Synthesis of aminocyclitols by intramolecular reductive coupling of carbohydrate derived δ- and ε-functionalized oxime ethers promoted by tributyltin hydride or samarium diiodide

Article abstract of DOI:10.1021/jo970987w

The intramolecular reductive coupling of a series of simple or polyoxygenated oxime ethers δ- or ε-functionalized with bromide, α,β- unsaturated ester, aldehyde, or ketone groups is reported. The cyclization of a nitrile-tethered aldehyde is also studied. These reductive couplings are promoted by tributyltin hydride or samarium diiodide. The reactions proceed under mild conditions, in good chemical yield, and with high stereoselectivity. When applied to highly functionalized substrates derived from carbohydrates, this approach provides a selective entry to enantiomerically pure aminocyclitols of varying regio- and stereochemistry. In particular, the reductive coupling reaction of carbonyl-tethered oxime ethers promoted by samarium diiodide can be performed in a one-pot sequence, following a Swern oxidation step, allowing the direct transformation of hydroxyl-tethered oxime ethers into the corresponding aminocyclitols. Moreover, the resultant O-benzylhydroxylamine products of these cyclizations can be further reduced in situ with excess samarium diiodide, in the presence of water, to the corresponding amino alcohols in excellent yields. Some transformations of these compounds are discussed.

Full text of DOI:10.1021/jo970987w

J . Org. Chem. 1997, 62, 7397-7412
7397
Syn th esis of Am in ocyclitols by In tr a m olecu la r Red u ctive Cou p lin g
of Ca r boh yd r a te Der ived δ- a n d E-F u n ction a lized Oxim e Eth er s
P r om oted by Tr ibu tyltin Hyd r id e or Sa m a r iu m Diiod id e†
J ose´ Marco-Contelles,* Pilar Gallego, Mercedes Rodr´ıguez-Ferna´ndez, Noureddine Khiar,‡
Christine Destabel, Manuel Bernabe´, Angeles Mart´ınez-Grau,§ and J ose Luis Chiara*
Instituto de Quı´mica Orga´nica, C.S.I.C., J uan de la Cierva, 3, E-28006 Madrid, Spain
Received J une 3, 1997X
The intramolecular reductive coupling of a series of simple or polyoxygenated oxime ethers δ- or
ꢀ-functionalized with bromide, R,â-unsaturated ester, aldehyde, or ketone groups is reported. The
cyclization of a nitrile-tethered aldehyde is also studied. These reductive couplings are promoted
by tributyltin hydride or samarium diiodide. The reactions proceed under mild conditions, in good
chemical yield, and with high stereoselectivity. When applied to highly functionalized substrates
derived from carbohydrates, this approach provides a selective entry to enantiomerically pure
aminocyclitols of varying regio- and stereochemistry. In particular, the reductive coupling reaction
of carbonyl-tethered oxime ethers promoted by samarium diiodide can be performed in a one-pot
sequence, following a Swern oxidation step, allowing the direct transformation of hydroxyl-tethered
oxime ethers into the corresponding aminocyclitols. Moreover, the resultant O-benzylhydroxylamine
products of these cyclizations can be further reduced in situ with excess samarium diiodide, in the
presence of water, to the corresponding amino alcohols in excellent yields. Some transformations
of these compounds are discussed.
In tr od u ction
Polyhydroxylated aminocyclopentanes are structural
motifs present in a growing number of natural products
and pharmacologically important drugs that show inter-
esting biological properties. Well known members of this
group are the carbocyclic glycosidase inhibitors man-
nostatin A (1),1 trehazolin (2),2 allosamidin (3),3 and the
carbocyclic nucleosides aristeromycin (4),4 neplanocin A
(5),5 and analogs such as epi-5′-nor-aristeromycin (6)6
(Figure 1). Polyhydroxylated aminocyclohexanes have
* Corresponding authors. Phone: +34-1-5622900. Fax: +34-1-
5644853. E-mail (J LCh): iqolc22@fresno.csic.es
† Dedicated to the memory of Prof. Eldiberto Ferna´ndez-Alvarez
(deceased August 23, 1996).
‡ Present address: Instituto de Investigaciones Qu´ımicas (CSIC),
Isla de la Cartuja, E-41092 Sevilla, Spain.
§ Present address: Departamento de Qu´ımica Orga´nica, Facultad
de Qu´ımica, Universidad Complutense, E-28040 Madrid, Spain.
X Abstract published in Advance ACS Abstracts, September 15, 1997.
(1) Recent syntheses: (a) Knapp, S.; Dhar, T. G. M. J . Org. Chem.
1991, 56, 4096. (b) Trost, B. M.; Van Kranken, D. L. J . Am. Chem.
Soc. 1993, 115, 444, and references cited therein. (c) King, S. B.;
Ganem, B. J . Am. Chem. Soc. 1994, 116, 562, and references cited
therein. (d) Li, C.; Fuchs, P. L. Tetrahedron Lett. 1994, 35, 5121. (e)
Ogawa, S.; Kimura, H.; Uchida, C.; Ohashi, T. J . Chem. Soc., Perkin
Trans. 1 1995, 1695, and references cited therein.
(2) Recent syntheses of trehazoline and its aglycon: (a) Kobayashi,
Y.; Miyazaki, H.; Shiozaki, M. J . Org. Chem. 1994, 59, 813, and
references therein. (b) Uchida, C.; Yamagishi, T.; Ogawa, S. J . Chem.
Soc., Perkin Trans. 1 1994, 589, and references cited therein. (c)
Knapp. S.; Purandare, A.; Rupitz, K.; Withers, S. G. J . Am. Chem. Soc.
1994, 116, 7461. (d) Ledford, B. E.; Carreira, E. M. J . Am. Chem. Soc.
1995, 117, 11811.
(3) Recent syntheses of allosamidine and its aglycon: (a) Nakata,
M.; Akazawa, S.; Kitamura, S.; Tatsuta, K. Tetrahedron Lett. 1991,
32, 5363. (b) Takahashi, S.; Terayama, H.; Kuzuhara, H. Tetrahedron
Lett. 1992, 33, 7565, and references cited therein. (c) Simpkins, N.
S.; Stokes, S.; Whittle, A. J . Chem. Soc., Perkin Trans. 1 1992, 2471,
and references cited therein. (d) Kitahara, T.; Suzuki, N.; Koseki, K.;
Mori, K. Biosci., Biotechnol., Biochem. 1993, 57, 1906. (e) Maloisel,
J .-L.; Vasella, A.; Trost, B. M.; Van Vranken, D. L. Helv. Chim. Acta
1992, 75, 1515. (f) Goering, B. K.; Ganem, B. Tetrahedron Lett. 1994,
35, 6997. (g) Blattner, R.; Furneaux, R. H.; Kemmit, T.; Tyler, P. C.;
Ferrier, R.; Tide´n, A.-K. J . Chem. Soc., Perkin Trans. 1 1994, 3411.
(h) Griffith, D. A.; Danishefsky, S. J . Am. Chem. Soc. 1996, 118, 9526,
and references cited therein. See also ref 1b.
F igu r e 1. Aminocyclopentitol-derived natural products.
also attracted much attention due to their therapeutic
applications.7 Different strategies have been employed
for the synthesis of such densely functionalized
carbocycles,1-3 but one of the most successful involves the
transformation of carbohydrates.8 Following this ap-
(6) (a) Siddiqi, S. M.; Chen, X.; Schneller, S. W. J . Med. Chem. 1994,
37, 1382. (b) Siddiqi, S. M.; Chen, X.; Schneller, S. W. J . Med. Chem.
1994, 37, 551, and references cited therein.
(7) Aminoglycoside antibiotics; Umezawa, H., Hooper, I. R., Eds.;
Springer-Verlag: New York, 1982.
(8) For a recent review on the use of carbohydrate templates for
the preparation of carbocycles, see: Ferrier, R. J .; Middleton, S. Chem.
Rev. 1993, 93, 2779.
(4) For a review, see: Quinkert, E., Ed. Synform 1989, 7, 192.
(5) For a review, see: Quinkert, E., Ed. Synform 1989, 7, 225.
S0022-3263(97)00987-0 CCC: $14.00 © 1997 American Chemical Society

7398 J . Org. Chem., Vol. 62, No. 21, 1997
Marco-Contelles et al.
Sch em e 1
proach, a series of carbocyclization methods have been
developed, a particularly interesting process being the
intramolecular trapping of a radical by an oxime ether9
or by a hydrazone.10 The efficiency of these reactions lies
in the additional stabilization of the intermediate aminyl
radical by a lone pair in the adjacent oxygen or nitrogen
atom.11 Our particular effort in this area during the last
few years has resulted in several new methodologies for
the synthesis of enantiomerically pure polyhydroxylated
cyclopentanes and cyclohexanes using radical cyclizations
promoted by tributyltin hydride12 or by samarium diio-
dide.13,14
In this paper we report in full our recent results in
the field, showing the scope and generality of some of
(9) (a) Hart, D. J .; Seely, F. L. J . Am. Chem. Soc. 1988, 110, 1631.
(b) Bartlett, P. A.; McLaren, K. L.; Ting, P. C. J . Am. Chem. Soc. 1988,
110, 1633. For recent examples, see: Booth, S. E.; J enkins, P. R.;
Swain, C. J .; Sweeney, J . B. J . Chem. Soc., Perkin Trans. 1 1994, 3499,
and references cited therein.
(10) (a) Kim, S.; Kee, I. S. Tetrahedron Lett. 1993, 34, 4213. (b)
Sturino, C. F.; Fallis, A. G. J . Am. Chem. Soc. 1994, 116, 7447. (c)
Sturino, C. F.; Fallis, A. G. J . Org. Chem. 1994, 59, 6514. (d) Bowman,
W. R.; Stephenson, P. T.; Terrett, N. K.; Young, A. R. Tetrahedron Lett.
1994, 35, 6369.
(11) Kim, S.; Yoon, K. S.; Kim, Y. S. Tetrahedron 1997, 53, 73.
(12) (a) Marco-Contelles, J .; Mart´ınez, L.; Mart´ınez-Grau, A.
Tetrahedron: Asymmetry 1991, 2, 961. (b) Marco-Contelles, J .; Ruiz,
P.; Mart´ınez, L.; Mart´ınez-Grau, A. Tetrahedron 1993, 49, 6669. For
a later report on exactly the same methodology, see: Ingall, A. H.;
Moore, P. R.; Roberts, S. M. Chem. Commun. 1994, 83 (corrigendum:
Chem. Commun. 1994, 675). (c) Marco-Contelles, J .; Sa´nchez, B. J .
Org. Chem. 1993, 58, 4293. (d) Marco-Contelles, J .; Destabel, C.;
Gallego, P.; Chiara, J . L.; Bernabe´, M. J . Org. Chem. 1996, 61, 1354.
(e) Marco-Contelles, J . In Carbohydrate Mimics: Concepts and Meth-
ods; Chapleur, Y., Ed.; VCH: Weinheim, in press.
(13) (a) Chiara, J . L.; Mart´ın-Lomas, M. Tetrahedron Lett. 1994, 35,
2969. (b) Chiara, J . L.; Valle, N. Tetrahedron: Asymmetry 1995, 6,
1547. (c) Chiara, J . L.; Marco-Contelles, J .; Khiar, N.; Gallego, P.;
Destabel, C.; Bernabe´, M. J . Org. Chem. 1995, 60, 6010. (d) Chiara,
J . L.; Mart´ınez, S.; Bernabe´, M. J . Org. Chem. 1996, 61, 6488. (e)
Chiara, J . L. In Carbohydrate Mimics: Concepts and Methods; Chap-
leur, Y., Ed.; VCH: Weinheim, in press.
(14) For recent reviews on applications of samarium diiodide in
organic synthesis, see: (a) Molander, G. A. Chem. Rev. 1996, 96, 307.
(b) Molander, G. A. Org. React. 1994, 46, 211. (c) Imamoto, T.
Lanthanides in Organic Synthesis; Academic Press: London, 1994.
F igu r e 2.
these protocols. In particular, we have investigated the
carbocyclizations outlined in Scheme 1. To this end, we
have prepared a series of simple or polyhydroxylated and
enantiomerically pure oxime ethers (Figure 2), δ- or
ꢀ-functionalized with a bromide (7a -e, 8), an R,â-
unsaturated ester (9), an aldehyde (11-16), or a ketone
group (17-20). All these compounds have been submit-
ted to typical conditions for carbocyclization promoted by
tributyltin hydride or samarium diiodide. The cyclization
of a nitrile-tethered aldehyde (10) has been also inves-
tigated.
Resu lts a n d Discu ssion
A. Tr ibu tyltin Hyd r id e Cycliza tion of δ-Br om o
Oxim e Eth er s. The 5-exo-trig free radical cyclization
of 5-bromo-5-deoxy-D-ribose derivatives, using an R,â-
unsaturated ester as radical trap, was first reported by

Synthesis of Aminocyclitols
Sch em e 2a
J . Org. Chem., Vol. 62, No. 21, 1997 7399
Ta ble 1. Tr ibu tyltin Hyd r id e Med ia ted Cycliza tion of
P r ecu r sor s 7a -e
radical
precursor
product ratios
entry
R
R
24/25a
yield (%)b
1c
2
3
4
5
7a
7b
7c
7d
7e
H
TBS
Ac
Bz
Bz
Bn
Bn
Bn
Bn
Me
>95:5
>95:5
>95:5
89:11
80:20
75
53
52
58
71
a
Product ratios computed from NMR analysis of crude mix-
tures. Isolated yield of cyclized products. c Reference 12b.
b
confirming the assigned absolute configuration at C-4 in
these carbocycles.
Since we were unable to separate the syn and anti
isomers of compounds 7a -e, we could not analyze
independently the stereochemical outcome of their radical
cyclization. In principle, each isomer could yield a
different trans/cis ratio of cyclic products. However,
according to previous reports,9b no significant differences
should be expected between the cyclizations of each oxime
isomer. The stereochemical results obtained in the
cyclization of these radical precursors can be rationalized
in terms of the model proposed by Wilcox for the cycliza-
tion of analogous R,â-unsaturated esters.15a According
to Beckwith,18 5-hexenyl radical species prefer chairlike
conformations in the transition state with most substit-
uents in pseudoequatorial position. In our case, confor-
mation S2 (Scheme 3) presents unfavorable 1,3-steric
interactions between substituents at C-2 and C-4. This
effect makes conformation S1 the most favorable and,
accordingly, isomers 24a -e should be formed preferen-
tially. Comparison of the cyclizations of compounds 7d
and 7e with those of 7a -c suggest a probable influence
of electronic effects of the aryl ester.12a
From a practical perspective, the cyclization of precur-
sor 7a could be scaled up to ∼4 mmol without loss of
chemical yield (∼80%).12b With compound 24a in hand,
we tried several chemical manipulations directed toward
the synthesis of carbocyclic nucleosides. Thus, treatment
of 24a with a THF solution of SmI219 at room temperature
cleanly gave the amino alcohol 26 (Scheme 4). Unfortu-
nately, subsequent reaction of 26 with 5-amino-4,6-
dichloropyrimidine to give the carbocyclic nucleoside 27,20
followed by reaction with triethyl orthoformate and acid
hydrolysis, afforded 2820 in very poor overall yield (7%),
and this approach was abandoned.
Wilcox in a seminal paper published in 1985.15 After this
report, Bartlett9b described the use of oxime ethers as
efficient radical traps, compared to aldehydes,16 for
similar ring closures. These reports encouraged us to
explore the synthesis and carbocyclization of 5-bromo-5-
deoxy-2,3-O-isopropylidene-D-ribose O-benzyl oxime ether
derivatives.12 This protocol should provide a simple and
ready access to chiral 4-amino-1,2,3-cyclopentanetriols
(B; Scheme 1), a structural motive found in interesting,
recently discovered antiviral agents such us 6.6
Compound 7a 12b and related 4-O-substituted deriva-
tives (7b-e)12a were prepared from commercially avail-
able D-ribonolactone derivative 21, following standard
methodologies (Scheme 2). These compounds were ob-
tained as inseparable mixtures of syn and anti isomers
1
in 70:30 ratio, respectively, as determined by H NMR
[H-1 (syn): 7.30 ppm, d, J ) 7.3 Hz; H-1 (anti): 6.80 ppm,
d, J ) 5.5 Hz)].
With these precursors in hand, we tried the tributyltin
hydride promoted cyclization. The reaction proceeded in
moderate to good yield and excellent diastereoselectivity
under standard conditions [for comparative purposes we
have also included the data for compound 7a ; see Table
1, entry 1]. For compounds 7b,c, exclusively exo-cyclized
products 24b ,c were obtained, with the O-alkylhy-
droxyamino group predominantly in trans relative ori-
entation with respect to the vicinal alkoxy substituent.17a
For compounds 7d or 7e (see Table 1, entries 4 and 5)
the minor cis isomers 25d and 25e could be detected in
an increased amount, but we were unable to isolate the
major isomers pure. Compounds 24b and 24d /25d (91:9
mixture) were transformed by mild acid hydrolysis and
sodium methoxide treatment, respectively, into 24a ,
(17) (a) This assignment was evident after 1H NMR detailed analysis
3
of these compounds: a J 3,4 ) 0 Hz clearly suggested a trans relative
stereochemistry for these carbons, establishing as R the absolute
configuration at the new stereocenter. (b) The absolute configuration
at the new stereocenters was established by detailed 1H NMR and 2D
NOESY studies (see the Supporting Information). (c) A detailed
3
analysis of the 1H NMR spectrum of 36a showed a J HC(NHOBn)-HC(OTBS)
) 9.4 Hz; this value strongly suggets a trans arrangement between
these vicinal protons, establishing as R the absolute configuration at
the new stereocenter.
(15) (a) Wilcox, C. S.; Thomasco, L. M. J . Org. Chem. 1985, 50, 546.
For a similar cyclization using samarium diiodide, see: (b) Zhou, Z.;
Bennett, S. M. Tetrahedron Lett. 1997, 38, 1153. See also: (c)
RajanBabu, T. V. J . Org. Chem. 1988, 53, 4522.
(16) Yeung, B, W.; Alonso, R.; Vite´, G. D.; Fraser-Reid, B. J .
Carbohydr. Chem. 1989, 8, 413, and references cited therein.
(18) (a) Beckwith, A. L. J .; Schiesser, C. H. Tetrahedron 1985, 41,
3925. (b) Beckwith, A. L. J . Tetrahedron 1981, 37, 3073 and references
therein.
(19) (a) Chiara, J . L.; Destabel, C.; Gallego, P.; Marco-Contelles, J .
J . Org. Chem. 1996, 61, 359. (b) Keck, G. E.; McHardy, S. F.; Wager,
T. T. Tetrahedron Lett. 1995, 36, 7419.

