New access to indolizidine and pyrrolizidine alkaloids from an enantiopure proline: Total syntheses of (-)-lentiginosine and (1R,2R,7aR)- dihydroxypyrrolizidine

Article abstract of DOI:10.1021/jo070462w

(Chemical Equation Presented) A new approach to the synthesis of indolizidine and pyrrolizidine skeletons is reported. (-)-Lentiginosine and (1R,2R,7aR)-dihydroxypyrrolizidine have both been synthesized in 13 steps from di-O-isopropylidene-D-mannitol. The

Full text of DOI:10.1021/jo070462w

New Access to Indolizidine and Pyrrolizidine Alkaloids from an
Enantiopure Proline: Total Syntheses of (-)-Lentiginosine and
(1R,2R,7aR)-Dihydroxypyrrolizidine
Steven R. Angle,* David Bensa, and Dominique S. Belanger
Department of Chemistry, UniVersity of California,
RiVerside, California 92521-0403
steVen.angle@wright.edu
ReceiVed March 20, 2007
A new approach to the synthesis of indolizidine and pyrrolizidine skeletons is reported. (-)-Lentiginosine
and (1R,2R,7aR)-dihydroxypyrrolizidine have both been synthesized in 13 steps from di-O-isopropylidene-
D-mannitol. The common key intermediate is (-)-dihydroxyproline benzyl ester 10.
Introduction
in 1990 from a sample of Astragalus lentiginosus,6 and in spite
of its low degree of hydroxylation, it is the most potent inhibitor
of amyloglucosidases among azasugars and their analogues. Our
group has recently developed a diastereoselective synthesis of
highly functionalized 3-hydroxyproline benzyl esters from
R-alkoxy N-protected aminoaldehydes and benzyl diazoacetate7
The polyhydroxylated indolizidine and pyrrolizidine alkaloids
display a wide range of biological activity,1a-e mainly as
glycosidase inhibitors and anti-HIV agents,1g-i and have been
the subject of a considerable number of synthetic studies.2-4
Lentiginosine 1, trans-1,2-dihydroxyindolizidine,5 was isolated
(3) For recent examples and leading references to the synthesis of
polyhydroxylated indolizidine alkaloids, see: (a) Fujita, T.; Nagasawa, H.;
Uto, Y.; Hashimoto, T.; Asakawa, Y.; Hori, H. Org. Lett. 2004, 6, 827-
830. (b) Felpin, F. X.; Lebreton, J. Eur. J. Org. Chem. 2003, 3693-3712.
(c) Kummeter, M.; Kazmaier, U. Eur. J. Org. Chem. 2003, 3330-3334.
(d) Zhang, H.; Ni, Y. K.; Zhao, G.; Ding, Y. Eur. J. Org. Chem. 2003,
1918-1922. (e) Socha, D.; Jurczak, M.; Chmielewski, M. Carbohydr. Res.
2001, 336, 315-318. (f) Paolucci, C.; Mattioli, L. J. Org. Chem. 2001, 66,
4787-4794. (g) Pandit, U. K.; Overkleeft, H. S.; Borer, B. C.; Biera¨ugel,
H. Eur. J. Org. Chem. 1999, 959-968. (h) Carretero, J. C.; Arrayas, R. G.
J. Org. Chem. 1998, 63, 2993-3005.
(4) For recent examples of and leading references to the synthesis of
polyhydroxylated pyrrolizidine alkaloids, see: (a) Ayad, T.; Ge´nisson, Y.;
Baltas, M.; Gorrichon, L. Chem. Commun. 2003, 582-583. (b) Izquierdo,
I.; Plaza, M. T.; Franco, F. Tetrahedron: Asymmetry 2002, 13, 1581-
1585. (c) Lindsay, K. B.; Tang, M.; Pyne, S. G. Synlett 2002, 731-734.
(d) An, D. K.; Duncan, D.; Livinghouse, T.; Reid, P. Org. Lett. 2001, 3,
2961-2963. (e) Izquierdo, I.; Plaza, M. T.; Robles, R.; Franco, F.
Tetrahedron: Asymmetry 2001, 12, 2481-2487. (f) Ha, D. C.; Yun, C. S.;
Lee, Y. J. Org. Chem. 2000, 65, 621-623. (g) Goti, A.; Cicchi, S.; Cordero,
F. M.; Fedi, V.; Brandi, A. Molecules 1999, 4, 1-12. (h) Denmark, S. E.;
Thorarensen, A. J. Am. Chem. Soc. 1997, 119, 125-137. (i) Casiraghi, G.;
Spanu, P.; Rassu, G.; Pinna, L.; Ulgheri, F. J. Org. Chem. 1994, 59, 2906-
2909. (j) Ikeda, M.; Sato, T.; Ishibashi, H. Heterocycles 1988, 27, 1465-
1487.
* Current address: Department of Chemistry, Wright State University, Dayton,
OH 45435.
(1) For references to the biological activity of indolizidine and pyrrolizi-
dine alkaloids, see: (a) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G.
W. J. Tetrahedron: Asymmetry 2000, 11, 1645-1680. (b) Michael, J. P.
Nat. Prod. Rep. 1997, 14, 21-41. (c) Molyneux, R. J.; Tropea, J. E.; Elbein,
A. D. J. Nat. Prod. 1990, 53, 609-614. (d) Howard, A. S.; Michael, J. P.
In The Alkaloids; Brossi, A., Ed.; Academic Press: New York, 1986; Vol.
28, Chapter 3. (e) Mattocks, A. R. Chemistry and Toxicology of the
Pyrrolizidine Alkaloids; Academic Press: San Diego, 1986. (f) Culvenor,
C. C. J.; Bull, L.; Dick, A. T. The Pyrrolizidine Alkaloids; North-Holland
Publishing Co.: Amsterdam, 1968. (g) Winkler, D. A.; Holan, G. J. Med.
