A Short, Efficient, and Stereoselective Procedure for the Synthesis of cis-3-Hydroxymethyl-aziridine-2-carboxylic Acid Derivatives, Important Intermediates in the Synthesis of Mitomycinoids

Full text of DOI:10.1021/jo000732+

6780
J . Org. Chem. 2000, 65, 6780-6783
steps (6% yield from L-methionine),5 a synthesis of 1b
A Sh or t, Efficien t, a n d Ster eoselective
has been described more recently in 10 steps (21% yield
from cis-2-butene-1,4-diol), but the final product was not
enantiomerically pure (88% ee).2 Here we present a short
route to the enantiomerically pure aziridines 6 and 7,
hydroxyl-activated analogues of 1a ,6 in only six steps and
47% yield from L-aspartic acid.
Several methods have been described in the literature
for the synthesis of cis-aziridine-2-carboxylic acids.7,8 We
envisioned a straightforward route to 6 and 7 involving
a regioselective cyclization of a suitable 3-amino-1,2-diol
(3), as reported by Perica`s and Riera.9 Aminodiol 3 should
be easily accessible from hydroxyaspartate 2, previously
reported by us and ultimately derived from L-aspartic
acid.10
P r oced u r e for th e Syn th esis of
cis-3-Hyd r oxym eth yl-a zir id in e-2-ca r boxylic
Acid Der iva tives, Im p or ta n t In ter m ed ia tes
in th e Syn th esis of Mitom ycin oid s
Eduardo Ferna´ndez-Meg´ıa, Marco A. Montaos, and
F. J avier Sardina*
Departamento de Quı´mica Orga´nica, Facultad de Quı´mica,
Universidad de Santiago de Compostela,
15706 Santiago de Compostela, Spain
qojskd@usc.es
Received May 15, 2000
Thus, chemoselective reduction of the R-hydroxyester
function in 2 with BH3‚SMe2 in the presence of catalytic
NaBH4, as reported by Moriwake,11 led to the desired diol
3 in 88% yield. Although NaBH4 alone has also been
reported for the selective reduction of R-hydroxyesters,12
it proved to be less satisfactory.13 Treatment of 3 with
excess MsCl or TsCl gave the dimesylated and ditosylated
products 4 and 5 in 97% and 83% yields, respectively.
The mitomycinoid family of natural products (mito-
mycin C, FR-900482, and congeners) has attracted and
retained the attention of the scientific community for a
long time as a result of the high antitumor activity
displayed by its members.1 Mitomycin C is a widely
prescribed antitumor agent with demonstrated clinical
value,1 and other congeners of mitomycin C and FR-
900482 are advancing toward clinical application.1,2 It is
well established that the mitomycinoid’s mode of anti-
tumor action requires a bioreductive activation to provide
an electrophilic mitosene capable to cross link DNA via
alkylation at two electrophilic sites (the aziridine ring
and the carbamoyloxy linkage). It can thus be seen that
mitomycinoids are actually naturally occurring pro-drugs
that must be activated in vivo.3 This extraordinary
antitumor activity along with mitomycinoid’s unique
structural features have attracted the interest of syn-
thetic chemists; several approaches and a few total
syntheses have been published.4 We have been deeply
fascinated by those synthetic programs involving a highly
functionalized four-carbon building block 1. Fragment 1
(4) Total syntheses: (a) Fukuyama, T.; Nakatsubo, F.; Cocuzza, A.
J .; Kishi, Y. Tetrahedron Lett. 1977, 18, 4295. (b) Fukuyama, T.; Yang,
L. J . Am. Chem. Soc. 1987, 109, 7881. (c) Fukuyama, T.; Yang, L. J .
Am. Chem. Soc. 1989, 111, 8303. (d) Fukuyama, T.; Xu, L.; Goto, S. J .
Am. Chem. Soc. 1992, 114, 383. (e) Schkeryantz, J . M.; Danishefsky,
S. J . J . Am. Chem. Soc. 1995, 117, 4722. (f) Katoh, T.; Itoh, E.; Yoshino,
T.; Terashima, S. Tetrahedron 1997, 53, 10229. (g) Yoshino, T.; Nagata,
Y.; Itoh, E.; Hashimoto, M.; Katoh, T.; Terashima, S. Tetrahedron 1997,
53, 10239. (h) Katoh, T.; Nagata, Y.; Yoshino, T.; Nakatani, S.;
Terashima, S. Tetrahedron 1997, 53, 10253.
