Reactivity of chiral α-amidoalkylphenyl sulfones with stabilized carbanions. Stereoselective synthesis of optically active 1-aminopyrrolizidine

Article abstract of DOI:10.1021/jo048882y

Metal enolates and functionalized allylzinc reagents react with optically active α-amidoalkylphenyl sulfones to give N-carbamoylamino derivatives with variable levels of anti diastereoselectivity. Zinc enolates provide comparable results with respect to l

Full text of DOI:10.1021/jo048882y

Rea ctivity of Ch ir a l r-Am id oa lk ylp h en yl Su lfon es w ith Sta bilized
Ca r ba n ion s. Ster eoselective Syn th esis of Op tica lly Active
1-Am in op yr r olizid in e
Nicola Giri, Marino Petrini,* and Roberto Profeta†
Dipartimento di Scienze Chimiche, Universita` di Camerino, via S. Agostino, 1, I-62032 Camerino, Italy
marino.petrini@unicam.it
Received J uly 2, 2004
Metal enolates and functionalized allylzinc reagents react with optically active R-amidoalkylphenyl
sulfones to give N-carbamoylamino derivatives with variable levels of anti diastereoselectivity. Zinc
enolates provide comparable results with respect to lithium enolates in terms of diastereoselectivity
but afford â-amino ester derivatives in lower yield. The synthetic utility of the obtained chiral
N-carbamoylamino esters is demonstrated by the first enantioselective synthesis of (-)-1-
aminopyrrolizidine a central intermediate for the preparation of various biologically active
substances.
SCHEME 1
In tr od u ction
Nucleophilic addition to imino derivatives represents
a viable procedure to many synthetic targets containing
primary or secondary amino groups.1 The electrophilic
character of the carbon-nitrogen double bond can be
suitably enhanced by linking electron-withdrawing sub-
stituents to the nitrogen atom.2 Among these imino
derivatives, N-acyl and N-carbamoylimines have emerged
as strong electrophilic compounds that react with a wide
range of nucleophilic reagents giving the corresponding
N-carbamoylamino derivatives.3 The consistent reactivity
of N-acylimines obtained from aliphatic aldehydes is
often associated with their instability that causes some
troubles in their preparation. Indeed, these N-acylimines
undergo to a fast tautomerization that leads to the
formation of the corresponding enecarbamates with
consequent loss of any electrophilic character. For this
reason, N-acylimines 2 are more profitably prepared from
N-acyl-R-substituted amines 1 by a base-promoted elimi-
nation (Scheme 1).
The ready availability of derivatives 1 is therefore
mandatory for a successful utilization of N-acylimino
intermediates.4 In this context, R-amidoalkylphenyl sul-
fones (1, X ) PhSO2) are easily prepared by reaction of
a carbamate with an aldehyde and sodium benzenesulfi-
nate in the presence of formic acid.5 When acid-labile
groups are present in the aldehyde, a modified procedure
using benzenesulfinic acid in anhydrous conditions can
be suitably used to access precursors 1. Asymmetric
induction in reactions involving imino derivatives can be
realized introducing stereogenic N-substituents that
(4) Reviews: (a) Weinreb, S. M.; Scola, P. M. Chem. Rev. 1989, 89,
9, 1525-1534. (b) Zaugg, H. A. Synthesis 1984, 85-110 and 181-212.
R-Alkoxy derivatives: (c) Kise, N.; Ueda, N. Org. Lett. 1999, 1, 1803-
1805. (d) Kise, N.; Ueda, N. J . Org. Chem. 1999, 64, 7211-7514. (e)
Vanier, C.; Wagner, A.; Mioskowsky, C. Chem. Eur. J . 2001, 7, 2318-
2323. (f) Chao, W.; Weinreb, S. M. Tetrahedon Lett. 2000, 41, 9199-
9204. R-Benzotriazolyl derivatives: (g) Katritzky, A. R.; Kirichenko,
K.; Elsaied, A. M.; J i, Y.; Fang, Y.; Steel, P. J . J . Org. Chem. 2002, 67,
4957-4959. (h) Katritzky, A. R.; Fang, Y.; Silina, A. J . Org. Chem.
1999, 64, 7622-7624.
(5) For some recent applications, see: (a) Pesenti, C.; Arnone, A.;
Arosio, P.; Frigerio, M.; Meille, S. V.; Panzeri, W.; Viani, F., Zanda,
M. Tetrahedron Lett. 2004, 45, 5125-5129. (b) Frantz, D. E.; Morency,
L.; Soheili, A.; Murry, J . A.; Grabowski, E. J . j.; Tillyer, R. D. Org.
Lett. 2004, 6, 843-846. (c) Mataloni, M.; Petrini, M.; Profeta, R. Synlett
2003, 1129-1132. (d) Petrini, M.; Profeta, R.; Righi, P. J . Org. Chem.