Chem. 1989, 32, 2084-2089 and references therein. (h) Karpas, A.; Fleet,
G. W. J.; Dwek, R. A.; Petursson, S.; Namgoong, S. K.; Ramsden, N. G.;
Jacob, G. S.; Rademacher, T. W. Proc. Natl. Acad. Sci. U.S.A. 1988, 85,
9229-9233. (i) Walker, B. D.; Kowalski, M.; Goh, W. C.; Kowarsky, K.;
Krieger, M.; Rosen, W. C.; Rohrschneider, L. R.; Haseltine, W. A.; Sodroski,
J. Proc. Natl. Acad. Sci. U.S.A. 1987, 84, 8120-8124.
(2) For a recent review of indolizidine and quinolizidine alkaloids, see:
(a) Michael, J. P. Nat. Prod. Rep. 2007, 24, 191-222. For recent examples
for the synthesis indolizidine and quinolizidine skeletons, see: (b) Quiroz,
T.; Corona, D.; Covarruvias, A.; Avila-Za´rraga, J. G.; Romero-Ortega, M.
Tetrahedron Lett. 2007, 48, 1571-1575. (c) Ma, D.; Zhu, W. Synlett 2006,
1181-1184. (d) Lee, H. K.; Chun, J. S.; Pak, C. S. J. Org. Chem. 2003,
68, 2471-2474.
10.1021/jo070462w CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/28/2007
5592
J. Org. Chem. 2007, 72, 5592-5597

Access to Indolizidine and Pyrrolizidine Alkaloids
chiral, naturally occurring compound, D-mannitol). Each mol-
ecule of protected D-mannitol 3 provides two molecules of chiral
aldehyde 9 after cleavage of the C3-C4 bond. We first used
the mild and stereospecific deoxygenation procedure described
by Hanessian and co-workers8a to convert the vicinal diol 3 into
the corresponding trans-olefin 48b,c in 86% yield. Removal of
the acetonides using the acidic resin Amberlyst-15 in methanol9a
led to the known tetraol 59b in 83% yield. Regioselective bis-
tosylation of the two primary hydroxy groups of 5 was achieved
in 66% yield to furnish compound 6 via the bis(dibutylstan-
nylene acetal) intermediate following Dureault’s procedure.10
The secondary hydroxy groups were protected as tert-butyldim-
ethylsilyl ethers11 to provide compound 7 in 92% yield. Reaction
of ditosylate 7 and NaNHTs12a in DMSO at 80 °C led to the
bis(p-toluenesulfonamide) derivative 8, which was cleaved by
ozone using thiourea12b to provide optically pure aldehyde 9 in
81% yield.
FIGURE 1. Structures of (-)-lentiginosine 1 and (1R,2R,7aR)-
dihydroxypyrrolizidine 2.
Synthesis of Prolinol 13. Aldehyde 9 was reacted with benzyl
diazoacetate with slow addition of BF3‚OEt2 in CH2Cl2 at
-78 °C to afford enantiopure proline 10 in 65% yield and
â-ketoester byproduct 11 in 24% yield (Scheme 2). We have
previously described the synthesis of racemic 10 and shown
that it has a trans-trans relative configuration between the
substituents.7 We were able to obtain reproducible results only
when BF3‚OEt2 and the aldehyde 9 were rigorously purified,
when 3.5 equiv of benzyl diazoacetate and 2.5 equiv of BF3‚
OEt2 were used, and when BF3‚OEt2 was added very slowly
(syringe pump). It is interesting to note that, while the yield of
proline increased from 37 to 65% from our previous work,
â-ketoester 11 was not isolated in our previous work, though
in this study, it is formed in 24% yield.
FIGURE 2. Retrosynthetic analysis.
that might find application as part of a general synthetic route
to enantiopure indolizidine and pyrrolizidine alkaloids. Our
working hypothesis for the mechanism of the proline and THF
forming reactions is one in which the diazoester acts as a
nucleophile toward the aldehyde or participates in a 1,3-dipolar
cycloaddition with the aldehyde.7 We report here the refinement
of this methodology and a new strategy for the synthesis of
non-natural (-)-lentiginosine 1 and its pyrrolizidine analogue
2 (Figure 1). This new approach, which allows access to
dihydroxyindolizidine (A, n ) 2) or dihydroxypyrrolizidine (A,
n ) 1), is illustrated in Figure 2.
The hydroxy group of proline 10 was then protected using
13
an excess of MEM-Cl and Hunig’s base in refluxing CHCl3
Reaction of the enantiopure aldehyde E with diazoester D
should diastereoselectively provide the chiral 3,4-dihydroxypro-
line ester C with a trans-trans relative configuration. Protection
of the hydroxy group and transformation of the ester functional-
ity to a homologated side chain (intermediate B) followed by
concomitant N-detosylation/cyclization should provide the target
molecules A after reduction of the lactam and deprotection of
the hydroxy groups.
to provide 12 in 78% yield (Scheme 3). Reduction with NaBH4
in EtOH gave the prolinol 13 in 88% yield, a key intermediate
for the synthesis of both the indolizidine and pyrrolizidine
skeletons. It should be noted that attempts to protect the free
hydroxy group of 10 as the tert-butyldimethylsilyl ether failed,
likely due to steric hindrance.
To evaluate the enantiomeric purity of proline 10, NMR
examination of chiral MEM-protected proline 12 was performed
Results and Discussion
(8) (a) Hanessian, S.; Bargiotti, A.; LaRue, M. Tetrahedron Lett. 1978,
19, 737-740. (b) Alkene 4 is a known compound: Tipson, R. S.; Cohen,
A. Carbohydr. Res. 1965, 1, 338-340. (c) Haines, A. H. Carbohydr. Res.
1965, 1, 214-228.
(9) (a) Mori, K.; Kinsho, T. Liebigs Ann. Chem. 1991, 1309-1315. (b)
Kuszmann, J.; Sohar, P. Carbohydr. Res. 1980, 83, 63-72.
(10) Fitremann, J.; Dure´ault, A.; Depezay, J. C. Tetrahedron 1995, 51,
9581-9594.
(11) Steel, P. G.; Thomas, E. J. J. Chem. Soc., Perkin Trans. 1 1997,
371-380.
(12) (a) Mekelburger, H. B.; Gross, J.; Schmitz, J.; Nieger, M.; Vo¨gtle,
F. Chem. Ber. 1993, 126, 1713-1721. (b) Gupta, D.; Soman, R.; Dev, S.
Tetrahedron 1982, 38, 3013-3018.