(5) J ones, R. J .; Rapoport, H. J . Org. Chem. 1990, 55, 1144.
(6) The nucleophilic displacement of an activated derivative of the
hydroxyl group in 1a in the context of mitomycinoids' synthesis has
been reported by Rapoport (ref 5).
(7) (a) Fujisawa, T.; Hayakawa, R.; Shimizu, M. Tetrahedron Lett.
1992, 33, 7903. (b) For a racemic synthesis of 1c (R ) MOM, PG ) Tr,
X ) OEt) involving a lithiated aziridine see: Vedejs, E.; Moss, W. O.
J . Am. Chem. Soc. 1993, 115, 1607. (c) For the synthesis of a trans
analogue of 1 see: Ziegler, F. E.; Belema, M. J . Org. Chem. 1994, 59,
7962. (d) Davis, F. A.; Zhou, P.; Reddy, G. V. J . Org. Chem. 1994, 59,
3243 and references therein. (e) Davis, F. A.; Reddy, G. V.; Liu, H. J .
Am. Chem. Soc. 1995, 117, 3651. (f) Cantrill, A. A.; Hall, L. D.; J arvis,
A. N.; Osborn, H. M. I.; Raphy, J .; Sweeney, J . B. Chem. Commun.
1996, 2631. (g) Dauban, P.; Chiaroni, A.; Riche, C.; Dodd, R. H. J . Org.
Chem. 1996, 61, 2488. (h) McLaren, A. B.; Sweeney, J . B. Org. Lett.
1999, 1, 1339. (i) For a synthesis of N-alkoxy analogues of 1 see:
Hanessian, S.; Cantin, L.-D. Tetrahedron Lett. 2000, 41, 787.
(8) Reviews on aziridine synthesis: (a) Tanner, D. Pure Appl. Chem.
1993, 65, 1319. (b) Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33,
599. (c) Pearson, W. H.; Lian, B. W.; Bergmeier, S. C. In Comprehensive
Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F.
V., Eds.; Elsevier Science Ltd.: New York, 1996; Vol. 1A, p 1. (d)
Osborn, H. M. I.; Sweeney, J . Tetrahedron: Asymmetry 1997, 8, 1693.
(e) Atkinson, R. S. Tetrahedron 1999, 55, 1519.
(9) Poch, M.; Verdaguer, X.; Moyano, A.; Perica`s, M. A.; Riera, A.
Tetrahedron Lett. 1991, 32, 6935.
(10) Diester 2 was synthesised by diastereoselective hydroxylation
of N-Pf-aspartate enolates (60%, three steps from L-aspartic acid) as
described in (a) Ferna´ndez-Meg´ıa, E.; Paz, M. M.; Sardina, F. J . J .
Org. Chem. 1994, 59, 7643. (b) Ferna´ndez-Meg´ıa, E.; Iglesias-Pintos,
J . M.; Sardina, F. J . J . Org. Chem. 1997, 62, 4770. For alternative
methods for the synthesis of hydroxyaspartates see: (c) Hanessian,
S.; Vanasse, B. Can. J . Chem. 1993, 71, 1401 and references therein.
(d) Charvillon, F. B.; Amouroux, R. Synth. Commun. 1997, 27, 395
and references therein. (e) Cardillo, G.; Gentilucci, L.; Tolomelli, A.;
Tomasini, C. Synlett 1999, 1727.
incorporates not only the very sensitive cis-aziridine ring
present in the aliphatic portion of mitomycinoids but also
two of the three stereogenic centers in the target mol-
ecules. Nevertheless, the reported procedures for the
synthesis of 1 are low yielding and time-consuming. Thus,
while Rapoport’s synthesis of aziridine 1a involves 12
(11) Saito, S.; Hasegawa, T.; Inaba, M.; Nishida, R.; Fujii, T.;
Nomizu, S.; Moriwake, T. Chem. Lett. 1984, 1389.
