A new route to 3-amino sugars. A concise synthesis of L-daunosamine and D-ristosamine derivatives

Article abstract of DOI:10.1021/jo970576f

An asymmetric aldol strategy has been developed for the synthesis of L- daunosamine and D-ristosamine derivatives starting from noncarbohydrate precursors. Lithium and boron enolate mediated aldol reactions of 12 with O- TBS lactaldehyde gave non-Evans syn and Evans syn aldol products, respectively, with high selectivity. The chemical efficiency of the lithium enolate reactions were higher than the corresponding reactions with the boron enolates. Curtius rearrangement of lactone acids 23 and 26 gave the corresponding N-BOC amino lactones 30 and 32 in 64% and 62%, respectively, with complete retention of configuration. Lactone 30 was converted by a two- step sequence to N-benzoyldaunosamide 40. The overall yield for the amino sugar 40 was 18% over six steps. Similary, lactone 32 was converted to N- benzoylristosamide 42 with an overall yield of 18% starting from 12.

Full text of DOI:10.1021/jo970576f

5864
J . Org. Chem. 1997, 62, 5864-5872
A New Rou te to 3-Am in o Su ga r s. A Con cise Syn th esis of
L-Da u n osa m in e a n d D-Ristosa m in e Der iva tives
Mukund P. Sibi,* J ianliang Lu, and J essica Edwards1
Department of Chemistry, North Dakota State University, Fargo, North Dakota 58105-5516
Received March 31, 1997X
An asymmetric aldol strategy has been developed for the synthesis of L-daunosamine and
D-ristosamine derivatives starting from noncarbohydrate precursors. Lithium and boron enolate
mediated aldol reactions of 12 with O-TBS lactaldehyde gave non-Evans syn and Evans syn aldol
products, respectively, with high selectivity. The chemical efficiency of the lithium enolate reactions
were higher than the corresponding reactions with the boron enolates. Curtius rearrangement of
lactone acids 23 and 26 gave the corresponding N-BOC amino lactones 30 and 32 in 64% and 62%,
respectively, with complete retention of configuration. Lactone 30 was converted by a two-step
sequence to N-benzoyldaunosamide 40. The overall yield for the amino sugar 40 was 18% over six
steps. Similarly, lactone 32 was converted to N-benzoylristosamide 42 with an overall yield of
18% starting from 12.
In tr od u ction
A number of clinically important anthracycline anti-
biotics contain a 3-aminohexose unit as part of their
structure. L-Daunosamine2 (1, 3-amino-2,3,6-trideoxy-L-
lyxo-hexose) is the glycosidic component of naturally
occurring anthracyclines daunomycin (2a ), adriamycin
(2b), and carminomycin (2c) (Figure 1).3 L-Acosamine
(3, 3-amino-2,3,6-trideoxy-L-arabino-hexose) was isolated
from the antibiotic actinoidin,4 and L-ristosamine (4,
3-amino-2,3,6-trideoxy-L-ribo-hexose) is a component of
glycoprotein ristomycin.5 The anthracycline antibiotics
have attracted attention because of their bioactivity
against a wide range of experimental and human tu-
mors.6 Adriamycin7 exhibits impressive activity against
solid tumors, especially toward soft tissues and bone
sarcomas. Additionally, daunomycin, adriamycin, and
their analogs have shown a strong effect on HIV-reverse
transcriptase,8 although their activity against HIV-
infected human cells has been rather limited.9 The
relative stereochemistry of the functional groups in
natural and unnatural amino sugars has a large impact
on the activity profile of the anthracycline antibiotics,10
especially with regards to the suppression of toxic side
effects.11
F igu r e 1.
Since their discovery in the 1960s, the amino sugar
components of anthracyclines have been popular targets
in the synthetic community. Numerous racemic12 and
asymmetric syntheses13,14 of daunosamine, ristosamine15-17
along with their fluoro18 and branched19 analogs have
been reported in the literature. Critical to the develop-
ment of new methods for the synthesis of 3-amino sugars
is the control of the relative as well as the absolute
stereochemistry of the amino alcohol functions at the C-3
and C-4 positions. Traditionally, approaches to 3- amino
sugars have relied on naturally occurring D- and L-
carbohydrates as starting materials. Recently, more
X Abstract published in Advance ACS Abstracts, August 1, 1997.
(1) Summer undergraduate research participant.
(2) (a) Arcamone, F.; Franceschi, G.; Orezzi, P.; Cassinelli, G.;
Barbieri, W.; Mondelli, R. J . Am. Chem. Soc. 1964, 86, 5334. (b)
Arcamone, F.; Cassinelli, G.; Franceschi, G.; Orezzi, P.; Barbieri, W.;
Mondelli, R. J . Am. Chem. Soc. 1964, 86, 5335.
(3) (a) Arcamone, F. Topics in Antibiotic Chemistry; Wiley: New
York, 1978; Vol. 2, pp 88-229. (b) Terashima, S. Yuki Gosei Kagaku
Kyokai Shi 1982, 40, 20.
(10) El Khadem, H. S. Anthracycline Antibiotics; Academic: New
York, 1982.
(11) (a) Arcamone, F.; Penco, S.; Vigevani, A.; Redaelli, S.; Tranchi,
G.; Di Marco, A.; Casazza, A. M.; Dasdia, T.; Formelli, F.; Necco, A.;
Coranzo, S. J . Med. Chem. 1975, 18, 703. (b) Arcamone, F. Med. Res.
Rev. 1984, 4, 153. (b) Arcamone, F.; Bargiotti, A.; Cassinelli, G.; Penco,
S. Carbohydr. Res. 1976, 46, C3.
(4) (a) Lomakina, N. N.; Spiridonova, I. A.; Sheinker, Y. N.; Vlasova,
T. F. Khim. Prir., Soedin. 1973, 9, 101; Chem. Abstr. 1973, 78,
148170m. (b) Spiridonova, I. A.; Yurina, M. S.; Lomakina, N, N.;
Sztaricskai, F.; Bognar, F. Antibiotiki 1976, 21, 304; Chem. Abstr. 1976,
85, 108925z.
(5) Gauze, G. F.; Kudrina, E. S.; Ukholina, R. S.; Gavrilina, G. V.
Antibiotiki 1963, 8, 387; Chem. Abstr. 1965, 62, 5843e.
(6) (a) Carter, S. K. J . Natl. Cancer Inst. 1975, 55, 1265. (b)
Skovsgaard, T.; Nissen, N. I. Dan. Ned. Bull. 1975, 22, 62.
(7) Arcamone, F.; Franceschi, G.; Ponco, S. Tetrahedron Lett. 1969,
1007.
(8) (a) Nakashima, H.; Yamamoto, N.; Inouye, Y.; Nakamura, S. J .
Antibiot. 1987, 40, 396. (b) Ajito, K.; Atsumi, S.; Ikeda, D.; Kondo, S.;
Takeuchi, T.; Umezawa, K. J . Antibiot. 1989, 42, 611.
(9) De Clereq, E.; Van Aerschot, A.; Herdewijn, P.; Baba, M.;
Pauwels, R.; Balkzarini, J . Nucleosides Nucleotides 1989, 8, 659.
(12) For a review on 3-amino sugars see: Hauser, F. M.; Ellenberger,
S. R. Chem. Rev. 1986, 86, 35. Racemic synthesis of daunosamine and
derivatives: (a) Dyong, I.; Weimann, R. Angew. Chem., Int. Ed. Engl.
1978, 17, 682. (b) DeShong, P.; Dicken, C. M.; Leginus, J . M.; Whitte,
R. R. J . Am. Chem. Soc. 1984, 106, 5598. (c) Iwataki, I.; Nakamura,
Y.; Takahashi, K.; Matsumoto, T. Bull. Chem. Soc. J pn. 1979, 52, 2731.
(d) Danishefsky, S. J .; Maring, C. J . J . Am. Chem. Soc. 1985, 107, 1269.
(e) Wong, C. M.; Ho, T.-L.; Niemczura, W. P. Can. J . Chem. 1975, 63,
3144. (f) Warm, A.; Vogel, P. Tetrahedron Lett. 1985, 26, 5127. (g)
DeShong, P.; Leginus, J . M. J . Am. Chem. Soc. 1983, 105, 1686. (h)
Sammes, P. G.; Thetford, D. J . Chem. Soc., Chem. Commun. 1985,
352. (i) Hauser, F. M.; Rhee, R. P. J . Org. Chem. 1981, 46, 227. (j)
Hirama, M.; Shigemoto, T.; Ito, S. Tetrahedron Lett. 1985, 26, 4137.
(k) Roush, W. R.; Straub, J . A.; Brown, R. J . J . Org. Chem. 1987, 52,
5127. (l) Hauser, F. M.; Ellenberger, S. R.; Glusker, J . P.; Smart, C.
J .; Carrell, H. L. J . Org. Chem. 1986, 51, 50.
S0022-3263(97)00576-8 CCC: $14.00 © 1997 American Chemical Society

A New Route to 3-Amino Sugars
J . Org. Chem., Vol. 62, No. 17, 1997 5865
Sch em e 1
attention has been focused on developing new methods
starting from noncarbohydrate precursors. We have been
exploring the diastereoselective aldol reactions of desym-
metrized succinates in the context of natural product
synthesis.20 The aldol reaction of desymmetrized succi-
nates in conjunction with the Curtius rearrangement
seemed an attractive method for the installation of the
amino functionality in 3-amino sugars. Our synthetic
strategy is shown retrosynthetically in Scheme 1 using
daunosamine as an example.
The key features of our synthetic strategy are (1) the
regio- and diastereoselective syn aldol reaction of a
desymmetrized chiral succinate with an O-protected
lactaldehyde (9 + 10 to 8) and (2) the Curtius rearrange-
ment of the acid 7 with retention of configuration to an
advanced intermediate 6. Further adjustments in the
oxidation state of 6 leads to the target amino sugar. The
generality of the methodology can be gleaned by the ease
with which one can control the relative as well as the
absolute stereochemistry of the aldol products by a simple
change of the auxiliary and by the nature of the metal
used for enolate generation. Additionally other amino
sugars such as D-ristosamine (5), the C-5 epimer of
daunosamine, can also be prepared using the same
methodology by using the (R)-O-protected lactaldehyde.
As can be seen from the disconnection, high degree of
stereoselection in aldol and Curtius reactions are es-
sential for a successful execution of our strategy.
(13) Asymmetric synthesis of L-daunosamine and derivatives: (a)
Horton, D.; Weckerle, W. Carbohydr. Res. 1975, 44, 227. (b) Kimura,
Y.; Matsumoto, T.; Suzuki, M.; Terashima, S. Bull. Chem. Soc. J pn.
1986, 59, 663. (c) Hiyama, T.; Kobayashi, K.; Nishide, K. Bull. Chem.
Soc. J pn. 1987, 60, 2127. (d) Abbaci, B.; Florent, J .-C.; Monneret, C.
Bull. Soc. Chim. Fr. 1989, 667. (e) Yamaguchi, T.; Kojima, M.
Carbohydr. Res. 1977, 59 , 343. (f) Gurjar, M. K.; Patil, V. J .; Yadav,
J . S.; Rao, A. V. R. Carbohydr. Res. 1984, 129, 267. (g) Hiyama, T.;
Nishide, K.; Kobayashi, K. Chem. Lett. 1984, 361. (h) Brimacombe, J .
