3, But), 26.8 (3CH3, But), 19.3 (Cq, SiBut), 19.2
(Cq, SiBut). Anal. Calcd for C47H64N2O4Si2: C, 72.63; H, 8.30; N,
3.60. Found: C, 72.88; H, 8.04; N, 3.75.
catalyst loading of 20 mol % in both instances, giving the
corresponding Mannich adduct in high yields and enantiose-
lectivities (80% yield, 82% ee).12c,13 On the basis of these results,
we surmized that unsymmetric bis-proline compounds of type
14 arising from conjugation of two proline nuclei through a
direct carbon-carbon linkage prove to be organocatalysts as
good as their monomeric proline counterparts.
In summary, short, diastereoselective syntheses of 4,5′-
bisproline enantiomers 14 and ent-14 have been accomplished
in 47-48% overall yields and nine steps from commercially
available L- and D-glutamic acid-derived hydroxymethylpyrrol-
idin-2-ones 5 and ent-5. Our strategy features a SmI2-driven
reductive dimerization of chiral N-acyloxyiminium ions for
accessing the unprecedented carbon-carbon-linked bis-pyrro-
lidine substructures of these compounds. Bis-proline 14 proved
to be a competent metal-free catalyst in direct asymmetric
crossed-aldol and Mannich reactions.
Conversion of 8 to 7 was effected as follows. To a stirring
solution of bipyrrolidine 8 (80 mg, 0.10 mmol) in dry CH2Cl2 (10
mL) were sequentially added Boc2O (27 mg, 0.12 mmol) and Et3N
(17 µL, 0.12 mmol). After 2 h, the reaction mixture was quenched
by addition of saturated aqueous NH4Cl (10 mL). The mixture was
extracted with CH2Cl2 (2 × 10 mL), and the combined organic
layers were dried (MgSO4), filtered, and concentrated under
vacuum. The resulting crude product was purified by flash
chromatography (hexanes/EtOAc 90:10) to afford bipyrrolidine 7
in a 95% yield.
(2R,3′R,5S,5′S)-2,3′-Bipyrrolidine-5,5′-dicarboxylic Acid Di-
hydrochloride (14‚2HCl). To solution of protected diacid 13 (136
mg, 0.32 mmol) in dioxane (3 mL) at room temperature was added
6 N aq HCl (2 mL), and the resulting mixture was stirred for 1 h.
The reaction mixture was concentrated under reduced pressure to
furnish 14‚2HCl (95 mg, 99%) as a white solid: mp >250 °C dec;
[R]25D -42.9 (c 1.0, H2O); IR (neat) 2886, 2736, 2545, 1726, 1205
cm-1; 1H NMR (600 MHz, D2O) δ 4.51 (dd, J ) 9.6, 4.8 Hz, 1H,
H5′), 4.39 (dd, J ) 9.6, 5.4 Hz, 1H, H5), 3.63 (dd, J ) 11.4, 7.2
Hz, 1H, H2′A), 3.60 (td, J ) 10.2, 6.6 Hz, 1H, H2), 3.08 (dd, J )
12.0, 9.6 Hz, 1H, H2′B), 2.69 (qt, J ) 9.6, 7.2 Hz, 1H, H3′), 2.53
(ddd, J ) 13.2, 7.8, 4.2 Hz, 1H, H4′A), 2.32 (m, 1H, H4A), 2.15-
2.25 (m, 3H, H4′B, H4B and H3A), 1.68 (m, 1H, H3B); 13C NMR
(150 MHz, D2O) 171.4 (CO2H), 171.1 (CO2H), 62.4 (C2), 59.9
(C5), 59.6 (C5′), 47.8 (C2′), 38.8 (C3′), 32.2 (C4′), 27.7 (C3), 27.2
(C4). Anal. Calcd for C10H18Cl2N2O4: C, 39.88; H, 6.02; N, 9.30.
Found: C, 39.77; H, 6.26; N, 9.24.
(2R,3′R,5S,5′S)-2,3′-Bipyrrolidine-5,5′-dicarboxylic Acid (14).
Crude diacid 14‚2HCl (95 mg, 0.32 mmol) was dissolved in a 1.5%
aqueous solution of NH4OH and passed through DOWEX 650C
ion-exchange resin (H+ form). Elution of the resin with 1.5% aq
NH4OH furnished free amino acid 14 (72 mg, 100%) as a white
solid: mp >250 °C dec; [R]25D -73.7 (c 0.6, H2O); 1H NMR (600
MHz, D2O) δ 4.15 (dd, J ) 9.6, 4.2 Hz, 1H, H5′), 4.03 (dd, J )
9.6, 4.2 Hz, 1H, H5), 3.58 (dd, J ) 12.0, 7.8 Hz, 1H, H2′A), 3.47
(td, J ) 10.2, 6.0 Hz, 1H, H2), 2.99 (dd, J ) 11.4, 10.2 Hz, 1H,
H2′B), 2.60 (qt, J ) 9.6, 7.2 Hz, 1H, H3′), 2.40 (ddd, J ) 12.6,
6.6, 4.2 Hz, 1H, H4′A), 2.19 (m, 1H, H4A), 2.04-2.12 (m, 3H,
H4B, H4′B and H3A), 1.57 (m, 1H, H3B); 13C NMR (150 MHz,
D2O) 174.3 (CO2H), 173.7 (CO2H), 62.5 (C2), 61.7 (C5), 61.1 (C5′),
47.8 (C2′), 39.4 (C3′), 33.1 (C4′), 28.5 (C3), 28.1 (C4); HRMS
(ESI) found [M + H]+ 229.1196, C10H17N2O4 requires 229.1188.