(1) Danishefsky, S. J .; Schkeryantz, J . M. Synlett 1995, 475.
(2) Williams, R. M.; Rollins, S. B.; J udd, T. C. Tetrahedron 2000,
56, 521.
(12) Tsuboi, S.; Furutani, H.; Utaka, M.; Takeda, A. Tetrahedron
Lett. 1987, 28, 2709.
(13) Lower yields of 3 (77%) along with some of the corresponding
triol from overreduction (5%) were obtained.
(3) Rajski, S. R.; Williams, R. M. Chem. Rev. 1998, 98, 2723.
10.1021/jo000732+ CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/09/2000

Notes
J . Org. Chem., Vol. 65, No. 20, 2000 6781
Sch em e 1
Sch em e 2
when dimesylate 10 was subjected to several different
cyclization conditions, azetidine 11 was always found as
the exclusive product (Scheme 2).15 The corresponding
trans-aziridine 12 was never observed, even under those
conditions (THF-Et3N, LiClO4, reflux) most favorable for
the formation of the diastereomeric cis-aziridine 6. Again,
as reported for 6 and 7, no elimination products were
detected in this reaction.
The different outcomes on the cyclization reactions of
4 (and 5) and 10 have been rationalized by inspection of
the Newman projections of the required conforma-
tions involved for the ring closure of each stereoiso-
mer. Thus, the cyclization of 4 (and 5) should proceed
mainly through the staggered conformation to provide
the aziridine 6 (and 7), since the eclipsed conformation
that leads to azetidine 8 has two very unfavorable
interactions (CO2Me-OMs and NHPf-CH2OMs). The ad-
Dimesylate 4 was subjected to the cyclization conditions
summarized in Scheme 1. While treatment of 4 with
THF-Et3N at reflux gave no conversion to cyclized
products (entry 1), the use of DMF as solvent afforded a
4:1 mixture of the desired aziridine 6 and the corre-
sponding azetidine 8 (entry 2).14,15 The introduction of
LiClO4 increased both reactivity and selectivity, and after
careful optimization of conditions, aziridine 6 could be
obtained as the sole reaction product in 91% yield (entry
5). Under identical reaction conditions, ditosylate 5 gave
aziridine 7 exclusively (67% yield).14 No products from
sulfonate elimination reactions were detected.
When the same reaction sequence was applied to the
diastereomeric hydroxyaspartate 9 (also readily available
in three steps from L-aspartic acid),10a dimesylate 10 was
obtained in 70% overall yield.16 However, in stark
contrast with 4 and 5 and other literature precedents,9
dition of LiClO4 favors the formation of the aziridine over
the azetidine, probably by chelation of the Li cation with
both mesylate groups. Although this point has not been
demonstrated, the proposed chelation could explain the
change in selectivity by placing the primary mesylate
away from the trajectory of the nucleophile and therefore
increasing the selectivity of the cyclization through the
staggered conformation. According to this proposal, the
LiClO4 effect increases when the complexing ability of
the solvent decreases (compare entries 3 and 5).
In the case of dimesylate 10, the cyclization to give
aziridine 12 should proceed through the staggered con-
formation. Here, as the nucleophile approaches C3, the
bulky Pf group must eclipse either the CH2OMs or the
carboxymethyl group. These unfavorable interactions
force the cyclization to proceed through the eclipsed
conformation to give azetidine 11. The lower bulkiness
of the diphenylmethyl nitrogen protecting group in the
(14) Aziridines 6 and 7 were characterized according to their 1H and
13C NMR spectroscopic data and by comparison with compound 1a (ref
5). See also ref 8c.
(15) Azetidines 8 and 11 were characterized according to their 1H
and 13C NMR spectroscopic data and by comparison with reported data
in the literature: (a) Dure´ault, A.; Portal, M.; Carreaux, F.; Depezay,
J . C. Tetrahedron 1993, 49, 4201. (b) Blythin, D. J .; Green, M. J .;
Lauzon, M. J . R.; Shue, H.-J . J . Org. Chem. 1994, 59, 6098. (c) De
Kimpe, N. In Comprehensive Heterocyclic Chemistry II; Katritzky, A.