S.; Hanna, R.; Tucker, L. C. N. Carbohydr. Res. 1985, 136, 419. (i)
Fuganti, C.; Grasselli, P.; Pedrocchi-Fantoni, G. J . Org. Chem. 1983,
48, 909. (j) Dyong, I.; Wiemann, R. Chem. Ber. 1980, 113, 2666. (k)
Dyong, I.; Friege, H.; zu Hone, T. Chem. Ber. 1982, 115, 256. (l)
Mukaiyama, T.; Goto, Y.; Shoda, S. Chem. Lett. 1983, 671. (m) Kita,
Y.; Itoh, F.; Tamura, O.; Ke, Y. Y.; Mike, T.; Tamura, Y. Chem. Pharm.
Bull. 1989, 37, 1446. (n) Nagumo, S.; Umezawa, I.; Akiyama, J .; Akita,
H. Chem. Pharm. Bull. 1995, 43, 171. (o) Pauls, H. W.; Fraser-Reid,
B. Carbohydr. Res. 1986, 150, 111. (p) Crugnola, A.; Lombardi, P.;
Gandolfi, C.; Arcamone, F. Gazz. Chim. Ital. 1981, 111. (q) Hamada,
Y.; Kawai, A.; Shioiri, T. Tetrahedron Lett. 1984, 25, 5409. (r) Gurjar,
M. K.; Yadav, J . S.; Rao, A. V. R. Indian J . Chem., Sect. B 1983, 22B,
1139. (s) Wovkulich, P. M.; Uskokovic, M. R. J . Am. Chem. Soc. 1981,
103, 3956. (t) Hirama, M.; Ito, S. Heterocycles 1989, 28, 1229. (u)
Monneret, C.; Gagnet, R.; Florent, J . C. J . Carbohydr. Chem. 1987, 6,
221. (v) Marsh, J . P.; Mosher, C. W.; Acton, E. M.; Goodman, L. J .
Chem. Soc., Chem. Commun. 1967, 973. (w) Iida, H.; Yamazaki, N.;
Kibayashi, C. J . Org. Chem. 1986, 51, 4245. (x) Fronza, G.; Fuganti,
C.; Grasselli, P. J . Chem. Soc., Chem. Commun. 1980, 442. (y) Gurjar,
M. K.; Pawar, S. M.; Mainkar, P. S. J . Carbohydr. Chem. 1989, 8, 785.
(z) Pauls, H. W.; Fraser-Reid, B. J . Chem. Soc., Chem. Commun. 1983,
1031. (aa) Hirama, M.; Nishizaki, I.; Shigemoto, T.; Ito, S. J . Chem.
Soc., Chem. Commun. 1986, 393. (bb) Hauser, F. M.; Rhee, R. P.;
Ellenberger, S. R. J . Org. Chem. 1984, 49, 2236. (cc) Sammes, P. G.;
Thetford, D. J . Chem. Soc., Perkin Trans. 1 1988, 111. (dd) Grethe,
G.; Mitt, T.; Williams, T. H.; Uskokovic, M. R. J . Org. Chem. 1983, 48,
5309. (ee) Grethe, G.; Sereno, J .; Williams, T. H.; Uskokovic, M. R. J .
Org. Chem. 1983, 48, 5315. (ff) Hatanaka, M.; Ueda, I. Chem. Lett.
1991, 61. (gg) Cardillo, G.; Orena, M.; Sandri, S.; Tomasini, C. J . Org.
Chem. 1984, 49, 3951. (hh) Servi, S. J . Org. Chem. 1985, 50, 5865. (ii)
Hanessian, S.; Kloss, J . Tetrahedron Lett. 1985, 26, 1261. (jj) St-Denis,
Y.; Lavallee, J .-F.; Nguyen, D.; Attardo, G. Synlett 1995, 272. (kk)
Herczegh, P.; Zsely, M.; Kovacs, I.; Batte, G.; Sztaricskai, F. J .
Tetrahedron Lett. 1990, 31, 1195. (ll) Czernecki, S.; Georgoulis, C.;
Stevens, C. L. Vijayakumaran, K. Synth. Commun. 1986, 16, 11. (mm)
Warm, A.; Vogel, P. J . Org. Chem. 1986, 51, 5348. (nn) Gallucci, J . C.;
Ha, D.-C.; Hart, D. J . Tetrahedron 1989, 45, 1283. (oo) Hamada, Y.;
Kawai, A.; Matsui, T.; Hara, O.; Shioiri, T. Tetrahedron 1990, 46, 4823.
(pp) Davies, S. G.; Smyth, G. D. Tetrahedron: Asymmetry 1996, 7,
1273. (qq) Fuganti, C.; Grasselli, P.; Pedrocchi-Fantoni, G. Tetrahedron
Lett. 1981, 22, 4017. (rr) J urczak, J .; Kozak, J .; Golebiowski, A.
Tetrahedron 1992, 48, 4231. (ss) Picq, D.; Carret, G.; Anker, D.; Abou-
Assali, M. Tetrahedron Lett. 1985, 26, 1863. (tt) Gurjar, M. K.; Pawar,
S. M. Tetrahedron Lett. 1987, 28, 1327. (uu) Kita, Y.; Itoh, F.; Tamura,
O.; Ke, Y. Y. Tetrahedron Lett. 1987, 28, 1431. (vv) Ha, D.-C.; Hart,
D. J . Tetrahedron Lett. 1987, 28, 4489. (ww) Dai, L.-X.; Lou, B.-L.;
Zhang, Y.-Z. J . Am. Chem. Soc. 1988, 110, 5195. (xx) Kolar, C.; Dehmel,
K.; Moldenhauer, H.; Gerken, M.; J . Carbohydr. Chem. 1990, 9, 873.
(yy) Medgyes, G.; Kuszmann, J . Carbohydr. Res. 1981, 92, 225.
(14) Synthesis of D-daunosamine and derivatives: (a) Baer, H. H.;
Capek, K.; Cook, M. C. Can. J . Chem. 1969, 47, 89. (b) Richardson, A.
C. J . Chem. Soc., Chem. Commun. 1965, 627. (c) Po, S.-Y.; Uang, B.-J .
Tetrahedron: Asymmetry 1994, 5, 1869. (d) Stewart, A. O.; Williams,
R. M. Carbohydr. Res. 1984, 135, 167. (e) Richardson, A. C. Carbohydr.
Res. 1967, 4, 422.
Resu lts a n d Discu ssion
Our synthesis starts with the attachment of the C-4
succinate side chain to the chiral auxiliary. Deprotona-
tion of the auxiliary21 11 with n-BuLi at -78 °C followed
by acylation with 3-carbomethoxypropionyl chloride fur-
nished the desymmetrized succinate 12 in excellent yield
(16) Synthesis of L-ristosamine and derivatives: (a) Lau, J .; Ped-
ersen, E. B.; Nielsen, C. M. Acta Chim. Scand. 1991, 45, 616. (b) Boivin,
J .; Monneret, M. C. Carbohydr. Res. 1980, 79, 193. (c) Heyns, K.;
Feldmann, J .; Hadamczyk, D.; Schwentner, J .; Thiem, J . Chem. Ber.
1981, 114, 232. (d) Pauls, H. W.; Fraser-Reid, B. J . Org. Chem. 1983,
48, 1392. (e) Pelyvas, I.; Sztaricskai, F.; Bognar, R. Carbohydr. Res.
1979, 76, 257. (f) Thiem, J .; Springer, D. Carbohydr. Res. 1985, 136,
325. (g) Suami, T.; Tadano, K.-I.; Suga, A.; Ueno, Y. J . Carbohydr.
Chem. 1984, 3, 429. (h) Brimacombe, J . S.; Hanna, R.; Saeed, M. S.;
Tucker, L. C. N. J . Chem. Soc., Perkin Trans. 1 1982, 2583. (i) Boivin,
J .; Pais, M.; Monneret, C. Carbohydr. Res. 1978, 64, 271. (j) Lee, W.
W.; Wu, H. Y.; Marsh, J . J ., J r.; Mosher, C. W.; Acton, E. M.; Goodman,
L.; Henry, D. W. J . Med. Chem. 1975, 18, 767. (k) Fronza, G.; Fuganti,
C.; Grasselli, P. Tetrahedron Lett. 1980, 21, 2999. (l) Hirama, M.;
Shigemoto, T.; Ito, S. J . Org. Chem. 1987, 52, 3342. (m) Walczak, K.;
Lau, J .; Pedersen, E. B. Synthesis 1993, 790. (n) Bongini, A.; Cardillo,
G.; Orena, M.; Sandri, S.; Tomasini, C. Tetrahedron 1983, 39, 3801.
(o) Heyns, K.; Lim, M.-J .; Park, J ., I. Tetrahedron Lett. 1976, 1477. (p)
Kovacs, I.; Herczegh, P.; Sztaricskai, J . Tetrahedron 1991, 47, 7837.
(q) Sztaricskai, F.; Pelyvas, I. Bognar, R. Tetrahedron Lett. 1975, 1111.
(r) Refs 13i, o, t, cc, ii, oo.
(17) Synthesis of D-ristosamine and derivatives: (a) Horton, D.;
Weckerle, W. Carbohydr. Res. 1976, 46, 227. (b) Baer, H. H.; Georges,
F. F. Z. Carbohydr. Res. 1977, 55, 253. (c) Horton, D.; Nickol, R. G.;
Weckerle, W.; Winter-Mihaly, E. Carbohydr. Res. 1979, 76, 269. (d)
Hamada, Y.; Kawai, A.; Matsui, T.; Hara, O.; Shioiri, T. Tetrahedron
1990, 46, 4823. (e) Pelyvas, I.; Sztaricskai, F.; Bognar, R. Carbohydr.
Res. 1979, 68, 321. (e) Pelyvas, I.; Sztaricskai, F.; Bognar, R. Carbo-
hydr. Res. 1977, 53, C17.
(18) (a) Baptistella, L. H. B. B.; Marsaioli, A. J . Carbohydr. Res.
1985, 140, 51. (b) Baer, H. H.; Mateo, F. H.; Siemsen, L. Carbohydr.
Res. 1990, 195, 225.
(19) Gonzalez, F. S.; Berenguel, A. V.; Mateo, F. H.; Mendoza, P.
G.; Baer, H. H. Carbohydr. Res. 1992, 237, 145.
(20) (a) Sibi, M. P.; Deshpande, P. K.; La Loggia, A. J . Synlett 1996,
343. (b) Sibi, M. P.; J i, J . Angew. Chem., Int. Ed. Engl. 1997, 37, 274.
(21) Synthesis: Sibi, M. P.; Deshpande, P. K.; La Loggia, A. J .;
Christensen, J . W. Tetrahedron Lett. 1995, 36, 8961. Applications: (a)
Sibi, M. P.; Deshpande, P. K.; J i, J . Tetrahedron Lett. 1995, 36, 8965.
(b) Sibi, M. P.; J asperse, C. P.; J i, J . J . Am Chem. Soc. 1995, 117, 10779.
(c) Sibi, M. P.; J i, J . Angew. Chem., Int. Ed. Engl. 1996, 36, 190.
(15) Racemic synthesis: (a) Heathcock, C. H.; Montgomery, S. H.
Tetrahedron Lett. 1983, 24, 4637. (b) Hirama, M.; Shigemoto, T.;
Yamazaki, Y.; Ito, S. Tetrahedron Lett. 1985, 26, 4133. (c) Refs. 12k, l.

5866 J . Org. Chem., Vol. 62, No. 17, 1997
Sibi et al.