Anal. Calcd for C10H16N2O4: C, 52.62; H, 7.07; N, 12.27. Found:
C, 52.54; H, 7.10; N, 12.30.
Experimental Section
(2R,3′R,5S,5′S)-1,1′-Di-tert-butoxycarbonyl-5,5′-bis(tert-butyl-
diphenylsilanyloxymethyl)-2,3′-bipyrrolidine (7). To a stirring
solution of hemiaminal 6 (0.70 g, 1.49 mmol) in dry THF (20 mL),
cooled to -15 °C under argon, was slowly added tert-butyldim-
ethylsilyl triflate (TBSOTf, 0.51 mL, 2.24 mmol). After 5 min, a
dark blue solution of SmI2 (0.1 M in THF, 22.4 mL, 2.24 mmol)
was slowly added, and the resulting mixture immediately turned
to yellow and was stirred at the same temperature for additional 5
min. The reaction mixture was quenched with solid Na2S2O3 (120
mg) and water (50 mL) and extracted with EtOAc (2 × 50 mL)
and CH2Cl2 (2 × 50 mL). The combined organic layers were dried
(MgSO4), filtered, and concentrated under reduced pressure giving
a crude residue which was purified by silica gel flash chromatog-
raphy (hexanes/EtOAc 90:10-0:100) to afford bipyrrolidine 7 (360
mg, 55%), along with minor amounts of stereoisomeric compounds
9 (36 mg, 5.5%) and 10 (16 mg, 2.5%), as well as partially
deprotected bipyrrolidine 8 (87 mg, 15%).
Bipyrrolidine 7: colorless oil; [R]25D -20.4 (c 1.0, CHCl3); 1H
NMR (300 MHz, CDCl3, mixture of rotamers) δ 7.64 (m, 8H),
7.37 (m, 12H), 3.8-4.1 (m, 4H), 3.4-3.8 (m, 3H), 3.0-3.4 (m,
2H), 2.30 (m, 1H), 1.8-2.2 (m, 5H), 1.60 (m, 1H), 1.47 (s, 9H),
1.31 (s, 9H), 1.07 (s, 9H), 0.97 (s, 9H); 13C NMR (75 MHz, CDCl3)
δ 155.9 (Cq), 154.5 (Cq), 135.6 (8C, CH), 133.7 (4C, Cq), 129.7
(4C, CH), 127.7 (8C, CH), 79.5 (Cq), 79.2 (Cq), 64.7 (2C, CH2),
60.1 (CH), 58.4 (2C, CH), 49.7 (CH2), 41.4 (CH), 32.2 (CH2), 29.9
(CH2), 28.6 (3C, CH3), 28.4 (3C, CH3), 26.9 (3C, CH3), 26.8 (4C,
CH3 and CH2), 19.3 (Cq), 19.2 (Cq). Anal. Calcd for C52H72N2O6-
Si2: C, 71.19; H, 8.27; N, 3.19. Found: C, 70.99; H, 8.36; N, 3.04.
Bipyrrolidine 8: colorless oil; [R]25D -13.5 (c 1.0, CHCl3); 1H
NMR (600 MHz, CDCl3, mixture of rotamers) δ 7.67 (m, 8H, Ph),
7.41 (m, 12H, Ph), 3.85-4.05 (m, 1H, H6′A), 3.71 (m, 2H, H6A
and H6′B), 3.63 (dd, J ) 10.2, 5.4 Hz, 1H, H6B), 3.53 (m, 1H,
H5′), 3.4-3.5 (m, 1H, H2′A), 3.30 (m, 1H, H5), 3.0-3.1 (m, 1H,
H2′B), 2.92 (m, 1H, H2), 2.2-2.4 (m, 1H, H3′), 1.7-1.9 (m, 4H,
H3A, H4′A, H4′B, and H4A), 1.62 (m, 1H, H4B), 1.35 (m, 1H, H3B),
1.33 (s, 9H, But), 1.07 (s, 9H, But), 1.04 (s, 9H, But); 13C NMR
(75 MHz, CDCl3) δ 154.4 (CdO), 135.6 (4CH, Ph), 135.5 (4CH,
Ph), 133.6 (4Cq, Ph), 129.6 (4CH, Ph), 127.6 (8CH, Ph), 79.1 (Cq,
OBut), 67.0 (C6), 64.6 (C6′), 62.3 (C2), 59.9 (C5), 58.7 (C5′), 49.9
(C2′), 42.2 (C3′), 32.9 (C4′), 30.4 (C3), 28.4 (3CH3, But), 27.5
Acknowledgment. We thank CNR and MIUR (PRIN
program 2004) for financial support. We also thank the Centro
Interdipartimentale Misure “G. Casnati” (University of Parma)
for instrumental facilities.
Supporting Information Available: Experimental procedures,
analytic and spectral data for intermediary compounds, NOE-
derived structure of N,N-deprotected 7, NMR-derived structural
parameters of 14, and copies of 1H and 13C NMR spectra of selected
key compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO062406L
J. Org. Chem, Vol. 72, No. 5, 2007 1817