A flexible strategy based on a C2-symmetric pool of chiral substrates: Concise synthesis of (+)-valienamine, key intermediate of (+)- pancratistatin, and conduramines A-1 and E

Article abstract of DOI:10.1021/ol9016194

A new strategy invoking a new application of the [3,3] sigmatropic rearrangement of allylic azides and the presence of a C₂ symmetry element within a pool of chiral substrates was evolved. Not only does this simple flexible strategy provide a concise approach to (+)-valienamine, but it also can readily be adopted for the synthesis of conduramines A-1 and E and the enantiopure azido carbonate 4, a key intermediate of (+)-pancratistatin.

Full text of DOI:10.1021/ol9016194

ORGANIC
LETTERS
2009
Vol. 11, No. 19
4278-4281
A Flexible Strategy Based on a
C2-Symmetric Pool of Chiral Substrates:
Concise Synthesis of (+)-Valienamine,
Key Intermediate of (+)- Pancratistatin,
and Conduramines A-1 and E
Yuan-Kang Chang, Hong-Jay Lo, and Tu-Hsin Yan*
Department of Chemistry, National Chung-Hsing UniVersity, Taichung 400, Taiwan,
Republic of China
thyan@mail.nchu.edu.tw
Received July 15, 2009
ABSTRACT
A new strategy invoking a new application of the [3,3] sigmatropic rearrangement of allylic azides and the presence of a C2 symmetry element
within a pool of chiral substrates was evolved. Not only does this simple flexible strategy provide a concise approach to (+)-valienamine, but
it also can readily be adopted for the synthesis of conduramines A-1 and E and the enantiopure azido carbonate 4, a key intermediate of
(+)-pancratistatin.
Aminocyclitols and structurally related compounds constitute
a continuing and growing class of important compounds for
biological function.1 The vast importance of the aminocy-
clitol unit valienamine 1, which occurs widely as a central
building block of pseudooligosaccharides and several com-
plex aminoglycoside antibiotics,2 has stimulated much
synthetic activity and enhanced interest in simplifying their
synthesis. Most reported total syntheses employ cyclitol
quebrachitol,3 D-glucose derivatives,4 or (-)-quinic acid5a,b
as the chiral building block, wherein new stereochemistries
are introduced into compounds bearing preexisting ones.
Such strategies are often limited by the need for lengthy
protecting group manipulation and/or the use of relatively
expensive chiral building blocks that are of limited avail-
ability. A noteworthy strategic exception is shown in the
asymmetric symthesis of (+)-valienamine 1 reported by
Trost, which uses Pd-catalyzed desymmetrization and cis-
hydroxyamination.6 In trying to devise a new convenient
flexible strategy whereby the same readily available inter-
mediate can be channeled into a different product by
(4) (a) Schmidt, R. R.; Kohn, A. Angew. Chem., Int. Ed. Engl. 1987,
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Aminocyclitol Antibiotics; American Chemical Society: Washington, DC,
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66, 7184. (b) Shing, T. K. M.; Li, T.-Y.; Kok, S. H. L. J. Org. Chem.
1999, 64, 1941. For an enantiospecific synthesis of bis-valienamine from
(-)-quinic acid, see:(c) Shing, T. K. M.; Kwong, C. S. K.; Cheung,
A. W. C.; Kok, S. H.-L.; Yu, Z.; Li, J.; Cheng, C. H. K. J. Am. Chem. Soc.
2004, 126, 15990.
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120, 1732. (b) Shing, T. K. M.; Li, T. Y.; Kok, S. H. L J. Org. Chem.
1999, 64, 1941.
10.1021/ol9016194 CCC: $40.75
Published on Web 08/27/2009
 2009 American Chemical Society