7400 J . Org. Chem., Vol. 62, No. 21, 1997
Marco-Contelles et al.
Sch em e 3
Sch em e 6
Sch em e 7
â-elimination M f P (Scheme 5) that could take place
after reduction of the initial radical L to an organosa-
marium intermediate M?; (b) is the stereochemical
outcome of the cyclization dependent on the reagent
Bu3SnH or SmI2 used for the reaction? Both questions
have been answered, and our results are as follows.
Sch em e 4
First of all, we observed that cyclization with the
bromide precursors did not proceed in the absence of
HMPA.10b After extensive experimentation, compound
7a gave in the best conditions a mixture of products 29,
24a , and 30 (Scheme 6). Compound 30 is the reduced,
uncyclized material accompanied with minor amounts of
the cyclized trans isomer 24a and epoxide 29, isolated
as a syn/anti mixture of oxime ethers, but diastereomeri-
cally pure at C-4.21 We then turned our attention to
precursor 7d , where epoxide formation would be pre-
vented. Under the same experimental conditions, we
isolated the cyclic product 24d as a single diastereoisomer
together with almost an equimolar amount of the reduc-
tive elimination product 31 (Scheme 7). Although no
epoxide was formed, elimination of the benzoate group
upon reduction of the initial radical by SmI2 competes
with cyclization. Very significantly, performing the
reaction at -78 °C prevents formation of 31 giving a
mixture of cyclized products 24d /25d in very poor yield
(16%) and lower stereoselectivity (70/30, respectively).
From these experiments we conclude that the tin-
mediated radical cyclization of 5-bromo-oxime ethers
derived from carbohydrates is clearly superior to the
corresponding SmI2-mediated reaction. In the latter
case, side reactions such as reductive elimination of the
alkoxide group at C-4, epoxide formation, or simple
dehalogenation of the substrate compete with cyclization.
The low yield of carbocycles is probably due also to partial
N-O reductive cleavage by excess SmI2 (see below).22
These problems probably could be overcome if precursors
with an iodide instead of bromide group were used.
However, this possibility was discarded since, in our
previous experience, this type of compound is rather
Sch em e 5
At this point, we considered the use of SmI2 as
reductive promotor in these carbocyclizations (Scheme 5).
Intramolecular Barbier-type reactions promoted by sa-
marium diiodide are known14 but, to our knowledge, have
never been applied to such highly functionalized sub-
strates as those derived from sugars. Besides, the first
examples of aza-Barbier couplings promoted by sa-
marium diiodide have been reported recently, but only
for simple substrates.10b,c Two questions attracted also
our interest at this point: (a) Will cyclization compete
favorably with other possible side-reactions such as the
(20) 27: yellowish foam; 1H NMR (CDCl3) δ 8.16 (s, 1H), 4.83 (d, J
) 4.4 Hz, 1H), 4.59 (m, 2H), 4.29 (m, 2H), 3.50 (br s, 2H), 2.54 (br s,
1H), 2.25-1.98 (m, 2H), 1.54 (s, 3H), 1.36 (s, 3H). 28: white solid; 1H
NMR (CDCl3) δ 8.28 and 8.23 (2s, 2H), 5.18 (m, 1H), 4.71 (m, 2H),
4.33 (t, J ) 4.2 Hz, 1H), 2.55 (m, 2H).
(21) The last product probably arises from a samarium(III) alkoxide
intermediate via intramolecular bromide displacement. This alkox-
ysamarium could be formed by deprotonation of 7a by the intermediate
anions formed from 7a in the reaction, although direct reduction of
the hydroxyl group of 7a by the SmI2/HMPA complex to the samari-
um(III) alkoxide with release of H2 cannot be discarded.
(22) In fact, in these reactions we detect always benzyl alcohol that
results from the N-O reductive cleavage. The presence of HMPA
made troublesome to isolate, for instance, the corresponding amino
alcohol 26 (Scheme 4).

Synthesis of Aminocyclitols
Sch em e 8a
J . Org. Chem., Vol. 62, No. 21, 1997 7401
Sch em e 9
9 was obtained as the E isomer at the CdC double bond
and as a mixture of syn/anti oxime isomers in 3:1 ratio,
respectively. We were unable to separate these isomers
that were submitted together to cyclization. When a
solution of 9 in THF was added to SmI2 (3 mol equiv) in
THF and HMPA (15 mol equiv) at room temperature,
compound 39 was formed after 3 h in 52% yield, as a
single isomer.17b When the reaction was performed at
-40 °C, a mixture of products resulted from which 39
could be isolated in a lower yield, together with other
uncharacterized products. Although no mechanistic
studies were performed, we hypothesize that this reaction
takes place via a homoenolate reactive species Q (Scheme
9), formed after one- (radical-anion) or two- (dianion)
electron transfers from SmI2, that attacks the oxime
ether. Some reports are also in support of this hypoth-
esis.26
C. Sa m a r iu m Diiod id e Med ia ted Cycliza tion of
Oxim e Eth er s δ- or E-F u n ction a lized w ith a Ca r bo-
n yl Gr ou p . We have previously reported on a new
approach to highly functionalized chiral aminocyclopen-
titols via the intramolecular reductive cross-coupling of
oxime ethers with aldehydes or ketones prepared from
readily available carbohydrate precursors.13c We now
report in full our recent results using this strategy,
including an example of cyclization to give a six-
membered ring. The first example of intramolecular
reductive cross-coupling of oxime ethers with carbonyl
compounds was described by Corey.27 More recently, this
reaction has been performed using electroreduction28 or
tributyltin hydride.29 Samarium diiodide has also been
used for the intermolecular coupling of aldehydes and
ketones with O-benzylformaldoxime30 and, more recently,
for the corresponding intramolecular coupling with
diphenylhydrazones.10b,c In both cases, the addition of
HMPA was found to be essential for a successful reaction.
Although the reported intermolecular cross-coupling with
O-benzylformaldoxime failed completely with other al-
doximes, we set out to study an intramolecular version
of this reaction with the hope that its lower entropic
barrier could make the process feasible. This process
could provide a straightforward access to branched (F )
unstable, and the chemical yields in the Bu3SnH medi-
ated cyclization are considerably lower.12b
Finally, we performed a comparative study of the
Bu3SnH and SmI2 mediated ring closure of compound 8,
a D-ribose derivative with a slightly different arrange-
ment of protecting groups. This substrate was obtained
from the protected D-ribonolactone 3223 after standard
manipulations, and it was submitted to cyclization as
shown in Scheme 8. The samarium diiodide ring closure
gave, in 40% total yield (61% taking into account the
recovered starting material), the major trans product
36a 17c with traces of the cis isomer 36b. The analogous
cyclization with tributyltin hydride gave compounds 36a /
36b in a 1.8:1 ratio, in 80% yield. Finally, samarium
diiodide reductive cleavage of the N-O bond19 followed
by acetylation in situ gave a mixture of silyl-migrated
compounds 37 (78%) which, after desilylation and acety-
lation, gave finally the acetamide 38.
B. Sa m a r iu m Diiod id e Cycliza tion of Oxim e
Eth er s δ-F u n ction a lized w ith a n r,â-Un sa tu r a ted
Ester . Although the SmI2 cyclization of sugar-derived
R,â-unsaturated esters tethered to carbonyl groups is
known,24 the similar protocol using oxime ethers has not
been described yet.25 This process, if successful, would
result in a simple entry into branched aminocyclitols of
type D from acyclic sugar derivatives C (Scheme 1).
To this end, we prepared the precursor 9 from alcohol
35 by standard manipulations (Scheme 9). Compound
(23) Shen, S. Y.; J ouille´, M. M. J . Org. Chem. 1984, 49, 2168.
Bagget, N.; Buchanan, J . G.; Fatah, M. Y.; Lachut, C. H.; McCullough,
K. J .; Webber, J . M.; J . Chem. Soc., Chem. Commun. 1985, 1826.
(24) (a) Enholm, E. J .; Trivellas, A. J . Am. Chem. Soc. 1989, 111,
6463. (b) Enholm, E. J .; Satici, H.; Trivellas, A. J . Org. Chem. 1989,
54, 5841. (c) Enholm, E. J .; Trivellas, A. Tetrahedron Lett. 1994, 35,
1627. (d) Tadano, K.-i.; Isshiki, Y.; Minami, M.; Ogawa, S. J . Org.
Chem. 1993, 58, 6266, and references cited therein.
(25) Aurrecoechea has recently described a related aproach using
R-benzotriazolylalkenylamines: (a) Aurrecoechea, J . M.; Ferna´ndez-
Acebes, A. Tetrahedron Lett. 1993, 34, 549. (b) Aurrecoechea, J . M.;
Lo´pez, B.; Ferna´ndez, A.; Arrieta, A.; Coss´ıo, F. P. J . Org. Chem. 1997,
62, 1125.
(26) Fry, A. J .; Little, R. D.; Leonetti, J . J . Org. Chem. 1994, 59,
5017.
(27) Corey, E. J .; Pyne, S. G. Tetrahedron Lett. 1983, 2821.
(28) (a) Shono, T.; Kise, N.; Fujimoto, T. Tetrahedron Lett. 1991,
32, 525. (b) Shono, T.; Kise, N.; Fujimoto, T.; Yamanami, A.; Nomura,
R. J . Org. Chem. 1994, 59, 1730.
(29) (a) Naito, T.; Tajiri, K.; Harimoto, T.; Ninomiya, I.; Kiguchi, T.
Tetrahedron Lett. 1994, 35, 2205. (b) Kiguchi, T.; Tajiri, K.; Ninomiya,
I.; Naito, T. Tetrahedron Lett. 1995, 36, 253.
(30) Hanamoto, T.; Inanaga, J . Tetrahedron Lett. 1991, 32, 3555.

7402 J . Org. Chem., Vol. 62, No. 21, 1997
Marco-Contelles et al.
Sch em e 10
Sch em e 11
and unbranched (H, n ) 1) aminocyclopentitols and to
aminoinositols (H, n ) 2) from precursors E and G
(Scheme 1). These precursors can be easily prepared in
two steps from readily available O-protected sugar hemi-
acetals by condensation with O-benzylhydroxylamine and
subsequent oxidation of the released hydroxyl group, as
discussed below.
C1. Sa m a r iu m Diiod id e Med ia ted Cycliza tion of
Su ga r -Der ived Oxim e E t h er s w it h a δ-Ca r b on yl
Gr ou p . The ketone/oxime ether cross-coupling was
studied first. Starting from readily available sugar
lactols 40-42,31 three substrates 17-19 were prepared
by condensation with O-benzylhydroxylamine followed by
PCC oxidation of the released hydroxyl group at C-5.
These substrates differed in the configuration at C-2
(sugar numbering), the center adjacent to the oxime ether
group, and at C-4, the center adjacent to the carbonyl
group (Scheme 10).
Sch em e 12
When a 0.02 M solution of ketone 17, derived from
D-glucose, in THF was added to SmI2 in THF (2.5 mol
equiv, 0.1 M) and t-BuOH (2.5 mol equiv) at -25 °C, the
reductive coupling took place smoothly to afford the
branched aminocyclopentitol 43 as a single diastereoi-
somer in good yield (Scheme 11).17b Interestingly, this
coupling proceeds in the absence of HMPA, in contrast
to the analogous intermolecular case30 and to the corre-
sponding coupling of hydrazones.10b It is also noteworthy
that a single diastereoisomer is obtained out of four
possible stereochemical results. A similar approach has
been reported very recently using a tributyltin hydride-
induced reductive coupling of the corresponding O-
methyloxime derivative of 17.29b In this case, a mixture
of two diastereoisomeric aminocyclopentitols was ob-
tained in 68% yield and 1.4:1 ratio. The minor isomer
corresponds to that obtained by us using SmI2.
Under the same conditions, ketone 18 derived from
D-mannose afforded a mixture of three aminocyclopen-
titols 44a -c17b (Scheme 11) in 15:3:1 ratio,32 respectively,
and in good yield. The major diastereoisomer 44a could
be isolated from this mixture in 60% yield by column
chromatography. Under the same conditions, ketone 19
derived from D-galactose afforded a cyclopentylhydroxy-
lamine 45 (Scheme 11) in moderate yield.17b,33 It should
be noted that compounds 43-45 can be readily converted,
by hydrogenolysis, into isomers of trehazolamine, the
aminocyclopentitol aglycon of the trehalase inhibitor
trehazoline (2). Thus, this sequence provides an efficient
and very short entry into different enantiomerically pure
analogues of this interesting aminocyclopentitol from
readily available starting materials. It should be stressed
that the fully functionalized cyclopentanes 43 and 44a -c
are obtained in just five steps from free D-glucose and
D-mannose, respectively.
We have also observed that the stereochemistry of the
cyclic products is independent of the geometry of the
starting oxime ether.9b Although syn/anti mixtures of
oximes have been used in all cases, a single stereochem-
ical outcome was obtained in one instance (cyclization of
17). In the case of 17, the syn-isomer could be isolated
and submited to cyclization separatedly, with the same
stereochemical outcome as when a mixture enriched in
the anti-isomer (anti/syn ) 76:24) was used. In most
cyclizations (see below), the major isomer shows a trans
relationship between the hydroxyl and the O-benzylhy-
droxylamino groups, and also between the latter and the
alkoxy group at C-2 (starting sugar numbering).
(31) Lactols 40 and 41 were easily obtained in two steps from the
corresponding free sugar: Decoster, E.; Lacombe, J .-M.; Strebler, J .-
L.; Ferrari, B.; Pavia, A. A. J . Carbohydr. Chem. 1983, 2, 329. Lactol
42 cannot be prepared using this methodology, and it was in turn
obtained from the corresponding thiophenyl glycoside (Garegg, P. J .;
Hultberg, H.; Lindberg, C. Carbohydr. Res. 1980, 83, 157) by oxidative
hydrolysis with NBS in aqueous acetone: Groneberg, R. D.; Miyasaki,
T.; Stylianides, N. A.; Schulze, T. J .; Stahl, W.; Schreiner, E. P.; Suzuki,
T.; Iwasbuchi, Y.; Smith, A. L.; Nicolaou, K. C. J . Am. Chem. Soc. 1993,
115, 7593 (for an analogous hydrolysis procedure, see: Motavia, M.
S.; Marcussen, J .; Moller, B. L. J . Carbohydr. Chem. 1995, 14, 1279).
(32) Determined from the 1H NMR of the crude reaction mixture.
(33) A minor cyclopentane product was also isolated in this case (see
Experimental Section and the Supporting Information), but its struc-
ture could not be fully determined.
In order to explore the scope of the method we also
examined the performance of aldehydes derived from
sugars. For this purpose, alcohols 35 (Scheme 8), 47, and
49 (Scheme 12) were prepared by straighforward syn-
thetic procedures using the known intermediates 4624a

Synthesis of Aminocyclitols
Sch em e 13a
J . Org. Chem., Vol. 62, No. 21, 1997 7403
Sch em e 14a
Sch em e 15a
and 48.34 These alcohols were isolated as inseparable
mixtures of syn and anti oximes.
Initially, Swern oxidation of 35 derived from D-ribose
and reductive cyclization of the isolated intermediate
aldehyde gave a mixture of products from which the
major cyclopentane (50a ) could be isolated in only 32%
overall yield from 35 (Scheme 13). However, the overall
yield was greatly improved when the Swern oxidation and
the SmI2 cyclization were performed in a one-pot sequence,
thus avoiding the isolation of the intermediate alde-
hyde.35 Under these conditions, compound 35 gave a
mixture of cyclopentanes 50a -d .17b,36 The formation of
compound 50d was unexpected and probably could arise
from an intermediate (methylthio)methyl ether formed
with the excess of Swern reagent after cyclization.
Simple treatment of compopund 50a with formaldehyde
in the presence of citric acid gave quantitatively com-
pound 50d , thus confirming the assigned structure.
When compound 47 derived from D-arabinose was
subjected to this one-pot procedure, a nonseparable
mixture of two cyclopentanes 51a ,b17b was obtained in
8:1 ratio,32 respectively, and good overall yield (Scheme
13). Using the same procedure, the more conformation-
ally labile precursor 49, derived from D-xylose, produced
an almost equimolar mixture of two cyclopentane dias-
teroisomers 52a ,b17b (Scheme 13).
explore also the corresponding cyclization of compounds
14, 15, and 20 (Figure 2) in order to extend this
methodology to simple deoxygenated substrates. Com-
pound 54, precursor of 14, was prepared from δ-valero-
lactone (53) by DIBALH reduction followed by oxime
ether formation (Scheme 14). Using the previous serial
oxidation-reductive cyclization conditions, compound 54
gave exclusively amino alcohol 55 in 49% yield. A 6-exo
cyclization was also tried with aldehyde 15. However,
when compound 56, precursor of 15, was submitted to
the same experimental conditions, a complex mixture of
products resulted from which we could not isolate any
carbocyclic compound (Scheme 14).
The cyclization of a 3,4,5-trideoxy-analog (20) of ke-
tones 17-19 was investigated. This precursor was
prepared from 1,2,6-hexanetriol (58) as shown in Scheme
15. Using our standard conditions for carbocyclization,
we obtained the expected carbocycle 62 in moderate yield
with minor amounts of 63 resulting from reductive
elimination of the benzyloxy group (Scheme 15). Curi-
ously enough, this side reaction was not observed in the
cyclization of the corresponding sugar derivatives. The
only diastereoisomers isolated in the cyclizations of these
simple precursors have the hydroxyl and the O-benzyl-
hydroxylamino groups in trans relative orientation, which
is also the general tendency found for the corresponding
polyhydroxylated precursors derived from sugars.
C3. Sa m a r iu m Diiod id e Med ia ted Cycliza tion of
Su ga r -Der ived Oxim e Eth er s w ith a n E-Ald eh yd e
Gr ou p . In spite of the precedent deceiving result for
aldehyde 15 (Figure 2), we prepared a sugar derivative
having a similar oxime ether ꢀ-functionalized with an
C2. Sa m a r iu m Diiod id e Med ia ted Cycliza tion of
Sim p le Oxim e Eth er s δ- or E-F u n ction a lized w ith a
Ca r bon yl Gr ou p . The above results moved us to
(34) Tejima, S.; Ness, R. K.; Kaufman, R. L.; Fletcher, H. G.
Carbohydr. Res. 1968, 7, 485.
(35) We have recently described a similar one-pot sequence consist-
ing of a Swern oxidation and a SmI2-induced pinacol coupling for the
direct transformation of alditol-derived 1,6-diols into inositol deriva-
tives: Chiara, J . L.; Mart´ın-Lomas, M. Tetrahedron Lett. 1994, 35,
2969. Chiara, J . L.; Valle, N. Tetrahedron: Asymmetry 1995, 6, 1895-
1898.
(36) Performing the reaction in larger scale than in our preliminary
communication13c allowed a more complete analysis of the different
products formed.