2002, 67, 4530-4535. (e) Dahmen, S.; Bra¨se, S. J . Am. Chem. Soc.
2002, 124, 5940-5941. (f) Hermanns, N.; Dahmen, S.; Bolm, C.; Bra¨se,
S. Angew. Chem., Int. Ed. 2002, 41, 3692-3694. (g) Palomo, C.;
Oiarbide, M.; Landa, A.; Gonza´lez-Rego, M. C.; Garc´ıa, J . M.; Gonza´lez,
A.; Odriozola, J . M.; Mart´ın-Pastor, M.; Linden, A. J . Am. Chem. Soc.
2002, 124, 8637-8643. (h) Zhang, J .; Wie, C.; Li, C.-J . Tetrahedron
Lett. 2002, 43, 5731-5733. (i) Klepacz, A.; Zwierzak, A. Tetrahedron
Lett. 2002, 43, 1079-1080. (j) Enders, D.; Oberbo¨rsch, S. Synlett 2002,
471-473. (k) Kimura, R.; Nagano, T.; Kinoshita, H.; Bull. Chem. Soc.
J pn. 2002, 75, 2517-2525.
* To whom correspondence should be addressed. Phone: +39 0737
402253. Fax: +39 0737 402297.
† Present address: GlaxoSmithKline Medicine Research Centre, via
Fleming 4, 37135 Verona, Italy.
(1) Review: (a) Co´rdova, A. Acc. Chem. Res. 2004, 37, 102-112. (b)
Taggi, A. E.; Hafez, A. M.; Lectka, T. Acc. Chem. Res. 2003, 36, 10-
19. (c) Kobayashi, S.; Ishitani, H. Chem. Rev. 1999, 99, 1069-1094.
(d) Bloch, R. Chem. Rev. 1998, 98, 1407-1438. (e) Enders, D.; Reinhold,
U. Tetrahedron: Asymmetry 1997, 8, 1895-1946.
(2) Review: (a) Ellman, J . A.; Owens, T. D.; Tang, T. P. Acc. Chem.
Res. 2002, 35, 984-995. (b) Weinreb, S. M. Top. Curr. Chem. 1997,
190, 131-194.
(3) (a) Trost, B. M.; J onasson, C. Angew. Chem., Int. Ed. 2003, 42,
2063-2066. (b) Kobayashi, S.; Matsubara, R.; Nakamura, Y.; Kita-
gawa, H.; Sugiura, M. J . Am. Chem. Soc. 2003, 126, 2507-2515. (c)
J ørgensen, K. A. Synthesis 2003, 1117-1125. (d) Nakamura, Y.;
Matsubara, R.; Kitagawa, H.; Kobayashi, S.; Kumagai, K.; Yasuda,
S.; Hanada, K. J . Med. Chem. 2003, 46, 3688-3695. (e) Saabi, S.;
Bayo´n, P.; Aburez, P. S.; J ørgensen, K. A. J . Org. Chem. 2002, 68,
4352-4361. (f) Patil, R. T.; Parveen, G.; Gumaste, V. K.; Bhaval, B.
M.; Deshmukh, A. R. A. S. Synlett 2002, 1455-1458.
10.1021/jo048882y CCC: $27.50 © 2004 American Chemical Society
Published on Web 09/11/2004
J . Org. Chem. 2004, 69, 7303-7308
7303

Giri et al.
SCHEME 2
SCHEME 3
SCHEME 4
provide a diastereofacial discrimination at the carbon-
nitrogen double bond.6 However, this practice is poorly
effective with N-acylimines 2 since the stereogenic center
in the carbamoyl group is too far from the reactive double
bond to produce consistent levels of diastereoselection.7
Alternatively, the chiral group can be included in the
alkyl framework of N-acylimine 2 as close as possible to
the reaction center in order to realize the maximum
stereodirecting effect toward the incoming nucleophilic
reagent.
Recently, we have demonstrated that (R)-2,3-iso-
propylideneglyceraldehyde 3 as well as other chiral
aldehydes, can be converted into the corresponding
R-amidoalkylphenyl sulfones 4 with enhanced syn dia-
stereoselectivity.8 Reaction of sulfones 4 with nitromethane
anion provides the nitro adduct 5 with high anti dia-
stereoselectivity and after a Nef reaction ultimately leads
to optically active â-hydroxy-R-amino acid esters 6 (Scheme
2).
the former addition is carried out at room temperature.11
Furthermore, as previously observed, sulfone 4a bearing
a N-Boc protecting group gives better diastereoselectivi-
ties than the N-Cbz derivative 4b.8
The absolute configuration of the newly formed stereo-
center in compound 8a has been evaluated by chemical
correlation (Scheme 4).
In this paper, we report on the reactivity of chiral
R-amidoalkylphenyl sulfones with other nucleophilic
reagents and the application of the obtained adducts to
the first enantioselective synthesis of (-)-1-amino-
pyrrolizidine.