R., Rees, C. W., Scriven, E. F. V., Eds.; Elsevier Science Ltd.: New
York, 1996; Vol. 1B, p 507. For syntheses of azetidine-2-carboxylic acid
derivatives see also: (d) Matsuura, F.; Hamada, Y.; Shioiri, T.
Tetrahedron 1994, 50, 265. (e) Rutjes, F. P. J . T.; Tjen, K. C. M. F.;
Wolf, L. B.; Karstens, W. F. J .; Schoemaker, H. E.; Hiemstra, H. Org.
Lett. 1999, 1, 717. (f) Hanessian, S.; Bernstein, N.; Yang, R.-Y.;
Maguire, R. Bioorg. Med. Chem. Lett. 1999, 9, 1437 and references
therein.
(16) The use of other reducing agents such as NaBH4 or DIBALH
led to the formation of substantial amounts of the corresponding
γ-butyrolactone.

6782 J . Org. Chem., Vol. 65, No. 20, 2000
Notes
Met h yl (2S,3R)-3,4-Dih yd r oxy-2-(9′-p h en ylflu or en -9′-
yla m in o)b u t yr a t e. The same procedure as above was used,
starting from hydroxyaspartate 9 (135 mg, 0.324 mmol). Reac-
tion time was 31 h. The (2S,3R) diol (99 mg, 79%) was obtained
Sch em e 3
as a white foam: [R]20D ) -296.6° (c 1.52, CHCl3); IR (film, cm-1
)
3369, 1729; 1H NMR δ 7.73-7.67 (m, 2H), 7.39-7.14 (m, 11H),
3.68-3.56 (m, 3H), 3.25 (s, 3H), 2.82 (bs, 1H), 2.67 (d, J ) 7.0
Hz, 1H); 13C NMR δ 175.1, 148.4, 148.1, 143.7, 141.2, 140.3,
128.8, 128.6, 128.4, 128.2, 127.5, 127.4, 126.1, 125.9, 124.9, 120.3,
120.1, 72.9, 72.6, 64.0, 58.0, 51.7. Anal. Calcd for C24H23NO4:
C, 74.0; H, 6,0; N, 3.6. Found: C, 73.7; H, 6.3; N, 3.5.
examples reported by Perica`s and Riera could explain the
formation of trans-aziridines there.9
Meth yl (2S,3S)-3,4-Bism eth an osu lfon iloxy-2-(9′-ph en ylflu -
or en -9′-yla m in o)bu tyr a te (4). MsCl (200 µL, 2.571 mmol, 404
mol %) was added to a solution of 3 (247 mg, 0.635 mmol), DMAP
(7.5 mg, 0.063 mmol, 10 mol %), and pyridine (0.309 mL, 3.81
mmol, 600 mol %) in CH2Cl2 (1.35 mL). The resulting solution
was stirred for 12 h at room temperature, and then it was
partitioned between CH2Cl2 (100 mL) and saturated NaHCO3
(100 mL). The aqueous layer was back extracted with CH2Cl2
(75 mL), and the combined organic extracts were washed with
10% aqueous H3PO4 (75 mL) and brine (75 mL), dried (Na2SO4),
and concentrated. The residue was purified by column chroma-
tography (silica gel, EtOAc/hexanes 1/1.8) to give 4 (335 mg, 97%)
as a white foam: [R]20 ) -184.2° (c 1.72, CHCl3); 1H NMR δ
D
7.70 (t, J ) 7.3 Hz, 2H), 7.45-7.18 (m, 11H), 4.78-4.75 (m, 1H),
4.58 (dd, J ) 8.1 Hz, J ) 11.4 Hz, 1H), 4.09 (dd, J ) 3.0 Hz, J
) 11.4 Hz, 1H), 3.38 (s, 3H), 3.32 (d, J ) 9.9 Hz, 1H), 3.00 (s,
3H), 2.98 (s, 3H), 2.80 (dd, J ) 3.1 Hz, J ) 10.0 Hz, 1H); 13C
NMR δ 171.7, 147.8, 147.2, 143.2, 140.9, 140.0, 128.8, 128.7,
128.4, 128.2, 127.5, 127.4, 126.4, 125.9, 125.4, 120.1, 120.0, 79.1,
72.5, 67.7, 55.9, 52.2, 38.5. 37.4; MS (FBA, positive ion) m/z
(relative intensity) 546 ([M + H]+, 3), 241 (100). Anal. Calcd for
C26H27NO8S2: C, 57.2; H, 5.0; N, 2.6. Found: C, 57.3; H, 4.8; N,
2.3.