(13) (a) Corey, E. J.; Gras, J. L.; Ulrich, P. Tetrahedron Lett. 1976, 17,
809-812. (b) MEM protection was also achieved using CH2Cl2 as the
solvent and in a sealed tube. The purity of this reaction was slightly superior,
though the yields were lower. The alternate procedure is as follows: To a
stirring solution of 10 (280 mg, 0.55 mmol) in a sealed tube in CH2Cl2 (17
mL) at -30 °C under N2 were added (i-Pr2)NEt (0.87 mL, 5.0 mmol) and
then MEM-Cl (0.38 mL, 3.3 mmol). The reaction mixture was allowed to
warm to room temperature, and the system was closed and heated at 80 °C
for 18 h. The mixture was then cooled, and saturated aqueous NaHCO3
(20 mL) was added. The aqueous layer was extracted with CH2Cl2 (2 × 20
mL), and the combined organic extracts were washed with brine (20 mL),
dried (Na2SO4), and concentrated. Flash chromatography (4:1 hexanes/
EtOAc) gave 12 (145 mg, 44%) as a clear oil.
Synthesis of the Enantiopure Aldehyde 9. Enantiomerically
pure R-hydroxyaldehyde 9 has been synthesized in 25% overall
yield and six steps (Scheme 1) from commercially available
di-O-isopropylidene-D-mannitol 3 (prepared from inexpensive,
(5) For leading references to the syntheses (+)- and (-)-lentiginosine,
see: (a) Brandi, A.; Cicchi, S.; Cordero, F. M.; Frignoli, R.; Goti, A.;
Picasso, S.; Vogel, P. J. Org. Chem. 1995, 60, 6806-6812. (b) McCaig,
A. E.; Meldrum, K. P.; Wightman, R. H. Tetrahedron 1998, 54, 9429-
9446. For leading references to the synthesis of (-)-lentiginosine, see: (c)
Yoda, H.; Kitayama, H.; Katagiri, T.; Takabe, K. Tetrahedron: Asymmetry
1993, 4, 1455-1456. (d) Kim, I. S.; Zee, O. P.; Jung, Y. H. Org. Lett.
2006, 8, 4101-4104. (e) Chaudhari, V. D.; Kumar, K. S. A.; Dhavale, D.
D. Tetrahedron 2006, 62, 4349-4354 and references therein. (f) Ayad, T.;
Ge´nisson, Y.; Baltas, M. Org. Biomol. Chem. 2005, 3, 2626-2631. For
leading references to the synthesis of (+)-lentiginosine, see: (g) Ichikawa,
Y.; Ito, T.; Nishiyama, T.; Isobe, M. Synlett 2003, 1034-1036. (h) El-
Nezhawy, A. O. H.; El-Diwani, H. I.; Schmidt, R. R. Eur. J. Org. Chem.
2002, 4137-4142. (i) Goti, A.; Cardona, F.; Brandi, A. Synlett 1996, 761-
763.
(6) Pastuszak, I.; Molyneux, R. J.; James, L. F.; Elbein, A. D.
Biochemistry 1990, 29, 1886-1891.
(7) Angle, S. R.; Belanger, D. S. J. Org. Chem. 2004, 69, 4361-4368.
J. Org. Chem, Vol. 72, No. 15, 2007 5593

Angle et al.
SCHEME 1. Synthesis of Enantiopure Aldehyde 9
SCHEME 2. Synthesis of Enantiopure Dihydroxyproline
Benzyl Ester 10
Synthesis of (-)-Lentiginosine. Treatment of prolinol 13
with I2 and PPh3 in CH2Cl2 in the presence of imidazole at reflux
for 12 h afforded iodide 14 in 86% yield (Scheme 4).15 Excess
imidazole was required to prevent cleavage of the protecting
groups of 13. Radical reaction of iodide 14 with methyl
acrylate16 afforded ester 15 in 57% yield. Treatment of 15 with
magnesium ribbon in methanol17 gave lactam 16 in 75% yield
after concomitant N-detosylation/cyclization. LiAlH4 reduction
of the lactam and cleavage of the tert-butyldimethylsilyl ether
of 16, followed by removal of the MEM ether using CBr4 in
refluxing methanol,18 provided (-)-lentiginosine 1 in 54% yield.
Spectral data for 1 were identical to those reported in the
literature.6
Synthesis of (1R,2R,7aR)-1,2-Dihydroxypyrrolizidine 2.
Swern oxidation19 of prolinol 13 followed by Wittig homolo-
gation using (carbethoxymethylene)triphenylphosphorane pro-
vided acrylate 17 in 92% yield (Scheme 5). Treatment of 17
with magnesium in methanol failed to afford the expected lactam
19. Instead, only reduction of the olefin and degradation of the
substrate were observed. We were able to obtain the desired
product by first reducing the alkene of 17 (H2, 10% Pd/C) to
afford the ester 18 in 93% yield. Treatment of 18 with
magnesium afforded lactam 19 in 98% yield. Reduction of the
lactam and cleavage of the protecting groups of 19 gave 1,2-
dihydroxypyrrolizidine 220 in 51% yield. For characterization
purposes, 2 was treated with HCl in methanol to afford the
corresponding hydrochloride salt, 2-HCl.20
SCHEME 3. Synthesis of the Key Intermediate 13
(15) He, R.; Kurome, T.; Giberson, K. M.; Johnson, K. M.; Kozikowski,
A. P. J. Med. Chem. 2005, 48, 7970-7979.
(16) (a) Giese, B. Angew. Chem., Int. Ed. Engl. 1985, 24, 553-565.
Also see: (b) Osornio, Y. M.; Miranda, L. D.; Cruz-Almanza, R.;
Muchowski, J. M. Tetrahedron Lett. 2004, 45, 2855-2858. (c) Porter, N.
A.; Lacher, B.; Chang, V. H. T.; Magnin, D. J. Am. Chem. Soc. 1989, 111,
8309-8310.
(17) (a) Jonsson, S. Y.; Lo¨fstro¨m, C. M. G.; Ba¨ckvall, J. E. J. Org. Chem.
2000, 65, 8454-8457. (b) Alonso, D. A.; Andersson, P. G. J. Org. Chem.
1998, 63, 9455-9461. (c) Hudlicky, T.; Sinai-Zingde, G.; Natchus, M. G.
Tetrahedron Lett. 1987, 28, 5287-5290.
(18) Lee, A. S. Y.; Hu, Y. J.; Chu, S. F. Tetrahedron 2001, 57, 2121-
2126.
in the presence of the chiral shift reagent14 Eu(hfc)3 and
compared to racemic 12 (see Supporting Information). This
study showed 12 to be >95% ee, and thus no racemization of
aldehyde 9 occurred in the reaction with BF3‚OEt2 and benzyl
diazoacetate. Thus, proline 10 must also be >95% ee.
