SCHEME 1. Aldol Reactions of Dioxanones
SCHEME 2. Synthesis of (S)-Isoserinal Hydrate
lectivity (anti/syn) was good or excellent. We were also able to
assign the absolute stereochemistry to the aldol products by
correlation with naturally occurring carbohydrates.6a Other
workers in the field reported analogous trends.7
SCHEME 3. Synthesis of L-1-Deoxyidonojirimycin and Its
N-Isopropyl Derivative
We were therefore intrigued when an organocatalytic reaction
of dioxanone 9b with a hydrate (13) resulted in the formation
of a product that, in contrast to all previously performed
experiments involving aldehydes (not hydrates), appeared to be
of syn relative configuration (Scheme 1, bottom, see the
Supporting Information for relevant spectral data of 14 and 15;
dr >95:5). Chloral hydrate gave a similar result.9 This welcome
development allowed us to plan synthesis of some less common
deoxynojirimycin isomers (vide infra).
The necessary chiral building block, the protected (S)-
isoserinal hydrate (23), is readily available from the com-
mercially available (S)-malic acid (16), and we synthesized this
compound following published procedures with some modifica-
tions. The synthesis is summarized in Scheme 2 (for full
experimental details, see the Supporting Information). Briefly,
isoserine hydrochloride (19) was synthesized in 62% yield from
malic acid (16) via a short sequence of reactions involving the
Curtius rearrangement without isolating the intermediates.10
Following the Schmidt protocol,11 amino acid 19 was trans-
formed into the Cbz-protected (S)-isoserinal acetonide 22, which
readily formed the stable hydrate (23).12 With the hydrate 23
in hand the stage was set for an organocatalytic aldol reaction.
(S)-Proline-catalyzed aldol reaction of 2-tert-butyl-2-meth-
yldioxanone (9b) with (S)-isoserinal hydrate derivative (23) gave
the aldol adduct (24) in 69% yield and high diastereoselectivity
(the syn isomer was the major product). The absolute stereo-
chemistry of the aldol adduct is believed to be as shown in
Scheme 3.13
In our initial experiments aimed at transformation of the aldol
adduct (24) to the corresponding iminocyclitol (3a), hydro-
genolysis of the Cbz group proceeded along with reductive ring
opening of the oxazolidine moiety to give the N-isopropyl
derivative (25).14 Compound 25 was then subjected to a
reductive amination/cyclization via hydrogenolysis under acidic
conditions that resulted in formation of N-isopropyl-L-ido-DNJ
(26) in 82% yield, which was characterized as the tetraacetate
derivative 27.
(6) (a) Majewski, M.; Nowak, P. J. Org. Chem. 2000, 65, 5152. (b) Majewski,
M.; Nowak, P. Tetrahedron: Asymmetry 1998, 9, 2611–2617. (c) Majewski, M.;
Niewczas, I.; Palyam., N. Synlett 2006, 15, 2387–2390. (d) Palyam, N.; Niewczas,
I.; Majewski, M. Tetrahedron Lett. 2007, 48, 9195–9198. (e) Niewczas, I.;
Majewski, M. Eur. J. Org. Chem. 2009, 3, 3–37.
(7) (a) Enders, D.; Narine, A. A. J. Org. Chem. 2008, 73, 7857–7870. (b)
Enders, D.; Voith, M.; Lenzen, A. Angew. Chem., Int. Ed. 2005, 44, 1304–
1325. (c) Grondal, C.; Enders, D. Tetrahedron 2006, 62, 329–337. (d) Suri, J. T.;
Mitsumori, S.; Albertshofer, K.; Tanaka, F.; Barbas, C. F., III. J. Org. Chem.
2006, 71, 3822–3828. (e) Casas, J.; Engqvist, M.; Ibrahem, I.; Kaynak, B.;
Co´rdova, A. Angew. Chem., Int. Ed. 2005, 44, 1343–1345. (f) Caldero´n, F.;
Doyagu¨ez, E. G.; Cheong, P. H.; Ferna´ndez-Mayoralas, A.; Houk, K. N. J. Org.
Chem. 2008, 73, 7916–7920. (g) Caldero´n, F.; Doyagu¨ez, E. G.; Ferna´ndez-
Mayoralas, A. J. Org. Chem. 2006, 71, 6258–6261. (h) Caldero´n, F.; Ferna´ndez,
R.; Sa´nchez, F.; Ferna´ndez-Mayoralas, A. AdV. Synth. Catal. 2005, 347, 1395–
1403. (i) Caldero´n, F.; Doyagu¨ez, E. G.; Ferna´ndez-Mayoralas, A. J. Org. Chem.
2007, 72, 9353–9356. (j) Markert, M.; Mahrwald, R. Chem.sEur. J. 2008, 14,
40–48, and references therein.
(12) Protected (S)-isoserinal (22) readily forms the corresponding hydrate
(23). The IR spectrum of this compound showed the absence of the carbonyl
and the presence of a broad peak corresponding to the hydroxyl functional groups
(3540-3090 cm-1). The H NMR spectrum showed a small signal for the aldehyde
(CHO) at δ of 9.7 (integration for 0.23 proton); addition of Et3N enhanced the
CHO peak (integration of 0.62 protons), due the equilibrium shifting to the
aldehyde form 22.
(13) It should be noted that the total number of stereoisomers possible in
this reaction is eight. The R configuration at the acetal stereogenic centre and
also the cis arrangement of the largest groups on the dioxanone ring were
established by previous studies in our group.6a,d The syn relative stereochemistry
assignments of the aldol adducts 24 and 30 were based on NMR studies. The
coupling constants from proton decoupling experiments were: peak at 4.47 ppm
(d, J ) 3.0 Hz, R-CH) for compound 24 and at 4.20 ppm (d, J ) 2.3 Hz, R-CH)
for 30 (for the full spectra and also 2D NMR data see the Supporting
Information). Note the agreement of the spectral data of the final products with
these of the known natural products L-DIJ and L-DMJ.
(8) Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis; Wiley: New
York, 1995.
(9) Syn-selective aldol: (a) Torii, H.; Nakadai, M.; Ishihara, K.; Saito, S.;
Yamamoto, H. Angew. Chem., Int. Ed. 2004, 43, 1983–1986. (b) Ramasastry,
S. S. V.; Albertshofer, K.; Utsumi, N.; Tanaka, F.; Barbas, C. F., III. Angew.
Chem., Int. Ed. 2007, 46, 5572–5575. (c) Utsumi, N.; Imai, M.; Tanaka, F.;
Ramasastry, S. S. V.; Barbas, C. F., III. Org. Lett. 2007, 9 (17), 3445–3448.
(10) Milewska, M.; Polonski, T. Synthesis 1988, 6, 475.
(11) (a) Schmidt, U.; Meyer, R.; Leitenberger, V.; Stabler, F.; Lieberknecht,
A. Synthesis 1991, 5, 409–413. (b) Schmidt, U.; Meyer, R.; Leitenberger, V.;
Lieberknecht, A.; Griesser, H. Chem. Commun. 1991, 275–277.
(14) Falb, E.; Bechor, Y.; Nudelman, A.; Hassner, A.; Albeck, A.; Gottlieb,
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