Variable strategy toward carbasugars and relatives as illustrated by diastereoselective synthesis of 1-deoxy-1-amino-pseudo-β-d-gulopyranose (alias 1,2,4-tri-epi-validamine)

Article abstract of DOI:10.1021/ol990880q

(Matrix presented) A quick arrival at chiral nonracemic cyclohexanoids is provided, which incorporates useful variability for large product diversity. Central to the construction is the exploitation of the dual nucleophilic character of an easily accessib

Full text of DOI:10.1021/ol990880q

ORGANIC
LETTERS
1
999
Vol. 1, No. 8
213-1215
Variable Strategy toward Carbasugars
and Relatives As Illustrated by
Diastereoselective Synthesis of
1
1
-Deoxy-1-amino-pseudo-â-D-gulopyranose
(Alias 1,2,4-Tri-epi-validamine)
,†
Gloria Rassu,* Luciana Auzzas, Luigi Pinna, Franca Zanardi,
Lucia Battistini, and Giovanni Casiraghi*
Istituto per l’Applicazione delle Tecniche Chimiche AVanzate ai Problemi
Agrobiologici, CNR, Via Vienna 2, I-07100 Sassari, Italy, and Dipartimento
Farmaceutico, UniVersit a` di Parma, Parco Area delle Scienze 27A,
I-43100 Parma, Italy
casirag@ipruniV.cce.unipr.it
Received July 28, 1999
ABSTRACT
A quick arrival at chiral nonracemic cyclohexanoids is provided, which incorporates useful variability for large product diversity. Central to
the construction is the exploitation of the dual nucleophilic character of an easily accessible triad of silyloxy diene synthons derived from the
popular five-membered heterocycles furan, pyrrole, and thiophene. To assess the reliability of the procedure, the total synthesis of 1-deoxy-
1-amino-pseudo-â-D-gulopyranose (10) (alias 1,2,4-tri-epi-validamine) is executed, in 12 steps and with a 17% overall yield, by starting with
N-tert-butoxycarbonyl-2-[(tert-butyldimethylsilyl)oxy]pyrrole (1) and 2,3-O-isopropylidene-D-glyceraldehyde (2).
Carbasugars, also called pseudosugars, are a family of
carbohydrate mimics which have attracted a great deal of
interest among organic and medicinal chemists. These small
annulation of acyclic, functionality rich carbon fragments,
cycloadditive procedures, or elaboration of proper carbo-
1
3
hydrates and carbocycles.
molecules were postulatedsand then provensto possess
activity as glycosidase enzyme inhibitors, the carbasugar
resembling the parent carbohydrate.
To arrive at these relevant constructs in a nonracemic
format, we addressed the retrosynthetic pathway in Scheme
1
, where the generic cyclohexanoid structure A was as-
Since the first representative of this compound class was
sembled by conjoining two complementary subunits, the
intrinsically chiral malondialdehyde-related segment F′ and
the butyric acid R,γ-dianion E′. Our choice, here, was to
exploit two easily accessible reaction components, the
2
synthesized in 1966, a variety of approaches have been
developed, in both racemic and chiral domains, to assemble
pseudofuranose and pseudopyranose entities, including either
†
rassu@hpj.area.ss.cnr.it.
(
1) Suami, T.; Ogawa, S. AdV. Carbohydr. Chem. Biochem. 1990, 48,
(3) For general pseudosugar synthesis, see: (a) Ogawa, S. J. Synth. Org.
Chem. Jpn. 1985, 43, 26-39. (b) Ogawa, S. In Carbohydrate Mimics;
Chapleur, Y., Ed.; Wiley-VCH: Weinheim, 1998; pp 87-106. (c) Pingli,
L.; Vandewalle, M. Synlett 1994, 228-230. (d) Hudlicky, T.; Entwistle,
D. A.; Pitzer, K. K.; Thorpe, A. J. Chem. ReV. 1996, 96, 1195-1220. (e)
Dalko, P. I.; Sina y¨ , P. Angew. Chem. Int. Ed. 1999, 38, 773-777.
2
1-90.
(2) (a) McCasland, G. E.; Furuta, S.; Durham, L. J. J. Org. Chem. 1966,
3
1, 1516-1521. (b) McCasland, G. E.; Furuta, S.; Durham, L. J. J. Org.