Sch em e 2
Sch em e 3
starting material. The aldol products were formed with
high syn selectivity. Additionally, the aldol products from
the two different aldehydes behaved differently with
regard to the lactonization process. The aldol adduct 14
from (S)-O-TBS-lactaldehyde 13 possessing a (2R,3R,4S)-
configuration underwent cyclization to form 15 during
silica gel chromatography. In contrast, the aldol adduct
18 derived from (R)-O-TBS-lactaldehyde 17 possessing
the (2R,3R,4R)-configuration was obtained as an insepa-
rable mixture with the lactone 19. Complete lactoniza-
tion of this substrate was accomplished with a catalyst
(PPTS) by heating the reaction to 60-65 °C. The slower
lactonization rate associated with this all syn configura-
tion aldol adduct 18 is presumably because of steric
reasons. A similar observation was also made in our
previous work.26 The chiral auxiliary was easily removed
(>90% yield) from the lactones by hydrolysis22 using
LiOH/H2O2. The absolute stereochemistry of the aldol
adducts and lactones were assigned based on their
conversion to natural products of known configuration
(vide infra).
The low chemical yield in the boron-mediated aldol
condensation led us to examine reactions with the more
reactive lithium enolates.27 We were delighted to find
that the lithium enolate mediated aldol condensation
gave a satisfactory chemical yield as well as high dias-
tereoselectivity (Scheme 3). Treatment of a THF solution
of 12 with LHMDS at -78 °C furnished the lithium
enolate which was immediately reacted with a freshly
prepared (S)- or (R)-O-TBS-lactaldehyde solution. The
aldol reactions were highly syn selective with the absolute
stereochemistry (non-Evans syn) opposite to that ob-
tained from the boron-mediated aldol reaction (Evans
syn). The aldol adduct 24 resulting from reaction be-
tween 12 and the (R)-O-TBS-lactaldehyde 17 underwent
(Scheme 2). With the appropriate substrate in hand, our
attention was directed toward the boron-mediated asym-
metric aldol condensation reaction using the protocol
developed by Evans.22 Key to the success of the aldol
strategy was obtaining high levels of regio- and diaste-
reoselectivities. Thus, deprotonation and subsequent
enolate formation has to take place on the R-carbon of
the imide carbonyl rather than the ester function to
ensure high regioselectivity.23 Support for this mode of
reactivity comes from literature precedents24 as well as
work from our laboratory.20a The boron enolate was
generated by treating a CH2Cl2 solution of 12 with freshly
prepared dibutylboron triflate at 0 °C, followed by the
addition of triethylamine. A solution of freshly prepared
aldehyde was added slowly at -78 °C, and the reaction
was allowed to warm to rt over 24 h. To our surprise,
the aldol reaction using either (S)- or (R)-O-TBS lactal-
dehyde25 was sluggish. A rather moderate chemical yield
(∼30%) was obtained in either case with recovery of the
(22) Evans, D. A.; Nelson, J . V.; Taber, T. R. J . Am. Chem. Soc. 1981,
103, 3099.
(23) For boron enolate aldol reactions of esters see: Akibo, A.; Liu,
J .-F.; Masamune, S. J . Org. Chem. 1996, 61, 2590.
(24) (a) Evans, D. A.; Bilodeau, M. T.; Somers, T. C.; Clardy, J .;
Cherry, D.; Kato, Y. J . Org. Chem. 1991, 56, 5750. (b) Oppolzer, W.;
Cintas-Moreno, P.; Tamura, O. Helv. Chim. Acta 1993, 76, 187.
(25) The aldehydes were prepared according to literature proce-
dures: (S)-O-TBS-lactaldehyde: (a) Cainelli, G.; Giacomini, D.; Mez-
zina, E.; Panunzio, M.; Zarantonello, P. Tetrahedron Lett. 1991, 32,
2967. (b) Ito, Y.; Kobayashi, Y.; Kawabata, T.; Takase, M; Terashima,
S. Tetrahedron 1989, 45, 5767. (c) Massad, S. K.; Hawkins, L. D.;
Baker, D. C. J . Org. Chem. 1983, 48, 5180. (R)-O-TBS-lactaldehyde:
Wakabayashi, S.; Ogawa, H.; Ueno, N.; Kunieda, N.; Mandai, T.;
Nokami, J . Chem. Lett. 1987, 875.
(26) Sibi, M. P.; Lu, J .; Talbacka, C. J . Org. Chem. 1996, 61, 7848.
(27) (a) Evans, D. A.; Ennis, M. D.; Mathre, D. J . J . Am. Chem. Soc.
1982, 104, 1737. (b) Bartroli, J .; Turmo, E.; Belloc, J .; Forn, J . J . Org.
Chem. 1995, 60, 3000.

A New Route to 3-Amino Sugars
J . Org. Chem., Vol. 62, No. 17, 1997 5867
lactonization easily providing the product 25 in an
isolated yield of 68%. A minor diastereomer 19 was also
isolated in 5% yield, along with the unreacted starting
material (6%) and cleaved chiral auxiliary (14%). The
isolation of ca. 14% of chiral auxiliary from lithium aldol
reaction was bothersome since it lowered the overall
chemical yield and made the chromatographic purifica-
tion difficult. Examples of chiral auxiliary cleavage
during enolate formation have been reported in the
literature.28 A set of control experiments were conducted
to evaluate the thermal stability of the lithium enolate
derived from compound 12. The enolate was generated
at -78 °C according to the standard protocol and then
stirred at two different temperatures for 10 min before
it was quenched. The extent of decomposition was
readily accessed by 1H-NMR integration of relevant
protons in the starting material 12 and auxiliary 11. At
-78 °C, only 3% cleavage was detected. While at 0 °C,
significant amounts of auxiliary (21%) was observed.
Other amide bases were also tested in the aldol reactions.
LDA gave similar result as LHMDS, whereas NaHMDS
gave the cleaved chiral auxiliary 11 (65%) as the major
product. Thus aldol reactions with 12 were conducted
at -78 °C using LHMDS as the base.
In contrast, the lithium aldol gave a non-Evans syn
product as a major compound along with a minor anti
isomer. The diastereoselectivity observed in our work
can be explained by using a three-point chelated chair
transition state postulated by Pridgen31 and thus account
for the non-Evans syn selectivity in the case of strongly
coordinating enolate counterion (e.g. Li+, Zn2+, Sn4+).
The next key step in our synthesis was the preparation
of the amino lactones using the Curtius rearrangement.32
A procedure33 utilizing ethyl chloroformate and sodium
azide failed to produce any amine product starting from
either 23 or 27. Only a mixed anhydride 27 was detected
by NMR and IR (1784, 1720, 1697 cm-1) analysis (eq 1).
Apparently, acyl azide 28 was not formed through azide
displacement which may be explained by the low solubil-
ity of the substrate and/or the azide.
Aldol reaction of 12 with the (S)-O-TBS lactaldehyde
13 gave an inseparable mixture of adduct 21 and the
corresponding lactone 22. Additionally, a minor diaste-
reomer 15 (5%), recovered starting material (8%), and
cleaved chiral auxiliary in 15% yield were also obtained
from the reaction. Treatment of the mixture of 21 and
22 with PPTS in THF at 60-65 °C gave the desired
lactone 22 in 61% yield. A new compound was also
detected on TLC analysis of the PPTS-catalyzed lacton-
ization reaction. This new compound was separated in
3% yield. 1H-NMR, 13C-NMR, and elemental analysis
indicated that it was another isomer of the lactone. A
Diphenylphosphoryl azide (DPPA) has been estab-
lished as a reagent of choice for the preparation of acyl
azides from carboxylic acids.34 As has been established
in the literature, the conversion of an acid to the
corresponding amino compound requires refluxing an
equimolar mixture of the carboxylic acid, DPPA, and
triethylamine in the presence of an alcohol (eq 2). When
23 was first refluxed with triethylamine and DPPA for
1 h and then with t-BuOH for 12 h, a consistent 32%
chemical yield of 30 was obtained along with significant
amounts of carbamoyl azide 31.35
large coupling constant for C3-H and C4-H (3J H
) 8.9
3,H4
Hz) suggested a cis relationship and the compound was
tentatively assigned the (3S,4R) configuration.29
The lactones 22 and 25 were hydrolyzed using the
same procedure as before to acids 23 and 26, respectively,
in high yields. Compounds 16 and 26 exhibited identical
1H- and 13C-NMR spectra and opposite optical rotation
indicating that they are enantiomeric. Compound 20 and
23 also displayed the same behavior and were enanti-
omers to each other as well. The assignment of syn vs
anti stereochemistry in aldol reactions was supported by
1H-NMR analysis of the lactone products and was further
corroborated by the absolute configuration of the target
natural products. The observed opposite facial selectivi-
ties of boron and lithium enolate aldol reactions is
precedented in the work of Pridgen et al.30 In their work,
the boron-mediated aldol reaction of an R-(halomethyl)-
N-acylimides furnished the Evans syn adduct exclusively.
(28) (a) D’Souza, A. A.; Motevalli, M.; Robinson, A. J .; Wyatt, P. B.
J . Chem. Soc., Perkin Trans 1 1995, 1. (b) Reference 27b.
We found that the formation of carbamoyl azide 31 was
(29) This minor isomer most likely arises from an anti aldol product.
The absolute stereochemistry of the product is unknown at the present
time. mp 65-67 °C; Rf 0.15 (65:35 hexane:ethyl acetate); 1H NMR (400
MHz, CDCl3) δ 0.01 (s, 3H), 0.03 (s, 3H), 0.61 (d, J ) 6.6 Hz, 3H), 0.88
(s, 9H), 2.45 (dd, J ) 17.7, 9.1 Hz, 1H), 3.28 (dd, J ) 17.7, 10.5 Hz,
1H), 3.71 (dq, J ) 6.6, 2.0 Hz, 1H), 4.19 (ddd, J ) 10.5, 9.1, 8.9 Hz,
1H), 4.33 (dd, J ) 9.5, 8.6 Hz, 1H), 4.48 (dd, J ) 9.5, 2.8 Hz, 1H), 4.78
(d, J ) 6.7 Hz, 1H), 4.97 (dd, J ) 8.9, 2.0 Hz, 1H), 5.24 (ddd, J ) 8.6,
6.7, 2.8 Hz, 1H), 7.19-7.35 (m, 10H); 13C NMR (100 MHz, CDCl3) δ
175.1, 168.3, 153.9, 139.5, 138.3, 129.4, 128.9, 128.8, 128.5, 128.0, 127.5,
83.9, 69.4, 66.2, 58.4, 52.6, 42.9, 32.1, 25.8, 18.0, 17.5, -4.5, -4.6; IR
(CH2Cl2) 3082, 1793, 1701 cm-1; [R]25D ) -52.5° (c 1.00, CH2Cl2). Anal.
calcd for C29H37NO6Si: C, 66.51; H, 7.12; N, 2.67. Found: C, 66.13; H,
6.74; N, 2.72.
significantly suppressed when the reaction was carried
(30) (a) Abdel-Magid, A. F.; Lantos, I.; Pridgen, L. N. Tetrahedron
Lett. 1984, 25, 3273. (b) Abdel-Magid, A. F.; Pridgen, L. N.; Eggelston,
D. S.; Lantos, I. J . Am. Chem. Soc. 1986, 108, 4595.
(31) Pridgen, L. N.; Abdel-Magid, A. F.; Lantos, I.; Shilcrat, S.;
Eggleston, D. S. J . Org. Chem. 1993, 58, 5107.
(32) (a) Buchler, C. A.; Pearson, D. E. Survey of Organic Synthesis;
Wiley-Interscience: New York, 1970; pp 494-503. (b) Smith, P. A. S.