Cleavage of the acetonide group in amino ester 8a
using p-TSA in methanol gives the corresponding diol 9
that is oxidized using NaIO4-KMnO4 to the N-Boc-L-
aspartic acid monoester 10.12 Methyl esterification of
monoacid 10 can be realized using Me3SiCHN2 in a
mixture of methanol-toluene,13 giving diester 11 that
shows the sign of the optical rotation congruent with
natural N-Boc-L-aspartic acid dimethyl ester.14 As ex-
pected, sulfones 4 are also reactive toward functionalized
allylzinc reagents giving N-carbamoyl homoallylamino
derivatives 13 (Scheme 5).
Allyl bromide 12a efficiently adds to sulfone 4a in the
presence of zinc metal with modest diastereoselectivity
(syn/anti ) 3:7), while substituted allylzinc reagent
obtained from bromoacrylate 12b gives the corresponding
adduct 13b with better diastereoselectivity (syn/anti )
1:9). The organozinc reagent prepared from 3-bromo-1-
Resu lts a n d Discu ssion
Reaction of imines with ester enolates provides a
straightforward entry to functionalized â-amino esters,
an emerging class of compounds present in a certain
number of biologically active compounds.9 Lithium and
zinc ester enolates 7 can be added to sulfones 4 under
different conditions to afford N-carbamoyl â-amino esters
8 (Scheme 3).10 The addition is anti diastereoselective,
and the utilization of the Reformatzky reagent 7a
produces the corresponding â-amino ester with higher
diastereoselectivity than lithium enolate 7c even though
(11) For a rationale of the observed anti diastereoselectivity see ref
8. We assume that the same hypothesis previously made for the
reaction of sulfones 4 and 19 with nitromethane anion can be taken
into account for the present process.
(12) Herna´ndez, N.; Martin, V. S. J . Org. Chem. 2001, 66, 4934-
4938.
(6) Alvaro, G.; Savoia, D. Synlett 2002, 651-673.
(7) (a) Mecozzi, T.; Petrini, M. Unpublished results. Interesting
diastereoselections can be obtained using structurally related N-
acyliminium ions: (b) Mu¨ller, R.; Ro¨ttele, H.; Henke, H.; Waldmann,
H. Chem. Eur. J . 2000, 6, 2032-2043. (c) Harding, K. E.; Davis, C. S.
Tetrahedron Lett. 1988, 29, 1891-1894.
(13) Hashimoto, N.; Aoyama, T.; Shioiri, T. Chem. Pharm. Bull.
1981, 29, 1475-1478.
(8) Foresti, E.; Palmieri, G.; Petrini, M.; Profeta, R. Org. Biomol.
Chem. 2003, 1, 4275-4281.
(14) (a) Herna´ndez, J . N.; Ramirez, M. A.; Martin, V. S. J . Org.
Chem. 2003, 68, 743-746. (b) Similarly, removal of the Cbz group in
the major diastereomer of compound 8c (H2, Pd/C, MeOH) gives the
(9) Reviews: (a) Liu, M.; Sibi, M. P. Tetrahedron 2002, 58, 7991-
8035. (b) Enantioselective Synthesis of â-Amino Acids; J uaristi, E., Ed.;
Wiley-VCH: New York, 1997. (c) Cole, D. C. Tetrahedron 1994, 50,
9517-9582.
corresponding anti amino derivative with [R]20 ) -4.6 (c 1.5, CHCl3)
D
[lit. [R]20 ) -5.2 (c 0.862, CHCl3)]; see: Kita, Y.; Tamura, O.; Itoh,
D
F.; Kishino, H.; Miki, T.; Kohn, M.; Tamura, Y. Chem. Pharm. Bull.
1989, 37, 2002-2007.
(10) Mecozzi, T.; Petrini, M. Tetrahedron Lett. 2000, 41, 2709-2712.
7304 J . Org. Chem., Vol. 69, No. 21, 2004

Synthesis of Optically Active 1-Aminopyrrolizidine
SCHEME 5
SCHEME 8
SCHEME 6
SCHEME 9
SCHEME 7
acetoxy-1-propene 14 is a useful reagent recently re-
ported by Lombardo et al. for the stereoselective synthe-
sis of functionalized 1,2-diols from aldehydes and ketones.15
Sulfone 4a reacts with 14 in the presence of zinc metal
to afford fully protected amino polyol 15 in good yield
and diastereoselectivity (Scheme 6).
SCHEME 10
As previously observed, the attack of the nucleophile
would preferentially occur from the si face of the inter-
mediate N-acylimine giving the anti stereoisomer with
respect to the 1,3-dioxolane ring oxygen. To establish the
relative stereochemistry between the newly created ste-
reocenters, compound 15 has been deacetylated in basic
conditions to the hydroxy derivative 16 that has been
cyclized using t-BuOK to the parent oxazolidin-2-one 17
(Scheme 7).