(14) (a) McCreary, M. D.; Lewis, D. W.; Wernick, D. L.; Whitesides,
G. M. J. Am. Chem. Soc. 1974, 96, 1038-1054. (b) Williams, D. H. Pure
Appl. Chem. 1974, 40, 25-40.
(19) Mancuso, A. J.; Huang, S. L.; Swern, D. J. Org. Chem. 1978, 43,
2480-2482.
5594 J. Org. Chem., Vol. 72, No. 15, 2007

Access to Indolizidine and Pyrrolizidine Alkaloids
SCHEME 4. Synthesis of (-)-Lentiginosine 1
SCHEME 5. Synthesis of (1R,2R,7aR)-1,2-Dihydroxypyrrolizidine 2
BF3‚OEt2 (0.440 mL, 3.50 mmol; freshly distilled over CaH2;
46 °C/10 mmHg) in CH2Cl2 (9.5 mL) was then added over 12 h
via syringe pump. The reaction mixture was stirred for an additional
2 h at -78 °C and then poured into a separatory funnel containing
saturated aqueous NaHCO3 (20 mL). The aqueous layer was
extracted with EtOAc (2 × 30 mL). The combined organic extracts
were washed with brine (2 × 20 mL), dried (Na2SO4), and
concentrated. Flash chromatography (4:1 hexanes/EtOAc) gave
proline 10 (417 mg, 65%) as a clear oil and â-ketoester 11 (150
mg, 24%) as a clear oil. 10: 1H NMR (CDCl3) δ 7.79 (d, J ) 8.2
Hz, 2H), 7.36 (m, 5H), 7.24 (d, J ) 8.2 Hz, 2H), 5.16 (ABq, J )
12.3 Hz, ∆ν ) 10.9 Hz, 2H), 4.38 (d, J ) 2.1 Hz, 1H), 4.35 (br s,
1H), 4.02 (dt, J ) 2.6, 5.1 Hz, 1H), 3.61 (dd, J ) 5.1, 10.3 Hz,
1H), 3.23 (dd, J ) 2.6, 10.3 Hz, 1H), 1.60-1.50 (br s, 1H), 2.40
(s, 3H), 0.81 (s, 9H), -0.01 (s, 6H); 13C NMR (CDCl3) δ 169.3,
143.6, 135.4, 135.3, 129.5, 128.5, 128.2, 128.0, 127.8, 79.9, 75.8,
67.4, 53.9, 25.5, 21.6, 17.9, -5.0, -5.0; IR (neat) 3486, 2947, 2928,
Conclusion
Syntheses of (-)-lentiginosine 1 and (1R,2R,7aR)-1,2-dihy-
droxyindolizidine 2 were accomplished in seven steps (14 and
29% overall yields) from enantiopure proline 10 obtained from
di-O-isopropylidene-D-mannitol 3 in six steps (16% overall
yield). These syntheses demonstrate the utility of our proline
annulation strategy for the synthesis of enantiopure indolizidine
and pyrrolizidine alkaloids.
Experimental Section
General Information. HPLC was carried out on a 4.6 × 250
mm column. Flow rate ) 0.5 mL/min; the appropriate mixture of
hexanes/methanol was used.
(2R)-N-[2-(tert-Butyldimethylsilyloxy)-3-oxopropyl]-4-meth-
ylbenzenesulfonamide (9). A solution of 8 (2.70 g, 3.95 mmol) in
CH2Cl2 (45 mL) at -78 °C was treated with ozone (10 min at 3
psi). Thiourea (0.72 g, 4.09 mmol) was added, and the reaction
mixture was stirred for 3 h at 0 °C under argon, filtered through a
short pad of Celite, and concentrated. Flash chromatography21 (2:1
hexanes/EtOAc) gave aldehyde 9 (2.3 g, 81%) as a colorless oil:
1H NMR (CDCl3) δ 9.57 (s, 1H), 7.73 (d, J ) 8.2 Hz, 2H), 7.33
(d, J ) 8.2 Hz, 2H), 4.74 (br t, J ) 6.4 Hz, 1H), 4.10 (t, J ) 5.4
Hz, 1H), 3.19 (m, 2H), 2.44 (s, 3H), 0.89 (s, 9H), 0.11 (s, 3H),
0.08 (s, 3H); 13C NMR (CDCl3) δ 202.1, 143.9, 136.5, 130.0, 127.3,
75.9, 44.9, 25.8, 21.7, 18.2, -4.6, -4.9; IR (CH2Cl2) 3365, 2931,
24
2893, 1759 cm-1; [R]D -39.6 (c 5, CH2Cl2); MS (CI, NH3) m/z
523 (MNH4+, 5), 506 (MH+, 100), 350 (67), 260 (13), 216 (41);
HRMS (CI, NH3) calcd for C25H36NO6SiS (MH+) 506.2033, found
1
506.2026. 11 (mixture of keto and enol tautomers, 80:20 by H
NMR): 1H NMR (keto form, CDCl3) δ 7.76 (d, J ) 8.2 Hz, 2H),
7.45 (m, 5H), 7.29 (d, J ) 8.2 Hz, 2H), 5.15 (m, 2H), 4.90 (br m,
1H), 3.61 (ABq, J ) 16.4 Hz, ∆ν ) 31.9 Hz, 2H), 3.35-2.98 (m,
2H), 2.42 (s, 3H), 0.87 (s, 9H), 0.06 (s, 6H); 13C NMR (keto form,
CDCl3) δ 204.4, 166.9, 143.6, 136.6, 135.1, 127.8, 127.7, 127.4,
127.1, 70.6, 66.1, 46.0, 45.3, 25.7, 21.6, 18.0, -4.6, -4.9; IR
(CDCl3) 3547, 3386, 3035, 2931, 2859, 1740, 1719 cm-1; [R]D
24
24
2858, 1735, 1598 cm-1; [R]D +1.7 (c 10, CH2Cl2); MS (FAB,
-3.4 (c 1, CH2Cl2); MS (CI/NH3) m/z 523 (MNH4+, 32), 375 (100),
332 (69), 213 (18), 184 (41), 174 (14); HRMS (CI/NH3) calcd for
C25H39N2O6SiS (MNH4+) 523.2298, found 523.2288.