Org. React. 1946, 3, 337.
(33) (a) Wienstock, J . J . Org. Chem. 1961, 26, 3511. (b) Overman,
L. E.; Taylor, G. F.; Petty, C. B.; J essup, P. J . J . Org. Chem. 1978, 43,
2164.

5868 J . Org. Chem., Vol. 62, No. 17, 1997
Sibi et al.
Sch em e 4
Sch em e 5
out in a mixed solvent with equal amounts of toluene and
t-BuOH at an elevated temperature (120 °C). The
chemical yield of the desired amino lactone 30 increased
dramatically to over 60%, besides the chromatographic
purification was also much easier. Thus, a solution of
23 or 26 in toluene and t-BuOH was treated with Et3N
at room temperature and then immediately heated to
reflux in a preheated oil bath at 120 °C. DPPA was then
added. The yellow solution was maintained at reflux for
an additional 12 h period. After removal of solvent and
subsequent silica gel column purification, the carbamates
30 and 32 were isolated in 64% and 62% yields, respec-
tively (eq 3).
that signals for a minor isomer (identity unknown) was
also observed in the NMR spectrum of 35. The H NMR
and analytical data for 35 was in excellent agreement
with that reported in the literature.37 Thus, a seven-step
total synthesis of L-methyl R-daunosamine hydrochloride
was accomplished in 14% overall yield.
1
A parallel synthesis of D-ristosamine derivative was
also carried out (Scheme 5). Thus, TBAF deprotection
of 32 followed by DIBALH reduction yielded 37 in 57%
yield as a complex mixture. Methanolic HCl treatment
did not produce a solid as expected, rather a mixture of
hydrochloride salts was isolated as a syrup. Although
DL-methyl R-ristosamine hydrochloride13cc and L-R-ris-
tosamine hydrochloride16n have been described as white
solids in the literature, there is still confusion about the
exact physical nature of ristosamine and its hydrochlo-
ride salt because of their extreme hygroscopic nature.38
To confirm the structure of the compounds from our
synthesis, the hydrochloride salt was reacted with ben-
zoyl chloride to form the known D-methyl N-benzoyl-
R-ristosamide (38)17b in 49% isolated yield. Therefore,
an eight-step synthesis of D-methyl N-benzoyl-R-ristosa-
mide (38) was achieved in 7.8% yield. Three other
isomers were also isolated during the conversion of 37
to 38 in 38% chemical yield with an isomeric ratio of
1:1.8:1.9. Analysis of the proton and carbon NMR indi-
cated that these were furanose and pyranose isomers of
the parent ristosamide.39
With the key amino lactone intermediates 30 and 32
at hand, the synthesis of L-daunosamine (Scheme 4) and
D-ristosamine derivatives (Scheme 5) was completed as
described below. Desilylation of 30 with TBAF at room
temperature furnished the known hydroxy lactone 33.13pp
The γ-lactone to δ-lactone isomerization36 has been
observed in several cases. The rate of this isomerization
was slow, and if chromatographic purification was con-
ducted immediately after the reaction, a clean γ-lactone
33 could be obtained. However, the presence of small
amount of δ-lactone isomer did not interfere with further
transformations.
The amino alcohol 33 has been converted to L-methyl
R-daunosamine hydrochloride (35) by Davies and Smyth
in two steps in an overall yield of 36%.13pp We were able
to make marginal improvement in the chemical yield for
these two steps (overall 44%). Thus, the hydroxy lactone
33 was reduced by DIBALH in THF at -78 °C to give
the lactol 34 as a complex mixture in 56% yield. Small
amounts of the starting material and over-reduction
product were also formed. Hauser et al.13bb encountered
similar problems in their approach to duanosamine. The
over-reduction and sluggish lactone reduction were at-
tributed to the low solubility of the substrate. Etherifi-
cation of the mixture of lactols 34 in methanolic hydrogen
chloride gave 35 in 79% yield. It is of interest to note
To improve the overall yield in the conversion of the
lactones 30 and 32 to the target amino sugars, an
alternate reduction and deprotection sequence was de-
vised. The DIBALH reduction of 30 gave the lactol 39
in 67% yield as a mixture of anomers in the ratio of 2.9/1
(Scheme 6). The double deprotection of the O-TBS and
N-BOC groups in 39 was carried out by trifluoroacetic
acid to yield the trifluoroacetate salt of daunosamine.
Without purification, this salt was converted to the
benzoate using BzCl to afford the L-N-benzoyl-daunosa-
mide 40 as a mixture of anomeric pyranosides and
furanosides, mp 146-149 °C, [R]25D ) -87.8 to -61.5° (c
0.50, EtOH), (lit.13i mp 152 °C, [R]25 ) -108° (c 0.50,
D
EtOH)). The ratios of isomers are pyranose/furanose )
3.4:1, and R-pyranose/â-pyranose ) 1.1:1.40 Thus, a six-
step total synthesis of L-N-benzoyldaunosamide (40) was
achieved in 18% overall yield.
(34) (a) Shioiri, T.; Ninomiya, K.; Yamada, S.-I. J . Am. Chem. Soc.
1972, 94, 6203. (b) Ninomiya, K.; Yamada, S. Tetrahedron 1974, 30,
2151.
(35) (a) Shioiri, T.; Yamada, S. Chem. Pharm. Bull. Tokyo 1974, 23,
855. (b) Csuk, R.; Schabel, M. J .; Scholz, Y. V. Tetrahedron: Asymmetry
1996, 7, 3505.
(37) Arcamone, F.; Cassinelli, G.; Franrecchi, G.; Mondelli, R.;
Orezzi, P.; Penco, S. Gazz. Chim. Ital. 1970, 100, 949.
(38) (a) Boganr, R.; Sztaricskai, F.; Munk, M. E.; Tamas, J . J . Org.
Chem. 1974, 39, 2971. (b) Reference 16j.
(39) The identity of each isomer was not established.
(40) Fronza, G.; Fuganti, C.; Grasselli, P. J . Chem. Soc., Perkin
Trans 1 1982, 885.
(36) References 13g, m, bb, ii, uu.

A New Route to 3-Amino Sugars
J . Org. Chem., Vol. 62, No. 17, 1997 5869
Sch em e 6
overall yields for these two amino sugars were 18% and
18%, respectively. Lithium- and boron-mediated aldol
reactions were examined, and the former was found to
be more effective in terms of chemical efficiency. The two
reactions provided products of opposite absolute stereo-
chemistry. An experimental modification of the Curtius
procedure was developed for the installation of the amino
functionality. The aldol-Curtius protocol developed in
this work is amenable to the synthesis of other amino
sugars such as acosamine and tolyposamine41 when
appropriate anti aldol condensation reaction conditions
are employed. Work along these lines is underway.
Sch em e 7
Exp er im en ta l Section
For general experimental procedures see ref 42. (-)-(R)-
3-(1-Oxo-3-ca r bom eth oxyp r op yl)-4-(d ip h en ylm eth yl)ox-
a zolid in -2-on e (12). To a flame-dried 250 mL three-necked
flask was added a solution of (R)-4-(diphenylmethyl)oxazolidin-
2-one (11) (6.64 g, 26.25 mmol) dissolved in freshly distilled
THF (80 mL) under N2. The solution was cooled to -78 °C in
a dry ice/acetone bath. n-BuLi (1.6 M, 17.2 mL, 27.6 mmol)
was added in a dropwise fashion via syringe over a period of
10 min at -78 °C. This red solution was further stirred at
-78 °C for 10 min. 3-Carbomethoxypropionyl chloride (3.4 mL,
27.6 mmol) was added slowly over 5 min. The light yellow
solution was stirred at -78 °C for 15 min and at 0 °C for 30
min. The reaction was quenched with saturated NH4Cl (30
mL) at 0 °C. The solvent was evaporated under reduced
pressure, and the residue was extracted with CH2Cl2 (3 × 30
mL). The combined organic layers were washed successively
with H2O (40 mL) and brine (40 mL) and dried with anhydrous
MgSO4 and filtered. Evaporation of solvent resulted in a
yellow oil. Purification of the crude compound by flash column
chromatography (eluted with 20% EtOAc in hexane) gave a
white solid (9.44 g, 25.72 mmol, 98%): mp 80-82 °C; Rf 0.60
(50:50 hexane:ethyl acetate); 1H NMR (400 MHz, CDCl3) δ 2.59
(t, J ) 6.3 Hz, 2H), 3.05-3.13 (m, 1H), 3.17-3.25 (m, 1H),
3.70 (s, 3H), 4.41 (dd, J ) 9.2, 2.9 Hz, 1H), 4.46 (dd, J ) 9.2,
7.3 Hz, 1H), 4.70 (d, J ) 5.4 Hz, 1H), 5.30 (ddd, J ) 7.3, 5.4,
2.9 Hz, 1H), 7.07-7.36(m, 10H); 13C NMR (100 MHz, CDCl3)
δ 173.4, 172.2, 153.8, 139.8, 138.2, 129.6, 129.2, 128.9, 128.6,
128.2, 127.3, 65.0, 56.1, 51.7, 50.3, 30.4, 27.6; IR (CDCl3) 1784,
1737, 1703 cm-1; [R]25D ) -145.3° (c 1.00, CH2Cl2). Anal. Calcd
for C21H21NO5: C, 68.65; H, 5.76; N, 3.81. Found: C, 68.42;
H, 5.95; N, 4.07.
Gen er a l P r oced u r e for th e Bor on -Med ia ted Ald ol
Con d en sa tion of 12 w ith 2-[[(1,1-Dim eth yleth yl)d im eth -
ylsilyl]oxy]p r op a n a l. To a flame-dried two necked 25 mL
flask under N2 was added 12 (0.507 g, 1.38 mmol) in CH2Cl2
(3 mL) and cooled to 0 °C in an ice bath. 1.0 M Dibutylboron
triflate solution in CH2Cl2 (1.52 mL, 1.52 mmol) was added
slowly over a period of 5 min, and the resultant brownish
solution was stirred for another 5 min. Freshly distilled
triethylamine (0.24 mL, 1.79 mmol) was then added dropwise
while maintaining the temperature at 0 °C. The pale yellow
solution was stirred at 0 °C from 45 min to 1 h. The boron
enolate solution was then cooled to -78 °C. Freshly prepared
(R)- or (S)-O-TBS-lactaldehyde (0.389 g, 2.07 mmol) in 1.5 mL
of CH2Cl2 was added dropwise over 10 min. The reaction
mixture was warmed gradually to 0 °C over a period of 24 h.
The progress of the reaction was monitored by TLC. The
reaction was quenched slowly by the addition of pH ) 7 buffer
(1.0 mL), MeOH (1.5 mL), and MeOH/30% H2O2 ) 2/1 (1.5 mL).
The cloudy mixture was stirred at 0 °C for 1 h. The aqueous
layer was separated and extracted with CH2Cl2 (4 × 5 mL).
The combined extracts were dried over Na2SO4 and filtered,
A similar transformation starting with lactone 32 gave
D-N-benzoyl ristosamide (42) as an anomeric mixture in
18% overall yield over 6 steps from 12 (Scheme 7). The
ratios for furanoside/pyranoside are 1.7/1, and R-fura-
nose/â-furanose ) 1.2/1, mp 103-107 °C, [R]25 ) 43.8
D
to 41.2° (c 1.00, EtOH), (lit.17a mp 128-129 °C, [R]23
)
D
13.5° (c 1.00, EtOH), and lit.17b mp 135-137 °C, [R] )
15.6 to 9.8° (c 1.00, EtOH)).