A measurement of the NOE effect between H-4 and
H-5 in compound 17 allowed us to assign the anti
relationship between the amino and the acetoxy groups.
On the other hand, a marked preference for the anti
diastereomer has been also observed in the reaction of
14 with racemic R-amidoalkylphenyl sulfones in similar
conditions.5d
The pyrrolidine ring is an important structural unit
present in alkaloids and other biologically active sub-
stances.16 Many approaches devoted to the stereoselective
synthesis of compounds featuring the pyrrolidine nucleus
employ L-proline or its derivatives as pivotal building
blocks. In particular, N-carbamoyl prolinals 18 can be
converted by the usual procedure into the corresponding
sulfones 19 with a variable degree of diastereoselectivity,
depending on the nature of the N-carbamoyl group
(Scheme 8).
Sulfones 19 react with Reformatzky reagent 7b and
lithium enolate 7c giving the corresponding adducts 20-
22 in good yield but with lower diastereoselectivity
compared to the same reaction of sulfones 4 (Scheme 9).
Specifically, reaction of enolate 7c with sulfones 19 is
able to produce the corresponding amino esters 22a ,b
with respectable anti diastereoselectivity. It is worth
noting that the epimeric composition of sulfones 19 does
not affect the stereochemical outcome of the subsequent
nucleophilic addition. Indeed, using pure syn-19b or
epimeric mixtures of the same sulfone gives the same
results in terms of diastereoselectivity. This probably
means that a common N-acylimine intermediate is
formed from each epimer of sulfone 19. Amino esters 22
are ideal candidates for the synthesis of 1-amino-
pyrrolizidine 23 that constitutes the heterocyclic core of
a number of biologically active compounds (Scheme 10).
The carbamate combination in compounds 19 has been
chosen in order to ensure a chemoselective cleavage of
the carbamoyl groups in the resulting adducts 20-22.
The natural product (+)-absouline 24 isolated from the
New Caledonian plants Hugonia oreogena and Hugonia
penicillanthenum possess a slight antivral activity.17 The
(15) (a) Lombardo, M.; Morganti, S.; Trombini, C. J . Org. Chem.
2003, 68, 997-1006. (b) Lombardo, M.; Morganti, S.; d’Ambrosio, F.;
Trombini, C. Tetrahedron Lett. 2003, 44, 2823-2826.
(16) (a) Felpin, F.-X.; Lebreton, J . Eur. J . Org. Chem. 2003, 3693-
3712. (b) Yoda, H. Curr. Org. Chem. 2002, 6, 223-243. (c) Enders, D.;
Thiebes, T. Pure App. Chem. 2001, 73, 573-578.
(17) (a) Ikhiri, K.; Ahond, A.; Poupat, C.; Potier, P.; Pusset, J .;
Se´venet, T. J . Nat. Prod. 1987, 50, 626-630. (b) Christine, C.; Ikhiri,
K.; Ahond, A.; Al Mourabit, A.; Poupat, C.; Potier, P. Tetrahedron 2000,
56, 1837-1850.
J . Org. Chem, Vol. 69, No. 21, 2004 7305

Giri et al.
ously prepared only in racemic form17b and this synthesis
also served us to confirm the stereochemical assignment
of the configuration of the amino stereocenter in com-
pounds 22.
SCHEME 11
Con clu sion
Chiral R-amidoalkylphenyl sulfones 4 and 19 react
with metal enolates and allylzinc reagents to afford the
corresponding amino derivatives with enhanced anti
diastereoselectivity. Sulfones 4 provide the corresponding
adducts with better diastereoselectivities than sulfones
19 expecially when are made to react with functionalized
organozinc reagents. The addition products obtained
using the present procedure are amenable of further
transformations as demonstrated by the enantioselective
synthesis of (-)-1-aminopyrrolizidine 23 prepared in four
steps from amino ester 22b. This optically active pyr-
rolizidine is a pivotal intermediate for the synthesis of
alkaloids endowed of interesting biological activity.
SCHEME 12
Exp er im en ta l Section
Gen er a l P r oced u r e for th e P r ep a r a tion of N-Ca r ba m -
oyla m in o Ester s 8 a n d Allyl Der iva tives 13, 15, 20, a n d
21 Usin g Or ga n ozin c Rea gen ts. To a suspension of zinc dust
(5 mmol) in dry THF (10 mL) was added the corresponding
allyl bromide or bromoester (3 mmol) at room temperature.