7404 J . Org. Chem., Vol. 62, No. 21, 1997
Marco-Contelles et al.
Sch em e 16a
Sch em e 17a
water (20-25 mol equiv).40 This one-pot two-step se-
quence takes place in excellent yield in the case of 17 f
68 and can be combined with a preceding Swern oxida-
tion step allowing the direct transformation of a 5-hy-
droxy-oxime ether into a 2-aminocyclopentitol in a strik-
ingly good overall yield, as exemplified for 35. In the
latter case, the sequence of Swern oxidation, reductive
carbocyclization and N-O reductive cleavage produced
an inseparable mixture of two products (4:1 ratio) in a
remarkable 86% overall yield, which resulted from partial
silyl migration to nitrogen during the reductive cleavage
step.41 Desilylation of the mixture with TBAF in THF
and in situ acetylation afforded 69 as a single product in
92% yield.
Although we have not performed mechanistic studies,
it seems reasonable that the samarium diiodide-promoted
CdO/CdNOR cross-coupling reaction is initiated by
single electron transfer to the carbonyl with generation
of a ketyl radical-anion which then adds to the CdN
double bond. The process is completed by reduction of
the resultant intermediate aminyl radical and protona-
tion.42 It seems likely that cyclization does not require
prior activation of the oxime ether by intramolecular
chelation to the Lewis acidic Sm(III) ion in the interme-
diate radical, at difference with what is thought to occur
in intramolecular pinacol coupling reactions promoted by
samarium diiodide.43 Thus, electronic repulsion between
the oxygen of the ketyl radical-anion and the nitrogen
atom of the oxime could account for the preferred trans
relative arrangement of the hydroxyl and the hydroxy-
lamino groups in the cyclic products. The same trans-
selectivity has been observed for the corresponding
electrochemical reaction28b and also for the analogous
coupling with diphenylhydrazones.10b Additionally, if the
radical cyclization step is reversible, the observation that
the stereochemistry of the cyclic products is independent
of the oxime isomer used could be explained. However,
aldehyde, but adding some conformational constraints in
order to favor the cyclization. Our selected precursor was
compound 16 (Figure 2), readily obtained from D-glucose
as previously described.37 Dess-Martin oxidation38 of the
primary hydroxyl of 64 gave the intermediate aldehyde
16 (Scheme 16). After extensive experimentation, we
found conditions for a successful cyclization reaction.
When a 0.02 M solution of purified 16 in THF was added
to a solution of SmI2 in THF at -45 °C, compounds
65a -c were formed in good overall yield but with rather
poor diastereoselection, as determined by 1H NMR of the
crude reaction mixture (Scheme 16). We were able to
separate and purify each diastereomer. These com-
pounds were transformed into derivatives 66a -c and 67
after reaction with 1,1′-thiocarbonyldiimidazole. The
1
analysis of their H NMR spectra helped to confirm the
assignment of the stereochemistry.17b This aldehyde/
oxime ether cyclization is important because it opens the
way for a new and exciting method for the preparation
of aminoinositols in enantiomerically pure form from
sugars. This result complements our previous observa-
tions on SmI2-induced pinacol coupling for the direct
transformation of an alditol-derived 1,6-diol into an
inositol derivative.13a,b
(39) To facilitate isolation, the crude reaction mixtures were treated
with Ac2O and pyridine at room temperature affording the N,O-
diacetylated compounds. The tertiary hydroxyl of compound 68 is
unreactive under these conditions, and when the acetylation was
performed in the presence of catalytic DMAP a complex mixture of
products resulted.
C4. Sequential Carbonyl-Oxime Ether Cyclization
and N-O Reductive Cleavage Promoted by Samarium
Diiodide. As we have seen above, the cyclic O-benzyl-
hydroxylamine products could further react in situ with
excess SmI2 by reduction of the N-O bond19 to give the
corresponding primary amine thus further enhancing the
utility of this methodology. This has been demonstrated
for the cyclizations of 17 and 35 (Scheme 17).39 The N-O
reductive cleavage reaction is accelerated by addition of
(40) For previous reports on SmI2-promoted reactions in the presence
of water, see for example: (a) Girard, P.; Namy, J . L.; Kagan , H. B. J .
Am. Chem. Soc. 1980, 102, 2693. (b) Otsubo, K.; Inanaga, J .;
Yamagushi, M. Tetrahedron Lett. 1986, 27, 5763. (c) Hasegawa, E.;
Curran, D. P. J . Org. Chem. 1993, 58, 5008. (d) Kamoshi, Y.; Kudo,
T. Chem. Lett. 1993, 1495. (e) Miyoshi, N.; Takeuchi, S.; Ohgo, Y.
Chem. Lett. 1993, 2129. (f) Miyoshi, N.; Takeuchi, S.; Ohgo, Y.
Heterocycles 1993, 36, 2383. (g) Hanessian, S.; Girard, C. Synlett 1994,
861; see also ref 19a.
(41) The other minor carbocyclic products 50b-d were not isolated
under these conditions.
(42) Shono et al.28b have recently shown that oxime ethers are not
electrochemically reducible under the same conditions as they are
coupled to ketones, which led them to propose a similar mechanism
for the corresponding electrochemical cross-coupling.
(37) Marco-Contelles, J .; Pozuelo, C.; J imeno, M. L.; Mart´ınez, L.;
Mart´ınez-Grau, A. J . Org. Chem. 1992, 57, 2625.
(38) Dess, D. B.; Martin, J . C.; J . Am. Chem. Soc. 1991, 113, 7277,
and references cited therein.
(43) (a) Molander, G. A.; Kenny, C. J . Am. Chem. Soc. 1989, 111,
8236. (b) Chiara, J . L.; Cabri, W.; Hanessian, S. Tetrahedron Lett.
1991, 32, 1125.

Synthesis of Aminocyclitols
Sch em e 18a
J . Org. Chem., Vol. 62, No. 21, 1997 7405
mediated radical cyclization is clearly superior to the
corresponding SmI2-mediated reaction. In the latter
case, side reactions such as reductive elimination, epoxide
formation, or simple dehalogenation of the substrate
compete with cyclization.
A new reductive coupling reaction has been uncovered.
The intramolecular coupling of an R,â-unsaturated ester
with an oxime ether can be promoted by samarium
diiodide in the presence of HMPA. The reaction proceeds
with good diastereoselection, although in moderate yield,
affording a branched aminocyclopentitol from a readily
prepared sugar precursor.
We have also shown that the intramolecular reductive
coupling of carbonyl-tethered oxime ethers can be pro-
moted by samarium diiodide under very mild conditions,
in the absence of HMPA, in good chemical yield and
stereoselectivity. Moreover, the reductive coupling reac-
tion can be performed in a one-pot sequence with a prior
Swern oxidation step, allowing the direct transformation
of hydroxyl-tethered oxime ethers into the corresponding
aminocyclitols, a process which is specially advantageous
when the cyclization involves an aldehyde. The resultant
cyclic hydroxylamine ethers can be efficiently converted
in situ to the corresponding aminocyclitols by N-O
reductive cleavage promoted by excess samarium diiodide
and water. These processes have been applied to highly
functionalized substrates derived from carbohydrates,
providing a short and selective entry to five- and six-
membered amino polyols of varying regio- and stereo-
chemistry.
preferential reaction of one of the oxime isomers con-
comitant with a rapid isomerization under the slightly
acidic reaction conditions could also account for the
observed results.44 Another general stereochemical ten-
dency observed in our radical cyclizations of oxime ethers
derived from carbohydrates with bromide, R,â-unsatur-
ated ester, and carbonyl functions is the preferred trans
disposition of the hydroxylamine group and its vicinal
alkoxy group in the cyclic products. Minimization of
dipolar interactions and allylic-type 1,3-strain between
the oxime and the R-alkoxy group in the transition state
of the cyclization could account for this tendency.
A
similar effect in the ketyl radical-anion moiety explains
also the preferred trans arrangement between the hy-
droxyl group and its vicinal alkoxy group in the cyclic
products.
Exp er im en ta l Section
Gen er a l. NMR sepctra were recorded at 200 MHz or 300
MHz and at 30 °C. Tetrahydrofuran (THF) was distilled under
argon from sodium-benzophenone, and CH2Cl2 and HMPA
from CaH2. All reactions were performed under argon with
anhydrous freshly distilled solvents. Samarium diiodide was
prepared immediately before use by adding ICH2CH2I in one
portion to a suspension of samarium metal powder (1.2 equiv)
in THF (10 mL/mmol of ICH2CH2I) under argon, and stirring
vigorously the resultant suspension for 1-2 h.40a All the
cyclizations were performed in the presence of the slight excess
of samarium metal used in the preparation of the reagent.
Gen er a l Meth od for Tr ibu tyltin Hyd r id e Med ia ted
Ca r bocycliza tion of Br om id es. Meth od A. To a solution
of the radical precursor in toluene (0.03 M), that has been
deoxygenated with argon for 1 h, a solution of tributyltin
hydride (2 equiv) and AIBN (cat.) in toluene (8 M) was slowly
added (via syringe pump) in the time indicated in each case.
The flask was cooled, and the solvent was removed at reduced
pressure. The residue was dissolved in Et2O and stirred
overnight with a 20% aqueous KF solution. The organic phase
was separated, dried (Na2SO4), and concentrated. Flash
chromatography gave the products.
Gen er a l P r oced u r e for Keton e/Oxim e Eth er Cr oss-
Cou p lin g. Meth od B. To a solution of freshly prepared SmI2
(0.1 M, 3 mol equiv) in THF and t-BuOH (5 mol equiv) at -25
°C was added dropwise a solution of the keto-oxime (0.025 M,
1 mol equiv) in THF. After stirring for 1.5 h at -25 °C, the
reaction was quenched at this temperature by addition of
aqueous saturated NaHCO3 (20 mL/mmol of substrate) and
EtOAc (20 mL/mmol of substrate). The mixture was vigor-
ously stirred at room temperature for 0.5 h, the phases were
separated, and the aqueous phase was extracted with EtOAc
(3×). The combined organic extracts were washed with 10%
aqueous Na2S2O3 (1×), and brine (1×) and dried over Na2SO4.
The solvent was removed at reduced pressure, and the residue
was purified by flash column chromatography.
D. Sa m a r iu m Diiod id e Med ia ted Cycliza tion of
δ-Nitr ile-Teth er ed Aldeh ydes. To conclude the present
study, we decided to investigate the reductive cyclization
of carbonyl compounds with nitriles promoted by sa-
marium diiodide, a process scarcely analyzed in the
literature (Scheme 18).43a Our one-pot oxidation and
samarium diiodide cyclization protocol from alcohol 71,
via aldehyde 10, gave the unexpected R,â-unsaturated
ketone 72 in poor yield (16%). The formation of this
adduct can be rationalized as shown in Scheme 18,
through imine R by â-elimination with excess Et3N from
the Swern oxidation step. Of the two possible acidic
protons in R-position to the imine (or the corresponding
ketone formed after hydrolysis), the one close to the
silyloxy group is more prone to elimination because of
its antiperiplanar orientation to the vicinal benzyloxy
moiety. No attempts were made to optimize this cycliza-
tion and explore other less basic reaction conditions to
avoid the eliminiation.
Con clu sion s
A stereoselective method for the preparation of chiral
4-amino-1,2,3-cyclopentanetriols by tributyltin hydride
cyclization of 5-bromo-5-deoxy-2,3-O-isopropylidene-D-
ribose O-benzyl oxime ether derivatives has been achieved.
The moderate yield in the cyclization is compensated for
the good to excellent diastereoselectivity of the reaction
and ready availability of the radical precursors. The tin-
Gen er a l P r oced u r e for On e-P ot Sw er n Oxid a tion /Sm I2
Cou p lin g Sequ en ce. Meth od C. To a solution of (COCl)2
(0.5 M, 2 mol equiv) in THF at -60 °C was added dropwise a
(44) In fact, experiments perfomed by Shono et al.28b may suggest
that the reaction of the anti-form of simple oximes is faster than that
of the syn-form under electrochemical conditions.