It has been reported that the N-benzoyl derivatives 40
and 42 (Scheme 6, 7) exist in solution as R- and â-ano-
mers of furanosides and pyranosides.40 In particular,
L-N-benzoyldaunosamide (40) exists as an R-pyranose
(100%), while L-N-benzoyl ristosamide (42) exists as a
mixture of R- and â-furanose anomers in a ratio of R/â )
57/43. In our synthesis we obtained a mixture of fura-
nose and pyranose anomers for both amino sugars 40 and
42. This observation most likely is a result of our
reaction conditions. The benzoylated sugars 40 and 42
were liberated from double deprotection of the corre-
sponding lactones by a strong acid, TFA. Furthermore,
when the pure R-pyranoside 38 was demethylated by
refluxing in HOAc/H2O as described in literature,17a,b 42
was produced as a mixture of four isomers. The isomer
composition from this experiment was identical to the
one obtained from the conversion of 41 to 42. It is known
that acid promotes anomerization; in some cases a base
can be added to the reaction to prevent anomerization
from trace amounts of free acid.14a Therefore, the dif-
ferences in physical properties of the target compounds
from our synthesis and those from the literature can be
rationalized by the presence of different isomeric ratios.
Nevertheless, NMR data for the major isomers were in
excellent agreement with that reported in the literature.
Satisfactory elemental analyses were also obtained for
40 and 42.
(41) Guanti, G.; Banfi, L.; Narisano, E.; Riva, R. Tetrahedron Lett.
1992, 33, 2221.
Con clu sion
(42) 1H and 13C NMR were recorded on J EOL-GSX instruments. IR
spectra were recorded on a Mattson Instruments, 2020 Galaxy series
FT-IR spectrophotometer. Optical rotations were recorded on a J ASCO-
DIP-370 instrument. For typical experimental protocols, see: Gaboury,
J . A.; Sibi, M. P. J . Org. Chem. 1993, 58, 2173.
An asymmetric aldol strategy has been developed for
the synthesis of L-daunosamine and D-ristosamine de-
rivatives starting from noncarbohydrate precursors. The

5870 J . Org. Chem., Vol. 62, No. 17, 1997
Sibi et al.
and the solvent was evaporated to dryness under reduced
pressure. Flash chromatography furnished pure aldol product
and the recovered starting material.
by flash chromatography, eluted with 20% EtOAc in hexane,
afforded 22 (9.7330 g, 18.61 mmol, 61%) along with a minor
lactone29 (0.4112 g, 0.7862 mmol, 3%): mp 172-174 °C; Rf 0.52
(65:35 hexane:ethyl acetate); 1H NMR (400 MHz, CDCl3) δ 0.04
(s, 3H), 0.06 (s, 3H), 0.08 (s, 9H), 1.09 (d, J ) 6.4 Hz, 3H),
2.72 (dd, J ) 17.4, 9.0 Hz, 1H), 2.80 (dd, J ) 17.4, 3.0 Hz,
1H), 3.49 (dd, J ) 1.8, 1.5 Hz, 1H), 4.02 (dq, J ) 6.4, 1.5 Hz,
1H), 4.06 (ddd, J ) 9.0, 3.0, 1.8 Hz, 1H), 4.41 (dd, J ) 9.7, 8.6,
Hz, 1H), 4.48 (dd, J ) 9.7, 3.1 Hz, 1H), 4.82 (d, J ) 6.8 Hz,
1H), 5.32 (ddd, J ) 8.6, 6.8, 3.1 Hz, 1H), 7.11-7.42 (m, 10H);
13C NMR (100 MHz, CDCl3) δ 176.1, 171.7, 153.5, 138.9, 137.5,
129.4, 129.3, 129.0, 128.3, 128.2, 127.4, 84.9, 70.2, 65.7, 56.7,
51.0, 42.6, 30.3, 25.8, 20.0, 17.9, -4.5, -4.7; IR (CH2Cl2) 1807,
(-)-(3R,4R,5R)-3-[[(R)-N-[2-oxo-4-(d ip h en ylm eth yl)ox-
a zolid in yl]]ca r b on yl]-4-h yd r oxy-5-[[(1,1-d im et h ylet h -
yl)d im eth ylsilyl]oxy]h exa n oic Acid γ-La cton e (19). The
general procedure described above was used. 12 (0.550 g, 1.5
mmol) was reacted with (R)-O-TBS-lactaldehyde 17 which gave
an inseparable mixture of the aldol adduct and lactone. This
mixture was subjected to PPTS-catalyzed (15 mg) cyclization
with THF as a solvent at 60-65 °C for 12 h. Purification by
chromatography gave 19 (0.1860 g, 0.3356 mmol, 22%, 2 steps)
as a white foam; Rf 0.52 (65:35 hexane:ethyl acetate); 1H NMR
(400 MHz, CDCl3) δ 0.04 (s, 3H), 0.05 (s, 3H), 0.85 (s, 9H),
1.18 (d, J ) 6.3 Hz, 3H), 2.02 (dd, J ) 18.0, 5.5 Hz, 1H), 2.76
(dd, J ) 18.0, 10.3 Hz, 1H), 4.00 (dq, J ) 6.3, 2.7 Hz, 1H),
4.16 (ddd, J ) 10.3, 5.5, 4.2 Hz, 1H), 4.36-4.42 (m, 2H), 4.59-
4.64 (m, 2H), 5.33 (ddd, J ) 7.4, 6.3, 4.4 Hz, 1H), 7.11-7.39
(m, 10H); 13C NMR (100 MHz, CDCl3) δ 174.9, 171.1, 153.2,
139.0, 137.7, 129.3, 129.1, 128.8, 128.6, 128.3, 127.5, 83.3, 69.4,
66.1, 56.7, 52.0, 41.3, 32.5, 25.8, 19.1, 17.9, -4.5, -4.9; IR
(CDCl3) 1782, 1703 cm-1; [R]25D ) -45.1° (c 1.00, CH2Cl2). Anal.
Calcd for C29H37NO6Si: C, 66.51; H,7.12; N, 2.67. Found: C,
66.47; H, 7.13; N, 2.74.
1687 cm-1; [R]25 ) -54.7° (c 1.00, CH2Cl2). Anal. Calcd for
D
C29H37NO6Si: C, 66.51; H, 7.12; N, 2.67. Found: C, 66.67; H,
7.26; N, 2.65.
(-)-(3S,4S,5R)-3-[[(R)-N-[2-Oxo-4-(d ip h en ylm eth yl)ox-
a zolid in yl]]ca r bon yl]-5-[[(1,1-d im eth yleth yl)d im eth ylsi-
lyl]oxy]h exa n oic Acid γ-La cton e (25). Lithium-mediated
aldol condensation of 12 (4.13 g, 11.247 mmol) with (R)-O-TBS
lactaldehyde 17 gave 25 (4.0 g, 7.648 mmol, 68%), 19 (0.2739
g, 0.5238 mmol, 5%), starting material 12 (0.2519 g, 6.1%),
and cleaved chiral auxiliary 11 (0.3927 g, 1.552 mmol, 14%):
mp 132-134 °C; Rf 0.45 (65:35 hexane:ethyl acetate); 1H NMR
(400 MHz, CDCl3) δ 0.03 (s, 3H), 0.06 (s, 3H), 0.09 (s, 9H),
0.97 (d, J ) 6.4 Hz, 3H), 2.40 (dd, J ) 18.0, 3.8 Hz, 1H), 2.91
(dd, J ) 18.0, 10.5 Hz, 1H), 4.02 (dq, J ) 6.4, 2.2 Hz, 1H),
4.16 (dd, J ) 2.6, 2.2 Hz, 1H), 4.38-4.42 (m, 2H), 4.51 (ddd, J
) 10.5, 3.8, 2.6 Hz, 1H), 4.67 (d, J ) 7.1 Hz, 1H), 5.31-5.39
(m, 1H), 7.10-7.39 (m, 10H); 13C NMR (100 MHz, CDCl3) δ
175.1, 153.1, 139.1, 137.9, 129.3, 129.1, 128.9, 84.3, 68.8, 65.7,
56.6, 51.7, 38.1, 33.3, 25.8, 19.0, 17.9, -4.8, -4.9; IR (CH2Cl2)
1799, 1682 cm-1; [R]25D ) -42.9° (c 1.00, CH2Cl2). Anal. Calcd
for C29H37NO6Si: C, 66.51; H, 7.12; N, 2.67. Found: C, 66.32;
H, 7.13; N, 2.57.
Gen er a l P r oced u r e for th e Hyd r olysis of Rem ovin g
th e Ch ir a l Au xilia r y. To a 250 mL round bottom flask was
placed 25 (4.0 g, 7.648 mmol) in 75 mL of THF/H2O ) 4/1
under N2. The solution was cooled to 0 °C in an ice bath. 30%
H2O2 (3.2 mL) was added dropwise over 10 min to the solution,
followed by the addition of LiOH (0.30 g) in H2O (15 mL) in
10 min. The temperature of the reaction was maintained at
0 °C. The mixture was stirred at 0 °C for 1 h. A solution of
Na2SO3 (3.8 g) in H2O (23 mL) was added. The organic solvent
was removed in vacuo. The remaining aqueous mixture was
extracted with CH2Cl2 (4 × 40 mL) to remove the chiral
auxiliary. The organic layers were dried with anhydrous
Na2SO4, and solvent was evaporated to give recovered auxil-
iary 12 (1.8382 g, 7.266 mmol, 95%). The aqueous solution
was cooled to 0 °C and neutralized with 6 M HCl carefully to
pH ) 3-4. This cloudy mixture was extracted with EtOAc (5
× 40 mL). The combined organic layers were dried with
anhydrous Na2SO4. Evaporation of the solvent to dryness
furnished a clear oil 26 (2.07 g, 7.189 mmol, 94%).
(-)-(3R,4R,5S)-3-[[(R)-N-[2-Oxo-4-(d ip h en ylm eth yl)ox-
a zolid in yl]]ca r b on yl]-4-h yd r oxy-5-[[(1,1-d im et h ylet h -
yl)d im eth ylsilyl]oxy]h exa n oic Acid γ-La cton e (15). Aldol
condensation of 12 (0.507 g, 1.38 mmol) with (S)-O-TBS-
lactaldehyde gave 15 (0.2352 g, 0.4497 mmol, 33%) as a white
1
foam: mp 49-51 °C; Rf 0.70 (50:50 hexane:ethyl acetate); H
NMR (400 MHz, CDCl3) δ 0.02 (s, 3H), 0.04 (s, 3H), 0.83 (s,
9H), 1.07 (d, J ) 6.3 Hz, 3H), 1.80 (dd, J ) 18.2, 6.4 Hz, 1H),
2.86 (dd, J ) 18.2, 11.0 Hz, 1H), 4.02 (dq, J ) 6.3, 3.3 Hz,
1H), 4.28 (ddd, J ) 11.0, 6.4, 4.4 Hz, 1H), 4.34-4.42 (m, 2H),
4.67 (d, J ) 7.5 Hz, 1H), 4.76 (dd, J ) 4.4, 3.3 Hz, 1H), 5.33
(ddd, J ) 7.5, 4.8, 2.4 Hz, 1H), 7.10-7.40 (m, 10H); 13C NMR
(100 MHz, CDCl3) δ 173.4, 171.3, 153.0, 138.9, 137.7, 129.4,
129.1, 128.9, 83.1, 68.8, 66.0, 56.6, 51.9, 39.5, 33.4, 25.7, 19.7,
17.9, -4.5, -4.9; IR (CDCl3) 1782, 1703 cm-1; [R]25 ) -62.1°
D
(c 1.00, CH2Cl2). Anal. Calcd for C29H37NO6Si: C, 66.51; H,
7.12; N, 2.67. Found: C, 66.45; H, 6.93; N, 2.62.