Meth yl (2S,3R)-3,4-Bism eth a n osu lfon iloxy-2-(9′-p h en yl-
flu or en -9′-yla m in o)bu tyr a te (10). The same procedure as
above was used, starting from the (2S,3R) diol (165 mg, 0.424
mmol). The reaction time was 5 h. Compound 10 (204 mg, 88%)
was obtained as a white foam: [R]20D ) -247.5° (c 0.96, CHCl3);
IR (KBr, cm-1) 1740, 1449, 1349; 1H NMR δ 7.73 (d, J ) 7.6 Hz,
1H), 7.68 (d, J ) 7.5 Hz, 1H), 7.41-7.34 (m, 5H), 7.29-7.23 (m,
5H), 7.15 (d, J ) 7.5 Hz, 1H), 4.78 (ddd, J ) 3.0 Hz, J ) 5.7 Hz,
J ) 7.7 Hz, 1H), 4.60 (dd, J ) 3.0 Hz, J ) 11.5 Hz, 1H), 4.39
(dd, J ) 5.8 Hz, J ) 11.4 Hz, 1H), 3.33 (s, 3H), 3. 20 (d, J ) 10.1
Hz, 1H), 2.97 (s, 3H), 2.93 (s, 3H), 2.87 (dd, J ) 7.8 Hz, J ) 10.1
Hz, 1H); 13C NMR δ 172.8, 147.6, 147.5, 143.3, 141.3, 139.9,
128.8, 128.6, 128.5, 127.7, 127.6, 125.9, 125.8, 125.6, 120.2 (2 ×
C), 79.5, 72.7, 66.8, 55.7, 52.5, 38.7, 37.7; MS (FBA, positive ion)
m/z (relative intensity) 546 ([M + H]+, 0.2), 241 (59), 155 (100).
Anal. Calcd for C26H27NO8S2: C, 57.2; H, 5.0; N, 2.6. Found: C,
57.2; H, 4.9; N, 2.5.
Met h yl (2S,3S)-3,4-Bis-p -t olu en su lfon yloxy-2-(9′-p h en -
ylflu or en -9′-yla m in o)bu tyr a te (5). TsCl (94 mg, 0.49 mmol,
400 mol %) was added to a solution of 3 (48 mg, 0.12 mmol),
DMAP (1.6 mg, 0.012 mmol, 10 mol %), and pyridine (0.06 mL,
3.81 mmol, 600 mol %) in CH2Cl2 (0.3 mL). The resulting solution
was stirred for 10 h at room temperature, then it was partitioned
between CH2Cl2 (25 mL) and 10% aqueous NaOH (25 mL). The
aqueous layer was back extracted with CH2Cl2 (25 mL), and the
combined organic layer was washed with 10% aqueous H3PO4
(25 mL) and brine (25 mL), dried, and concentrated to afford a
residue, which was purified by column chromatography (silica
gel, EtOAc/hexanes 1/2.5) to give 5 as a white solid (71 mg,
83%): mp 175-178 °C; [R]20D ) -76.0° (c 0.83, CHCl3); IR (KBr,
cm-1) 1745, 1348; 1H NMR δ 7.8-7.1 (m, 13H), 4.54 (m, 1H),
4.10 (ddd, J ) 4.1 Hz, J ) 6.9 Hz, J ) 11.3 Hz, 2H), 3.30 (s,
3H), 3.20 (d, J ) 8.4 Hz, 1H), 2.80 (dd, J ) 3.5 Hz, J ) 5.3 Hz,
1H); 13C NMR δ 172.2, 148.4, 147.9, 145.5, 145.4, 144.0, 141.5,
140.4, 133.5, 132.8, 130.3, 130.1, 129.2, 129.1, 128.8, 128.6, 128.5,
128.4, 127.9, 127.8, 126.8, 126.4, 125.7, 120.6, 120.4, 79.6, 73.1,
68.2, 56.3, 52.7, 22.1. Anal. Calcd for C38H35NO8S2: C, 65.4; H,
5.1; N, 2.0. Found: C, 65.3; H, 5.2; N, 2.1.