Scheme 1
.
Retrosynthesis of (+)-Valienamine, Conduramines
Scheme 2
.
Convergent Construction of Allylic Azides 10a and
A-1 and E, and a Key Intermediate of (+)-Pancratistatin
10b
changing the reaction profile, we sought a concise and
convergent approach, designed to afford easy access to both
(+)-valienamine 1 and a variety of analogues. We chose
cyclic diol 8, readily prepared from C2-symmetric L-tartaric
acid,7 as a versatile bridging intermediate en route to
aminocyclitols and envisioned using azide to introduce amino
group in the equivalent of a protected form (Scheme 1).
catalyst afforded the corresponding cyclic diol 8.7e Construc-
tion of allylic azide 10a or 10b called for a controlled
introduction of an azido group. The high propensity of allylic
azides to undergo [3,3] sigmatropic rearrangement8 suggested
that a simple route to both of the allylic azides 10a and 10b
was potentially available. After considering a number of
possibilities for installation of the azido alcohol unit with
complete control of regio- and stereochemistry, we chose to
use the in situ generated allylic epoxide 9 as a valuable key
intermediate to allylic azides 10a and 10b. Gratifyingly,
sequential addition of triflimide/sodium hydride and a
solution of sodium azide in 1.5:1:1 DMF/EtOH/H2O at room
temperature to cyclic vinyl carbinol 8 led to only the 1,2-
type azido alcohol 10a in 66% yield. We surmise that this
interesting transformation involves conversion of the diol to
A key aspect of this new flexible strategy is the installation
of the azido alcohol unit via the ring opening of the diol
8-derived allylic epoxide with an azide nucleophile with a
complete control of regio- and stereochemistry.
Following the reported procedures (Scheme 2), the syn-
thesis commenced with commercially available and cheap
L-tartaric acid 5 or its derivative dimethyl 2,3-O-isopropy-
lidenetartrate 6. Reduction of 6 with DIBALH, followed by
a highly diastereoselective divinylzinc addition to the in situ
generated dialdehyde, afforded the desired vinyl carbinol 7.7
Subsequent RCM using the second generation Grubbs
(7) (a) Gaul, C.; Njardarson, J. T.; Shan, D.; Dorn, D. C.; Wu, K.-D.;
Tong, W. P.; Huang, X.-Y.; Moore, M. A. S.; Danishefsky, S. J. J. Am.
Chem. Soc. 2004, 126, 11326. (b) Gaul, C.; Njardarson, J. T.; Danishefsky,
S. J. J. Am. Chem. Soc. 2003, 125, 6042. (c) Jorgensen, M.; Iversen, E. H.;
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Madsen, R. J. Am. Chem. Soc. 2000, 122, 8444. (e) Ackermann, L.; Tom,
D. E.; Furstner, A. Tetrahedron 2000, 56, 2195. (f) Khanapure, S. P.; Najafi,
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1960, 82, 5956. (b) Vanderwerf, C. A.; Heasley, V. L. J. Org. Chem. 1966,
31, 3534. (c) Trost, B. M.; Pulley, S. R. Tetrahedron Lett. 1995, 36, 8737.
(d) Podeschwa, M. A. L.; Plettenburg, O.; ltenbach, H.-J. Org. Biomol.
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1 1997, 1779.
Org. Lett., Vol. 11, No. 19, 2009
4279