(-)-(3S,4S,5S)-3-[[(R)-N-[2-Oxo-4-(d ip h en ylm eth yl)ox-
a zolid in yl]]ca r b on yl]-4-h yd r oxy-5-[[(1,1-d im et h ylet h -
yl)d im eth ylsilyl]oxy]h exa n oic Acid γ-La cton e (22). In a
flame dried three-necked 250 mL round bottom flask under
N2 was placed 12 (11.19 g, 30.51 mmol). THF (60 mL) was
added, and it was stirred at rt to form a clear solution. The
solution was then cooled to -78 °C in a dry ice/2-propanol bath.
A solution of LHMDS (5.36 g, 32.04 mmol) in THF (30 mL)
was added against the glass wall of the flask at a rate of 0.81
mL/min by a syringe pump. The resultant yellow solution was
further stirred at -78 °C for 10 min. A solution of (S)-O-TBS-
lactaldehyde 13 (8.60 g, 45.77 mmol) in THF (10 mL) was
added at a rate of 0.57 mL/min by a syringe pump. The
reaction was further stirred at -78 °C for 10 min. (TLC
analysis indicated completion of the reaction). The reaction
was quenched subsequently with HOAc (1.7 mL) and saturated
NH4Cl (10 mL) at -78 °C. It was further stirred at -78 °C
for 10 min and warmed to rt. The bulk of the solvent was
removed in vacuo. The mixture was partitioned between
CH2Cl2 (100 mL) and H2O (100 mL). The aqueous layer was
extracted with CH2Cl2 (2 × 50 mL). The combined organic
layers were washed with 10% citric acid (2 x 50 mL), H2O (100
mL), and brine (100 mL) and dried with anhydrous Na2SO4.
The solvent was evaporated. Purification of the crude product
by flash chromatography, eluting with a solvent gradient from
15% to 40% EtOAc in hexane, gave a 4.7/1 mixture of lactone
and aldol adduct (10.97 g), along with 15 (0.7793 g, 1.49 mmol,
5%), starting material 12 (0.8995 g, 8.0%), and cleaved chiral
auxiliary 11 (1.1205 g, 4.42 mmol, 15%). The lactone and aldol
adduct mixture (10.97 g) was dissolved in THF (50 mL) with
PPTS (1.0 g), and the solution was refluxed for 18 h. At this
point, TLC analysis indicated lactone cyclization was com-
pleted, but a new compound in a small amount appeared. The
reaction mixture was filtered through a pad of silica gel, and
the solvent was evaporated. Purification of the crude mixture
(+)-(3R,4R,5S)-3-Ca r boxyl-4-h yd r oxy-5-[[(1,1-d im eth yl-
eth yl)d im eth ylsilyl]oxy]h exa n oic Acid γ-La cton e (16).
Following the general hydrolysis procedure, 15 (0.3517 g, 0.67
mmol) gave 16 (0.1762 g, 0.62 mmol, 92%) as a clear oil: Rf
0.36 (ethyl acetate); 1H NMR (400 MHz, CDCl3) δ 0.04 (s, 3H),
0.07 (s, 3H), 0.85 (s, 9H), 1.18 (d, J ) 6.4 Hz, 3H), 2.75 (dd, J
) 18.1, 10.5 Hz, 1H), 2.87 (dd, J ) 18.1, 5.3 Hz, 1H), 3.44 (ddd,
J ) 10.5, 5.3, 3.9 Hz, 1H), 4.13 (dq, J ) 6.4, 2.4 Hz, 1H), 4.58
(dd, J ) 3.9, 2.4 Hz, 1H), 9.26 (b, 1H); 13C NMR (100 MHz,
CDCl3) δ 177.8, 175.2, 84.9, 68.9, 38.2, 31.7, 31.0, 25.8, 19.3,
17.9, -4.7, -4.9; IR (neat) 3500-3200, 1780, 1720 cm-1; [R]25
D
) 17.8° (c 1.00, CH2Cl2). Anal. Calcd for C13H24O5Si: C, 54.14;
H, 8.39. Found: C, 54.54; H, 8.11.
(-)-(3S,4S,5R)-3-Ca r boxyl-4-h yd r oxy-5-[[(1,1-d im eth yl-
eth yl)d im eth ylsilyl]oxy]h exa n oic Acid γ-La cton e (26).
Using the general hydrolysis procedure, 25 (4.0 g, 7.648 mmol)
gave 26 (2.07 g, 7.189 mmol, 94%) as a clear oil, which was
the enantiomer of 16; [R]25 ) -17.6° (c 1.00, CH2Cl2). Anal.
D
Calcd for C13H24O5Si: C, 54.14; H, 8.39. Found: C, 53.99; H,
8.03.
(-)-(3R,4R,5R)-3-Ca r boxyl-4-h yd r oxy-5-[[(1,1-d im eth -
yleth yl)d im eth ylsilyl]oxy]Hexa n oic Acid γ-La cton e (20).

A New Route to 3-Amino Sugars
J . Org. Chem., Vol. 62, No. 17, 1997 5871
Using the general hydrolysis procedure, 19 (0.186 g, 0.3556
mmol) gave 20 (0.0952 g, 0.3307 mmol, 93%) as a clear oil: Rf
0.52 (ethyl acetate); 1H NMR (400 MHz, CDCl3) δ 0.08 (s, 3H),
0.09 (s, 3H), 0.87 (s, 9H), 1.25 (d, J ) 6.4 Hz, 3H), 2.81 (dd, J
) 18.1, 10.1 Hz, 1H), 2.88 (dd, J ) 18.1, 6.5 Hz, 1H), 3.32 (ddd,
J ) 10.1, 6.5, 5.0 Hz, 1H), 4.03 (dq, J ) 6.4, 2.6 Hz, 1H), 4.59
(dd, J ) 5.0, 2.6 Hz, 1H), 9.10 (b, 1H); 13C NMR (100 MHz,
CDCl3) δ 177.3, 175.1, 84.3, 69.2, 41.4, 31.5, 25.8, 19.3, 18.0,
d ih yd r oxyh exa n oic Acid γ-La cton e (33). Deprotection of
30 (1.12g, 3.14 mmol) gave 33 (0.6847 g, 2.79 mmol, 89%) as
a white solid: mp 105-107 °C; Rf 0.27 (50:50 hexane:ethyl
acetate); 1H NMR (400 MHz, CDCl3) δ 1.30 (d, J ) 6.4 Hz,
3H), 1.49 (s, 9H), 2.43 (dd, J ) 18.2, 5.0 Hz, 1H), 2.75 (bs,
1H), 2.99 (dd, J ) 18.2, 8.8 Hz, 1H), 3.98 (m, 1H), 4.20 (dd, J
) 3.9, 3.1 Hz, 1H), 4.33 (m, 1H), 5.18 (d, J ) 5.1 Hz, 1H); 13
C
NMR (100 MHz, CDCl3) δ 175.6, 155.4, 89.2, 80.6, 67.7, 49.4,
-4.2, -4.8; IR (neat) 3477-3036, 1774, 1720 cm-1; [R]25
)
35.5, 28.5, 19.2; IR (neat) 3580-3200 (br), 1780, 1693 cm-1
;
D
-6.7° (c 1.00, CH2Cl2). Anal. Calcd for C13H24O5Si: C, 54.14;
H, 8.39. Found: C, 54.25; H, 8.01.
[R]25 ) 8.6° (c 1.00, CH2Cl2). Anal. Calcd for C11H19NO5: C,
D
53.87; H, 7.81; N, 5.71. Found: C, 53.92; H, 7.56; N, 5.54.
(-)-(3S,4S,5R)-3-[N-(ter t-Bu tyloxyca r bon yl)a m in o[-4,5-
d ih yd r oxyh exa n oic Acid γ-La cton e (36). Using the pro-
cedure for O-TBS deprotection, 32 (0.7752 g, 2.17 mmol) gave
36 (0.4507 g, 1.84 mmol, 85%) as a white solid: mp 108-110
(+)-(3S,4S,5S)-3-Ca r boxyl-4-h yd r oxy-5-[[(1,1-d im eth yl-
eth yl)d im eth ylsilyl]oxy]Hexa n oic Acid γ-La cton e (23).
Using the general hydrolysis procedure, 22 (0.9858 g, 1.88
mmol) gave 23 (0.5128 g, 1.79 mmol, 95%) as a clear oil, which
was enantiomer of 20: [R]25 ) 6.9° (c 1.00, CH2Cl2). Anal.
°C; Rf 0.26 (50:50 hexane:ethyl acetate); H NMR (400 MHz,
1
D
Calcd for C13H24O5Si: C, 54.14; H, 8.39. Found: C, 53.84; H,
8.07.
CDCl3) δ 1.31 (d, J ) 7.2 Hz, 3H), 1.44 (s, 9H), 2.45 (dd, J )
18.2, 5.9 Hz, 1H), 2.82 (bs, 1H), 3.00 (dd, J ) 18.2, 8.8 Hz,
1H), 3.93-4.05 (m, 1H), 4.11-4.17 (m, 1H), 4.32-4.43 (m, 1H),
4.91 (d, J ) 7.1 Hz, 1H,); 13C NMR (100 MHz, CDCl3) δ 174.6,
155.5, 89.0, 81.0, 68.2, 48.6, 35.7, 28.4, 19.0; IR (neat) 3600-
Gen er a l P r oced u r e for th e Cu r tiu s Rea r r a n gem en t.
To a flame-dried two-necked 25 mL round bottom flask,
equipped with a condenser, was placed 26 (1.00 g, 3.49 mmol)
in 8 mL of toluene (dry) and 8 mL of t-BuOH (dried over Na)
under N2. Freshly distilled triethylamine (0.56 mL, 4.02
mmol) was added dropwise with fast stirring at rt over 5 min.
This solution was immediately heated to reflux in a preheated
oil bath at 120 °C. DPPA (0.83 mL, 3.84 mmol) was then
added dropwise in 2 min. The resultant yellow solution was
maintained at reflux for 12 h. The solvent was removed in
vacuo. Purification of the crude product by flash chromatog-
raphy (elution with 10-15% EtOAc) yielded 32 as a colorless
oil (0.7752 g, 2.17 mmol, 62%).