After the mixture was stirred for 30 min, the appropriate
sulfone 4, 19 (2 mmol) dissolved in dry THF (8 mL) was added
dropwise. Stirring was continued for 1 h, and then the mix-
ture was quenched by addition of satd NH4Cl (8 mL). The
mixture was extracted with CH2Cl2 (4 × 15 mL) and dried over
MgSO4. The crude product obtained after removal of the
solvent was purified by column chromatography (7:3 hexanes-
ethyl acetate).
two enantiomers of absouline have been previously
prepared by resolution of the racemic mixture on a
preparative chiral column, and therefore, our procedure
represents a synthetic approach toward the first enantio-
selective total synthesis of (-)-24. Furthermore, 1-amido-
pyrrolizidines 26 act as potent and selective 5-HT3
antagonists for serotonine receptor.18 As a first attempt
we planned to originate the pyrrolizidine ring system by
cleavage of the carbamoyl protecting group in compound
22b followed by a lactamization under basic conditions
(Scheme 11).
Although the formation of pyrrolizidinone 27 was
successful, the subsequent reduction to the saturated
byciclic derivative was proved to be quite troublesome.
Thus, we exploited an alternative synthetic proce-
dure that involves a preliminary selective reduction of
the ester function in compound 22b with NaBH4-CaCl2
in EtOH-THF19 to afford primary alcohol 28 followed
by the N-Boc cleavage to give amino alcohol 29 (Scheme
12).
Met h yl (3S)-3-[(ter t-b u t oxyca r b on yl)a m in o]-3-[(4S)-
2,2-d im eth yl-1,3-d ioxola n -4-yl]p r op a n oa te 8a : yield 70%;
waxy solid; [R]20 ) +4.2 (c 1.3, CHCl3); IR (cm-1, neat) 3350,
D
1716; 1H NMR δ 1.33 (s, 3H), 1.41 (s, 3H), 1.43 (s, 9H), 2.64-
2.69 (m, 2H), 3.70 (s, 3H), 3.85 (dd, 1H, J ) 5.2, 8.4 Hz), 3.90-
4.01 (m, 1H), 4.04 (dd, 1H, J ) 6.2, 8.4 Hz), 4.09-4.22 (m,
1H), 5.24 (d, 1H, J ) 9.2 Hz); 13C NMR δ 25.4, 26.8, 28.4, 35.1,
52.0, 60.3, 66.2, 77.0, 80.3, 110.0, 155.1, 172.3. Anal. Calcd
for C14H25O6 (303.35): C, 55.43; H, 8.31; N, 4.62. Found: C,
55.49; H, 8.27; N, 4.66.
ter t-Bu tyl N-(1S)-1-[(4S)-2,2-d im eth yl-1,3-d ioxola n -4-
yl]-3-bu ten ylca r ba m a te 13a : yield 83%; mp 60-62 °C; [R]20
D
) +6.9 (c 1.05, CHCl3); IR (cm-1, KBr) 3350, 1680; 1H NMR δ
1.33 (s, 3H), 1.42 (s, 12H), 2.15-2.47 (m, 2H), 3.62-3.90 (m,
2H), 3.98-4.10 (m, 2H), 4.48 (d, 0.7H, J ) 9.2 Hz), 4.67 (d,
0.3H, J ) 9.2 Hz), 5.05-5.16 (m, 2H), 5.71-5.91 (m, 1H); 13
C
Ring closure of compound 29 to the bicyclic derivative
30 can be carried out by intramolecular SN2 displacement
of the corresponding in situ generated mesylate.20 Re-
moval of the carbamoyl group in 30 by hydrogenolysis
leads to (-)-1-aminopyrrolizidine 23 that has been previ-
NMR δ 25.2, 26.5, 28.5, 35.5, 52.4, 67.1, 77.8, 79.6, 109.7, 118.2,
134.2, 155.8. Anal. Calcd for C14H25NO4 (271.35): C, 61.97;
H, 9.29; N, 5.16. Found: C, 62.02; H, 9.24; N, 5.19.
Gen er a l P r oced u r e for th e P r ep a r a tion of N-Ca r ba m -
oyla m in o Ester s 8 a n d 22 Usin g Lith iu m En ola tes. To a
solution of diisopropylamine (6 mmol) in dry THF (20 mL) was
added BuLi (1.6M in hexanes, 6.5 mmol, 4.1 mL) at 0 °C, and
stirring was continued for 0.5 h at 0 °C. Dry ethyl acetate (6
mmol) was then added at -78 °C, and after the mixture was
stirred at the same temperature for 0.5 h sulfone 4, 19 (2
mmol) dissolved in dry THF (8 mL) was added. Stirring was
continued for 1 h at -78 °C, and then the mixture was
quenched by addition of satd NH4Cl (8 mL).The mixture was
extracted with CH2Cl2 (4 × 15 mL) and dried over MgSO4. The
crude product obtained after evaporation of the solvent was
purified by column chromatography (75:25 hexanes-ethyl
acetate).
(18) (a) Becker, D. P.; Flynn, D. L.; Villamil, C. I. Bioorg. Med. Chem.