At this point, there was an important question to
address: the deprotection of the Pf group. Despite the
reported difficulty of the hydrogenolytic deprotection of
N-benzyl aziridines due to easy ring opening,8c,17 the Pf
group in 6 was successfully removed [H2, 50 psi, Pd/C,
(Boc)2O] affording the corresponding N-Boc-aziridine 13
quantitatively (Scheme 3).18
In conclusion, an efficient route to the mesylated and
tosylated N-Pf aziridines 6 and 7 has been described in
three steps from aspartate 2 (six steps from L-aspartic
acid). Under closely related conditions, azetidine 11 was
obtained from aspartate 9. The easy deprotection of the
Pf group in 6 should spread the use of these building
blocks in future synthetic programs directed toward
mitomycinoids.
Exp er im en ta l Section
Gen er a l Meth od s. General experimental aspects have been
published elsewhere.19 N-Phenylfluorenyl-hydroxyaspartates 2
and 9 were prepared according to the published procedure.10
Met h yl (2S,3S)-3,4-Dih yd r oxy-2-(9′-p h en ylflu or en -9′-
yla m in o)bu tyr a te (3). A solution of BH3‚SMe2 in THF (75 µL,
3.3 M, 0.31 mmol, 120 mol %) was added to a solution of
hydroxyaspartate 2 (100 mg, 0.26 mmol) in THF (0.5 mL) at
room temperature. The mixture was stirred for 30 min, and then
NaBH4 (1 mg) was added. Stirring was continued for 46 h, then
MeOH and KH2PO4 were added, and the resulting suspension
was stirred for an additional 30 min. Four such reactions were
pooled, and the mixture was concentrated. The residue was
purified by column chromatography (silica gel, EtOAc/hexanes
1/0.8) to give 3 (331 mg, 88%) as a white foam: [R]20 ) -272.3
D
(c 1.11, CHCl3); 1H NMR δ 7.71-7.68 (m, 2H), 7.38-7.33 (m,
5H), 7.27-7.23 (m, 5H), 7.17 (d, J ) 7.6 Hz, 1H), 3.55-3.49 (m,
2H), 3,34 (dd, J ) 3.2 Hz, J ) 11.2 Hz, 1H), 3.31 (s, 3H), 2.69
(d, J ) 5.8 Hz, 1H); 13C NMR δ 174.1, 147.9, 147.4, 143.3, 141.1,
140.2, 128.8, 128.6, 128.5, 128.3, 127.5, 127.4, 126.5, 125.8, 125.0,
120.2, 120.0, 72.6, 71.5, 63.4, 57.7, 52.0; MS (FBA, positive ion)
m/z (relative intensity) 390 ([M + H]+, 2), 241 (100). Anal. Calcd
for C24H23NO4: C, 74.0; H, 6,0; N, 3.6. Found: C, 73.6; H, 6.2;
N, 3.4.
(17) Ambrosi, H.-D.; Duczek, W.; Ramm, M.; J a¨hnisch, K. Tetrahe-
dron Lett. 1994, 35, 7613.
(18) For the successful deprotection of a N-trityl aziridine-2-car-
boxylate see: Korn, A.; Rudolph-Bo¨hner, S.; Moroder, L. Tetrahedron
1994, 50, 1717.
Meth yl (2S,3R)-3-Meth a n osu lfon yloxym eth yl-1-(9′-p h en -
ylflu or en -9′-yl)a zir id in e Ca r boxyla te (6). A suspension of 4
(137 mg, 0.343 mmol), LiClO4 (365 mg, 3.43 mmol, 1000 mol
%), and s-collidine (100 µL, 0.69 mmol, 200 mol %) in dioxane
(2.3 mL) was stirred at 70 °C for 8 h. The reaction mixture was
(19) Blanco, M.-J .; Sardina, F. J . J . Org. Chem. 1996, 61, 4748.