(+)-(3S,4S,5S)-3-[N-(ter t-Bu t yloxyca r b on yl)a m in o]-4-
h y d r o x y -5-[[(1,1-d im e t h y le t h y l)d im e t h y ls ily l]o x y ]-
h exa n oic Acid γ-La cton e (30). Following the general Cur-
tius rearrangement procedure, 23 (0.1004 g, 0.351 mmol) gave
30 (0.0802 g, 0.2246 mmol, 64%) as a colorless oil: Rf 0.35
(65:35 hexane:ethyl acetate); 1H NMR (400 MHz, CDCl3) δ 0.08
(s, 3H), 0.09 (s, 3H), 0.86 (s, 9H), 1.23 (d, J ) 6.3 Hz, 3H),
1.43 (s, 9H), 2.28 (dd, J ) 16.7, 1.9 Hz, 1H), 2.99 (dd, J )
16.7, 8.6 Hz, 1H), 4.05-4.14 (m, 1H), 4.14-4.26 (m, 2H), 4.91
(d, J ) 5.0 Hz, 1H); 1H NMR (400 MHz, C6D6) δ -0.08 (s, 3H),
-0.02 (s, 3H), 0.85 (s, 9H), 1,00 (d, J ) 6.4 Hz, 3H), 1.39 (s,
9H), 1.79 (dd, J ) 18.1, 2.5 Hz, 1H), 2.67 (dd, J ) 18.1, 9.1
Hz, 1H), 3.77 (dq, J ) 6.4, 1.3 Hz, 1H), 3.89 (dd, J ) 1.3, 1.3
Hz, 1H), 4.10 (dddd, J ) 9.1, 6.7, 2.5, 1.3 Hz, 1H), 4.39 (d, J )
6.9 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 175.6, 155.2, 89.9,
80.5, 69.3, 50.1, 35.8, 28.4, 25.9, 19.8, 18.0, -4.2, -4.7; 13C
NMR (100 MHz, C6D6) δ 174.2, 154.9, 89.5, 79.2, 69.3, 49.4,
35.1, 28.1, 25.6, 19.5, 17.8, -4.7, -5.0; IR (neat) 3360 (br),
1793, 1707 cm-1; [R]25D ) 10.70° (c 1.00, CH2Cl2). Anal. Calcd
for C17H33NO5Si: C, 56.79; H, 9.25; N, 3.90. Found: C, 56.51;
H, 8.85; N, 3.83.
3200 (br), 1780, 1701 cm-1; [R]25 ) -24.5° (c 0.40, CH2Cl2).
D
Anal. Calcd for C11H19NO5: C, 53.87; H, 7.81; N, 5.71.
Found: C, 53.77; H, 7.63; N, 5.50.
Gen er a l P r oced u r e for th e DIBALH Red u ction . In a
flame-dried 10 mL round bottom flask was placed 36 (0.0998
g, 0.407 mmol) in THF (3.0 mL) under N2. It was stirred at rt
to form a clear solution. Then it was cooled to -78 °C in a
dry ice/acetone bath. 1.0 M DIBALH in hexane (1.4 mL, 1.4
mmol) was added slowly over 10 min with a fast stirring.
When the reaction was stirred at -78 °C for 1.5 h, it was
quenched with CH3OH/H2O ) 4/1 (2.0 mL) at -78 °C and
further stirred at -78 °C for 5 min. The mixture was warmed
to rt. A solution of saturated NaHCO3 (0.5 mL) was added.
The mixture was filtered through a pad of celite. The filter
cake was washed thoroughly with acetone, and the solvent was
evaporated. The residue was purified by silica gel column
(eluted with benzene/acetone ) 5/3) to give 37 (0.0673 g, 0.272
mmol, 67%) as a complex mixture.
(-)-L-N-(ter t-Bu tyloxycar bon yl)dau n osam ide (34). Fol-
lowing the general DIBALH reduction procedure (purification
by the elution with benzene/acetone ) 4/3), 33 (0.1964 g, 0.80
mmol) gave 34 as a complex mixture (0.1098 g, 56%): IR (neat)
3616-3115 (br), 1716, 1691 cm-1; [R]25 ) -64.7° (c 1.00,
D
CH3OH, 2 h). Anal. Calcd for C11H21NO5: C, 53.43; H, 8.56;
N, 5.66. Found: C, 53.26; H, 8.28; N, 5.32.
(+)-D-N-(ter t-Bu t yloxyca r b on yl)r ist osa m id e
(37).
DIBALH reduction of 36 (0.0998 g, 0.407 mmol) gave an
isomeric mixture of 37 (0.0673 g, 0.272 mmol, 67%) as an oil:
IR (neat) 3649-3095 (br), 1710, 1692 cm-1; [R]25 ) 17.2-
D
15.18° (c 0.90, CH3OH, 3 h). Anal. Calcd for C11H21NO5: C,
53.43; H, 8.56; N, 5.66. Found: C, 53.25; H, 8.30; N, 5.26.
(+)-[4S,5S,5-(1S)]-2-Hyd r oxy-4-[N-(ter t-bu tyloxyca r bo-
n yl)a m in o]-5-[1-[[(1,1-d im e t h yle t h yl)d im e t h ylsilyl]-
oxy]eth yl]tetr a h yd r ofu r a n (39). DIBALH reduction of
(using 2.5 equiv of DIBALH for the reaction and 20% EtOAc
in hexane for chromatography purification) 30 (60 mg, 0.1681
mmol) furnished 39 as a clear oil (40.6 mg, 0.1131 mmol, 67%)
as a mixture of two isomers in a ratio of 2.9:1 by NMR
integration; Rf 0.24 (80:20 hexane:ethyl acetate); 1H NMR (400
MHz, C6D6) major isomer: δ 0.03 (s, 3H), 0.11 (s, 3H), 0.96 (s,
9H), 1.14 (d, J ) 6.3 Hz, 3H), 1.41 (s, 9H), 1.67 (ddd, J ) 13.4,
13.2, 1.5 Hz, 1H), 1.96 (ddd, J ) 13.4, 8.6, 4.6 Hz, 1H), 3.85
(dq, J ) 6.3, 3.9 Hz, 1H), 4.00 (m, 1H), 4.21 (m, 1H), 5.29 (dd,
J ) 13.2, 4.6 Hz, 1H), 5.45 (d, J ) 2.2 Hz, 1H); minor isomer:
δ 0.02 (s, 3H), 0.18 (s, 3H), 0.91 (s, 9H), 1.16 (d, J ) 6.7 Hz,
3H), 1.54 (s, 9H), 1.29-1.36 (m, 1H), 2.08-2.14 (m, 1H), 3.91-
3.97 (m, 1H), 4.09-4.14 (m, 1H), 4.37-4.46 (m, 1H), 5.29 (m,
1H), 5.45 (b, 1H); 13C NMR (100 MHz, C6D6) δ major isomer:
155.2, 98.2, 89.5, 78.7, 51.6, 39.9, 28.2, 25.8, 20.1, 18.0, -4.6,
-4.8; minor isomer: 155.2, 98.5, 89.8, 78.8, 51.5, 42.3, 28.2,
25.8, 19.4, 17.9, -4.7, -4.9; IR (neat) 3120-3556 (br), 1720,
(-)-(3S,4S,5R)-3-[N-(ter t-Bu t yloxyca r b on yl)a m in o]-4-
h y d r o x y -5-[[(1,1-d im e t h y le t h y l)d im e t h y ls ily l]o x y ]-
h exa n oic Acid γ-La cton e (32). Using Curtius procedure
described above, 26 (1.0 g, 3.49 mmol) gave 32 (0.7752 g, 2.17
mmol, 62%) as a colorless oil; Rf 0.35 (80:20-hexane:ethyl
acetate); 1H NMR (400 MHz, CDCl3) δ 0.04 (s, 3H), 0.07 (s,
3H), 0.86 (s, 9H), 1.25 (d, J ) 6.7 Hz, 3H), 1.43 (s, 9H), 2.32
(d, J ) 17.9, Hz, 1H), 2.98 (dd, J ) 17.9, 8.7 Hz, 1H), 4.06 (dq,
J ) 6.7, 2.4 Hz, 1H), 4.18 (dd, J ) 2.5, 2.4 Hz, 1H), 4.31-4.48
(m, 1H), 4.93 (d, J ) 7.1 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ 175.6, 154.9, 89.7, 80.5, 68.9, 47.3, 36.8, 28.4, 25.8, 19.4, 17.9,
-4.8, -5.0; IR (neat) 3365, 1793, 1707 cm-1; [R]25 ) -24.5°
D
(c 1.00, CH2Cl2). Anal. Calcd for C17H33NO5Si: C, 56.79; H,
9.25; N, 3.90. Found: C, 56.43; H, 8.86; N, 3.76.
Gen er a l P r oced u r e for th e Silicon Dep r otection . The
amino lactone 32 (0.7752 g, 2.17 mmol) was dissolved in THF
(4 mL) under N2. The solution was cooled to 0 °C in an ice
bath. 1.0 M TBAF (2.2 mL, 2.2 mmol) was added dropwise
over 10 min. The ice bath was removed, and the resultant
yellow solution was stirred at rt for 16 h. The solvent was
evaporated, and purification of the resultant yellow crude
product by flash chromatography (eluted with 50% EtOAc)
yielded 36 (0.4507 g, 1.84 mmol, 85%) as a white solid.
(+)-(3S,4S,5S)-3-[N-[ter t-Bu tyloxyca r bon yl)a m in o]-4,5-
1693 cm-1; [R]25 ) 39.5° (c 1.00, CH2Cl2); HRMS m/ z calcd
D
for C17H35NO5Si [MH]+ 362.2363, obsd 362.2364.
(+)-[4S,5S,5-(1R)]-2-Hyd r oxy-4-[N-(ter t-bu tyloxyca r bo-
n yl)a m in o]-5-[1-[[(1,1-d im eth yleth yl)d im eth ylsilyl]oxy-

5872 J . Org. Chem., Vol. 62, No. 17, 1997
Sibi et al.
]eth yl]tetr a h yd r ofu r a n (41). DIBALH reduction (using 2.5
equiv of DIBALH for reaction, and 20% EtOAc in hexane for
chromatography purification) of 32 (0.1004 g, 0.28 mmol)
furnished 41 as a clear oil (0.0727 g, 0.2025 mmol, 72%) as a
mixture of two isomers in a ratio of 8.5:1 by NMR integration;
Rf 0.21 (80:20 hexane:ethyl acetate); 1H NMR (400 MHz, C6D6)
major isomer: δ 0.02 (s, 3H), 0.05 (s, 3H), 0.94 (s, 9H), 1.18
(d, J ) 6.4 Hz, 3H), 1.41 (s, 9H), 1.67 (ddd, J ) 13.3, 4.2, 1.4
Hz, 1H), 1.97 (ddd, J ) 13.3, 8.6, 4.2 Hz, 1H), 3.79 (dq, J )
6.4, 3.0 Hz, 1H), 3.93 (dd, J ) 3.0, 3.0 Hz, 1H), 4.32 (dddd, J
) 8.8, 8.6, 3.0, 1.4 Hz, 1H), 5.24 (dd, J ) 4.2, 4.2 Hz, 1H), 5.35
(d, J ) 8.8 Hz, 1H); minor isomer: δ 0.04 (s, 3H), 0.11 (s, 3H),
0.97 (s, 9H), 1.27 (d, J ) 6.0 Hz, 3H), 1.42 (s, 9H), 1.65 (dd, J
) 10.7, 4.7 Hz, 1H), 2.32-2.37 (m, 1H), 3.76-3.86 (m, 1H),
3.87-3.90 (m, 1H), 4.40-4.60 (m, 1H), 5.15-5.18 (m, 1H),
5.56-5.59 (b, 1H); 13C NMR (100 MHz, C6D6) major isomer:
δ 155.0, 98.8, 89.9, 78.8, 69.3, 50.1, 40.5, 28.2, 25.8, 20.2, 18.0,
-4.7, -5.0; minor isomer: 155.0, 98.4, 88.0, 78.8, 69.3, 54.1,
46.0, 28.4, 25.9, 20.4, 17.4, -4.5, -4.8; IR (neat) 3500-3220
stirred at rt for 6 h. The solvent was evaporated and the
aqueous layer was extracted with EtOAc (5 × 3 mL). The
organic extract was evaporated and the crude product was
purified by preparative TLC to give 42 as a white solid (0.0213
g, 0.0849 mmol, 71%).