7406 J . Org. Chem., Vol. 62, No. 21, 1997
Marco-Contelles et al.
solution of DMSO (3 M, 4 mol equiv) in THF. After stirring
for 15 min at -60 °C, a solution of the 5-hydroxyoxime ether
(0.15 M, 1 mol equiv) in THF was added dropwise via cannula.
After stirring at -60 °C for 1 h, Et3N (5 mol equiv) was added,
and the reaction was stirred at -60 °C to 0 °C for 3 h. The
resultant solution was diluted with THF (final substrate
concentration ) 0.025 M) and added dropwise via cannula to
a solution of freshly prepared SmI2 (0.1 M, 3 mol equiv) in
THF and t-BuOH (3 mol equiv) at -25 °C. The reaction
mixture was stirred at -25 °C for 1.5 h. The reaction was
quenched and worked up as described in method B.
1H), 2.26 (ddd, J ) 13.3, 7, 6.4, 1H), 2.03 (dd, J ) 6.4, 13 Hz,
1H), 1.41, 1.26 (s, s, 3 H, 3 H). Anal. Calcd for C22H25NO5:
C, 68.91; H, 6.57; N, 3.65. Found: C, 66.42; H, 6.16; N. 3.96.
(1R,2R,3S,4RS)-1-O-Ben zoyl-2,3-O-isop r op ylid en e-4-
(m eth oxyam in o)-1,2,3-cyclopen tan etr iol (24e+25e). Com-
pound 7e45 (999 mg, 2.58 mmol), dissolved in toluene (130 mL),
was treated according to method A with tributyltin hydride
(1.67 mL, 6.21 mmol), AIBN (cat.); slow addition for 4 h; 3 h
at reflux. Flash chromatography (hexane/EtOAc 7:3) gave a
mixture of isomers 24e+25e (556 mg, 71%); 1H NMR analysis
of the crude reaction mixture showed that the ratio 24e/25e
was 80:20, respectively; careful chromatography allowed us
to isolate enriched fractions of 24e+25e in 88:12 ratio): oil;
(1R ,2R ,3S ,4R )-4-[(B e n zy lo x y )a m in o ]-2,3-O-iso p r o -
p ylid en e-1,2,3-cyclop en ta n etr iol (24a ). This compound
has been prepared as described.12b Compound 24a has been
also obtained from 24d+25d as follows. A mixture of 24d+25d
(9:1) (339 mg, 0.88 mmol) was treated with excess NaOMe in
MeOH at rt for 2 h. The solvent was evaporated, the residue
diluted with CH2Cl2, washed with brine and dried (Na2SO4).
A compound (100 mg, 42%) was isolated after flash chroma-
tography (hexane/EtOAc 7:3) identical to 24a .12b Rf ) 0.35
(hexane/EtOAc 1:1); mp 47.5-49.5 °C; [R]20D +9.8 (c 1, CHCl3);
1
IR (film) ν 3250, 3060, 1720 cm-1; H NMR (CDCl3) δ (major
isomer 24e) 8.01-8.00 (m, 2H), 7.99-7.98 (m, 1H), 7.38-7.33
(m, 2H), 5.24 (m, 1H), 4.79 (t, J ) 5.6 Hz, 1H), 4.44 (d, J )
5.6, 1H), 3.48 (s, 3 H), 3.47 (m, 1H), 2.21 (ddd, J ) 6.4, 9.8,
13.4 Hz, 1H), 1.94 (ddt, J ) 0.9, 6.6, 13.4 Hz, 1H), 1.33, 1.23
(s, s, 3H, 3 H). Anal. Calcd for C17H23NO5: C, 63.53; H, 7.21;
N, 4.36. Found: C, 61.48; H, 7.33; N, 7.10.
(1R,2R,3S,4R)-4-Am in o-2,3-O-isop r op ylid en e-1,2,3-cy-
clop en ta n etr iol (26). A 0.1 M solution of SmI2 (4.3 mL, 4.33
mmol) in THF was added via cannula to a 0.05 M solution of
24a (394 mg, 1.41 mmol) in THF at rt. After stirring for 2 h,
the reaction mixture was filtered through a small pad of silica,
rinsing with CH2Cl2/MeOH 4:1. The filtrate was concentrated
at reduced pressure and the residue was purified by flash-
chromatography (EtOH/AcOEt 1:19 to 1:9), to give 26 (193 mg,
79%) as a waxy solid. Rf ) 0.16 (EtOAc/EtOH 4:1); [R]20D +3.7
(c 0.2, EtOH); IR (film) ν 3400, 1640 cm-1; 1H NMR (acetone-
d6): δ 5.04 (d, J ) 5.6 Hz, 1H), 4.73 (t, J ) 5.5 Hz, 1H), 4.54
(ddd, J ) 4.9, 5.3, 9.0 Hz, 1H), 4.35 (m, 1H), 2,27 (ddd, J )
4.3, 4.9, 13.4 Hz, 1H), 2.21 (ddd, J ) 6.6, 9.0, 13.4 Hz, 1H),
1.45 (s, 3H), 1.30 (s, 3H). 13C NMR (DMSO-d6) δ 111.4, 82.0,
80.0, 69.7, 53.5, 34.5, 26.4 , 24.7. This compound did not give
correct microanalytical data.
1
IR (KBr) ν 3450, 1495, 1455 cm-1; H NMR (CDCl3) δ 7.35-
7.27 (m, 5H), 5.33 (br s, 1H), 4.65 (s, 2H), 4.39 (dd, J ) 5.2,
5.8 Hz, 1H), 4.35 (d, J ) 5.8 Hz, 1H), 4.19 (ddd, J ) 5.2, 7.6,
8.0 Hz, 1H), 3.42 (dd, J ) 3.7, 4.2 Hz, 1H), 2.36 (br s, 1H),
1.81 (m, 2H), 1.35 (s, 3H), 1.16 (s, 3H); 13C NMR (CHCl3) δ
137.5, 128.6, 128.3, 127.9, 111.0, 82.3, 78.9, 76.7, 71.7, 63.0,
35.9, 26.9, 24.1. Anal. Calcd for C15H21NO4: C, 64.51; H, 7.52;
N, 5.01. Found: C, 64.80; H, 7.80; N, 4.99.
(1R ,2R ,3S,4R )4-[(Be n zyloxy)a m in o]-1-O-(t er t -b u t yl-
d im e t ilsilyl-2,3-O-isop r op ylid e n e -1,2,3-cyclop e n t a n e -
tr iol (24b). Compound 7b45 (783 mg, 1.65 mmol) in dry
benzene (166 mL) was treated according to method A with
tributyltin hydride (1.10 mL, 3.96 mmol) and AIBN (cat.) in
benzene (5 mL); 6 h slow addition; 23 h at reflux. Flash
chromatography (hexane/EtOAc 4:1) gave 24b (346 mg, 53%):
1
oil; [R]25 +14 (c 3.2, CHCl3); IR (film) ν 3250, 1495 cm-1; H
Rea ction of Oxim e Eth er 7a w ith Sm I2. To a solution
of 7a 45 (115 mg, 0.22 mmol) in THF (11 mL) and HMPA (1.3
mL, 7.3 mmol) at -40 °C was added a 0.1 M solution of SmI2
(1.5 mL, 1.46 mmol) in THF. After stirring at -40 °C to -5
°C for 3 h, the reaction mixture was added to saturated
aqueous NaHCO3. The aqueous phase was extracted with
EtOAc (3 × 30 mL), and the combined organic extracts were
washed with 10% aqueous Na2S2O3 and brine. The solvent
was evaporated at reduced pressure, and the residue was
purified by flash-chromatography (hexane/EtOAc 4:1) to give
29 (24 mg, 27%), 30 (6 mg, 7%), and 24a (7 mg, 8%). 29: oil;
E/Z ) 4:1; IR (film) ν 2995, 1495, 1450 cm-1; 1H NMR (CDCl3)
δ E-isomer: 7.54 (d, J ) 7.9 Hz, 1H), 5.14 (s, 2H), 4.83 (dd, J
) 6.5, 7.9 Hz, 1H), 4.01 (t, J ) 6.4 Hz, 1H), 2.98 (ddd, J ) 2.5,
3.9, 6.3 Hz, 1H), 2.82 (dd, J ) 3.9, 5.0 Hz, 1H), 2.73 (dd, J )
2.5, 5.0 Hz, 1H), 1.52 (s, 3H), 1.38 (s, 3H); Z-isomer: 6.95 (d,
J ) 6,3 Hz, 1H), 5.12 (s, 2H), 4.80 (t, J ) 6.5 Hz, 1H), 1.47 (s,
3H), 1.36 (s, 3H); 13C NMR (CDCl3) δ E-isomer: 146.4, 137.1,
128.4, 128.2, 128.0, 110.4, 77.8, 76.3, 75.2, 49.4, 45.5, 27.5, 25.1.
D
NMR (CDCl3) δ 7.34-7.29 (m, 5H), 4.66 (d, J ) 12 Hz, 1 H),
4.64 (d, J ) 12.0 Hz, 1H), 4.32 (t, J ) 5 Hz, 1H), 4.17-4.20
(m, 2H), 3.35 (m, 1H), 2.02 (ddd, J ) 13.5, 7.1, 5.5 Hz, 1 H),
1.60 (m, 1H), 1.43, 1.26 (s, s, 3 H, 3 H), 0.89 (s, 9 H); 13C NMR
(CDCl3) δ 137.5, 129.4-127.9, 110.9, 81.9, 80.0, 72.8, 76.6, 63.2,
34.78, 26.2, 24.5, 25.9. Anal. Calcd for C21H35NSiO4: C, 64.08;
H: 8.96; N, 3.55. Found: C, 61.38; H, 8.83; N, 3.12.
(1R,2R,3S,4R)1-O-Acet yl-4-[(b en zyloxy)a m in o]-2,3-O-
isop r op ylid en e-1,2,3-cyclop en ta n etr iol (24c). Compound
7c45 (540 mg, 1.35 mmol), dissolved in benzene (70 mL), was
treated according to method A with tributyltin hydride (0.9
mL, 3.24 mmol, 2.4 equiv), AIBN (cat.); slow addition for 5 h,
10 h at reflux. Flash chromatography (hexane/EtOAc 3:7) gave
24c (201 mg, 52%): mp 45-47 °C; [R]25 +35 (c 1.4, CHCl3);
D
IR (film) ν 3300, 1735 cm-1; 1H NMR (CDCl3) δ 7.30-7.27 (m,
5H), 4.93 (ddd, J ) 5.1, 6.1, 10.5 Hz, 1H), 4.58 (d, J ) 12 Hz,
1H), 4.53 (d, J ) 12 Hz, 1H), 4.52 (t, J ) 5.4 Hz, 1H), 4.21 (d,
J ) 5.6 Hz, 1H), 3.33 (d, J ) 5.9 Hz, 1H), 1.99 (s, 3 H), 1.98
(m, 1H), 1.77 (ddd, J ) 13.6, 0.7, 6.1 Hz, 1 H), 1.35, 1.16 (s, s,
3 H, 3 H); MS (70 eV) m/z 321(M+, 3), 306 (M+-15, 1), 91(100).
Anal. Calcd for C17H23NO5: C, 63.53; H, 7.21; N, 4.36.
Found: C, 63.40; H, 6.98; N, 4.48.
30: white solid; only E-isomer; mp 54.5-57 ˚C; [R]20 +158 (c
D
0.2, CHCl3); IR (film) ν 3450, 1380, 1270 cm-1; 1H NMR (CDCl3)
δ 7.38-7.34 (m, 5H), 6.95 (d, J ) 4.8 Hz, 1H), 5.32 (dd, J )
4.8, 6.9 Hz, 1H), 5.16 (m, 2H), 4.30 (dd, J ) 4.9, 6.9 Hz, 1H),
2.93 (ddq, J ) 3.2, 4.9, 9.3 Hz, 1H), 2.73 (d, J ) 3.2 Hz, 1H),
2.65 (d, J ) 9.3 Hz, 3H), 1.51 (s, 3H), 1.36 (s, 3H).
(1R,2R,3S,4RS)-1-O-Ben zoyl-4-[(ben zyloxy)a m in o]-2,3-
O-isopr opyliden e-1,2,3-cyclopen tan etr iol (24d+25d). Com-
pound 7d 45 (700 mg, 1.52 mmol), dissolved in toluene (151 mL),
was treated according to method A with tributyltin hydride
(0.98 mL, 3.6 mmol, 2.4 equiv), AIBN (cat.); slow addition for
5 h 30 min, 5 h at reflux. Flash chromatography (hexane/
EtOAc 7:3) gave a mixture of isomers 24d +25d (339 mg, 58%;
1H NMR analysis of the crude reaction mixture showed that
the ratio 24d /25d was 89:11, respectively; careful chromatog-
raphy allowed us to isolate enriched fractions of 24d +25d in
Rea ction of Oxim e Eth er 7d w ith Sm I2. Compound 7d 45
(98 mg, 0.21 mmol) was treated with SmI2 following the
procedure described for 7a . Flash chromatography (hexane/
EtOAc 4:1) afforded 24d (34 mg, 42%) and 31 (21 mg, 37%).
31: colorless oil; E/Z ) 9:1; Rf ) 0.42 (hexane/EtOAc 4:1); 1H
NMR (CDCl3) δ (E-isomer) 7.38-7.35 (m, 5H), 7.33 (d, J )
3.6 Hz, 1H), 5.72 (ddd, J ) 6.3, 10.5, 16.7 Hz, 1H), 5.40 (dd, J
) 1.5, 16.7 Hz, 1H), 5.29 (dd, J ) 1.5, 10.5 Hz, 1H), 5.10 (s,
2H), 4.72 (m, 2H), 1.54 (s, 3H), 1.42 (s, 3H); 13C NMR (CDCl3)
δ (E-isomer) 148.7, 137.9, 133.0, 129.1, 128.9, 128.6, 119.8,
110.6, 79.8, 76.8, 76.6, 28.6, 26.1. Anal. Calcd for
C15H19NO3: C, 68.93; H, 7.34; N, 5.36. Found: C, 68.83; H,
7.49; N, 5.64.
1
91:9 ratio): oil; IR (KBr) ν 3500-3200, 1725 cm-1; H NMR
(CDCl3) δ (major isomer 24d ) 8.25-8.10 (m, 2H), 7.60-7.25
(m, 7H), 5.77 (dt, J ) 5.6, 9.3 Hz, 1H), 4.75 (t, J ) 5.6 Hz,
1H), 4.70 (s, 2H), 4.40 (d, J ) 5.6 Hz, 1H), 3.55 (q, J ) 5.2 Hz,
3,4-O-Ben zylid en e-2-O-(ter t-b u t yld im et h ylsilyl)-D-r i-
bose O-Ben zyl Oxim e Eth er (35). To a solution of 3,4-O-
(45) See the Supporting Information.