the pivotal allylic epoxide via base-promoted monotriflation
of the hydroxyl group and intramolecular displacement by
hydroxyl nucleophile and SN2 ring opening of the allylic
epoxide at the allylic carbon with an azide ion with inversion
of configuration. A significant advantages of this one-pot
transformation is that no resolution steps are required and,
because of the presence of a C2 symmetry axis within the
diol 8 before monotriflation, there is no loss in yield due to
the formation of diastereomers. On the other hand, perform-
ing this one-pot conversion process at reflux (∼90 °C)
smoothly redirects the reaction to the 1,4-type azido alcohol
10b (70%) with complete control of stereo- and regiochem-
istry. This result strongly implies that the less stable 1,2-
type azido alcohol would be initially formed and would then
undergoes [3,3] sigmatropic rearrangement to provide the
more stable 1,4-type azido alcohol 10b. Further evidence
for this isomerization was obtained by heating allylic azide
10a in 1.5:1:1 DMF/EtOH/H2O at 90 °C and comparing the
product to azide 10b. Molecular models reveal that this
surprisingly high 1,4-type selectivity derives from effects of
azido group orientation depicted in 10a and 10b. The
difference between an axial and a pseudoequatorial environ-
ment of an azido group can lead to significant difference in
the stability of 1,2- and 1,4-azido alcohols. Considering that
intramolecular hydrogen bonding plays an important role in
stabilizing the 1,2-azidocyclohexenol,8c this thermal isomer-
ization of 1,2- to 1,4-type allylic azide represents a particu-
larly intriguing success.
Scheme 3
. Completion of the Total Synthesis of
(+)-Valienamine 1 and Conduramine E 2
Both allylic azides 10a and 10b serve as valuable
intermediates to approach aminocyclitols. Elaboration of 10a
to (+)-valienamine 1 was initiated by oxidation of 10b with
Dess-Martin periodinane, producing enone 11 (96%) (Scheme
3). The availability of 11 allowed for direct introduction of
a hydroxymethyl group via the Baylis-Hillman reaction.9
Treatment of 11 with formaldehyde solution (37% in H2O)
in THF at room temperature followed by addition of
imidazole (1.5 equiv) and aqueous NaHCO3 (1 M) resulted
in efficient formation of the desired hydroxymethylcyclo-
hexenone 12 in 65% yield. Controlled reduction of enone
12 with NaBH4 in methanol solution containing cerium
chloride at -78 °C gave a 80% yield of alcohol 13 with
excellent stereoselectivity (>16:1). Finally, reduction of azido
alcohol 13 with LiAlH4 followed by quenching with H2O/
HOAc provided (+)-valienamine 1, which was characterized
as its tetraacetate 14 (50%). Comparison of the physical
properties to those recorded confirms its identity.6 This
synthesis based on a C2-symmetric pool of chiral substrates
requires 8 steps from very cheap L-tartaric acid 5 to give
(+)-valienamine in 8.4% overall yield. Another interesting
synthetic application of 1,4-azido alcohol 10b is found in
the one-pot transformation of 10b to the tetraacetate of
conduramine E 15 (90%).8c,10
Scheme 4. Completion of the Total Synthesis of Conduramine
A-1 and a Key Intermediate of (+)-Pancratistatin
Applying the same one-flask reduction/acylation condition
to the 1,2-type allylic azide 10a cleanly effected the desired
transformation to afford conduramine A-1 tetraacetate 16
(79%) (Scheme 4).11 The azido carbonate 4, a pivotal
bridging intermediate en route to (+)-pancratistatin,12 was
also accessible from azide 10a. Thus CF3COOH-catalyzed
migration of the 2,3-O-isopropylidene group with relief of
(9) (a) Masson, G.; Housseman, C.; Zhu, J. Angew. Chem., Int. Ed. 2007,
46, 4614. (b) Declerck, V.; Martinez, J.; Lamaty, F. Chem. ReV. 2009, 109,
1. (c) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. ReV. 2003, 103,
811.
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1994, 116, 5108. (b) Johnson, C. R.; Ple, P. A.; Su, L.; Heeg, M. J.; Adams,
J. P. Synlett 1992, 388. (c) Hudlicky, T.; Luna, H.; Olivo, H. F.; Andersen,
C.; Nugent, T.; Price, J. D. J. Chem. Soc., Perkin Trans. 1 1991, 2907. (d)
Werbitzky, O.; Klier, K.; Felber, H. Liebigs Ann. Chem. 1990, 267. (e)
Umezawa, S. AdV. Carbohydr. Chem. Biochem. 1974, 30, 111.
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1999, 64, 9613. (b) Chida, N.; Sakata, N.; Murai, K.; Tobe, T.; Nagase, T.;
Ogawa, S. Bull. Chem. Soc. Jpn. 1998, 71, 259
.
(12) Trost, B. M.; Pulley, S. R. J. Am. Chem. Soc. 1995, 117, 10143.
4280
Org. Lett., Vol. 11, No. 19, 2009

strain in the trans fused bicyclic system followed by in situ
trapping of the azido alcohol with ClCOOMe/NaH resulted
in efficient formation of the enantiopure carbonate 4 in 60%
yield.
the construction of various structurally related natural
products and other members of aminocyclitols. In addition,
this study opens the question of the importance of the 1,3-
diaxial interactions on the equilibrations of the allylic azides.
In summary, a new strategy invoking a new application
of the [3,3] sigmatropic rearrangement of allylic azides and
the presence of a C2 symmetry element within the pool of
chiral substrates was evolved. Not only does this simple
flexible strategy provide a concise approach to (+)-valie-
namine, but it also can readily be adopted for the synthesis
of conduramine A-1, conduramine E, and the enantiopure
azido carbonate 4, a key intermediate of pancratistatin. This
flexible technology provided above should be applicable to
Acknowledgment. We thank the National Science Council
of the Republic of China for generous support.
Supporting Information Available: Experimental pro-
cedures and characterization data for 4, 6-8, 10a, 10b,
11-13, 1-derived pentaacetate 14, 2-derived tetraacetate 15,
and 3-derived tetraacetate 16. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL9016194
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