NBA/NaCl) m/z 380 (MNa+, 7), 358 (MH+, 9), 327 (19), 281 (22),
207 (28), 184 (45); HRMS (FAB, NBA/PEG) calcd for C16H28-
NO4SiS (MH+) 358.1508, found 358.1500.
(2S,3R,4R)-Benzyl-4-(tert-butyldimethylsilyloxy)-3-hydroxy-
1-(toluene-4-sulfonyl)pyrrolidine-2-carboxylate (10) and (4R)-
Benzyl-4-(tert-butyldimethylsilyloxy)-3-oxo-5-(toluene-4-sulfo-
nylamino)pentanoate (11). To a solution of 9 (450 mg, 1.26 mmol)
in CH2Cl2 (5 mL) at -78 °C under N2 was added benzyl
diazoacetate (860 mg, 4.89 mmol) in CH2Cl2 (2 mL) via cannula.
(2S,3R,4R)-Benzyl-4-(tert-butyldimethylsilyloxy)-3-(2-meth-
oxyethoxymethoxy)-1-(toluene-4-sulfonyl)pyrrolidine-2-carboxy-
late (12).13 To a stirring solution of 10 (340 mg, 0.67 mmol) in
CHCl3 (15 mL) at -25 °C under N2 were added (i-Pr2)NEt (1.8
mL, 10.1 mmol) and then MEM-Cl (0.92 mL, 8.1 mmol).13 The
reaction mixture was allowed to warm to room temperature and
then refluxed for 6 h. The mixture was then cooled, and saturated
aqueous NaHCO3 (20 mL) was added. The aqueous layer was
extracted with CH2Cl2 (2 × 20 mL), and the combined organic
extracts were washed with 1 M KHSO4 (20 mL), followed by brine
(20 mL), dried (Na2SO4), and concentrated. Flash chromatography
(4:1 hexanes/EtOAc) gave 12 (313 mg, 78%) as a clear oil: 1H
NMR (CDCl3) δ 7.79 (d, J ) 8.2 Hz, 2H), 7.36 (m, 5H), 7.22 (d,
(20) The NMR obtained for 2 was the same as the enantiomer synthesized
by Ha and co-workers4f but totally different from that published by Genisson
and co-workers.4a We believe that the last authors might have synthesized
the hydrochloride form of 2 and not the free base since the spectral data
for 2-HCl are similar to those reported by Genisson and co-workers.4a
(21) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923-
2925.
J. Org. Chem, Vol. 72, No. 15, 2007 5595

Angle et al.
J ) 8.2 Hz, 2H), 5.15 (s, 2H), 4.64 (ABq, J ) 7.0 Hz, ∆ν ) 26.6
Hz, 2H), 4.56 (d, J ) 1.2 Hz, 1H), 4.32 (br s, 1H), 4.18 (dt, J )
2.1, 4.1 Hz, 1H), 3.51-3.59 (m, 3H), 3.45-3.51 (m, 2H), 3.35
(s, 3H), 3.23 (dd, J ) 1.7, 11.1 Hz, 1H), 2.40 (s, 3H), 0.81 (s, 9H),
-0.01 (s, 6H); 13C NMR (CDCl3) δ 168.8, 143.3, 135.6, 135.4,
129.3, 128.4, 128.1, 127.9, 127.8, 94.6, 84.7, 74.8, 71.6, 67.5, 67.2,
65.6, 59.0, 54.4, 25.6, 21.6, 18.0, -4.9; IR (CDCl3) 3068, 3035,
9H), 0.03 (s, 3H), 0.02 (s, 3H); 13C NMR (CDCl3) δ 173.9, 143.3,
134.6, 129.5, 127.9, 94.0, 84.1, 75.1, 71.6, 67.2, 65.6, 59.2, 55.0,
51.7, 34.0, 33.4, 25.7, 21.9, 21.6, -4.9; IR (CH2Cl2) 2954, 2888,
2859, 1732 cm-1; [R]D22 -46.7 (c 1.3, CH2Cl2); MS (FAB, NBA)
m/z 582 (MNa+, 10), 560 (MH+, 6), 496 (5), 474 (4), 401 (6), 355
(5), 281 (21); HRMS (FAB, NBA/NaCl) calcd for C26H45NO8NaSiS
(MNa+) 582.2533, found 582.2539.
24
2931, 1754, 1599 cm-1; [R]D -43.9 (c 10, CH2Cl2); MS (FAB,
(1R,2R,9aR)-2-(tert-Butyldimethylsilyloxy)-1-(2-methoxy-
ethoxymethoxy)hexahydroindolizidin-5-one (16). To a stirred
suspension of activated Mg ribbon (43.0 mg, 0.090 mmol) in MeOH
(2 mL) under N2 at room temperature was added 15 (50.0 mg, 0.09
mmol) dissolved in MeOH (2 mL) via cannula.17 After 15 h at
room temperature, the reaction mixture was concentrated, and the
residue was dissolved in EtOAc (10 mL), filtered through a short
pad of Celite, and concentrated. Flash chromatography (1:3 hexanes/
EtOAc) gave 16 (25.0 mg, 75%) as a colorless oil: 1H NMR
(CDCl3) δ 4.82 (ABq, J ) 6.7 Hz, ∆ν ) 35.8 Hz, 2H), 4.19 (dd,
J ) 6.2, 13.3 Hz, 1H), 3.82-3.58 (m, 4H), 3.58-3.52 (m, 2H),
3.46 (dd, J ) 6.2, 12.3 Hz, 1H), 3.39 (s, 3H), 3.40-3.28 (partially
m, 1H), 2.47-2.16 (m, 3H), 2.02-1.90 (m, 1H), 1.78-1.56 (m,
1H), 1.52-1.22 (m, 1H), 0.86 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H);
13C NMR (CDCl3) δ 169.2, 95.6, 86.6, 74.3, 71.8, 67.4, 61.0, 59.2,
50.0, 31.0, 27.4, 25.8, 20.8, -4.2, -4.8, IR (CH2Cl2) 3054, 2931,
NBA/NaCl) m/z 616 (MNa+, 100), 594 (MH+, 31), 488 (6), 370
(10), 327 (6), 281 (12), 207 (18); HRMS (FAB, NBA/NaCl) calcd
for C29H43NO8NaSiS (MNa+) 616.2382, found 616.2376.