Synthesis of Aminocyclitols
J . Org. Chem., Vol. 62, No. 21, 1997 7407
benzylidene-2-O-(tert-butyldimethylsilyl)-δ-D-ribonolactone 3323
(1.4 g, 4.0 mmol), in toluene (50 mL) at -78 °C, was added a
1 M solution of DIBALH in cyclohexane (8.0 mL, 8.0 mmol)
dropwise. The reaction mxture was stirred at this temperature
for 1 h, MeOH (35 mL) was added dropwise, and the mixture
was allowed to warm to rt. After stirring for 3 h, the resultant
suspension was filtered through Celite, and the filter was
washed with MeOH (3 × 50 mL). The filtrate was concen-
trated at reduced pressure, and the residue was purified by
flash-chromatography (hexane/EtOAc 3:1), to give 34 [(1.4 g,
98%); 1H NMR (CDCl3) δ 7.61-7.36 (m, 5H), 5.81 (s, 1H), 5.16
(dd, J ) 3.4, 6.3 Hz, 1H), 4.45 (dd, J ) 2.9, 7.9 Hz, 1H), 4.38
(m, 1H), 3.90 (dd, J ) 2.9, 13.2 Hz, 1H), 3.78 (m, 2H), 2.75 (d,
J ) 3.7 Hz, 1H), 0.92 (s, 9H), 0.15 (s, 6H)]. This compound
(1.35 g, 3.83 mmol) was treated with O-benzylhydroxylamine
hydrochloride following the procedure applied for 7a . Flash-
chromatography (hexane/EtOAc 4:1) afforded 35 (1.42 g, 81%)
as a white semisolid, inseparable 85:15 mixture of E/Z isomers,
respectively. Rf ) 0.21 (hexane/EtOAc 4:1); IR (film) ν 3460,
1460, 1255, 1090 cm-1; 1H NMR (CDCl3) δ 7.52-7.29 (m, 11H),
6.78 (d, J ) 5.1 Hz, 1H, Z-isomer), 5.82 (s, 1H), 5.09 (s, 2H),
4.65 (t, J ) 7.0 Hz, 1H), 4.41-4.24 (m, 2H), 3.87-3.79 (m, 2H),
2.42 (t, J ) 6.9 Hz, 1H), 0.87 (s, 9H), 0.08 (s, 3H), 0.01 (s, 3H).
Anal. Calcd for C25H35NO5Si: C, 65.60; H, 7.72; N, 3.06.
Found: C, 65.24; H, 7.92; N, 3.05.
3,4-O-Ben zylid en e-5-br om o-2-O-(ter t-bu tyld im eth ylsi-
lyl)-5-d eoxy-D-r ibose Oxim e Eth er (8). To a solution of 35
(769 mg, 1.68 mmol) and Ph3P (1.76 g, 6.72 mmol) in pyridine
(20 mL) at 0 °C was added CBr4 (1.11 g, 3.36 mmol). The
solution was warmed to rt and then heated at reflux for 17 h.
After cooling to rt, MeOH (15 mL) was added, and the solvent
was removed at reduced pressure. Flash-chromatography of
the residue (hexane/EtOAc 19:1) afforded 8 (422 mg, 48%) as
a colorless oil, inseparable 85:15 mixture of E/Z isomers. Rf
) 0.27 (hexane/EtOAc 19:1); IR (film) ν 1465, 1255, 1090, 1020
cm-1; 1H NMR (CDCl3) δ (E-isomer) 7.55-7.30 (m, 10H), 7.52
(d, J ) 7.0 Hz, 1H), 5.88 (s, 1H), 5.11 (s, 2H), 4.62-4.52 (m,
2H), 4.31 (t, J ) 6.5 Hz, 1H), 3.75 (dd, J ) 3.0, 11.0 Hz, 1H),
3.56 (m, 1H), 0.89 (s, 9H), 0.06 (s, 3H), 0.01 (s, 3H); 13C NMR
(CDCl3) δ (E-isomer) 149.5, 137.4, 136.4, 129.5, 128.4, 128.3,
128.2, 128.0, 126.9, 103.8, 79.8, 78.7, 76.2, 69.2, 31.5, 25.7, 18.5,
-4.0, -4.1. Anal. Calcd for C25H34BrNO4Si: C, 57.67; H, 6.60;
N, 2.69. Found: C, 57.98; H, 6.90; N, 2.65.
(2 mL) and pyridine (4 mL) were added at rt, and the mixture
was stirred for 15 h. The reaction mixture was diluted with
EtOAc (25 mL) and washed with aqueous saturated NaHCO3.
The aqueous phase was extracted with EtOAc (3 × 50 mL),
and the combined organic extracts were washed with 10%
aqueous Na2S2O3, and brine. The solvent was removed at
reduced pressure and the crude was purified by flash-chro-
matography (hexane/EtOAc 1:4) affording 37 (77 mg, 78%) as
a white solid, 5:1 mixture of regioisomers (see text). Rf ) 0.12
(hexane/EtOAc 2:3); IR (KBr) ν 3500, 1655, 1580, 1470 cm-1
;
1H NMR (CDCl3) δ (major product) 7.57-7.37 (m, 5H), 5.71
(s, 1H), 5.47 (brd, J ) 5.0 Hz, 1H), 4.60 (t, J ) 5.8 Hz, 1H),
4.41 (t, J ) 5.1 Hz, 1H), 4.12-4.05 (m, 2H), 2.24 (dd, J ) 6.1,
14.0 Hz, 1H), 1.97 (s, 3H), 1.78 (ddd, J ) 5.5, 11.5, 14.0 Hz,
1H), 0.91 (s, 9H), 0.11 (s, 6H); (minor product) 5.74 (s, 1H),
2.10 (s, 3H), 0.91 (s, 9H), 0.14 (s, 6H); 13C NMR (CDCl3) δ
(major product) 170.3, 136.5, 129.4, 128.2, 127.0, 104.1, 78.3,
77.5, 76.3, 54.4, 32.2, 25.7, 18.2, -4.5, -4.8; (minor product)
128.4, 126.7, 79.3, 77.3, 76.7, 56.2, 30.9, 23.7. Anal. Calcd
for C20H31NO4Si: C, 63.63; H, 8.29; N, 3.70. Found: C, 63.84;
H, 8.48; N, 3.72.
(1R,2R,3S,4R)-4-N-Acetyl-3-O-acetyl-1,2-O-ben zyliden e-
1,2,3-cyclop en ta n etr iol (38). To a solution of 37 (62 mg, 0.16
mmol) in THF (5 mL) was added a 1.0 M solution of tetrabu-
tylammonium fluoride (0.49 mL, 0.49 mmol) in THF at rt.
After stirring for 2 h, Ac2O (2 mL) and pyridine (4 mL) were
added. The reaction mixture was stirred at rt for 5 h, and
the solvent was removed at reduced pressure. The residue
was suspended in EtOAc (30 mL) and water (25 mL). The
phases were separated, and the aqueous phase was extracted
with EtOAc (3 × 25 mL). The combined organic extracts were
dried over Na2SO4 and evaporated at reduced pressure. Flash-
chromatography (EtOAc) of the residue afforded 38 (40 mg,
81%) as a white solid. Rf ) 0.25 (EtOAc); mp 188-190 °C;
[R]22 +30 (c 1.3, CHCl3); IR (KBr) ν 3450, 1735, 1645, 1560
D
cm-1; 1H NMR (CDCl3) δ 7.54-7.40 (m, 5H), 5.74 (m, 1H), 5.70
(s, 1H), 4.84 (ddd, J ) 5.5, 9.4, 11.6 Hz, 1H), 4.69-4.56 (m,
3H), 2.53 (dd, J ) 6.9, 14.3 Hz, 1H), 2.11 (s, 3H), 1.97 (s, 3H),
1.61 (ddd, J ) 5.5, 11.6, 14.3 Hz, 1H); 13C NMR (CDCl3) δ
172.1, 170.9, 136.1, 130.3, 128.9, 127.5, 105.1, 78.1, 77.3, 76.9,
51.8, 34.1, 23.9, 21.3. Anal. Calcd for C16H18NO5: C, 62.03;
H, 6.29; N, 4.59. Found: C, 62.97; H, 6.25; N, 4.58.
Syn th esis of Oxim e Eth er 9. To a solution of (COCl)2
(0.60 mL, 6.21 mmol) in CH2Cl2 (12 mL) at -60 °C was added
dropwise DMSO (0.88 mL, 12.42 mmol). After stirring for 15
min at -60 °C, a solution of 35 (945 mg, 2.07 mmol) in dry
CH2Cl2 (15 mL) was added dropwise. After stirring at -60
°C for 45 min, Et3N (4,3 mL, 31.05 mmol) was added dropwise
and the reaction stirred at -60 to 0 °C for 3 h. The reaction
mixture was diluted with CH2Cl2 (30 mL) and washed with
aqueous saturated NH4Cl. The aqueous phase was extracted
with CH2Cl2 (3 × 30 mL), and the combined organic layers
were dried over Na2SO4 and concentrated at reduced pressure,
affording the corresponding crude aldehyde 11. To a stirred
solution of crude 11 in toluene (20 mL) at room temperature
was added Ph3PdCHCO2Et (1.80 g, 5.17 mmol). After stirring
at 25 °C for 16 h the mixture was heated at 70 °C for 5 h until
the reaction was complete. After cooling, the toluene was
removed at reduced pressure, and the residue was purified
by flash column chromatography (hexane/EtOAc 9:1) to afford
9 (798 mg, 73%) as a colorless oil, mixture of two isomers. A
fraction of pure major isomer (E oxime ether/E CdC) was
obtained followed by mixed fractions of both isomers (E oxime
ether/E CdC and Z oxime ether/E CdC). Major isomer (E
oxime ether/E CdC): Rf ) 0.28 (hexane/EtOAc 9:1); IR (film):
Cycliza tion of Oxim e Eth er 8. With Bu 3Sn H. Com-
pound 8 (365 mg, 0.71 mmol) in toluene (35 mL) was treated
according to method A with tributyltin hydride (0.46 mL, 1.70
mmol) and AIBN (cat.) in benzene (2 mL); 3 h slow addition;
3 h at reflux. Flash-chromatography (hexane/EtOAc 100:0 to
85:15) afforded 36a (159 mg, 51%) and 36b (89 mg, 29%). With
Sm I2. Compound 8 (53 mg, 0.10 mmol) in THF (5 mL) was
treated with SmI2 as indicated for 7a . Flash-chromatography
(hexane/EtOAc 9:1) afforded unreacted 8 (19 mg) and 36a (18
mg, 40%, 61% based on recovered 8). The 1H NMR of the crude
showed also the presence of traces of 36b. 36a : Colorless oil;
Rf ) 0.29 (hexane/EtOAc 85:15); [R]20 + 92 (c 4.0, CHCl3); IR
D
(KBr) ν 3400, 1460, 1400, 1250, 1140 cm-1; H NMR (CDCl3)
1
δ 7.56-7.27 (m, 10H), 5.90 (br s, 1H), 5.70 (s, 1H), 4.69 (s,
2H), 4.58 (t, J ) 5.8 Hz, 1H), 4.40 (t, J ) 5.7 Hz, 1H), 3.90
(dd, J ) 5.4 and 9.4 Hz, 1H), 3.53 (ddd, J ) 6.3, 9.4, 11.5 Hz,
1H), 2.10 (dd, J ) 6.3, 14.0 Hz, 1H), 1.65 (ddd, J ) 5.6, 11.5,
14.0 Hz, 1H), 0.91 (s, 9H), 0.11 (s, 3H), 0.10 (s, 3H); 13C NMR
(CDCl3) δ 137.6, 136.8, 129.3, 128.3, 128.2, 127.8, 127.0, 104.2,
79.1, 77.7, 76.8, 73.5, 63.9, 31.1, 25.6, 16.2, -4.5, -4.8. Anal.
Calcd for C25H34NO4Si: C, 67.98; H, 8.00; N, 3.17. Found: C,
67.69; H, 7.99; N, 3.42. 36b: Rf ) 0.19 (hexane/EtOAc 85:
15); [R]20 -108 (c 1.5, CHCl3); IR (film) ν 3400, 1460, 1400,
1725, 1660 cm-1; H NMR (CDCl3) δ 7.49 (m, 2H), 7.40-7.27
1
D
1250, 1220 cm-1; 1H NMR (CDCl3) δ 7.61-7.28 (m, 10H), 5.78
(s, 1H), 4.67 (s, 2H), 4.68-4.39 (m, 4H), 2.04 (dd, J ) 5.7, 14.2
Hz, 1H), 1.85 (m, 1H), 0.90 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H);
13C NMR (CDCl3) δ 140.7, 136.7, 129.4, 128.5, 128.2, 127.5,
127.0, 126.9, 104.7, 80.0, 79.0, 78.1, 76.7, 65.2, 31.7, 25.8, 16.2,
-4.6.
(m, 9H), 7.06 (dd, J ) 15.6, 5.2 Hz, 1H), 6.12 (dd, J ) 15.6,
1.6 Hz, 1H), 5.06 (s, 2H), 4.89 (ddd, J ) 1.6, 1.7, 5.2 Hz, 1H),
4.33 (m, 2H), 4.19 (q, J ) 7.1 Hz, 2H), 1.28 (t, J ) 7.1 Hz,
3H), 0.86 (s, 9H), 0.03 (s, 3H), 0.00 (s, 3H); 13C NMR (CDCl3)
δ 165.8, 149.8, 142.2, 137.5, 136.2, 129.5, 128.3, 128.2, 127.8,
127.0, 123.5, 104.0, 80.5, 77.2, 76.1, 69.6, 60.4, 25.8, 17.9, 14.2,
-3.8, -5.1; [R]25 -33.9 (c 1.3, CHCl3). Anal. Calcd for
Red u ction of 36a w ith Sm I2. A solution of 36a (116 mg,
0.26 mmol) in THF (5 mL) was added to a 0.1 M solution of
SmI2 (7.9 mL, 0.79 mmol) in THF at rt. Water (0.10 mL, 5.26
mmol) was added, and the mixture was stirred for 3.5 h. Ac2O
D
C29H39NO6Si: C, 66.12; N, 2.66; H, 7.67. Found: C, 66.36; N,
2.70; H, 7.64.
Minor isomer (Z oxime ether/E CdC): Rf ) 0.26 (hexane/

7408 J . Org. Chem., Vol. 62, No. 21, 1997
Marco-Contelles et al.
EtOAc 9:1); 1H NMR (CDCl3) δ (aromatic protons not in-
cluded): 7.14 (dd, J ) 6.3, 15.7 Hz, 1H), 6.71 (d, J ) 6.5 Hz,
1H), 6.11 (dd, J ) 1.4, 15.7 Hz, 1H), 5.82 (s, 1H), 5.10 (s, 2H),
4.79 (ddd, J ) 1.3, 1.4, 6.3 Hz, 1H), 4.33 (m, 2H); 4.20 (q, J )
7.1 Hz, 2H), 1.28 (t, J ) 7.1 Hz, 3H), 0.86 (s, 9H), 0.01 (s, 3H),
-0.02 (s, 3H).
chromatography of the residue (hexane/EtOAc 1:1) afforded
42 (400 mg, 80%) as a colorless oil. Rf ) 0.31 (hexane/EtOAc
1
1:1); H NMR (CDCl3) δ 7.32 (m, 20 H), 5.26 (d, J ) 3,5 Hz,
1H), 4.95-4.53 (m, 6H), 4.42 (m, 2H), 4.15 (brt, J ) 6.6 Hz,
1H), 4.02 (dd, J ) 3.5, 9.5 Hz, 1H), 3.93 (m, 2H), 3.89 (dd, J )
2.7, 9.7 Hz, 1H), 3.74 (dd, J ) 7.4, 9.7 Hz, 1H), 3.56 (dd, J )
5.3, 9.7 Hz, 1H).
Cycliza tion of Oxim e Eth er 9. A solution of compound
9 (83 mg, 0.16 mmol) in THF (8 mL) was added dropwise via
cannula to a 0.1 M solution of SmI2 (4.8 mL, 0.48 mmol) in
THF and HMPA (0.42 mL, 2.4 mmol) at room temperature.
The SmI2 was consumed immediately after finishing the
addition. The reaction mixture was worked up as described
in method B. Flash chromatography (hexane/EtOAc 4:1) of
Syn th esis of Oxim e Eth er 19. Following the same
procedure as for 17, compound 19 was obtained from 42 in
69% overall yield as a colorless oil, 3:1 mixture of E/Z-oximes,
respectively. Rf ) 0.35 (hexane/EtOAc 4:1); 1H NMR (CDCl3)
δ E-isomer: 7.53 (d, J ) 7.9 Hz, 1H), 7.37-7.24 (m, 25H), 5.11
(s, 2H), 4.62-4.12 (m, 13H); Z-isomer: 6.94 (d, J ) 6.5 Hz,
1H), 5.10 (s, 2H), 5.01 (dd, J ) 5.0 y 6.5 Hz, 1H); 13C NMR
(CDCl3) δ (aromatic carbons not included) E-isomer: 206.8,
149.0, 81.8, 81.3, 76.7, 76.1, 74.3, 74.1, 73.2, 73.1, 71.3;
Z-isomer: 151.1, 80.8, 80.4, 76.4, 74.5, 74.4, 72.9, 72.3, 71.7.
Anal. Calcd for C41H41NO6: C, 76.49; H, 6.42; N, 2.18.
Found: C, 76.46; H, 6.48; N, 2.34.
the crude afforded 39 as a colorless oil (43 mg, 52%). [R]25
D
-25.9 (c 2.4, CHCl3); 1H NMR (acetone-d6) δ 7.50-7.28 (m,
10H), 6.22 (d, J ) 2.9 Hz, 1H), 5.70 (s, 1H), 4.68 (m, 2H), 4.66
(dd, J ) 5.5, 5.9 Hz, 1H), 4.53 (dd, J ) 5.4, 5.9 Hz, 1H), 4.20
(dd, J ) 5.4, 9.3 Hz, 1H), 4.18 (q, J ) 7.1 Hz, 2H), 2.96 (ddd,
J ) 2.9, 9.3, 11.7 Hz, 1H), 2.58 (, J ) 4.5, 16.8 Hz, 1H), 2.50
(dd, J ) 9.9, 16.8 Hz, 1H), 1.24 (t, J ) 7.1 Hz, 3H), 0.90 (s,
9H), 0.12 (s, 3H), 0.10 (s, 3H); 13C NMR (CDCl3) δ 173.1, 137.9,
136.9, 129.2, 128.4, 128.3, 128.1, 127.7, 127.0, 126.6, 103.9,
78.4, 78.0,76.5 71.3, 67.3, 60.2, 35.4, 31.2, 25.8, 18.2, 14.1, -4.6,
-4.9. Anal. Calcd for C29H41NO6Si: C, 66.03; H, 7.78; N, 2.66.
Found: C, 65.88; H, 8.01; N, 2.58.
Cycliza tion of Oxim e Eth er 17. Following method B,
oxime 17 (640 mg, 0.99 mmol) gave aminocyclitol 43 (520 mg,
81%): Rf ) 0.26 (hexane/EtOAc 2:1); [R]20 +20.6 (c 1.6,
D
1
CHCl3); H NMR (CDCl3) δ 7.40-7.22 (m, 25H), 6.03 (d, J )
6.0 Hz, 1H), 4.77-4.38 (m, 10H), 4.13 (dd, J ) 6.3, 7.5 Hz,
1H), 3.86 (d, J ) 7.5 Hz, 1H), 3.76 (t,, J ) 6.2 Hz, 1H), 3.59 (d,
J ) 10.2 Hz, 1H), 3.46 (t, J ) 6.1 Hz, 1H), 3.45 (d, J ) 10.2
Hz, 1H), 2.89 (br s, 1H); 13C NMR (CDCl3) δ 138.0 (2C), 137.8,
137.7, 128.4, 128.3, 128.0, 127.9 (2C), 127.7, 127.5, 86.9, 82.3,
82.1, 77.7, 76.1, 73.7, 73.2, 72.4 (2C), 71.7, 71.2. Anal. Calcd
for C41H43NO6: C, 76.25; H, 6.71; N, 2.17. Found: C, 76.17;
H, 6.83; N, 2.23.
Syn th esis of Oxim e Eth er 17. A suspension of 2,3,4,6-
tetra-O-benzyl-R-D-glucopyranose (40)31 (990 mg, 1.83 mmol)
and O-benzylhydroxylamine hydrochloride (352 mg, 2.20
mmol) in MeOH (12 mL) and pyridine (1 mL) was heated at
60 °C for 8 h. The solvent was removed at reduced pressure,
and the residue was purified by flash column chromatography
(hexane/EtOAc 3:1) to afford 1.13 g (96%) of a mixture of
oximes (E/Z ) 3.3:1, by 1H NMR), as a colorless oil. A solution
of this mixture (980 mg, 1.52 mmol) in CH2Cl2 (4 mL) was
added to a suspension of PCC (1.29 g, 6.00 mmol), NaOAc (70
mg, 0.81 mmol), and 3 Å MS (1 g) in CH2Cl2 (10 mL) at room
temperature. After stirring for 2 h at room temperature, the
mixture was diluted with Et2O (200 mL), and the resultant
suspension was filtered through a short column of silica,
eluting thoroughly with Et2O. The filtrate was concentrated
at reduced pressure, and the crude was purified by flash
column chromatography (hexane/EtOAc 6:1) to afford 17 (820
mg, 84%), as a colorless oil. 1H NMR (CDCl3) δ E isomer: 7.54
(d, J ) 7.8 Hz, 1 H), 7.4-7.1 (m, 25 H), 5.13 (s, 2 H), 4.73-
4.21 (series of m, 13 H), 4.18 (d, J ) 3.3 Hz), 4.07 (dd, J ) 6.7,
3.3 Hz); Z isomer: 7.4-7.1 (m, 25 H), 6.92 (d, J ) 6.6 Hz),
5.07 (s, 2 H), 5.04 (dd, J ) 6.6, 2.0 Hz), 4.54-4.19 (series of
m, 13H), 4.14 (d, J ) 7.1 Hz), 4.06 (Ψt, J ) 4.6 Hz); 13C NMR
(CDCl3) δ (aromatic carbons not included) E isomer: 207.7,
148.5, 82.7, 80.5, 76.3, 76.0, 74.5, 74.4, 74.0, 73.2, 71.6; Z
isomer: 206.5, 150.7, 81.7, 79.7, 76.4, 74.3, 74.2, 73.7, 73.2,
72.6, 71.1. Anal. Calcd for C41H43NO6: C, 76.49; H, 6.42; N,
2.18. Found: C, 76.30; H, 6.25; N, 1.98.
Syn th esis of Oxim e Eth er 18. Following the same
procedure as for 17, compound 18 was obtained from 2,3,4,6-
tetra-O-benzyl-R-D-mannopyranose (41)31 in 88% overall yield
as a colorless oil. 1H NMR (CDCl3) (aromatic protons not
included) (E/Z ) 3:1) δ 7.39 (d, J ) 8.1 Hz, 1 H, E isomer),
6.81 (d, J ) 7.3 Hz, 1 H, Z isomer), 5.14 (s, 2 H, E isomer),
5.13 (s, 1H, Z isomer), 5.05 (dd, J ) 7.3, 6.4 Hz, 1 H, Z isomer),
4.55-4.17 (series of multiplets), 4.10 (dd, J ) 7.6, 3.3 Hz, E
isomer); 13C NMR (CDCl3) δ (aromatic carbons not included)
E isomer: 208.1, 148.4, 83.7, 80.3, 76.1, 75.7, 74.4, 74.2, 73.2,
70.6; Z isomer: 207.4, 149.7, 83.1, 80.1, 76.3, 74.1, 71.6, 70.3.
Anal. Calcd for C41H43NO6: C, 76.49; H, 6.42; N, 2.18.
Found: C, 76.21; H, 6.32; N, 2.22.
Cycliza tion of Oxim e Eth er 18. Following method B,
oxime 18 (256 mg, 0.40 mmol) gave aminocyclitol 44a (154 mg,
60%) and an inseparable 3:1 mixture of 44b and 44c (38 mg,
15%). 44a : Rf ) 0.50 (hexane/EtOAc 1:1); [R]20 -32.0 (c 1.2,
D
1
CHCl3); H NMR (CDCl3) δ 7.40-7.22 (m, 25H), 6.43 (d, J )
7.5 Hz, 1H), 4.74 (m, 2H), 4.71-4.47 (m, 8H), 4.17 (dd, J )
0.8, 8.4 Hz, 1H), 4.11 (dd, J ) 6.3, 8.4 Hz, 1H), 4.02 (br s, 1H),
3.85 (dd, J ) 4.3, 6.3 Hz, 1H), 3.73 (d, J ) 9.5 Hz, 1H), 3.70
(d, J ) 9.5 Hz, 1H), 3.64 (ddd, J ) 0.8, 4.3, 7.5 Hz, 1H); 13C
NMR (CDCl3) δ 138.6, 138.3 (2C), 137.7, 137.5, 128.6, 128.4,
128.2, 128.1, 127.9, 127.8, 127.6, 127.4, 88.1, 80.3, 79.6, 76.1,
76.0, 73.7, 73.1, 72.3, 72.1, 71.5, 69.8. Anal. Calcd for
C41H43NO6: C, 76.25; H, 6.71; N, 2.17. Found: C, 76.41; H,
6.68; N, 2.19. 44b (as an inseparable mixture with 44c): Rf
) 0.60 (hexano/AcOEt 1:1); 1H NMR (acetone-d6) δ 7.41-7.22
(m, 25H), 6.41 (d, J ) 10.5 Hz, 1H), 4.91-4.48 (m, 10H), 4.25
(dd, J ) 3.7, 4.6 Hz, 1H), 4.19 (d, J ) 8.8 Hz, 1H), 3.97 (dd, J
) 3.7, 8.8 Hz, 1H), 3.61 (d, J ) 9.2 Hz, 1H), 3.60 (br s, 1H),
3.57 (dd, 4.6, 10.5 Hz, 1H), 3.48 (d, J ) 9.2 Hz, 1H); 13C NMR
(CDCl3) δ 138.7, 138.3, 138.1, 137.9, 128.4, 128.3, 127.7, 127.6,
127.5 (2C), 84.0, 83.7, 75.8, 75.4, 74.4, 73.9, 73.6, 73.4, 72.4,
69.3. 44c (as an inseparable mixture with 44b): Rf ) 0.60
(hexane/EtOAc 1:1) 1H NMR (acetone-d6) δ 7.41-7.22 (m,
25H), 6.39 (d, J ) 8.9 Hz, 1H), 4.91-4.48 (m, 10H), 4.11 (d, J
) 7.1 Hz, 1H), 4.05 (dd, J ) 6.3, 7.1 Hz, 1H), 3.78 (dd, J )
5.1, 6.3 Hz, 1H), 3.73 (s, 1H), 3.65 (dd, J ) 5,1, 8.9 Hz, 1H),
3.62 (d, J ) 9.1 Hz, 1H), 3.55 (d, J ) 9.1 Hz, 1H); 13C NMR
(CDCl3) δ 128.6, 128.1, 128.0, 127.9, 127.8, 82.5, 81.4, 79.7,
76.6, 76.2, 74.0, 73.5, 72.0, 71.3, 66.2.
Cycliza tion of Oxim e Eth er 19. Following method B,
oxime 19 (112 mg, 0.17 mmol) gave aminocyclitol 45 (57 mg,
51%) and a minor compound (28 mg, structure not deter-
mined), as colorless oils. 45: Rf ) 0.21 (hexane/EtOAc 4:1);
[R]20D +21.6 (c 0.9, CHCl3); 1H NMR (CDCl3): see Table 2; 13
C
2,3,4,6-Tetr a -O-ben zyl-â-D-ga la ctop yr a n ose (42). To a
solution of phenyl 2,3,4,6-tetra-O-benzyl-1-thio-â-D-galactopy-
ranoside31 (584 mg, 0.92 mmol) in acetone (20 mL) at -15 °C
were added H2O (18 µL, 1.02 mmol) and NBS (210 mg, 1.11
mmol). After stirring at -15 °C for 1 h, the reaction mixture
was partioned between CH2Cl2 (100 mL) and aqueous satu-
rated NaHCO3 (30 mL). The organic layer was separated, and
the aqueous phase was extracted with CH2Cl2 (2 × 30 mL).
The combined organic extracts were washed with brine, dried
over Na2SO4, and concentrated at reduced pressure. Flash
NMR (CDCl3) δ 138.7, 138.6, 138.4, 137.9, 137.8, 128.5, 128.4,
128.2, 128.1, 127.9, 127.8, 127.5, 127.4 (2C), 127.3, 87.1, 85.5,
82.2, 80.4, 75.7, 73.8, 73.6, 72.3 , 72.0, 71.5, 69.8. Anal. Calcd
for C41H43NO6: C, 76.25; H, 6.71; N, 2.17. Found: C, 75.98;
H, 7.00; N, 2.46. Minor compound: Rf ) 0.19 (hexane/EtOAc
4:1); 1H NMR (CDCl3) δ 7.30-7.05 (m, 25H), 4.71-4.44 (4 m,
8H), 4.51 (dd, J ) 5.2, 5.6 Hz, 1H), 4.21 (t, J ) 5.1 Hz, 1H),
3.93 (d, J ) 5.0 Hz, 1H), 3.89 (d, J ) 5.6 Hz, 1H), 3.85 (d, J )
9.6 Hz, 1H), 3.73 (d, J ) 9.6 Hz, 1H), 3.38 (s, 1H); 13C NMR