Chem. 1968, 33, 2835-2841. (c) McCasland, G. E.; Furuta, S.; Durham,
L. J. J. Org. Chem. 1968, 33, 2841-2844.
1
0.1021/ol990880q CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/23/1999

Scheme 1. Design of Carbasugar Synthesis
Scheme 2. Synthesis of
-Deoxy-1-amino-pseudo-â-D-gulopyranose
a
1
4
vinylogous enoxysilane E, a synthetic equivalent of E′, and
the glyceraldehyde-derived chiral synthon F, a chiral sur-
rogate of F′. The guidelines to be followed were to
implement the C3-C4 juncture, leading to D and C, in
advance of the installation of the C1-C6 linkage that
terminated the pseudopyranose ring closure and produced
B, the immediate precursor of A. Central to this construction
was a sort of [3 + 3] cycloadditive maneuver featuring
sequential vinylogous cross aldolization-intramolecular al-
dolization. Remarkably, this plan incorporates useful
malleability for large synthetic variability, allowing for one
to play around one ternary heteroatom variable (X) and four
binary variables (Y, Z, W, and the starter chirality).
a
(
a) SnCl
TBSOTf, 2,6-lutidine, CH
ii) TBSOTf, 2,6-lutidine, Et
DMAP; (d) (i) 80% aqueous AcOH, 20 °C, (ii) (COCl)
CH Cl , Et N, -78 °C; (e) LDA, THF, -80 °C, 15 min; (f) TESCl,
pyridine, DMAP; (g) NaBH (4 equiv), wet THF, 25 °C; (h) 6 N
HCl, THF, MeOH (1:2:2); then SiO chromatography, MeOH,
EtOAc, 25% aqueous NH OH (2:2:1).
4
, Et
2
O, -80 °C, 1 h; (b) (i) H
Cl ; (c) (i) 70% aqueous AcOH, 50 °C,
N, CH Cl , 50 °C, (iii) Boc O, MeCN,
, DMSO,
2
, Pd/C, THF, (ii)
2
2
(
3
2
2
2
2
2
2
3
4
2
Our inaugural synthesis, which forms the subject of this
Letter, was targeted to 1-deoxy-1-amino-pseudo-â-D-gulo-
pyranose (10)sa pseudo-aminohexose of the validamine
4
5
1
family sby adopting the variable combination X ) N; Y,
selectivity (g95% de by H NMR analysis). Exposure to
catalytic hydrogenation and silylation cleanly furnished
saturated lactam 4 in 90% yield (two steps), on which
permutation of the terminal acetonide to robust tert-but-
yldimethylsilyl protecting groups was effected. Owing to the
sluggish nature of this protection reaction, no conditions were
found that obviated the concomitant unmasking of the
nitrogen substituent. Therefore, reintroduction of the N-Boc
protecting group was required. We thus arrived at persilylated
lactam 5 with a good 65% yield for three steps. Following
liberation of the primary carbinol within 5 and Swern
oxidation to aldehyde 6 (86% yield for two steps), the stage
was set to perform the crucial cycloaldolization.
In a series of preliminary experiments using a variety of
bases and solvent systems, we recognized that attempts to
obtain complete consumption of aldehyde 6 resulted in
unwanted destruction of the aldol cycloadduct itself. An
acceptable compromise was to allow aldolization to proceed
to 50-60% aldehyde consumption and to recycle the
unconverted 6. Using LDA in THF at -80 °C (15 min), the
cycloaldolization step revealed a spectacular level of dia-
stereocontrol with the binuclear adduct 7 being formed in a
Z, W ) O; starter chirality ) R.
As shown in Scheme 2, the synthesis was initiated with
the vinylogous cross-aldol addition of N-tert-butoxycarbonyl-
2
-[(tert-butyldimethylsilyl)oxy]pyrrole (1) to 2,3-O-iso-
propylidene-D-glyceraldehyde (2) under the influence of
6
SnCl
,3-anti-3,4-syn configured adduct 3 formed in a high
chemical yield (84%) with excellent regio- and diastereo-
4
in diethyl ether. As previously experienced, crystalline
2
(
4) For general reviews on the use of furan-, pyrrole-, and thiophene-
based 2-silyloxy dienes, see: (a) Casiraghi, G.; Rassu, G. Synthesis 1995,
07-629. (b) Casiraghi, G.; Rassu, G.; Zanardi, F.; Battistini, L. In AdVances
in Asymmetric Synthesis; Hassner, A., Ed.; JAI Press: Stamford; 1998; Vol.
, pp 113-189.
5) For recent syntheses of validamine and related stereoisomers, see:
6
3
(
(
a) Shing, T. K. M.; Tai, V. W.-F. J. Org. Chem. 1995, 60, 5332-5334.