(2R,3R,4R)-[4-(tert-Butyldimethylsilyloxy)-3-(2-methoxy-
ethoxymethoxy)-1-(toluene-4-sulfonyl)pyrrolidin-2-yl]metha-
nol (13). To a stirring solution of 12 (180 mg, 0.3 mmol) in
EtOH(1.0 mL) at 0 °C under N2 was added NaBH4 (57.0 mg, 1.51
mmol). After stirring at room temperature for 7 h, the reaction
mixture was poured into EtOAc (1 mL). The organic layer was
combined with 5% aqueous citric acid (5 mL), extracted with EtOAc
(3 × 5 mL), dried (Na2SO4), and concentrated. Flash chromatog-
raphy (2:1 hexanes/EtOAc) gave prolinol 13 (130 mg, 88%) as a
colorless oil: 1H NMR (CDCl3) δ 7.74 (d, J ) 8.2 Hz, 2H), 7.31
(d, J ) 8.2 Hz, 2H), 4.48 (apparent q, J ) 6.7 Hz, 2H), 3.98-3.88
(m, 5H), 3.80 (dd, J ) 4.6, 11.5 Hz, 1H), 3.62 (dt, J ) 2.0, 5.4
Hz, 1H), 3.51-3.40 (m, 4H), 3.38 (s, 3H), 2.44 (s, 3H), 0.86 (s,
9H), 0.08 (s, 3H), 0.04 (s, 3H); 13C NMR (CDCl3) δ 143.1, 134.0,
127.9, 94.5, 83.7, 74.5, 71.7, 67.3, 67.2, 64.1, 59.2, 55.3, 25.8, 21.7,
24
2888, 2858, 1634 cm-1; [R]D +16.2 (c 0.85, CH2Cl2); MS (CI/
NH3) m/z 374 (MH+, 100), 316 (42), 286 (11), 133 (28); HRMS
(CI/NH3) calcd for C18H36NO5Si (MH+) 374.2363, found 374.2369.
(1R,2R,8aR)-1,2-Dihydroxyindolizidine (1), ((-)-Lentigi-
nosine). LiAlH4 (14.0 mg, 0.374 mmol) was added to a solution
of 16 (35 mg, 0.094 mmol) in THF (3 mL) at 0 °C under N2. After
stirring for 5 min, the suspension was refluxed for 6 h. The
suspension was then cooled to 0 °C, and water (0.4 mL), 15%
aqueous NaOH (0.8 mL), water (0.4 mL) and Na2SO4 were
sequentially added. The crude mixture was filtered through a short
pad of Celite, rinsed with EtOAc (20 mL), and concentrated. The
reduction was incomplete by 1H NMR analysis, and the crude
product was resubmitted to treatment with LiAlH4 (14.0 mg, 0.374
mmol) in THF (3 mL) at 0 °C under N2. After stirring for 5 min,
the suspension was refluxed for 12 h. Workup as above afforded
24 mg of crude product. The crude product was then dissolved in
MeOH (1 mL), and CBr4 (62.0 mg, 0.188 mmol) was added. The
resulting solution was refluxed under N2 for 22 h and then
concentrated. Flash chromatography (80:19:1 CH2Cl2/MeOH/30%
NH4OH) gave the known5a compound 1 (8 mg, 54%) as a white
24
18.1, -4.6, -4.9; IR (CH2Cl2) 3503, 2931, 2892, 1598 cm-1; [R]D
-32.2 (c 7.5, CH2Cl2); MS (FAB, NBA) m/z 512 (MNa+, 58), 490
(MH+, 19), 414 (100), 222 (24), 155 (29); HRMS (FAB, NBA)
calcd for C22H40NO7SiS (MH+) 490.2298, found 490.2295.
(2R,3S,4R)-4-(tert-Butyldimethylsilyloxy)-2-iodomethyl-3-(2-
methoxyethoxymethoxy)-1-(toluene-4-sulfonyl)pyrrolidine (14).
I2 (114 mg, 0.45 mmol) was added to a stirred solution of PPh3
(118 mg, 0.45 mmol) in CH2Cl2 (2 mL) at room temperature under
N2.15 After 5 min, imidazole (70 mg, 1.02 mmol) was added. After
an additional 5 min, 13 (100 mg, 0.20 mmol) dissolved in CH2Cl2
(3 mL) was added via cannula to the reaction mixture, and the
resulting solution was refluxed for 12 h. The crude mixture was
filtered through Celite, washed with CH2Cl2 (20 mL), and concen-
trated. The residue was dissolved in EtOAc (15 mL), washed with
10% aqueous Na2S2O3 (15 mL) and brine (15 mL), dried (Na2-
SO4), and concentrated. Flash chromatography (4:1 hexanes/EtOAc)
gave 14 (105 mg, 86%) as a colorless oil: 1H NMR (CDCl3) δ
7.70 (d, J ) 8.2 Hz, 2H), 7.29 (d, J ) 8.2 Hz, 2H), 4.42 (ABq, J
) 6.9 Hz, ∆ν ) 50.5 Hz, 2H), 4.17 (br s, 1H), 4.08 (br d, J ) 4.1
Hz, 1H), 3.79-3.60 (m, 2H), 3.60-3.41 (m, 6H), 3.36 (s, 3H),
3.30 (dd, J ) 4.6, 10.3 Hz, 1H), 2.42 (s, 3H), 0.88 (s, 9H), 0.07 (s,
3H), 0.06 (s, 3H); 13C NMR (CDCl3) δ 143.6, 133.7, 129.4, 127.7,
93.5, 83.5, 74.3, 71.5, 67.1, 67.0, 59.1, 56.3, 25.6, 21.5, 17.9, -5.1,
1
solid: mp ) 106-108 °C (lit.5a mp ) 106-107 °C); H NMR
(D2O) δ 4.04 (ddd, J ) 2.1, 3.9, 7.4 Hz, 1H), 3.62 (dd, J ) 3.8,
8.5 Hz, 1H), 2.93 (br d, J ) 10.8 Hz, 1H), 2.81 (dd, J ) 1.5, 11.3
Hz, 1H), 2.59 (dd, J ) 7.7, 11.3 Hz, 1H), 2.02 (dt, J ) 2.9, 11.6
Hz, 1H), 1.91 (m, 2H), 1.79 (m, 1H), 1.62 (br d, J ) 15.4 Hz, 1H),
1.43 (m, 1H), 1.23 (br t, J ) 9.2 Hz, 2H); 13C NMR (D2O) δ 85.1,
77.8, 70.6, 62.4, 54.7, 29.8, 26.2, 25.2; IR (neat) 3757, 3692, 2986
cm-1; [R]D23 -2.5 (c 1.2, MeOH), [R]D25 -4.2 (c 1.2, MeOH) (lit.5b
24
-5.2; IR (CDCl3) 2931, 2892, 2859 1471, 1347 cm-1; [R]D
-139.0 (c 0.5, CH2Cl2); MS (FAB, NBA) m/z 600 (MH+, 71),
524 (100), 494 (16), 366 (10), 281 (6); HRMS (FAB, NBA/PEG)
calcd for C22H39INO6SiS (MH+) 600.1335, found 600.1312.