Synthesis of Aminocyclitols
J . Org. Chem., Vol. 62, No. 21, 1997 7409
(CDCl3) δ 138.5, 138.2, 137.7, 137.5, 128.4, 128.3, 128.2, 128.0,
127.8, 127.6, 127.5, 87.9, 84.3, 83.0, 81.7, 81.4, 73.6, 73.3, 72.4,
71.8, 69.8.
8.78; N, 3.46. 51a :1H NMR (CDCl3) δ 7.38-7.31 (m, 5H), 5.65
(br s, 1H), 4.72 (m, 2H), 4.42 (ddd, J ) 0.9, 2.5, 7.0 Hz, 1H),
4.32 (ddd, J ) 0.9, 2.8, 7.0 Hz, 1H), 4.07 (dd, J ) 2.8, 5.5 Hz,
1H), 3.96 (ddd, J ) 0.9, 2.5, 5.8 Hz, 1H), 3.13 (dt, J ) 0.9, 1.0,
5.5 Hz, 1H), 2.40 (s, 1H), 1.39 (s, 3H), 1.26 (s, 3H), 0.88 (s,
9H), 0.12 (s, 3H), 0.10 (s, 3H); 13C NMR (CDCl3) δ 37.7, 128.5,
128.4, 128.0, 111.4, 84.9, 84.6, 76.9, 76.5, 76.3, 73.2, 26.3, 25.7,
24.0, 17.9, -4.8, -5.1. 51b: 1H NMR (CDCl3) δ 7.38-7.31 (m,
5H), 5.65 (br s, 1H), 4.73 (s, 2H), 4.54 (dd, J ) 5.6, 5.8 Hz,
1H), 4.29 (d, J ) 5.8 Hz, 1H), 4.06 (d, J ) 3.9 Hz, 1H), 3.75
(dd, J ) 5.6, 9.6 Hz, 1H), 3.37 (dd, J ) 3.9, 9.6 Hz, 1H), 2.41
(s, 1H), 1.44 (s, 3H), 1.28 (s, 3H), 0.86 (s, 9H), 0.10 (s, 3H),
0.09 (s, 3H); 13C NMR (CDCl3) δ 128.2, 127.7, 111.4, 82.9, 76.2,
72.3, 71.6, 67.3, 26.0, -5.3.
Syn th esis of O-(ter t-Bu tyld im eth ylsilyl)-3,4-O-isop r o-
p ylid en e-D-a r a bin ose O-Ben zyl Oxim e Eth er (47).
A
solution of 3,4-O-isopropylidene-2-O-(tert-butyldimethylsilyl)-
D-arabinose (46)24a (1.52 g, 5.00 mmol) was treated with
O-benzylhydroxylamine hydrochloride as described for 35, to
give 47 (1.70 g, 80%) as a colorless oil, 9:1 mixture of E and Z
oximes. Rf ) 0.32 (hexane/EtOAc 2:1); IR (film) ν 3475, 1470,
1460 cm-1; 1H NMR (CDCl3) δ (aromatic protons not included)
E-isomer: 7.47 (d, J ) 6.6 Hz, 1H), 5.08 (s, 2H), 4.43 (t, J )
6.5 Hz, 1H), 4.23 (m, 2H), 3.75-3.69 (m, 2H), 2.39 (d, J ) 6.5
Hz, 1H), 1.42 (s, 3H), 1.34 (s, 3H), 0.87 (s, 9H), 0.06 (s, 3H),
0.03 (s, 3H); Z-isomer: 6.79 (d, J ) 7.1 Hz, 1H), 5.10 (s, 2H),
4.77 (dd, I) 2.0, 7.6 Hz, 1H). Anal. Calcd for C21H35NO5Si:
C, 61.56; H, 8.63; N, 3.42. Found: C, 61.81; H, 8.60; N, 3.17.
2,3,4-Tetr a -O-ben zyl-D-xylose O-Ben zyl Oxim e Eth er
(49). To a solution of 4834 (895 mg, 2.13 mmol) in CH2Cl2 (20
mL) O-benzylhydroylamine hydrochloride (849 mg, 5.32 mmol)
and pyridine (0.52 mL, 6.39 mmol). After heating the reaction
mixture at reflux for 15 h, it was partitioned between CH2Cl2
(35 mL) and aqueous saturated NaHCO3. Usual extractive
workup and flash-chromatography (hexane/EtOAc 4:1) of the
resultant residue afforded 49 (940 mg, 84%) as a colorless oil,
3:1 mixture of E and Z oximes. Rf ) 0.26 (hexane/EtOAc 2:1);
IR (film) ν 3450, 1500, 1455 cm-1; 1H NMR (CDCl3) δ E-isomer:
7.48 (d, J ) 7.7 Hz, 1H), 7.39-7.25 (m, 20H), 5.12 (s, 2H),
4.70-4.32 (m, 9H), 4.24 (dd, J ) 5.1, 7.7 Hz, 1H), 3.78-3.60
(m, 3H), 1.91 (brt, J ) 6.4 Hz, 1H). Anal. Calcd for
C33H35NO5: C, 75.40; H, 6.71; N, 2.67. Found: C, 75.70; H,
6.92; N, 2.71.
Cycliza tion of Oxim e Eth er 49. Following method C,
oxime 49 (63 mg, 0.12 mmol) gave aminocyclitols 52a (17 mg,
27%) and 52b (13 mg, 21%). 52a : colorless oil; Rf ) 0.30
(hexane/EtOAc 2:1); [R]20 -7.1 (c 2.1, CHCl3); 1H NMR
D
(CDCl3) δ 7.40-7.28 (m, 20H), 5.85 (brs 1H), 4.77-4.50 (m,
8H), 4.08 (m, 1H), 3.95 (ddd, J ) 0.6, 4.6, 5.9 Hz, 1H), 3.82
(dd, J ) 5.9, 8.0 Hz, 1H), 3.81 (dd, J ) 3.5, 4.6 Hz, 1H), 3.51
(dd, J ) 5.7, 8.0 Hz, 1H), 2.70 (br s, 1H); 13C NMR (CDCl3) δ
138.2 (2C), 138.1, 137.3, 128.6, 128.5, 128.4, 128.3, 128.2,
127.9, 127.7, 127.6, 87.3, 86.7, 81.9, 76.5, 72.2, 72.0, 71.8, 65.1.
Anal. Calcd for C33H35NO5: C, 75.40; H, 6.71; N, 2.66.
Found: C, 75.10; H, 6.71; N, 2.86. 52b: white solid; mp 73-
75 °C; Rf ) 0.20 (hexane/EtOAc 2:1); [R]20D -6.0 (c 0.7, CHCl3);
1H NMR (CDCl3) δ 7.33-7.10 (m, 20H), 5.40 (br s, 1H), 4.57
(m, 3H), 4.38 (m, 2H), 4.23 (t, J ) 5.6 Hz, 1H), 4.10 (t, J ) 5.4
Hz, 1H), 3.96 (t, J ) 5.5 Hz, 1H), 3.82 (t, J ) 5.3 Hz, 1H), 3.52
(t, J ) 5.4 Hz, 1H), 2.35 (br s, 1H); 13C NMR (CDCl3) δ 138.4,
138.2, 137.7, 128.7, 128.5, 128.4, 128.1, 128.0, 127.9, 127.7,
127.6, 85.7, 82.1, 81.4, 76.7, 72.2, 72.0, 70.8, 70.2. Anal. Calcd
for C33H35NO5: C, 75.40; H, 6.71; N, 2.66. Found: C, 75.53;
H, 6.44; N, 2.67.
Cycliza tion of Oxim e Eth er 35. Following method C,
oxime 35 (515 mg, 1.12 mmol) gave aminocyclitols 50a (325
mg, 63%), 50b (26 mg, 5%), 50c (10 mg, 2%), and 50d (22 mg,
4%). 50a : Rf ) 0.34 (hexane/EtOAc 7:3); [R]20 -77.2 (c 2.4,
Cycliza tion of 54. DMSO (0.057 mL, 0.80 mmol) was
added dropwise to a stirred solution of oxalyl chloride (0.035
mL, 0.40 mmol) in dry THF (1 mL) at -78 °C. The solution
was stirred for 5 min and oxime 5445
D
1
CHCl3); H NMR (acetone-d6) δ 7.61-7.34 (m, 10H), 6.22 (br
s, 1H), 5.76 (s, 1H), 4.72 (s, 2H), 4.57 (dd, J ) 5.3, 6.1 Hz,
1H), 4.44 (d, J ) 6.1 Hz, 1H), 4.03 (d, J ) 4.3 Hz, 1H), 3.98
(dd, J ) 5.3, 9.9 Hz, 1H), 3.64 (dd, J ) 4.3, 9.9 Hz, 1H), 0.89
(s, 9H), 0.13 (s, 3H), 0.10 (s, 3H); 13C NMR (CDCl3) δ 137.1,
136.3, 129.5, 128.7, 128.6, 128.3, 126.9, 104.8, 82.7, 76.8, 76.4,
72.4, 70.3, 66.6, 25.8, 18.1, -4.5, -4.9. Anal. Calcd for
C25H35NO5Si: C, 65.62; H, 7.71; N, 3.06. Found: C, 65.64; H,
7.59; N, 2.99. 50b: Rf ) 0.21 (hexane/EtOAc 7:3); [R]20D -52.2
(c 1.3, CHCl3); 1H NMR (acetone-d6) δ 7.66-7.28 (m, 10H), 6.25
(d, J ) 7.0 Hz, 1H), 5.73 (s, 1H), 4.75 (m, 2H), 4.60 (ddd, J )
0.8, 5.0, 6.9 Hz, 1H), 4.49 (dd, J ) 5.0, 5.6 Hz, 1H), 4.43 (ddd,
J ) 1.0, 1.8, 6.9 Hz, 1H), 4.22 (d, J ) 3.8 Hz, 1H), 4.17 (ddd,
J ) 1.8, 3.8, 4.2 Hz, 1H), 3.47 (ddd, J ) 1.0, 4.2, 5.6 Hz, 1H),
0.87 (s, 9H), 0.15 (s, 3H), 0.02 (s, 3H); 13C NMR (CDCl3) δ
137.8, 136.1, 129.3, 128.4, 128.0, 127.8, 127.4, 106.8, 85.0, 79.2,
77.0, 76.3, 70.7, 70.5, 25.9, 18.4, -4.4, -5.4. 50c: Rf ) 0.18
(0.033 g, 0.16 mmol) in
dry THF (1 mL) was added dropwise. The reaction mixture
was stirred at -78 °C for 1 h 50 min, Et3N (0.225 mL, 1.60
mmol) was added, and the reaction mixture was stirred from
-78 °C to -50 °C for 2.5 h. Dry THF (5 mL) was added to
this mixture, and the crude aldehyde 14 was added dropwise
over 30 min via cannula to a stirred solution of SmI2 in THF
(0.1 M in THF, 7 mL, 0.70 mmol) and t-BuOH (0.040 mL, 0.42
mmol) at -70 °C under argon. The reaction mixture was
stirred from -70 °C to -55 °C for 1 h, and at rt for 45 min
before being partioned between EtAOc (20 mL) and aqueous
saturated NaHCO3
(15 mL). The reaction was worked up as
described in method B and the residue was purified by flash
column chromatography (hexane/EtAOc 4:1 to 3:2) affording
55 (16 mg, 49% yield) as a pale yellow oil. Rf
) 0.28 (hexane/
1
(hexane/EtOAc 7:3); [R]20 -39.7 (c 0.3, CHCl3); 1H NMR
EtOAc 3:2); IR (film) ν 3350, 3030 cm-1
7.36 (m, 5 H), 4.73 (s, 2 H), 4.08 (br q, J ) 6 Hz, 1H), 3.35 (dt,
C NMR (CDCl3) δ 138.0,
; H NMR (CDCl3) δ
D
(CDCl3) δ 7.53-7.29 (m, 10H), 5.84 (s, 1H), 4.78 (m, 2H), 4.54
(dd, J ) 5.7, 5.9 Hz, 1H), 4.48 (dd, J ) 4.9, 5.9 Hz, 1H), 3.99
(dd, J ) 4.9, 9.9 Hz, 1H), 3.93 (dd, J ) 5.7, 9.8 Hz, 1H), 3.20
(t, J ) 9.9 Hz, 1H), 2.30 (d, J ) 9.7 Hz, 1H), 0.92 (s, 9H), 0.13
(s, 3H), 0.12 (s, 3H); 13C NMR (CDCl3) δ 137.7, 136.1, 129.6,
128.4, 128.2, 127.6, 126.9, 104.7, 78.5, 77.2, 76.7, 69.3, 66.6,
66.4, 25.8, 18.3, -4.6, -4.8. 50d : Rf ) 0.34 (hexane/EtOAc
J ) 7, 6 Hz, 1H), 1.22-2.04 (m, 6H); 13
128.9, 128.8, 128.7, 128.5, 78.1, 77.0, 69.3, 33.2, 27.7, 21.4.
Anal. Calcd for C12H17NO2: C, 69.54; H, 8.27; N, 6.76.
Found: C, 69.78; H, 8.17; N, 6.68.
1-O-Ben zyl-1,2,6-h exa n et r iol (59). A mixture of 1,2,6-
hexanetriol (500 mg, 3.73 mmol) in toluene (10 mL) and
dibutyltin oxide (700 mg, 2.80 mmol) was heated at reflux in
a Dean-Stark apparatus for 6 h. Benzyl bromide (1.8 mL,
15.1 mmol) and tetrabutylammonium bromide (840 mg, 2.61
mmol) were added and the solution was heated at reflux for 5
h. The reaction mixture was diluted with CH2Cl2 (30 mL) and
poured into aqueous 15% NaHCO3. The phases were sepa-
rated and the aqueous phase was extracted with CH2Cl2 (3 ×
25 mL). The combined organic extracts were washed with
brine and dried over Na2SO4. The solvent was removed at
reduced pressure and the residue was purified by flash-
chromatography (EtOAc) affording 59 (504 mg, 60%) as a
colorless oil. Rf ) 0.31 (EtOAc); IR (film) ν 3400(br), 1125,
1030 cm-1; 1H NMR (CDCl3) δ 7.32 (m, 5H), 4.55 (s, 2H), 3.82
(m, 1H), 3.63 (m, 3H), 3.50 (dd, J ) 3.2, 9.4 Hz, 1H), 3.33 (dd,
J ) 7.9, 9.4 Hz, 1H), 2.58 (br s, 1H), 1.84-1.38 (m, 6H).
4:1); [R]20 -66.3 (c 1.2, CHCl3); IR (film) ν 1495, 1405, 1255,
D
1210; 1H NMR (C6D6) δ 7.52-7.31 (m, 10H), 5.57 (s, 1H), 4.86
(d, J ) 8.9 Hz, 1H), 4.76 (d, J ) 5.5 Hz, 1H), 4.72 (s, 2H), 4.56
(d, J ) 5.2 Hz, 1H), 4.53 (dd, J ) 5.5, 8.5 Hz, 1H), 4.44 (d, J
), 8.9 Hz, 1H), 4.26 (dd, J ) 4.4, 5.2 Hz, 1H), 3.67 (dd, J )
4.4, 8.5 Hz, 1H), 0.94 (s, 9H), 0.16 (s, 3H), 0.11 (s, 3H); 13C
NMR (CDCl3) δ 137.3, 136.6, 129.4, 128.9, 128.6, 128.3, 128.0,
127.8, 126.9, 105.5, 90.1, 82.5, 82.2, 81.6, 77.7, 75.3, 74.6, 25.8,
18.3, -4.6, -4.9. Anal. Calcd for C26H35NO5Si: C, 66.49; H,
7.53; N, 2.98. Found: C, 66.61; H, 7.80; N, 3.06.
Cycliza tion of Oxim e Eth er 47. Following method C,
oxime 47 (109 mg, 0.27 mmol) gave an inseparable mixture of
aminocyclitols 51a and 51b (85 mg, 78%, 51a /51b ) 8:1).
Colorless oil; Rf ) 0.32 (hexane/EtOAc 2:1). Anal. Calcd for
C21H35NO5Si: C, 61.58; H, 8.61; N, 3.42. Found: C, 61.87; H,