Notes
J . Org. Chem., Vol. 65, No. 20, 2000 6783
allowed to reach room temperature, and then it was partitioned
between EtOAc (50 mL) and 5% aqueous HCl (50 mL). The
aqueous layer was back extracted with EtOAc (20 mL), and the
combined organic layer was washed with brine (30 mL), dried,
and concentrated. The residue was purified by column chroma-
tography (silica gel, EtOAc/hexanes 1/3) to give 6 (102 mg, 91%)
(25 mL). The aqueous layer was back extracted with EtOAc (10
mL), and the combined organic layer was washed with H2O (3
× 15 mL) and brine (20 mL), dried, and concentrated. The
residue was purified by column chromatography (silica gel,
EtOAc/hexanes 1/2.5) to give 11 (24 mg, 73%) as an oil, which
crystallized on standing: mp 169 °C; [R]20 ) -106.5° (c 0.55,
D
as a white solid: mp 164 °C; [R]20 ) -92.2° (c 1.33, CHCl3); IR
CHCl3); IR (KBr, cm-1) 1747, 1355; H NMR δ 7.77 (d, J ) 7.5
1
D
(KBr, cm-1) 1737, 1348; 1H NMR δ 7.71 (t, J ) 7.5 Hz, 2H), 7.44-
7.12 (m, 11H), 4.31 (dd, J ) 6.3 Hz, J ) 10.8 Hz, 1H), 4.20 (dd,
J ) 5.8 Hz, J ) 10.7 Hz, 1H), 3.73 (s, 3H), 2.81 (s, 3H), 2.54 (d,
J ) 6.2 Hz, 1H), 1.95 (q, J ) 6.1 Hz, 1H); 13C NMR δ 169.3,
147.6, 144.5, 142.2, 141.5, 139.8, 129.3, 128.9, 128.3, 128.1, 127.6,
127.4, 126.8, 126.2, 125.8, 120.3, 120.1, 75.4, 67.3, 52.2, 37.3,
37.2, 37.0. Anal. Calcd for C25H23NO5S: C, 66.8; H, 5.2; N, 3.1.
Found: C, 66.7; H, 5.3; N, 3.1. Azetidine 8 was isolated in small
amounts from reactions in which DMF was used as solvent: mp
Hz, 1H), 7.68 (d, J ) 7.5 Hz, 1H), 7.47-7.16 (m, 11H), 5.07 (q,
J ) 6.2 Hz, 1H), 3.68 (t, J ) 7.3 Hz, 1H), 3.47 (d, J ) 5.5 Hz,
1H), 3.29 (s, 3H), 3.23 (t, J ) 6.9 Hz, 1H), 2.84 (s, 3H); 13C NMR
δ 170.3, 145.4, 144.4, 141.6, 140.5, 140.4, 129.1, 128.9, 128.4,
127.7, 127.6, 127.5, 127.2, 126.7, 126.4, 120.4, 120.1, 75.7, 69.0,
66.6, 53.4, 51.8, 37.7. Anal. Calcd for C25H23NO5S: C, 66.8; H,
5.2; N, 3.1. Found: C, 66.9; H, 5.1; N,3.0.