Lett. 2004, 14, 3073-3075. (b) Flynn, D. L.; Zabrowski, D. L.; Becker,
D. P.; Nosal, R.; Villamil, C. I.; Gullickson, G. W.; Moummi, C.; Yang,
D.-C. J . Med. Chem. 1992, 35, 1489-1491. Polyhydroxypyrrolizidines
are also known as powerful glycosidase inhibitors: (c) Asano, N.; Nash,
R, J .; Molyneux, R. J .; Fleet, G. W. J . Tetrahedron: Asymmetry 2000,
11, 1645-1680. (d) Goti, A.; Cicchi, S.; Cordero, F. M.; Fedi, V.; Brandi,
A. Molecules 1999, 4,1-12.
(19) Lewis, N.; McKillop, A.; Taylor, R. J . K.; Watson, R. J . Synth.
Commun. 1995, 25, 561-568.
(20) (a) Donohoe, T. J .; Sintim, H. O. Org. Lett. 2004, 6, 2003-2006.
(b) Kuba´n, J .; Kolarovicˇ, A.; Fisˇera, L.; J a¨ger, V.; Humpa, O.; Pro´nay-
ova´, N. Synlett 2001, 1866-1868.
7306 J . Org. Chem., Vol. 69, No. 21, 2004

Synthesis of Optically Active 1-Aminopyrrolizidine
ter t-Bu tyl (2S)-2-((1R)-1-[(Ben zyloxy)ca r bon yl]a m in o-
3-eth oxy-3-oxop r op yl)tetr a h yd r o-1H-1-p yr r oleca r boxy-
7.0 Hz) 7.29-7.37 (m, 5H); 13C NMR δ 26.8, 30.9, 41.7, 53.5,
62.2, 67.2, 68.5, 128.4, 128.5, 128.8, 136.4, 156.1, 171.9. Anal.
Calcd for C15H18N2O3 (274.52): C, 65.68; H, 6.61; N, 10.21.
Found: C, 65.73; H, 6.57; N, 10.25.
la te 22b: yield 95%; oil [R]20D ) -21.7 (c 2.5, CHCl3); IR (cm-1
,
1
neat) 3360, 1715; H NMR δ 1.23 (t, 3H, J ) 7.0 Hz), 1.46 (s,
9H), 1.68-2.05 (m, 4H), 2.40-2.60 (m, 2H), 3.15-3.32 (m, 1H),
3.35-3.58 (m, 1H), 3.88-4.20 (m, 4H), 5.05-5.20 (m, 2H),
6.20-6.35 (m, 1H), 7.29-7.40 (m, 5H); 13C NMR δ 14.3, 23.9,
28.5, 29.1, 36.1, 46.9, 47.6, 51.5, 60.8, 66.8, 80.0, 128.1, 128.2,
128.6, 136.7, 156.2, 156.3, 171.9. Anal. Calcd for C22H32N2O6
(420.50): C, 62.84; H, 7.67; N, 6.66. Found: C, 62.88; H, 7.65;
N, 6.63.
ter t-Bu tyl (2R)-2-((1S)-1-[(Ben zyloxy)ca r bon yl]a m in o-
3-h ydr oxypr opyl)tetr ah ydr o-1H-1-pyr r olecar boxylate 28.
To a solution of amino ester 22b (2.0 g, 4.75 mmol) in ethanol-
THF (2:1, 24 mL) were added CaCl2 (1.1 g, 10 mmol) and
NaBH4 (0.78 g, 20 mmol) at 0 °C. After the mixture was stirred
overnight at room temperature, the solvent was partially
removed at reduced pressure, and the resulting slurry was
taken up in ethyl acetate (50 mL) and then quenched with
citric acid (1 M, 20 mL). The aqueous solution obtained after
separation of the organic phase was extracted with ethyl
acetate (3 × 15 mL), and the collected organic phases were
dried over MgSO4. The crude product obtained after removal
of the solvent was purified by column chromatography (6:3:1
hexanes-ethyl acetate-ethanol) affording 1.31 g (73%) of
Clea va ge of Am in o Ester 8a . Syn th esis of N-Boc-L-
d im eth yl Asp a r ta te 11. N-Boc amino ester 8a (0.32 g, 1.0
mmol) was dissolved in methanol (10 mL), and p-toluene-
sulfonic acid (0.025 g) was added at room temperature. The
solution was stirred for 18 h at room temperature, and
methanol was then removed at reduced pressure to give crude
diol 9 that was dissolved in dioxane-water (7:3, 10 mL). This
mixture was treated sequentially with Na2CO3 (0.065 g, 0.6
mmol) dissolved in water (0.6 mL), NaIO4 (0.86 g, 4 mmol),
and KMnO4 (0.035 g, 0.2 mmol) and was stirred at room
temperature for 45 min after which time reaction was com-
plete. The reaction mixture was diluted with ethyl acetate (20
mL) and acidified with 1 N HCl until pH ) 1. The resulting
organic phase was washed with brine and dried over MgSO4.