(b) Ace n˜ a, J. L.; Arjona, O.; Fern a´ ndez de la Pradilla, R.; Plumet, J.; Viso,
A. J. Org. Chem. 1994, 59, 6419-6424. (c) Yoshikawa, M.; Murakami,
N.; Yokokawa, Y.; Inoue, Y.; Kuroda, Y.; Kitagawa, I. Tetrahedron 1994,
5
0, 9619-9628. (d) Takahashi, T.; Kotsubo, H.; Iyobe, A.; Namiki, T.;
Koizumi, T. J. Chem. Soc., Perkin Trans. 1 1990, 3065-3072. (e) Ogawa,
S.; Suzuki, M.; Tonegawa, T. Bull. Chem. Soc. Jpn. 1988, 61, 1824-1826.
(f) Ogawa, S.; Ara, M.; Kondoh, T.; Saitoh, M.; Masuda, R.; Tokokuni,
T.; Suami, T. Bull. Chem. Soc. Jpn. 1980, 53, 1121-1126.
6) Casiraghi, G.; Rassu, G.; Spanu, P.; Pinna, L. J. Org. Chem. 1992,
7, 3760-3763.
(
5
1214
Org. Lett., Vol. 1, No. 8, 1999

6
0% yield for two cycles, with no stereoisomer contamina-
4
tions, using NaBH in wet THF, furnishing amino pseudo-
1
tion, as judged by 300 MHz H NMR analysis. In this
intramolecular aldol reaction, advantage can be taken of the
location of the aldehyde segment that orientates the incoming
C1 carbonyl on the R-surface of the transient lithium enolate.
The anti-Felkin facial selectivity favoring the C1-C2 syn
sugar 9 in 70% yield. Exposure of 9 to 6 N HCl in THF/
methanol finally completed the synthesis, giving 1-deoxy-
1-amino-pseudo-â-D-gulopyranose (10) (1,2,4-tri-epi-valid-
amine), which was isolated as the free base in 95% yield
after chromatography over silica gel with MeOH/EtOAc/
9
(threo) orientation can be, instead, assumed to be dictated
4
25% aqueous NH OH as eluant.
by the favorable trans-diequatorial arrangement of the C1
and C2 hydroxyl functions as in compound 7.
Configurational and conformational assignment of the
target pseudosugar 10 (Figure 1) was determined upon
1
4
Protection of the free hydroxyl at C1 as a triethylsilyl ether
by a conventional protocol quantitatively gave rise to the
inspection of its H NMR spectrum in D
2
O. The C
1
-D-gulo
1
configuration ( C
4
using target numbering) was attributed
1
crystalline bicyclic lactam 8, whose H NMR spectrum
mainly based on the measurement of large coupling constants
involving axially disposed H3, H4, H5ax, and H6 protons,
with J3,4 ) J4,5ax ) 12.3 Hz and J5ax,6 ) 12.6 Hz. In addition,
the equatorial disposition of the H1 and H2 protons was
supported by the expected small vicinal coupling constants
proved to be richly detailed and guided us in the definitive
7
structural assignment of this product. The relative config-
4
uration of 8 and the C
1
conformation of its cyclohexane
1
4
ring ( C conformation using sugar numbering) (Figure 1)
(J
1,6 ) 4.8 Hz; J2,3 ) J1,2 ) 3.0 Hz).
To summarize, we have discovered a strategic methodol-
ogy for the construction of chiral nonracemic carbasugars
and related cyclohexanoids and applied it successfully to the
total synthesis of 1-deoxy-1-amino-pseudo-â-D-gulopyranose
(10) (17% yield over 12 steps). Expansion of the scope of
this synthesis plan to include wide permutation of the
heteroatom and chirality variables is underway. Once com-
pleted, this study will allow us to determine whether and to
what extent the vast theoretical structural variability of such
a plan is able to be implemented in practice.
Figure 1. Proposed structures for compounds 8 and 10.
Acknowledgment. The financial support of the Ministero
dell′Universit a` e della Ricerca Scientifica e Tecnologica
(Cofin 1998-1999), Italy, is gratefully acknowledged.
Thanks are due to the Centro Interdipartimentale di Misure
G. Casnati, Parma, Italy, for instrumental facilities.
were ascertained by the large coupling constants of the
axially disposed H1 and H2 protons (J1,2 ) 8.7 Hz) and by
two long-range W couplings between equatorial H4 and H6
and H3 and H5eq ( J4,6 ) 1.2 Hz; 4
4
J
3,5eq ) 0.9 Hz).
Supporting Information Available: 1H and 13C NMR
spectra (300 and 75.4 MHz, respectively) of compounds 8
and 10. This material is available free of charge via the
Internet at http://pubs.acs.org.
Furthermore, the equatorial disposition of the H3 and H4
protons was corroborated by their small coupling constant
values (J2,3 ) 3.9 Hz; J3,4 ) 4.8 Hz; J4,5eq ) 4.8 Hz), whereas
the J4,5ax and J6,5ax couplings near to zero were diagnostic of
a dihedral angle involving these protons approaching to 90°.