7410 J . Org. Chem., Vol. 62, No. 21, 1997
Marco-Contelles et al.
6-O-Ben zyl-5,6-d ih yd r oxyh exa n a l O-Ben zyl Oxim e
Eth er (61). To a suspension of PDC (843 mg, 2.24 mmol),
NaOAc (63 mg, 0.75 mmol), and 3 Å MS (350 mg) in CH2Cl2
(10 mL) was added at rt a solution of 59 (335 mg, 1.49 mmol)
in CH2Cl2 (5 mL). The mixture was stirred at rt for 5 h, Et2O
(20 mL) was added, and the suspension was filtered through
a small pad of silica eluting with Et2O. The filtrate was
concentrated a reduced pressure and the residue was purified
by flash-chromatography (hexane/EtOAc 3:1) affording 60
mmol) in CH2Cl2 (1.2 mL) at rt. After stirring vigorously for
2 h, Et2O (10 mL) was added and the mixture was poured into
10 mL of saturated aqueous NaHCO3 containing 2.3 g of
Na2SO3. The mixture was stirred for 5 min, Et2O was added
(20 mL), phases were separated, and the aqueous phase was
extracted with Et2O (3 × 30 mL). The combined organic
extracts were washed with 10 mL of aqueous saturated
NaHCO3 and 10 mL of water and dried (MgSO4). The solvent
was removed at reduced pressure, and the residue was purified
by flash-chromatography (hexane/EtOAc 5:1) affording 16
[(487 mg, 76%) as a colorless oil, 3:1 mixture of E and Z
isomers. 1H NMR (200 MHz, CDCl3) δ 9.63 (d, J ) 2.1 Hz,
1H, E-isomer), 9.56 (d, J ) 3.5 Hz, 1H, Z-isomer), 7.41 (d, J )
6.4 Hz, 1H, E-isomer), 6.88 (d, J ) 4.6 Hz, 1H, Z-isomer)]. To
a solution of 16 (75.1 mg, 0.21 mmol) in THF (10.5 mL) at
-45 °C was added dropwise a 0.1M THF solution of SmI2 (6.0
mL, 0.60 mmol), and the reaction was stirred at -45 °C to rt
for 6 h. The reaction mixture was worked up as described in
method B. The residue was purified by flash-chromatography
(hexane/EtOAc 5:1 to 3:2) affording, in order of elution, 65a
(16.8 mg, 22%), 65b (18.4 mg, 24%), and 65c (15.3 mg, 20%).
1
[(130 mg, 40%); IR (film) ν 3430, 1725, 1455 cm-1; H NMR
(CDCl3) δ 9.73 (m, 1H), 7.32 (m, 5H), 4.65 (m, 2H), 4.00 (m,
1H), 3.79 (br s, 1H, OH), 2.59-1.37 (m, 6H)]. A solution of
this compound (120 mg, 0.54 mmol) in MeOH (10 mL) was
treated with O-benzylhydroxylamine hydrochloride (173 mg,
1.08 mmol) and pyridine (0.13 mL, 1.62 mmol) as described
for 17. Flash-chromatography (hexane/EtOAc 7:3) afforded 61
(166 mg, 93%) as a colorless oil, 56:44 mixture of E and Z
oximes, respectively. Rf ) 0.31 (hexane/EtOAc 7:3); IR (film):
3450, 1500, 1220 cm-1; 1H NMR (CDCl3) δ (E-isomer) 7.45 (t,
J ) 6.3 Hz, 1H), 7.39 (m, 10H), 5.07 (s, 2H), 4.58 (s, 2H), 3.81
(m, 1H), 3.48 (dd, J ) 3.9, 10.8 Hz, 1H), 3.34 (m, 1H), 2.38 (d,
J ) 3.9 Hz, 1H), 2.22 (q, J ) 6.9 Hz, 2H), 1.78-1.40 (m, 4H);
(Z-isomer) 7.37 (m, 10H), 6.71 (t, J ) 5.2 Hz, 1H), 5.12 (s, 2H),
4.59 (s, 2H), 3.85 (m, 1H, 1H), 3.33 (dd, J ) 8.0, 9.1 Hz, 1H),
2.49-2.38 (m, 3H), 1.78-1.40 (m, 4H). Anal. Calcd for
C20H25NO3: C, 73.35; H, 7.71; N, 4.28. Found: C, 73.61; H,
7.47; N, 3.99.
65a : colorless oil; Rf ) 0.36 (hexane/EtOAc 7:3); [R]25 +7.1
D
(c 0.2, CHCl3); 1H NMR (acetone-d6) δ 7.42-7.29 (m, 5H), 6.40
(d, J )1.9 Hz, 1H), 4.74 (s, 2H), 4.35 (dd, J )3,9, 5.6 Hz, 1H),
4.31 (m, J )4.2, 3.9, 3.4 Hz, 1H), 4.24 (dd, J )8.3, 5.6 Hz,
1H), 4.04 (d, J )3.4 Hz, 1H), 3.69 (dd, J )9.9, 8.3 Hz, 1H),
3.57 (t, J )10.0, 9.9 Hz, 1H), 3.37 (dd, J )10.0, 4.2 Hz, 1H),
1.28 (s, 3H), 1.31 (s, 3H), 1.34 (s, 3H), 1.43 (s, 3H); 13C NMR
(CDCl3) δ: 137.0, 128.7, 128.6, 128.3, 111.9, 109.5, 80.8, 78.7,
76.7, 71.9, 68.1, 61.8, 28.1 , 26.9, 26.9, 25.7. Anal. Calcd for
C19H27NO6: C, 62.45; H, 7.45; N, 3.83. Found: C, 62.25; H,
7.40; N, 3.64. 65b: Colorless oil; Rf ) 0.24 (hexane/EtOAc
1-(Ben zyloxy)-6-[(b en zyloxy)im in o]-2-h exa n on e (20).
To a suspension of PDC (82 mg, 0.38 mmol), NaOAc (11 mg,
0.13 mmol), and 3 Å MS (100 mg) in CH2Cl2 (8 mL) was added
a solution of 61 (82 mg, 0.25 mmol) in CH2Cl2 (5 mL). After
stirring at rt for 8 h, Et2O (15 mL) was added, and the
suspension was filtered through a small pad of silica eluting
with Et2O thoroughly. The filtrate was concentrated at
reduced pressure, and the residue was purified by flash-
chromatography (hexane/EtOAc 7:3) affording 20 (58 mg, 71%)
as a colorless oil, 56:44 mixture of E and Z isomers. Rf ) 0.37
7:3); [R]25 -3.7 (c 1.3, CHCl3); IR (KBr) ν 3450, 1495, 1455,
D
1
1220 cm-1; H NMR (CDCl3) δ 7.37-7.35 (m, 5H), 5.94 (br s,
(hexane/EtOAc 3:7); IR (film) ν 1750, 1495, 1370, 1210 cm-1
;
1H), 4.73 (s, 2H), 4.41 (dd, J )6.7, 3.9 Hz, 1H), 4.27 (t, J )
8.0, 6.7 Hz, 1H), 4.07 (dd, J ) 10.0, 8.0 Hz, 1H), 4.03 (t, J )
3.9, 3.8, 3.0 Hz, 1H), 3.51 (t, J ) 10.4, 10.0 Hz, 1H), 3.31(dd,
J ) 10.4, 3.8 Hz, 1H), 2.55 (dd, J ) 3.0 Hz, 1H), 1.55 (s, 3H),
1.44 (s, 3H), 1.43 (s, 3H), 1.38(s, 3H); 13C NMR (CDCl3) δ 138.1,
129.5, 129.3, 129.0, 113.1, 111.3, 79.3, 78.1, 77.5, 77.3, 74.6,
71.4, 64.9, 27.9, 25.6. Anal. Calcd for C19H27NO6: C, 62.45;
H, 7.45; N, 3.83. Found: C, 62.41; H, 7.30; N, 3.82. 65c:
White solid; Rf ) 0.16 (hexane/EtOAc 7:3); mp 102-104 °C;
1H NMR (CDCl3) δ (E-isomer) 7.40 (t, J ) 6.0 Hz, 1H), 7.31
(m, 10H), 5.03 (s, 2H), 4.58 (s, 2H), 4.00 (m, 2H), 2.48 (dt, J )
3.6, 7.3 Hz, 2H), 2.37 (dt, J ) 5.5, 7.6 Hz, 1H), 2.19 (m, 1H),
1.78 (dq, J ) 3.0, 7.1 Hz, 2H); Z-isomer: 6.65 (t, J ) 5.6 Hz,
1H), 5.08 (s, 2H), 4.56 (s, 2H). Anal. Calcd for C20H23NO3:
C, 73.80; H, 7.14; N, 4.31. Found: C, 74.06; H, 6.95; N, 4.19.
Rea ction of 20 w ith Sm I2. Oxime 20 (0.109 g, 0.33 mmol)
in dry THF (10 mL) was added dropwise over 25 min to a
stirred solution of SmI2 in THF (0.1 M in THF, 10 mL, 1.0
mmol) and t-BuOH (0.080 mL, 0.83 mmol) at -78 °C under
argon. The reaction mixture was stirred for 3.5 h from -78
to -30 °C and then filtered through a short silica gel column
eluting with EtOAc/hexane (1:1). The eluate was concentrated
under reduced pressure. The crude product (0.12 g) was
purified by flash column chromatography. Elution with hex-
ane/EtOAc (4:1) gave 62 (0.046 g, 42%) and 63 (0.013 g, 18%,
as a 1:2 mixture of E/Z isomers). 62: Colorless oil; Rf ) 0.38
(hexane/EtOAc 7:3); IR (film) ν 3450, 3040 cm-1; 1H NMR (200
MHz, CDCl3) δ 1.52-2.20 (m, 6 H), 2.67 (br s, 1 H), 3.46 (m,
1 H), 3.53 (d, J ) 9.4 Hz, 1 H), 3.64 (d, J ) 9.4 Hz, 1 H), 4.55
(s, 2 H), 4.66 (s, 2 H), 5.76 (br s, 1 H), 7.34 (br s, 10 H); 13C
NMR (50.32 MHz, CDCl3) δ 138.5, 138.1, 128.9, 128.8, 128.7,
128.5, 128.2, 82.5, 76.7, 74.0, 69.8, 35.8, 29.1, 21.5; MS (70 eV
m/z 328 (M++H, 2), 91 (100), 77 (4), 65 (5). Anal. Calcd for
C20H25NO3: C, 73.37; H, 7.70; N, 4.28. Found: C, 73.60; H,
7.65; N, 4.28. 63: Colorless oil; Rf ) 0.46 (hexane/EtOAc 7:3);
IR (film) ν 2920, 1720 cm-1; 1H NMR (200 MHz, CDCl3) δ 7.42
(t, J ) 6.0 Hz, 0.5 H, E), 7.34 (m, 5 H + 2.5 H, Z and E), 6.67
(t, J ) 5.5 Hz, 1 H,Z), 5.10 (s, 2 H, Z), 5.05 (s, 1 H E), 2.15-
2.49 (m, 4 H + 2H, Z and E), 2.11 (s, 3 H+ 1.5 H, Z and E),
1.72 (m, 2 H + 1H, Z and E); 13C NMR (50.32 MHz, CDCl3) δ
207.8, 207.7, 151.3, 150.2, 137.7, 137.5, 128.3, 128.1, 128.0,
127.7, 127.5, 127.4, 127.2, 126.7, 75.6, 75.3, 42.5, 42.1, 29.5,
28.5, 29.7, 29.7, 20.1, 19.9. Anal. Calcd for C13H17NO2: C,
71.21; H, 7.81; N, 6.39. Found: C, 71.39; H, 7.58; N, 6.12.
Syn th esis a n d Rea ction of Ald eh yd e 16 w ith Sm I2. To
a suspension of Dess-Martin periodinane38 (1.00 g, 2.36 mmol)
in CH2Cl2 (6 mL) was added a solution of 6437 (664 mg, 1.82
[R]25 +35.6 (c 1.4, CHCl3); IR (KBr) ν 3450, 1450, 1375, 1290
D
1
cm-1; H NMR (CDCl3) δ 7.37-7.30 (m, 5H), 6.10 (br s, 1H),
4.76 (m, 2H), 4.31 (dd, J ) 7.5, 7.2 Hz, 1H), 4.21 (dd, J ) 8.8
Hz, 7.5 Hz, 1H), 4.15 (dd, J ) 10.8, 7.2 Hz, 1H), 3.90 (dd, J )
8.8, 5.5 Hz, 1H), 3.68 (dd, J ) 10.8, 7.0 Hz, 1H), 3.40 (dd, J )
7.0, 5.5 Hz, 1H), 2.40 (brs , 1H), 1.51 (s, 3H), 1.42 (s, 3H), 1.40
(s, 3H), 1.33 (s, 3H); 13C NMR (CDCl3) δ 137.2, 129.4, 128.7,
128.0, 112.9, 110.5, 78.1, 76.8, 76.7, 75.9, 74.8, 73.3, 60.2, 27.3,
27.0, 26.5, 24.5. Anal. Calcd for C19H27NO6: C, 62.45; H, 7.45;
N, 3.83. Found: C, 62.77; H, 7.28; N, 3.51.
Rea ction of 65a w ith Th ioca r bon yl Diim id a zole.
A
solution of 65a (51 mg, 0.14 mmol) and 1,1′-thiocarbonyldi-
imidazole (99 mg, 0.56 mmol) in THF (14 mL) was heated at
reflux for 21 h. The solvent was removed at reduced pressure,
and the residue was purified by flash-chromatography (hexane/
EtOAc 4:1) affording 66a (31 mg, 54%) as a white solid. Rf )
0.29 (hexane/EtOAc 4:1); mp 213-215 °C; [R]25 +7.1 (c 0.2,
D
CHCl3); IR (KBr) ν 1475, 1460, 1390, 1375 cm-1 1H NMR
;
(CDCl3) δ 7.56-7.39 (m, 5H), 5.23 (m, 2H), 4.79 (dd, J ) 9.4,
5.7 Hz, 1H), 4.47 (dd, J ) 7.5, 5.8 Hz, 1H), 4.33 (dd, J ) 7.7,
7.6 Hz, 1H), 4.06 (dd, J ) 9.4, 7.9 Hz, 1H), 3.53 (dd, J ) 10.6,
7.8 Hz, 1H), 3.44 (dd, J ) 10.6, 7.9 Hz, 1H), 1.50 (s, 3H), 1.45
(s, 3H), 1.34 (s, 3H); 13C NMR (CDCl3) δ 191.9, 133.9, 129.6,
129.0, 128.4, 113.3, 110.7, 81.2, 77.4, 76.6, 76.5, 75.4, 75.1, 60.5,
30.6, 26.9, 26.7, 24.4. Anal. Calcd for C20H25NO6S: C, 58.95;
H, 6.18; N, 3.44; S, 7.87. Found: C, 58.60; H, 6.28; N, 3.25; S,
7.57.