The residue obtained after evaporation of the solvent was
dissolved in MeOH-toluene (2:5, 12 mL) and treated with
Me3SiCHN2 (2.0 M in ether, 1.2 mL). The mixture was stirred
for 30 min, and excess of Me3SiCHN2 was destroyed with
AcOH (0.1 mL). After evaporation of the solvent, the crude
diester was purified by column chromatography (7:3 hexanes-
ethyl acetate) giving 0.165 g of pure 11 as a white solid: mp
alcohol 28 as a colorless oil: [R]20 ) -11.7 (c 1.4, CHCl3); IR
D
(cm-1, neat) 3300, 1710; 1H NMR δ 1.44 (s, 9H), 1.80-2.03
(m, 5H), 2.07-2.20 (m, 1H), 3.08-3.26 (m, 1H), 3.42-3.70 (m,
4H), 3.75-4.00 (m, 2H), 5.05-5.15 (m, 2H), 7.21 (d, 1H, J )
8.9 Hz), 7.29-7.43 (m, 5H); 13C NMR δ 24.3, 28.5, 30.7, 32.2,
48.4, 51.9, 58.6, 62.0, 67.0, 80.3, 128.3, 128.4, 128.7, 136.0,
156.5, 158.0. Anal. Calcd for C20H30N2O5 (378.46): C, 63.47;
H, 7.99; N, 7.40. Found: C, 63.42; H, 8.04; N, 7.36.
Ben zyl N-(1S)-3-Hyd r oxy-1-[(2R)tetr a h yd r o-1H-2-p yr -
r olyl]p r op ylca r ba m a te 29. N-Boc-amino alcohol 28 (1.2 g,
3.2 mmol) was dissolved in THF (20 mL), and 37% HCl (10
mL) was then added at room temperature. The mixture was
stirred for 30 min at room temperature, cooled in an ice bath,
and made alkaline by addition of NaOH pellets. THF was
partially removed at reduced pressure, and the resulting
solution was extracted with ethyl acetate (6 × 15 mL) and
dried over MgSO4. After evaporation of the solvent, the crude
amino alcohol was purified by column chromatography (90:
9:1 dichloromethane-methanol-35% NH4OH) giving 0.75 g
64-65 °C; [R]20 ) +27.3 (c 3.5, CHCl3) [lit.14a mp 65-66 °C;
D
[R]20D ) +28.02 (c 5, CHCl3)]. Spectroscopic data for compound
11 are in agreement with those reported.
(4S,5S)-4-[(4S)-2,2-Dim eth yl-1,3-d ioxola n -4-yl]-5-vin yl-
1,3-oxa zolid in -2-on e 17. N-Boc amino ester 15 (0.30 g, 0.9
mmol) was dissolved in methanol (10 mL), and 2 M K2CO3 (2
mL) was added at room temperature. After the mixture was
stirred for 30 min at room temperature, methanol was partially
removed at reduced pressure and the resulting solution was
extracted with CHCl3 (3 × 15 mL). The crude product obtained
after evaporation of the solvent was dissolved in THF (6 mL),
and t-BuOK (0.11 g, 1 mmol) was then added at room
temperature. The mixture was stirred for 1 h at room tem-
perature, and after removal of the solvent at reduced pressure
the residue was taken up with ethyl acetate (25 mL), washed
with brine (3 × 5 mL), and dried over MgSO4. After evapora-
tion of the solvent the crude oxazolidinone was purified by
column chromatography (6:3:1 hexanes-ethyl acetate-etha-
(85%) of pure 29 as a white solid: mp 106-108 °C; [R]20
)
D
-13.1 (c 1.0, CHCl3); IR (cm-1, KBr) 3300, 1718; H NMR δ
1.40-1.95 (m, 6H), 2.81-2.98 (m, 2H), 3.10-3.30 (m, 1H),
3.40-3.73 (m, 4H), 3.75-3.90 (m, 1H), 5.08 (s, 2H), 5.43 (d,
1H, J ) 9.5 Hz), 7.28-7.43 (m, 5H); 13C NMR δ 25.9, 30.1,
35.1, 46.8, 53.1, 58.7, 62.1, 67.1, 128.3, 128.4, 128.7, 136.5,
156.9. Anal. Calcd for C15H22N2O3 (278.35): C, 64.73; H, 7.97;
N, 10.06. Found: C, 64.76; H, 8.01; N, 10.03.