3-Ben za m id o-2,3,6-tr id eoxy-L-lyxo-h exose (N-Ben zoyl-
L-d a u n osa m in e) (40). Following the general benzoylation
procedure, 39 (33.3 mg, 0.0921 mmol) gave 40 as a white solid
(17.1 mg, 0.0681 mmol, 74%). This product is a mixture of
four isomers in a ratio of pyranose/furanose ) 3.4/1, and
R-pyranose/â-pyranose ) 1.1:1: mp 146-149 °C; Rf 0.24 (93:7
CH2Cl2:MeOH); 1H NMR (400 MHz, DMSO-d6) δ for the
â-pyranose: 1.13 (d, J ) 6.3 Hz, 3H), 1.59 (dd, J ) 12.7, 4.3,
2.0 Hz, 1H), 1.74 (dd, J ) 12.7, 12.4, 9.7 Hz, 1H), 3.46 (bd,
1H), 3.54 (dq, J ) 6.3 Hz. 1H), 4.02 (m, J ) 12.4, 4.3 Hz, 1H),
4.67 (ddd, J ) 9.7, 6.3, 2.0 Hz, 1H), 4.75 (d, J ) 6.2 Hz, 1H),
6.51 (d, J ) 6.4 Hz, 1H), 7.43-7.97 (m, 4H), 8.04 (d, J ) 7.9
Hz, 1H); for the R-pyranose: 1.08 (d, J ) 6.7 Hz, 3H), 1.44
(dd, J ) 12.5, 5.1, 4.4 Hz, 1H), 1.99 (dd, J ) 12.9, 12.5, 2.2
Hz, 1H), 3.46 (bd, 1H), 3.54 (m, 1H), 4.04 (m, J ) 6.7 Hz, 1H),
4.37 (m, J ) 12.9, 5.1 Hz, 1H), 4.75 (d, J ) 6.2 Hz, 1H), 5.14
(ddd, J ) 4.4, 3.3, 2.2 Hz, 1H), 6.09 (d, J ) 3.3 Hz, 1H), 7.43-
7.97 (m, 4H), 7.97 (d, J ) 7.7 Hz, 1H); 13C NMR (100 MHz,
DMSO-d6) for the â-pyranose δ 164.1, 135.3, 131.6, 128.8,
128.0, 94.8, 71.5, 67.4, 50.2, 33.6, 17.8; for the R-pyranose
166.3, 135.1, 131.7, 128.7, 128.0, 90.9, 68.7, 66.0, 46.2, 30.9,
17.7; IR (KBr) 3500-3121 (br), 1647, 1604 cm-1; [R]25D ) -87.8
(br), 1728, 1687 cm-1; [R]25 ) 20.6° (c 1.00, CH2Cl2); HRMS
D
m/ z calcd for C17H35NO5Si [MH]+ 362.2363, obsd 362.2364.
(-)-Meth yl 3-Am in o-2,3,6-tr id eoxy-r-L-lyxo-p yr a n osid e
Hyd r och lor id e ((-)-L-O-Meth yl-r-d a u n osa m in e Hyd r o-
ch lor id e) (35). In a 10 mL round bottom flask was placed
34 (52 mg, 0.2105 mmol). A 2.0 mL volume of methanolic HCl
was added at rt. The solution was stirred at rt for 6 h. The
solvent was removed by an aspirator (connected with a drying
tube) to give a light yellow solid. The solid was dissolved in
0.5 mL of CH3OH (dry), and 35 was precipitated out as a white
solid by the addition of anhydrous ethyl ether (4.0 mL) (32.9
to -61.8° (c 0.50, EtOH, 3 h), lit.13i mp 152 °C, [R]25 ) -108°
D
(c 0.50, EtOH). Anal. Calcd for C13H17NO4: C, 62.12; H, 6.82;
N, 5.58. Found: C, 61.97; H, 6.74; N, 5.22.
1
3-Ben za m id o-2,3,6-tr id eoxy-D-r ibo-h exose (N-Ben zoyl-
D-r istosa m in e) (42). Lactol 38 (44 mg, 0.166 mmol) was
dissolved in HOAc (1.0 mL) and H2O (1.0 mL). This solution
was heated to reflux in an oil bath for 1.5 h. It was evaporated
to dryness to yield a light yellow solid, which was purified via
chromatography (eluted with EtOAc) to yield 42 as a white
solid. This solid was a mixture of four isomers in the ratio of
furanose/pyranose ) 1.7/1, and R-furanose/â-furanose ) 1.2/
1: mp 103-107 °C; Rf 0.32 (93:7 CH2Cl2:CH3OH); 1H NMR
(400 MHz, DMSO-d6) for the â-furanose: δ 1.08 (d, J ) 6.0
Hz. 3H), 2.01-2.04 (m, 2H), 3.68 (m, 2H), 4.59 (d, J ) 2.8 Hz,
1H), 5.40 (bs, 1H), 6.37 (d, J ) 4.9 Hz, 1H), 7.42-7.89 (m,
4H), 8.57 (d, J ) 7.9 Hz, 1H); for the R-furanose: δ 1.16 (d, J
) 6.3 Hz. 3), 1.76 (ddd, J ) 13.2, 5.0, 2.2 Hz, 1H), 2.31 (ddd,
J ) 13.2, 9.2, 5.2 Hz, 1H), 3.63 (ddq, J ) 6.3, 4.5, 4.4 Hz, 1H),
3.88 (dd, J ) 5.3, 4.5 Hz, 1H), 4.39 (dddd, J ) 9.2, 7.8, 5.3, 5.0
Hz, 1H), 4.69 (d, J ) 4.4 Hz, 1H), 5.40 (bs, 1H), 6.37 (d, J )
4.9 Hz, 1H), 7.42-7.89 (m, 4H), 8.41 (d, J ) 7.8 Hz, 1H); 13C
NMR (100 MHz, DMSO-d6) for the â-furanose: δ 166.6, 134.8,
131.8, 128.8, 127.9, 97.8, 86.2, 67.2, 50.3, 40.9, 19.7; for the
R-furanose: 166.4, 134.9, 131.8, 128.9, 127.3, 97.5, 87.7, 68.3,
mg, 0.167 mmol, 79%): mp 187-190 °C; H NMR (400 MHz,
pyridine-d5) δ 1.36 (d, J ) 6.6 Hz, 3H), 2.42 (dd, J ) 12.3, 1.5
Hz, 1H), 2.49 (dd, J ) 12.3, 12.3 Hz, 1H), 3.25 (s, 3H), 3.91
(dq, J ) 6.6, 0.8 Hz, 1H), 4.28 (ddd, J ) 12.3, 5.0, 2.8 Hz, 1H),
4.50 (dd, J ) 2.8, 0.8 Hz, 1H), 4.83 (dd, J ) 3.3, 1.5 Hz, 1H),
10.5 (bs, 2H); 13C NMR (100 MHz, pyridine-d5) δ 97.7, 67.0,
66.4, 54.3, 47.9, 29.2, 17.2; IR (KBr) 3452-3281, 3066-2777
cm-1; [R]25 ) -139.4° (c 0.48, CH3OH), lit.37 mp 188-90 °C,
D
[R]D ) -140° (c 1.0, CH3OH)).
(+)-Meth yl 3-Ben za m id o-2,3,6-tr id eoxy-r-D-r ibo-h ex-
op yr a n osid e ((+)-D-O-Meth yl-r-3-ben za m id or istosa m id e)
(38). In a 10 mL round bottom flask was placed 37 (66.4 mg,
0.2688 mmol). Methanolic HCl (2.0 mL) was added at rt. The
solution was stirred at rt for 6 h. The solvent was removed
by an aspirator connected with a drying tube to give a light
yellow solid. The crude reaction mixture (0.0499 g, 0.2532
mmol) was dissolved in pyridine (2.0 mL). To this solution
was added benzoyl chloride (0.03 mL, 0.26 mmol). After the
reaction was stirred at rt for 1 h, pyridine was removed in
vacuo. The residue was dissolved in CH2Cl2 (5 mL), washed
with 10% citric acid and H2O (5 mL), and dried with anhydrous
MgSO4. The solvent was removed in vacuo to furnish a brown
oil. This crude product was purified by preparative TLC
(eluted with 50% EtOAc in hexane) to yield 38 (32.7 mg, 0.1234
mmol, 49%) as a clear oil. Rf 0.36 (50:50 hexane:ethyl acetate);
1H NMR (400 MHz, CDCl3) δ 1.29 (d, J ) 7.2 Hz, 3H), 2.01
(ddd, J ) 14.6, 3.0, 1.2 Hz, 1H), 2.13 (ddd, J ) 14.6, 4.0 4.0
Hz, 1H), 3.44 (s, 3H), 3.54 (ddd, J ) 9.6, 3.2, 2.5 Hz, 1H), 3.79
(dq, J ) 9.6, 7.2 Hz, 1H), 4.05 (d, J ) 2.5 Hz, 1H), 4.64 (dddd,
J ) 6.4, 4.0, 3.2, 3.0 Hz, 1 H), 4.79 (dd, J ) 4.0, 1.2 Hz, 1H),
7.25-7.79 (m, 5H), 7.96 (d, J ) 6.4 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 169.8, 133.5, 132.0, 128.7, 127.2, 98.1, 74.8,
50.3, 41.0, 19.6; IR (KBr) 3500-3100 (br), 1641, 1601 cm-1
;
[R]25 ) 43.8-41.2° (c 1.00, EtOH, 1.0 h), lit.17a mp 128-129
D
°C, [R]23 ) 13.5° (c 1.00, EtOH), and lit.17b mp 135-137 °C,
D
[R] ) 15.6-9.8° (c 1.00, EtOH). Anal. Calcd for C13H17NO4:
C, 62.12; H, 6.82; N, 5.58. Found: C, 61.72; H, 6.52; N, 5.22.
Compound 42 (21.3 mg, 0.0849 mmol, 71%) was also obtained
from 41 (43 mg, 0.1198 mmol) following the general benzoy-
lation procedure.
Ack n ow led gm en t. We thank NSF (OSR-9452892),
National Institutes of Health, SC J ohnson&Wax, and
FMC Lithium for financial support of our research
programs. Partial support for this work was provided
by the NSF’s Instrumentation and Laboratory Improve-
ment Program through grant no. USE-9152532 and by
NRICGP (95-37501-2300) for upgrade of the NMR data
acquisition system.
64.8, 55.3, 48.4, 33.3, 17.5; IR (neat) 3431, 1655 cm-1; [R]25
)
D
122.8° (c 0.86, benzene), lit.17a [R]22D ) 122.5° (c 1.4, benzene).
Another fraction (25.7 mg, 0.969 mmol, 38%), a mixture of the
other three isomers, was also isolated in a ratio of 1:1.8:1.9
(NMR integration on OCH3 peaks). Rf 0.24 (50:50 hexane:
ethyl acetate); [R]25 ) 8.1° (c 1.00, benzene).
D
Gen er a l Ben zoyla tion P r oced u r e. A mixture of 41
(0.0430 g, 0.1198 mmol) was dissolved in CH2Cl2 (2.0 mL), and
trifluoroacetic acid (0.2 mL) was added dropwise at rt. The
solution was stirred at rt for 1.5 h. The solvent and acid were
removed in a fumehood using an aspirator. The residue was
dissolved in H2O (1.0 mL). NaHCO3 (53 mg, 0.5990 mmol) and
a solution of benzoyl chloride (0.015 mL, 0.1318 mmol) in
acetone (1.0 mL) were added subsequently. This solution was
Su p p or tin g In for m a tion Ava ila ble: 1H NMR and 13C
NMR spectra for selected compounds (13 pages). This material
is contained in libraries on microfiche, immediately follows this
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