Met h yl (2S,3R)-3-Met h a n osu lfon yloxym et h yl-1-(ter t-
bu toxyca r bon yl)a zir id in e Ca r boxyla te (13). A suspension
of 6 (63 mg, 0.14 mmol), Boc2O (122 mg, 0.56 mmol, 400 mol
%), and Pd/C (10 w%, 10 mg) in deoxygenated CH3OH (4 mL)
was shaken under a pressure of 50 psi of H2 for 15 h. The
reaction mixture was filtered through a pad of Celite. The filtrate
and the washings were concentrated to a residue, which was
purified by column chromatography (silica gel, EtOAc/hexanes
160 °C; [R]20 ) -103.5° (c 1.20, CHCl3); IR (NaCl, cm-1) 1751,
D
1
1350; H NMR δ 7.76 (d, J ) 7.4 Hz, 1H), 7.63 (d, J ) 7.4 Hz,
1H), 7.53-7,14 (m, 11H), 4.99 (dt, J ) 3.0 Hz, J ) 6.9 Hz, 1H),
3.83-3.75 (m, 2H), 3.69 (d, J ) 7.6 Hz, 1H), 3.45 (s, 3H), 2.96
(s, 3H); 13C NMR δ 168.4, 146.3, 144.8, 142.0, 140.5, 139.6, 129.2,
128.8, 128.5, 127.8, 127.7, 127.6, 127.4, 127.1, 126.2, 120.3, 119.7,
75.5, 69.2, 63.5, 53.9, 51.6, 38.5. Anal. Calcd for C25H23NO5S:
C, 66.8; H, 5.2; N, 3.1. Found: C, 66.4; H, 5.0; N, 3.3.
1/4) to give 13 (41 mg, quant.) an oil: [R]20 ) -122.3° (c 1.32,
D
1
CHCl3); IR (KBr, cm-1) 2935, 1752, 1525; H NMR (2 rotamers
Met h yl
(2S,3R)-3-p -Tolu en su lfon yloxym et h yl-1-(9′-
in a 1/1.8 ratio) δ 4.75 (dd, J ) 6.0 Hz, J ) 11.6 Hz, 1H), 4.29
(dd, J ) 6.6 Hz, J ) 11.6 Hz, 1H), 4.30-4.22 (m, 1 H), 3.74 and
3.64 (s, 3H), 3.00 and 2.97 (s, 3H), 3.17 and 2.60 (d, J ) 6.28, J
) 5.65, 1H), 1.39 and 1.37 (s, 9H); 13C NMR δ 167.5, 159.4, 83.7,
66.3, 53.2, 40.1, 39.0, 38.2, 28.1. Anal. Calcd for C11H19NO7S:
C, 42.7; H, 6.2; N, 4.5. Found: C, 42.6; H, 6.0; N,4.9.
p h en ylflu or en -9′-yl)a zir id in e Ca r boxyla te (7). The same
procedure as above was used, starting from ditosylate 5 (126
mg, 0.138 mmol). Reaction time was 5 h. Compound 7 (64 mg,
67%) was obtained as a white solid: mp 173 °C; [R]20D ) -105.5°
(c 0.55, CHCl3); IR (KBr, cm-1) 1750, 1365; 1H NMR δ 7.47-
7.16 (m, 13H), 4.4 (m, 1H), 4.13 (m, 2H) 3.67 (s, 3H), 2.68 (s,
3H), 2.44 (d, J ) 6.3 Hz, 1H); 13C NMR δ 169.4, 147.6, 145.2,
145.0, 142.6, 141.8, 140.3, 133.3, 130.2, 129.6, 129.4, 128.8, 128.5,
128.3, 128.0, 127.7, 127.2, 126.6, 126.2, 120.6, 120.5, 75.8, 68.2,
52.6, 38.0, 37.8, 30.1, 21.1. Anal. Calcd for C31H27NO5S: C, 70.8;
H, 5.2; N, 2.7. Found: C, 70.6; H, 5.5; N,3.0.
Meth yl (2S,3S)-3-Meth a n osu lfon yloxy-1-(9′-p h en ylflu o-
r en -9′-yl)a zetid in e Ca r boxyla te (11). A solution of dimesylate
10 (40 mg, 0.073 mmol) and Et3N (51 µL, 0,37 mmol, 500 mol
%) in DMF (0.24 mL) was stirred at 110 °C for 7 h. The reaction
mixture was allowed to reach room temperature, and then it
was partitioned between EtOAc (30 mL) and 5% aqueous HCl
Ack n ow led gm en t . Financial support from the
CICYT (Spain, grant SAF99-0127) and the Xunta de
Galicia (grant XUGA 20912B96) is gratefully acknowl-
edged, as well as fellowships from the Xunta de Galicia
and the Universidad de Santiago de Compostela (to
E.F.-M.). We also thank Prof. Rafael Suau (Universidad
de Ma´laga, Spain) for the elemental analyses.
J O000732+