1
Ben zyl N-[(1S,7a R)-P er h yd r o-1-p yr r olizin yl]ca r ba m -
a te 30. To a solution of amino alcohol 29 (0.7 g, 2.5 mmol) in
dry dichloromethane (15 mL) was added MsCl (0.34 g, 3 mmol)
at -10 °C followed by dropwise addition of Et3N (0.38 g, 3.8
mmol). After being stirred for 1 h at -10 °C, the cooling bath
was removed and stirring was continued for a further 2 h. The
solvent was evaporated at reduced pressure, and the residue
was directly purified by column chromatography (55:30:15)
dichloromethane-methanol-35% NH4OH) affording 0.46 g
nol) giving 0.077 g (40%) of pure 17 as a waxy solid: [R]20
)
D
+4.45 (c 0.2, CHCl3); IR (cm-1, neat); H NMR δ 1.32 (s, 3H),
1.42 (s, 3H), 3.74 (dd, 1H, J ) 5.6, 8.4 Hz), 4.01 (dd, 1H, J )
6.2, 8.4 Hz), 4.11-4.20 (m, 2H), 5.14-5.24 (m, 1H), 5.37-5.69
(m, 2H), 5.79-5.97 (m, 2H); 13C NMR δ 24.9, 26.6, 57.3, 65.1,
1
(70%) of pyrrolizidine 30 as a yellow oil: [R]20 ) -18.15 (c
D
74.7, 78.3, 109.4, 119.8, 130.8, 158.9. Anal. Calcd for C10H15
-
2.7, CHCl3); IR (cm-1, neat) 3350, 1715; 1H NMR δ 1.80-2.30
(m, 6H), 2.65-2.83 (m, 2H), 3.25-3.42 (m, 1H), 3.51-3.70 (m,
1H), 3.71-3.83 (m, 1H), 3.92-4.10 (m, 1H), 5.07 (s, 2H), 6.46
(d, 1H, J ) 7.7 Hz), 7.23-7.38 (m, 5H); 13C NMR δ 25.3, 30.2,
31.9, 53.3, 55.2, 56.4, 67.0, 71.3, 128.2, 128.3, 128.7, 136.6,
156.5. Anal. Calcd for C15H20N2O2 (260.33): C, 69.20; H, 7.74;
N, 10.76. Found: C, 69.24; H, 7.71; N, 10.79.
NO4 (213.23): C, 56.33; H, 7.09; N, 6.57. Found: C, 56.28, H,
7.12; N, 6.54.
Ben zyl N-[(1S,7a R)-3-Oxop er h yd r o-1-p yr r olizin yl]ca r -
ba m a te 27. N-Boc amino ester 22b (0.63 g, 1.5 mmol) was
dissolved in THF (10 mL), and 37% HCl (5 mL) was then added
at room temperature. The mixture was stirred for 30 min at
room temperature, cooled in an ice bath, and made alkaline
by addition of NaOH pellets. After being stirred for 15 min,
the solution was extracted with CHCl3 (4 × 15 mL) and dried
over MgSO4. After evaporation of the solvent, the crude lactam
was purified by column chromatography (95:5 dichloro-
methane-methanol) giving 0.27 g (65%) of pure 27 as a yellow
(1S,7a R)-P er h yd r o-1-p yr r olizin a m in e 23. Carbamate 30
(0.9 g 3.5 mmol) dissolved in MeOH (20 mL) was hydrogenated
(2 atm) in the presence of 10% Pd-C (0.1 g) for 5 h at room
temperature. After removal of the catalyst by filtration, the
solvent was evaporated to give 0.38 g (88%) of pure pyrrolizi-
dine 23 as a waxy solid: [R]20 ) -24.1 (c 5.5, MeOH); IR
oil: [R]20 ) -27.5 (c 1.3, CHCl3); IR (cm-1, neat) 3350, 1670;
D
D
(cm-1, neat) 3200; 1H NMR δ 1.78-2.35 (m, 6H), 2.90-3.15
(m, 2H), 3.27-3.40 (m, 2H), 3.45-3.70 (m, 2H), 4.90 (s, 2H);
13C NMR δ 25.8, 30.4, 34.4, 54.2, 56.1, 57.7, 74.4. Anal. Calcd
1H NMR δ 1.80-2.20 (m, 4H), 2.63 (dd, 1H, J ) 10.6, 14.1
Hz), 2.78 (dd, 1H, J ) 8.4, 14.1 Hz), 2.98-3.15 (m, 1H), 3.45-
3.77 (m, 2H), 3.95-4.15 (m, 1H), 5.08 (s, 2H), 5.46 (d, 1H, J )
J . Org. Chem, Vol. 69, No. 21, 2004 7307

Giri et al.
for C7H14N2 (126.20): C, 66.62; H, 11.18; N, 22.20. Found: C,
66.66; H, 11.14; N, 22.24.
Su p p or tin g In for m a tion Ava ila ble: Spectral and physi-
cal data for the following compounds not included in the
Experimental Section: 8b,c, 13b, 15, 19b, 20a ,b, 21, and 22a .
This material is available free of charge via the Internet at
http://pubs.acs.org.
Ack n ow led gm en t. Financial support from Univer-
sity of Camerino (National Project “Sintesi e Reattivita`-
attivita` di Sistemi Insaturi Funzionalizzati”) is grate-
fully acknowledged. R.P. thanks CINMPIS (Bari) for a
postgraduate fellowship.
J O048882Y
7308 J . Org. Chem., Vol. 69, No. 21, 2004