Stereodivergent syntheses of conduramines and aminocyclitols

Article abstract of DOI:10.1021/ol061022e

The diastereomers of 6-amino-cyclohex-3-ene-1,2-diols 1 (4-deoxy-3-conduramines), key building blocks for the syntheses of a large range of natural products, have been enantioselectively prepared. Diastereoselective dihydroxylation of the compounds provid

Full text of DOI:10.1021/ol061022e

ORGANIC
LETTERS
2006
Vol. 8, No. 14
3069-3072
Stereodivergent Syntheses of
Conduramines and Aminocyclitols
Carlos Alegret,† Jordi Benet-Buchholz,‡ and Antoni Riera*,†
Unitat de Recerca en S´ıntesi Asime`trica (URSA-PCB), Institut de Recerca Biome´dica
(IRB), and Departament de Qu´ımica Orga`nica, UniVersitat de Barcelona,
Parc Cient´ıfic de Barcelona, C/ Josep Samitier 1-5, 08028 Barcelona, and
Institute of Chemical Research of Catalonia (ICIQ), AVda dels Pa¨ısos Catalans, 16,
43007 Tarragona, Spain
ariera@pcb.ub.es
Received April 28, 2006
ABSTRACT
The diastereomers of 6-amino-cyclohex-3-ene-1,2-diols 1 (4-deoxy-3-conduramines), key building blocks for the syntheses of a large range of
natural products, have been enantioselectively prepared. Diastereoselective dihydroxylation of the compounds provided a new family of
aminocyclitols 2 (deoxyinosamines). The key reactions of our syntheses are Sharpless catalytic asymmetric epoxidation, diastereoselective
addition of vinylmetal reagents to the aldehydes, and ring-closing metathesis (RCM).
Amino alcohols are ubiquitous in nature. Some cyclic
polyhydroxylated amines are saccharide-like compounds with
diverse biological activities1 (Figure 1). Diaminocyclitols
such as 2-deoxystreptamine2 are key structural fragments of
aminoglycoside antibiotics,3 a large class of clinically
important antibiotics with a broad antibacterial spectrum and
proven efficacy in the treatment of serious infections. Owing
to their sugar-mimetic structure, aminocyclitols such as
deoxyinosamines have garnered interest as key intermediates
in aminoglycoside biosynthesis4 and as potential inhibitors
of important metabolic processes such as glycolysis.5 Note-
worthy examples of this family include validamine6 and
valienamine,6b,7 which are specific R-D-glucosidase inhibitors.
Conduramines8 are purely synthetic aminocyclohexenetriols
that also have significant glycosidase inhibitory activity, such
as that of the N-benzyl derivative of conduramine B-1.9
† URSA-PCB, IRB.
‡ ICIQ.
(1) (a) Iminosugars as glycosidase inhibitors; Stu¨tz, A., Ed.; Wiley-
VHC: Weinheim, 1999. (b) Berecibar, A.; Crandjean, C.; Siriwardena, A.
Chem. ReV. 1999, 99, 779.
(2) For a recent review about deoxystreptamine, see: Busscher, G. F.;
Rutjes, F. P. J. T.; van Delf, F. L. Chem. ReV. 2005, 105, 775.
(3) (a) Umezawa, W. AdV. Carbohydr. Chem. Biochem. 1974, 30, 111.
(b) Rinehart, K. L.; Stroshane, R. M. J. Antibiot. 1976, 29, 319. (c) Daniels,
P. J. L. Kirk-Othmer Encycl. Chem. Technol. 1978, 2, 819. (d) Rinehart,
K. L.; Suami, T. Aminocyclitol Antibiotics; ACS Symposium Series 125;
American Chemical Society: Washington, DC, 1980.
(4) (a) Kakinuma, K.; Ogawa, Y.; Sasaki, T.; Seto, H.; Otake, N. J. Am.
Chem. Soc. 1981, 103, 5614. (b) Kakinuma, K.; Ogawa, Y.; Sasaki, T.;
Seto, H.; Otake, N. J. Antibiot. 1989, 42, 926. (c) Nango, E.; Eguchi, T.;
Kakinuma, K. J. Org. Chem. 2004, 69, 593.
Figure 1. Some conduramines, aminocyclitols, and related com-
pounds with biological interest.
10.1021/ol061022e CCC: $33.50
© 2006 American Chemical Society
Published on Web 06/14/2006