Synthesis of Aminocyclitols
J . Org. Chem., Vol. 62, No. 21, 1997 7411
Rea ction of 65b w ith Th ioca r bon yl Diim id a zole.
A
ane/EtOAc 1:2 to 1:4) affording 108 mg (86%) of a 5.4:1 mixture
of silyl-migrated products. Rf ) 0.52 (hexane/EtOAc 1:4); IR
(film) ν 3320, 1760, 1750, 1655, 1560, 1380, 1230; 1H NMR
(CDCl3) δ (major product) 7.58-7.37 (m, 5H), 5.76 (s, 1H), 5.52
(d, J ) 8.8 Hz, 1H), 5.06 (d, J ) 5.0 Hz, 1H), 4.80 (ddd, J )
5.0, 9.0, 10.3 Hz, 1H), 4.47 (dd, J ) 4.9, 6.1 Hz, 1H), 4.39 (d,
J ) 6.1 Hz, 1H), 4.05 (dd, J ) 4.9, 10.5 Hz, 1H), 2.10 (s, 3H),
2.00 (s, 3H), 0.91 (s, 9H), 0.13 (s, 6H); (minor product) 5.81 (s,
1H), 5.01 (d, J ) 5.0 Hz, 1H), 4.50 (dd, J ) 4.8, 6.4 Hz, 1H),
4.15 (dd, J ) 4.8, 10.2 Hz, 1H), 2.08 (s, 3H), 0.94 (s, 9H), 0.14
(s, 6H); 13C NMR (CDCl3) δ 169.6, 169.2, 135.6, 129.6, 128.3,
127.0, 105.4, 81.1, 77.6, 75.4, 73.6, 53.6, 25.6, 23.3, 20.9, 18.1,
-4.5, -4.9; EM (70 eV) m/ z: 379 (11), 378 (45), 273 (18), 272
(97), 188 (11), 170 (27), 158 (25), 129 (39), 116 (24), 105 (32),
96 (23), 75 (56), 73 (66), 59 (19), 43 (100). Anal. Calcd for
C22H33NO6Si: C, 60.66; H, 7.64; N, 3.22. Found: C, 60.42; H,
7.38; N, 3.09.
solution of 65b (42 mg, 0.12 mmol) and 1,1′-thiocarbonyldi-
imidazole (85 mg, 0.48 mmol) in THF (10 mL) was heated at
reflux for 26 h. The solvent was removed at reduced pressure,
and the residue was purified by flash-chromatography (hexane/
EtOAc 3:1) affording 66b (36 mg, 76%) as a white solid. Rf )
0.30 (hexane/EtOAc 7:3); mp 222-224 °C; [R]25 -50.1 (c 0.6,
D
CHCl3); IR (KBr) ν 1460, 1420, 1375, 1320 cm-1
;
1H NMR
(CDCl3) δ 7.60-7.30 (m, 5H), 5.15 (m, 2H), 4.71 (dd, J ) 4.8,
3.0 Hz, 1H), 4.36 (dd, J )8.6, 4.8 Hz, 1H), 4.17 (dd, J ) 12.2,
3.0 Hz, 1H), 4.05 (dd, J ) 12.2, 9.5 Hz, 1H), 3.58 (t, J ) 9.0,
8.6 Hz, 1H), 3.36 (t, J ) 9.5, 9.0 Hz, 1H), 1.51 (s, 3H), 1.42 (s,
3H), 1.40 (s, 3H), 1.33 (s, 3H); 13C NMR (CDCl3) δ 192.5, 135.0,
130.5, 129.4, 128.9, 114.1, 113.6, 83.0, 78.4, 78.3, 76.5, 76.1,
72.0, 64.2, 29.1, 27.2, 27.1, 26.1. Anal. Calcd for
C20H25NO6S: C, 58.95; H, 6.18; N, 3.44; S, 7.87. Found: C,
58.90; H, 6.07; N, 3.375; S, 7.78.
Rea ction of 65c w ith Th ioca r bon yl Diim id a zole.
A
A portion of this mixture (16.0 mg) was dissolved in THF
(1 mL), and it was treated with a 0.1 M solution of TBAF (0.12
mL, 0.12 mmol) in THF at rt. After stirring the mixture for 3
solution of 65c (41 mg, 0.11 mmol) and 1,1′-thiocarbonyldi-
imidazole (78 mg, 0.44 mmol) in THF (10 mL) was heated at
reflux for 24 h. The solvent was removed at reduced pressure,
and the residue was purified by flash-chromatography (hexane/
EtOAc 4:1) affording 66c (2 mg, 4%) as a white solid, and 67
(30 mg, 57%) as a light yellow oil. 66c: Rf ) 0.44 (hexane/
h, pyridine (0.2 mL) and Ac2
O (0.1 mL) were added, and the
mixture was stirred for 16 h. The solvent was removed at
reduced pressure, and the residue was purified by flash-
chromatography (EtOAc), affording 69 (12 mg, 90%) as a white
EtOAc 7:3); mp 213-215 °C; [R]25 -4.5 (c 0.1, CHCl3); IR
foam. Rf: 0.33 (EtOAc); mp 65-67 °C; [R]20 -63.0 (c 1.0,
D
D
(KBr) ν 1375, 1320, 1270, 1235 1160 cm-1; 1H NMR (CDCl3) δ
7.56-7.31 (m, 5H), 5.18 (m, 2H), 4.71-4.48 (m, 3H), 4.09 (dt,
J ) 9.6, 8.7 Hz, 1H), 3.85-3.75 (m, 2H), 3.78 (s, 3H), 1.59 (s,
3H), 1.58 (s, 3H), 1.56 (s, 3H), 1.37 (s, 3H); 13C NMR (CDCl3)
δ 195.3, 135.1, 130.5, 129.3, 128.9, 115.1, 113.6, 79.7, 79.1, 79.0,
75.5, 75.3, 71.6, 61.6, 27.2, 27.1, 26.9, 24.0. Anal. Calcd for
C20H25NO6S: C, 58.95; H, 6.18; N, 3.44; S, 7.87. Found: C,
58.77; H, 6.32; N, 3.38; S, 7.63. 67: Rf ) 0.27 (hexane/EtOAc
EtOH); IR (KBr) ν 3300, 1750, 1660, 1550; 1H NMR (CDCl3) δ
7.55-7.40 (m, 5H), 5.83 (d, J ) 8.2 Hz, 1H), 5.75 (s, 1H), 5.19
(d, J ) 4.6 Hz, 1H), 5.11 (dd, J ) 4.8, 10.8 Hz, 1H), 5.02 (ddd,
J ) 4.6, 8.2, 10.8 Hz, 1H), 4.77 (dd, J ) 4.8, 6.1 Hz, 1H), 4.49
(d, J ) 6.1 Hz, 1H), 2.13 (s, 3H), 2.12 (s, 3H), 1.99 (s, 3H); 13
NMR (CDCl3) δ 171.5, 169.9, 169.1, 134.9, 130.0, 128.5, 127.0,
105.8, 81.1, 75.7, 74.7, 73.1, 51.8, 23.2, 20.8; EM (70 eV) m/ z:
362 (2), 257 (10), 214 (12), 155 (12), 148 (11), 139 (20), 115
(15), 105 (22), 101 838), 91 (13), 84 (17), 77 (12), 59 (15), 43
(100). Anal. Calcd for C18H21NO7‚H2O: C, 56.68; H, 6.08; N,
3.67. Found: C, 56.80; H, 5.64; N, 3.70.
Com p ou n d 70. To a solution of 34 (550 mg, 1.56 mmol) in
pyridine (10 mL) was added hydroxylamine hydrochloride (326
mg, 4.69 mmol), and the mixure was stirred at rt for 4 h. The
reaction mixture was diluted with Et2O (25 mL), and the
solution was washed with brine and dried (MgSO4). The
solvent was removed at reduced pressure, and the residue was
purified by flash-chromatography (hexane/EtOAc 3:1) affording
70 (480 mg, 84%) as a colorless oil, 4:1 mixture of E and Z
oximes, respectively. Rf ) 0.16 (hexane/EtOAc 7:3); IR (film)
ν 3350, 1465, 1415, 1260 cm-1; 1H NMR (CDCl3) δ (E-isomer)
8.71 (br s, 1H), 7.47 (m, 1H), 7.45-7.36 (m, 5H), 5.82 (s, 1H),
4.67 (t, J ) 7.1 Hz, 1H), 4.36 (m, 2H), 3.87 (brd, 2H), 2.71
(brt, 1H), 0.90 (s, 9H), 0.13 (s, 3H), 0.10 (s, 3H); (Z-isomer)
8.22 (br s, 1H), 6.82 (d, J ) 6.2 Hz, 1H). Anal. Calcd for
C18H29NO5Si: C, 58.81; H, 7.97; N, 3.81. Found: C, 59.03; H,
7.77; N, 3.79.
C
1:1); [R]25 -4.5 (c 0.1, CHCl3); IR (KBr) ν 1375, 1320, 1270,
D
1235 cm-1
;
1H NMR (CDCl3) δ 7.56-7.31 (m, 5H), 5.18 (m,
2H), 4.58 (m, 3H), 4.09 (dt, J ) 9.6, 8.7 Hz, 1H), 3,78 (s, 3H),
1.59 (s, 3H), 1.58 (s, 3H), 1.56 (s, 3H), 1.37 (s, 3H); 13C NMR
(CDCl3) δ 195.3, 135.1, 130.5, 129.3, 128.9, 115.1, 113.6, 79.7,
79.1, 79.0, 75.5, 75.3, 71.6, 61.6, 27.2, 27.1, 26.9, 24.0. Anal.
Calcd for C23H29N3O6S: C, 58.09; H, 6.15; N, 8.84; S, 6.74.
Found: C, 57.87; H, 6.04; N, 8.65; S, 6.55.
Com p ou n d 68. To a 0.1 M solution of SmI2 (6 mL, 0.60
mmol) in THF at -25 °C was added dropwise a solution of 17
(66 mg, 0.10 mmol) in THF (2 mL). After stirring at -25 °C
for 1, water (50 µL, 2.8 mmol) was added and the reaction
mixture was stirred at -25 °C to rt for 2 h. Pyridine (1 mL)
and Ac2O (1 mL) were added and the mixture was stirred at
rt for 15 h. The reaction mixture was worked up as described
in method B, and the product was purified by flash-chroma-
tography (hexane/EtOAc 1:1) affording 68 (49 mg, 82%) as a
white solid. Rf ) 0.24 (hexane/EtOAc 2:1); mp 143.5-144.5
°C; [R]20D +2.7 (c 1.1, CHCl3); 1H NMR (CDCl3) δ 7.33 (m, 20H),
5.99 (d, J ) 7.9 Hz, 1H), 4.71 (s, 2H), 4.69 (s, 2H), 4.62 (s,
2H), 4.40 (m, 2H), 4.31 (dd, J ) 7.0, 7.9 Hz, 1H), 4.12 (t, J )
6.6 Hz, 1H), 3.99 (d, J ) 6.8 Hz, 1H), 3.71 (dd, J ) 6.5, 7.0 Hz,
1H), 3.48 (s, 1H), 3.45 (d, J ) 10.2 Hz, 1H), 3.28 (d, J )10.2
Hz, 1H), 1.75 (s, 3H); 13C NMR (CDCl3) δ 170.3, 138.3, 138.1,
137.7, 137.1, 128.6, 128.4, 128.3, 128.1, 128.0, 127.9, 127.8,
127.7, 86.3, 83.4, 80.7, 76.0, 73.6, 73.0, 72.5, 72.1, 71.7, 60.8,
23.0. Anal. Calcd for C36H39NO6: C, 74.33; H, 6.76; N, 2.41.
Found: C, 74.61; H, 7.01; N, 2.44.
Com p ou n d 69. To a solution of (COCl)2 (51 µL, 0.58 mmol)
in THF (1 mL) at -60 °C was added DMSO (82 µL, 1.16 mmol)
dropwise. After stirring at -60 °C for 15 min, a solution of
35 (135 mg, 0.29 mmol) in THF (2 mL) was added. The
reaction mixture was stirred for 1 h at -60 °C, Et3N was added
(0.2 mL, 1.45 mmol), the cooling bath was removed, and the
reaction mixture was stirred at rt for 4 h. After diluting with
THF (5 mL), the mixture was added dropwise via cannula to
a 0.1 M solution of SmI2 (17.5 mL, 1.75 mmol) in THF at -25
°C. The reaction was stirred for 1 h at -25 °C, water (50 µL,
5.40 mmol) was added, the cooling bath was removed, and the
mixture was stirred at rt for 2 h. Pyridine (1 mL) and Ac2O
(1 mL) were added and the mixture was stirred at rt for 15 h.
The reaction mixture was worked up as described in method
B, and the crude was purified by flash-chromatography (hex-
Com p ou n d 71. To a solution of 70 (445 mg, 1.22 mmol) in
CH2Cl2 (15 mL) were added pyridine (0.60 mL, 7.32 mmol)
and trifluoroacetic anhydride (0.52 mL, 6.1 mmol) at rt. After
stirring for 5h at rt, the reaction mixture was diluted with
CH2Cl2, and the solution was washed with brine and dried
(MgSO4). The solvent was removed at reduced pressure, and
the residue was purified by flash-chromatography (hexane/
EtOAc 4:1) affording 71 (233 mg, 55%) as a colorless oil. Rf )
0.28 (hexane/EtOAc 9:1); [R]20 29.3 (c 2.6 , CHCl3); IR (film)
D
1
ν 3450, 2340, 1455, 1410 cm-1; H NMR (CDCl3) δ 7.53-7.39
(m, 5H) 5.87 (s, 1H), 4.82 (m, 1H), 4.37 (m, 2H), 3.93 (m, 2H),
2.12 (t, J ) 6.0 Hz, 1H), 0.93 (s, 9H), 0.28 (s, 3H), 0.20 (s, 3H);
13C NMR (CDCl3) δ 135.8, 129.7, 128.5, 126.5, 118.4, 103.6,
78.5, 77.7, 62.0, 60.1, 25.5, 18.0, -4.9, -5.2. Anal. Calcd for
C18H27NO4Si: C, 61.85; H, 7.80; N, 4.01. Found: C, 62.04; H,
8.01; N, 3.96.
Cycliza tion of 71 th r ou gh Oxid a tion -Sm I2 Red u ctive
Cou p lin g Sequ en ce. To a solution of (COCl)2 (35 µL, 0.40
mmol) in THF (1.5 mL) at -60 °C was added DMSO (57 µL,
0.80 mmol) dropwise. After stirring the mixture at -60 °C
for 10 min, a solution of 71 (56 mg, 0.16 mmol) in THF (3 mL)
was added dropwise. The reaction mixture was stirred at -60
°C for 1 h, Et3N (0.34 mL, 2.40 mmol) was added, and the
mixture was slowly warmed to rt for 5 h. The reaction mixture

7412 J . Org. Chem., Vol. 62, No. 21, 1997
Marco-Contelles et al.
was diluted with THF (3 mL), t-BuOH (31 µL, 0.32 mmol) was
added, and the resultant solution was added to a 0.1 M solution
of SmI2 in THF (6.5 mL, 0.65 mmol) at -40 °C. The reaction
mixture was stirred at -40 °C to -20 °C for 15 h. The reaction
was worked up as described in method B, and the product was
purified by flash-chromatography (hexane/EtOAc 9:1 to 1:3)
affording 72 (6 mg, 16%) as a pale fellow oil. Rf ) 0.15 (hexane/
EtOAc 1:1); [R]20D -16.1 (c, 0.5, CHCl3); IR (film) ν 3375, 1730,
munidad Auto´noma de Madrid (grant AE-0094/94), and
the European Union (Human Capital and Mobility
Programme; contract ERBCHRXCT 92-0027) is greate-
fully acknowledged. We thank Luis Mart´ınez for pre-
liminary experimental work in this subject.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization data for compounds 7b-e, 23,
54, and 56, and tables of 1H NMR and 2D NOESY cross-peak
intensities for the carbocyclic products 39, 43, 44a -c, 45, 50a -
d , 51a ,b, 52a ,b, 65a -c (8 pages). This material is contained
in libraries on microfiche, immediately follows this article in
the microfilm version of the journal, and can be ordered from
the ACS; see any current masthead page for ordering
instructions.
1630, 1465, 1335 cm-1 1H NMR (CDCl3) δ 6.39 (d, J ) 2.5
;
Hz, 1H), 4.69 (t, J ) 2.2 Hz, 1H), 4.12 (d, J ) 2.0 Hz, 1H),
3.00 (br s, 2H), 0.96 (s, 9H), 0.24 (s, 3H), 0.22 (s, 3H); 13C NMR
(acetone-d6) δ 206.5, 135.1, 122.6, 80.7, 73.7, 25.8, 19.2, -3.7,
-4.1.
Ack n ow led gm en t. Financial support from DGICYT
(grants PB93-0127-C02-01, SAF97-0048-C02-02 and
SAF94-0818-C02-02), CICYT (grant CE93-0023), Co-
J O970987W