(2R,3S,4R)-Methyl-4-[4-(tert-butyldimethylsilyloxy)-3-(2-meth-
oxyethoxymethoxy)-1-(toluene-4-sulfonyl)pyrrolidin-2-yl]bu-
tyrate (15). A solution of Bu3SnH (0.094 mL, 0.35 mmol) and
AIBN (8.5 mg, 0.052 mmol) in C6H6 (1 mL) was added via syringe
pump over 4 h to a refluxing solution of 14 (105 mg, 0.175 mmol),
methyl acrylate (0.16 mL, 1.75 mmol), and AIBN (5.5 mg, 0.035
mmol) in C6H6 (1.5 mL) under N2.16 After an additional 0.5 h, the
reaction mixture was cooled and concentrated. The residue was
dissolved in CH3CN (10 mL), washed with hexanes (2 × 5 mL),
and concentrated. Flash chromatography (4:1 hexanes/EtOAc) gave
15 (56 mg, 57%) as a colorless oil: 1H NMR (CDCl3) δ 7.71 (d,
J ) 8.2 Hz, 2H), 7.28 (d, J ) 8.2 Hz, 2H), 4.41 (ABq, J ) 6.7 Hz,
∆ν ) 22.1 Hz, 2H), 3.98 (br m, 1H), 3.78 (br m, 1H), 3.68 (s,
3H), 3.53 (partially obscured br t, J ) 6.7 Hz, 1H), 3.50-3.41 (m,
3H), 3.37 (s, 3H), 3.35 (m, 1H), 2.37 (s, 3H), 2.35 (m, 2H), 1.94-
1.85 (m, 2H), 1.75-1.60 (m, 2H), 1.43-1.26 (m, 2H), 0.86 (s,
23
25
[R]D -3.05 (c 1.0, MeOH), [R]D -1.6 (c 0.24, MeOH),5a [R]D
-4.5 (c 0.8, MeOH)5i); MS (EI+) m/z 157 (M+, 21), 140 (11),
126 (9), 97 (100); HRMS (EI+) calcd for C8H15NO2 (M+)
157.1103, found 157.1106.
Methyl-(2R,3R,4R)-[4-(tert-butyldimethylsilyloxy)-3-(2-meth-
oxyethoxymethoxy)-1-(toluene-4-sulfonyl)pyrrolidin-2-yl]acry-
late (17). DMSO (0.16 mL, 2.2 mmol) in CH2Cl2 (0.65 mL) was
added carefully to a stirring solution of (COCl)2 (0.095 mL, 1.1
mmol) in CH2Cl2 (1.2 mL) at -60 °C under N2.19 The reaction
mixture was stirred for 15 min at -60 °C, and then alcohol 13
(310 mg, 0.63 mmol) in CH2Cl2 (2.5 mL) was added via cannula.
After an additional 15 min, Et3N (0.70 mL, 5.05 mmol) was added.
The reaction mixture was kept at -50 °C for 0.5 h and then warmed
in a brine-ice bath for 1.5 h. CH2Cl2 (6 mL) and methyl-
(triphenylphosphoranylidene)acetate (450 mg, 1.34 mmol) were
added, and the reaction mixture was allowed to warm up to room
temperature. After 5 h, H2O (5 mL) was added, and the aqueous
layer was extracted with CH2Cl2 (3 × 15 mL). The combined
5596 J. Org. Chem., Vol. 72, No. 15, 2007

Access to Indolizidine and Pyrrolizidine Alkaloids
organic extracts were washed with brine (15 mL), dried (Na2SO4),
and concentrated. Flash chromatography (2:1 hexanes/EtOAc) gave
17 (315 mg, 92%) as a colorless oil: 1H NMR (CDCl3) δ 7.71 (d,
J ) 8.2 Hz, 2H), 7.29 (d, J ) 8.2 Hz, 2H), 6.96 (dd, J ) 6.9, 15.9
Hz, 1H), 6.08 (d, J ) 15.9 Hz, 1H), 4.50 (ABq, J ) 7.2 Hz, ∆ν )
21.3 Hz, 2H), 4.26 (d, J ) 7.2 Hz, 1H), 4.08 (m, 1H), 3.83 (br s,
1H), 3.72 (s, 3H), 3.49 (s, 4H), 3.48 (partially obscured dd, J )
4.1, 10.7 Hz, 1H), 3.41 (partially obscured dd, J ) 1.7, 10.3 Hz,
1H), 3.37 (s, 3H), 2.43 (s, 3H), 0.83 (s, 9H), 0.03 (s, 3H), 0.01 (s,
3H); 13C NMR (CDCl3) δ 166.4, 145.8, 143.5, 129.5, 127.8, 122.1,
94.5, 86.0, 74.9, 71.6, 67.4, 65.8, 59.2, 55.2, 51.6, 25.7, 21.7, 18.0,
(m, 4H), 3.60-3.52 (m, 3H), 3.39 (s, 3H), 3.24 (dd, J ) 5.4, 12.1
Hz, 1H), 2.62 (m, 1H), 2.34 (m, 2H), 1.96 (m, 1H), 0.85 (s, 9H),
0.07 (s, 6H); 13C NMR (CDCl3) δ 176.9, 95.5, 87.3, 77.4, 71.8,
67.5, 65.1, 59.2, 49.6, 33.7, 26.7, 25.8, 18.1, -4.6; IR (CDCl3)
2930, 2892, 2858, 1684 cm-1; [R]D24 -0.6 (c 2, CH2Cl2); MS (CI,
NH3) m/z 360 (MH+, 100), 302 (10), 272 (22); HRMS (CI, NH3)
calcd for C17H34NO5Si (MH+) 360.2206, found 360.2201.