Scheme 1. Deoxyconduramines as Key Building Blocks
Scheme 2. Retrosynthetic Analysis of Aminocyclitols 2
addition of vinylmetal reagents. Moreover, all of the stereo-
isomers of aldehyde 4 had already been synthesized in our
research group13 from chiral unsaturated epoxide 5 or its
enantiomer.
Moreover, these compounds have proven most useful as
synthetic precursors of amino- and diaminocyclitols, having
been used as intermediates for azasugars, aminosugars,
sphingosines, and narcissus alkaloids. Oseltamivir phosphate
(Tamiflu), an orally administered drug for the treatment and
prevention of influenza infections, is an important example
of a clinically useful aminocyclitol.10 Much effort has been
devoted to the development of synthetic routes to these
compounds and their derivatives,9-11 which are normally
accessed via functional group manipulation of carbohydrates
or other natural products.
Building blocks for carbasugar synthesis can be obtained
through manipulation of the double bond of the synthetic
4-deoxy-3-conduramines (1). A few strategies have been
developed to convert this class of compound or synthetic
equivalents into conduramines11a and deoxystreptamines.12
With this in mind, we sought to develop a stereodivergent
and practical asymmetric synthesis of 4-deoxy-3-con-
duramines 1 (Scheme 1). We envisaged that dihydroxylation
of deoxyconduramines 1 would be a convenient entry to
deoxyinosamines 2, a new family of aminocyclitols.
As shown in Scheme 2, in our approach, all of the
stereoisomers of deoxyconduramines 1 would be obtained
from the ring-closing metathesis (RCM) of dienes 3 which,
in turn, would be obtained from the known aldehydes 4 by
Our synthesis started from epoxy alcohol 5, prepared
according to a literature procedure14 in 93% ee by Sharpless
epoxidation15 of 2,5-hexadien-1-ol, which is readily available
in multigram quantities from propargyl alcohol and allyl
bromide. The product was then subjected to a high-yielding
procedure (epoxide ring opening, azide reduction, and
protection) developed in our laboratory to yield amino
alcohol 6a13 with the anti configuration. Protection as the
acetal followed by deprotection afforded the cis isomer of
alcohol 8 (Scheme 3). Oxidation of the alcohol gave the cis
isomer of aldehyde 4, which could be epimerized16 in the
presence of catalytic base to afford an 84:16 trans/cis mixture
of 4. However, to avoid using a mixture of products in the
following steps, the trans isomer of 8 was prepared by a
completely stereoselective alternative procedure based on
inversion of the secondary alcohol. Compound 6a was
subjected to Mitsunobu conditions17 (p-nitrobenzoic acid and
DIAD in toluene, as THF led to lower yields) to give the
p-nitrobenzoate ester with the syn configuration, which was
reduced with RedAl (attempts to use Dibal-H resulted in a
decreased yield) to yield 6b. Alcohol 6b was then submitted
to the same reaction sequence as 6a to afford the diastereo-
merically pure trans isomer of 8 (Scheme 3).
With both isomers of alcohol 8 in hand, we proceeded to
study the diastereoselective addition of vinylmetal reagents
(5) Ogawa, S.; Asada, M.; Ooki, Y.; Mori, M.; Itoh, M.; Korenaga, T.
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G. F.; Rutjes, F. P. J. T.; van Delft, F. L. Tetrahedron Lett. 2004, 45, 3629.
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Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765.
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T.; Matsui, K.; Horii, S.; Fukase, H. J. Antibiot. 1984, 37, 1301
(8) (a) Posternack, T. The Cyclitols; Holden-Day, Inc.: San Francisco,
1965; pp 211-212. (b) Balci, M.; Su¨tbeyaz, Y.; Sec¸en, H. Tetrahedron
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1998, 63, 3235 and references therein. (b) McDonough, M. J.; Stick, R.
V.; Tilbrook, M. G. Aust. J. Chem. 1999, 52, 143. (c) Akgu¨n, H.; Hudlicky,
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3070
Org. Lett., Vol. 8, No. 14, 2006