At this stage, what remained was the breakage of the five-
membered lactam ring and the reduction of the carbonyl
OL990880Q
(8) Methanolysis of lactam 8 cleanly afforded the corresponding amino
acid ester, a nice example of functional, conformationally restricted GABA
8
function to a hydroxymethyl. Indeed, reductive cleavage of
analogue.
1
(
9) Compound 10: glassy solid; [R]20D -82.0 (c 0.5, D2O); H NMR
the amide linkage proceeded uneventfully under mild condi-
(
300 MHz, D2O) δ 3.99 (dd, J ) 4.8, 3.0 Hz, 1H, H1), 3.97 (t, J ) 3.0 Hz,
1
H, H2), 3.82 (dd, J ) 10.8, 3.0 Hz, 1H, H3), 3.63 (dd, J ) 11.1, 7.5 Hz,
(
7) All new compounds shown in Scheme 2, as well as the numerous
1H, H7a), 3.52 (dd, J ) 11.1, 6.6 Hz, 1H, H7b), 3.32 (td, J ) 12.3, 4.2 Hz,
1H, H4), 2.05 (m, 1H, H6), 1.87 (dt, J ) 12.6, 4.2 Hz, 1H, H5eq), 1.44 (q,
1
13
intermediates not indicated, were fully characterized by H and C NMR
13
analyses. Satisfactory elemental analyses were provided for compounds 6,
J ) 12.6 Hz, 1H, H5ax); C NMR (75.4 MHz, D2O) δ 72.2, 69.6, 69.4,
2
0
8
, 9, and 10. Compound 8: colorless needles; [R] D ) +27.0 (c 1.0,
62.3, 50.5, 36.5, 25.7. Penta-N,O,O,O,O-acetyl derivative: white crystals;
1
20
1
CHCl3); H NMR (300 MHz, CDCl3) δ 4.26 (td, J ) 3.6, 0.9 Hz, 1H, H3),
mp 194-195 °C; [R] D +5.0 (c 0.6, CDCl3); H NMR (300 MHz, CDCl3)
δ 5.63 (d, J ) 8.1 Hz, 1H, NH), 5.31 (t, J ) 3.6 Hz, 1H, H2), 5.10 (bt, J
) 3.6 Hz, 1H, H1), 5.03 (dd, J ) 11.1, 3.3 Hz, 1H, H3), 4.36 (tdd, J )
11.7, 8.5, 4.5 Hz, 1H, H4), 4.02 (dd, J ) 11.1, 8.1 Hz, 1H, H7a), 3.84 (dd,
J ) 11.1, 6.6 Hz, 1H, H7b), 2.43 (m, 1H, H6), 2.14 (s, 3H, Me), 2.11 (s,
3H, Me), 2.04 (s, 3H, Me), 2.03 (s, 3H, Me), 1.94 (s, 3H, Me), 1.64 (m,
4
3
.11 (td, J ) 4.8, 1.2 Hz, 1H, H4), 3.87 (dd, J ) 8.7, 2.7 Hz, 1H, H1),
.57 (dd, J ) 8.7, 3.9 Hz, 1H, H2), 2.52 (ddd, J ) 5.4, 2.7, 1.2 Hz, 1H,
H6), 2.24 (d, J ) 13.5 Hz, 1H, H5ax), 1.87 (dddd, J ) 13.5, 5.4, 5.4, 0.9
t
Hz, 1H, H5eq), 1.52 (s, 9H, Bu ), 0.99 (t, J ) 8.1 Hz, 9H, CH3), 0.91 (s,
t
1
8H, Bu ), 0.65 (q, J ) 8.1 Hz, 6H, CH2), 0.12 (s, 3H, CH3), 0.09 (s, 3H,
1
3
13
CH3), 0.06 (s, 3H, CH3), 0.04 (s, 3H, CH3); C NMR (75.4 MHz, CDCl3)
1H, H5eq), 1.37 (q, J ) 12.9 Hz, 1H, H5ax); C NMR (75.4 MHz, CDCl3)
δ 176.2, 145.1, 82.6, 74.2, 72.2, 70.2, 59.4, 48.9, 28.1 (3C), 27.1, 26.3
δ 171.7, 170.8, 169.9, 169.1 (2C), 70.7, 68.4, 68.3, 63.2, 47.4, 33.9, 29.1,
(3C), 25.8 (3C), 18.0 (2C), 6.8 (3C), 5.1 (3C), -4.0, -4.2 (2C), -4.7.
23.4, 20.9 (2C), 20.7 (2C).
Org. Lett., Vol. 1, No. 8, 1999
1215