(1R,2R,7aR)-1,2-Dihydroxypyrrolizidine (2). The procedure
given for the preparation of 1 was carried out using 19 (50.0 mg,
0.139 mmol), LiAlH4 (21.0 mg, 0.556 mmol) in THF (4.4 mL),
then CBr4 (92.0 mg, 0.278 mmol) in MeOH (1.5 mL). Flash
chromatography (50:5:1 CH2Cl2/MeOH/30% NH4OH) gave 2 (10.0
24
-4.8; IR (CDCl3) 2932, 2887, 2859, 1715, 1664 cm-1; [R]D
-101.7 (c 4, CH2Cl2); MS (FAB, NBA) m/z 566 (MNa+, 62), 544
(MH+, 44), 468 (53), 270 (27). HRMS (FAB, NBA/PEG) calcd
for C25H42NO8SiS (MH+) 544.2400, found 544.2424.
mg, 51%) as a white solid: mp ) 141-143 °C; H NMR (CD3-
1
OD) δ 4.09 (q, J ) 6.0 Hz, 1H), 3.75 (t, J ) 4.9 Hz, 1H), 3.29-
3.19 (m, 2H), 3.00-2.94 (m, 1H), 2.79-2.71 (m, 1H), 2.56 (dd, J
) 6.0, 11.0 Hz, 1H), 2.10-1.70 (m, 4H); 13C NMR (CD3OD) δ
82.6, 78.6, 71.2, 59.6, 56.7, 31.3, 26.3; IR (CH2Cl2) 3684, 3600,
Methyl-(2R,3R,4R)-3-[4-(tert-butyldimethylsilyloxy)-3-(2-meth-
oxyethoxymethoxy)-1-(toluene-4-sulfonyl)pyrrolidin-2-yl]propi-
onate (18). To a solution of 17 (300 mg, 0.55 mmol) in EtOAc
(15 mL) at room temperature under N2 was added 10% Pd/C (120
mg, 0.027 mmol). A balloon of H2 was then attached, and the
reaction mixture was stirred for 6 h. The suspension was then
filtered through a short pad of Celite and concentrated. Flash
chromatography (2:1 hexanes/EtOAc) gave 18 (280 mg, 93%) as
a colorless oil: 1H NMR (CDCl3) δ 7.70 (d, J ) 8.4 Hz, 2H), 7.29
(d, J ) 8.4 Hz, 2H), 4.43 (ABq, J ) 6.9 Hz, ∆ν ) 37.5 Hz, 2H),
3.94 (overlapping dt, J ) 1.8, 3.8 Hz, 1H), 3.75 (t, J ) 1.5 Hz,
1H), 3.70 (s, 3H), 3.52-3.43 (m, 5H), 3.37 (s, 3H), 3.42-3.29
(partially obscured m, 2H), 2.67-2.42 (m, 2H), 2.42 (s, 3H), 2.26-
2.02 (m, 2H), 0.85 (s, 9H), 0.02 (s, 3H), 0.01 (s, 3H); 13C NMR
(CDCl3) δ 173.7, 143.3, 134.6, 129.4, 128.1, 94.0, 84.8, 75.3, 71.8,
67.3, 64.7, 59.2, 55.3, 51.7, 30.9, 25.9, 21.7, 18.2, -4.8; IR (neat)
2986 cm-1; [R]D -6.4 (c 1, MeOH) (lit.5f [R]D +7.6 (c 1.3,
MeOH)); MS (EI+) m/z 143 (M+, 17), 83 (100), 70 (39); HRMS
(EI+) calcd for C7H13NO2 (M+) 143.0946, found 143.0941.
(1R,2R,7aR)-1,2-Dihydroxypyrrolizidine hydrochloride (2-
HCl). HCl (0.05 mL) was added to a solution of 2 (10.0 mg) in
MeOH (2 mL) and stirred for 2 min at room temperature. Na2SO4
was added, and the suspension was filtered on a short pad of Celite
and concentrated. The residue was rinsed with dry Et2O (5 mL)
and dried under vacuum to give 2-HCl (8 mg) as a white solid:
24
25
1
mp ) 174-176 °C; H NMR (CD3OD) δ 4.30 (m, 1H), 4.16 (br
s, 1H), 4.02 (br t, J ) 8.7 Hz, 1H), 3.80-3.67 (m, 1H), 3.72
(partially obscured dd, J ) 4.1, 12.8 Hz, 1H), 3.40-3.30 (m, 1H),
2.40-2.10 (m, 4H), 2.02-1.85 (m, 2H), 13C NMR (CD3OD) δ 81.0,
24
80.1, 78.9, 61.4, 60.0, 31.4, 28.6; [R]D -11.2 (c 1.6, MeOH).
24
2930, 1734, 1598 cm-1; [R]D -26.8 (c 5, CH2Cl2); MS (FAB,
Acknowledgment. We thank UCR for support of this
research. We thank Professor M. Mark Midland for helpful
discussions.
NBA) m/z 568 (MNa+, 84), 546 (MH+, 75), 470 (22), 281 (29),
207 (23). HRMS (FAB, NBA/PEG) calcd for C25H44NO8SiS (MH+)
546.2557, found 546.2568.
(6R,7R,8aR)-6-(tert-Butyldimethylsilyloxy)-7-(2-methoxy-
ethoxymethoxy)pyrrolizidin-3-one (19). The procedure given for
the preparation of 16 was carried out using Mg ribbon (250 mg,
10.3 mmol) in MeOH (8 mL) and 18 (280 mg, 0.51 mmol) in
MeOH (8 mL), stirring for 6 h. Flash chromatography (3:1 hexanes/
EtOAc) gave 19 (180 mg, 98%) as a colorless oil: 1H NMR
(CDCl3) δ 4.77 (s, 2H), 4.30 (dd, J ) 3.8, 8.9 Hz, 1H), 3.81-3.63
Supporting Information Available: Detailed procedures for
the preparation of 4, 5, 6, 7, and 8; copies of 1H and 13C NMR spec-
tra for all the compounds described in this paper; determination of
the enantiopurity of proline 10 using shift reagent Eu(hfc)3. This ma-
terial is available free of charge via the Internet at http://pubs.acs.org.
JO070462W
J. Org. Chem, Vol. 72, No. 15, 2007 5597