Scheme 3. Synthesis of the Cis and Trans Isomers of
Oxazolidine Alcohol 8
Scheme 4. Syntheses of All Isomers of Deoxyconduramines
10 by RCM of the Corresponding Dienes 9
in moderate to good selectivity. As expected, vinylmagne-
sium bromide reagents afforded a mixture of acetates with
poor selectivity. Attempts to use Lewis acids to improve the
selectivity resulted in decomposition of the aldehydes. The
influence of the stereochemistry at the â-position of the
aldehyde is especially noteworthy: if the oxazolidine is cis,
a syn addition is favored, whereas the trans-oxazolidine
increases the proportion of the anti product.18
cis-anti-9 and cis-syn-9 were easily separated by conven-
tional chromatography; however, the corresponding trans
dienes were impossible to separate at this stage. Fortunately,
the final aminocyclitol products derived from trans isomers
could be easily purified on column. All isomeric dienes 9
were subjected to RCM19 using the first generation Grubbs
catalyst to afford the protected 4-deoxy-3-conduramines 10
in good to excellent yields (Scheme 4).
to the corresponding cis and trans aldehydes 4. The aldehydes
were readily obtained via Swern oxidation and subsequently
reacted without purification with various vinylmetal reagents.
The crude reaction products were acetylated to facilitate
workup and chromatography. The most interesting results
are shown in Table 1. In close agreement with our previous
work,13 addition of lithium divinylcuprate in diethyl ether
afforded the syn diastereomers in good to excellent diaste-
reoselectivity, whereas vinyllithium provided the anti isomer
Table 1. Preparation of Dienes 9 from Alcohols 8
At this point, changing the protecting groups in 10a
allowed us to obtain a crystalline compound 11a (Scheme
5). Single-crystal X-ray diffraction of this compound con-
Scheme 5. Derivatization of Compound 10a
firmed the stereochemistry and facilitated the unambiguous
stereochemical assignment of all isomeric dienes 10.20
Finally, deoxyconduramines 10 were subjected to dihy-
droxylation using catalytic osmium tetraoxide, and the crude
a Overall yield (three steps). b Determined by GC.
Org. Lett., Vol. 8, No. 14, 2006
3071

Scheme 6. Syntheses of Aminocyclitols 12
Figure 2. General approach to aminocyclitols 2 featuring full
control of the stereogenic centers.
ments. In cis bicyclic acetals 10a and 10b, the dihydroxy-
lation takes place anti to the bulky oxazolidine group.
Conversely, in trans isomers 10c and 10d, dihydroxylation
occurs anti to the contiguous acetoxy group. An alternative
procedure involved the protecting group cleavage by acidic
hydrolysis after the dihydroxylation reaction of 10 to afford
aminocyclitols 2.
In summary, we have developed a new enantioselective
entry to 4-deoxy-3-conduramines 1 with full stereochemical
control of the three contiguous stereogenic centers. In
addition, the compounds have been derivatized to obtain the
new family of aminocyclitols 2 by simple diastereoselective
cis dihydroxylation of the double bond (Figure 2).
products were directly protected as acetates yielding the
protected aminocyclitols 12 (Scheme 6). In all cases, the
diastereoselectivity was very high, yielding a single isomer
of 12 in high yields. The stereochemistry of aminocyclitols
12 was established by X-ray analysis of the crystalline
product 12d20 combined with NOESY spectroscopic experi-
Acknowledgment. We thank MEC (CTQ2005-00623) for
financial support. C.A.M. thanks CIRIT (Generalitat de
Catalunya) for a doctoral fellowship. We thank Serveis
Cient´ıficote`cnics (U.B.) for technical support.
Supporting Information Available: Full experimental
details and characterization data of all new compounds as
well as crystallographic data concerning compounds 11a and
12d (CCDC 610276 and 610277). This material is available
free of charge via the Internet at http://pubs.acs.org.
(18) For discussions about vinyl addition to the Garner’s aldehyde, see:
(a) Coleman, R. S.; Carpenter, A. J. Tetrahedron Lett. 1992, 33, 1697. (b)
Williams, L.; Zhang, Z.; Shao, F.; Carroll, P. J.; Joullie´, M. Tetrahedron
1996, 52, 11673.
(19) (a) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995,
28, 446. (b) Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1997,
36, 2036. (c) Maier, M. E. Angew. Chem., Int. Ed. 2000, 39, 2073.
(20) See Supporting Information for crystallographic data.
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