Synthesis of (+)-casuarine.

Article abstract of DOI:10.1021/ol9909886

[formula: see text] The first synthesis of (+)-casuarine, a pentahydroxy pyrrolizidine alkaloid, is described. The key bond-forming events occur in a tandem [4 + 2]/[3 + 2] nitroalkene cycloaddition involving nitroalkene 6, chiral vinyl ether 7b, and viny

Full text of DOI:10.1021/ol9909886

ORGANIC
LETTERS
1999
Vol. 1, No. 8
1311-1314
Synthesis of (+)-Casuarine
Scott E. Denmark* and Alexander R. Hurd
Roger Adams Laboratory, Department of Chemistry, UniVersity of Illinois,
600 South Mathews AVenue, Urbana, Illinois 61801
denmark@scs.uiuc.edu
Received August 27, 1999
ABSTRACT
The first synthesis of (+)-casuarine, a pentahydroxy pyrrolizidine alkaloid, is described. The key bond-forming events occur in a tandem
[4 + 2]/[3 + 2] nitroalkene cycloaddition involving nitroalkene 6, chiral vinyl ether 7b, and vinyl silane 4. This process also creates five of the
six stereocenters present in this potent glycosidase inhibitor. Completion of the synthesis required only four additional steps and delivered
(+)-casuarine in 20% overall yield.
Polyhydroxy pyrrolizidine and indolizidine alkaloids display
a variety of interesting biological activities. Potential anti-
cancer1 and antiviral2 properties of these metabolites stem
from their resemblance to sugars, and not surprisingly, many
display significant glycosidase inhibition activity. (+)-
Casuarine (1), isolated in 1994 from the bark of Casuarina
equisetfolia L. (Casuarinaceae)3 represents one of the more
potent members of this class. It is an effective inhibitor of
glucosidase I (72% inhibition at 5 µg/mL), rivaling that of
the indolizidine alkaloid castanosperime (84% inhibition at
5 µg/mL).4 The C(3) hydroxymethyl substituent places (+)-
casuarine in the alexine/australine5 subclass of pyrrolizidine
alkaloids and differentiates it from the more common necines
which bear a C(1) hydroxymethyl group. The five hydroxyl
groups make (+)-casuarine the most highly oxygenated
amino-sugar analogue yet identified.
Recent publications from these laboratories have docu-
mented the use of tandem [4 + 2]/[3 + 2] nitroalkene
cycloadditions for the succinct syntheses of several polyhy-
droxylated pyrrolizidine and indolizidine alkaloids.6 These
studies had clearly demonstrated the ability of the tandem
cycloaddition strategy to assemble these skeletons with
excellent control over as many as four contiguous stereogenic
centers. However, (+)-casuarine with its densely oxygenated
periphery represented a still greater challenge to install five
of the six contiguous stereocenters by the cycloaddition
construct.
To accommodate the installation of so many hydroxyl
groups in a stereodefined fashion, suitably functionalized
nitroalkenes, dienophiles, and dipolarophiles were needed.
From previous endeavors, we knew that oxygenated nitro-
alkenes6 and dienophiles7 were amenable to [4 + 2]
cycloaddition but that oxygenated dipolarophiles gave re-
gioreversed cycloadducts.8 Thus, we made recourse to the
phenyldimethylsilyl substituent as a surrogate for a hydroxyl
group at C(1).9
(1) (a) Dennis, J. W. Cancer Res. 1986, 46, 5131. (b) Humphries, K. J.
Matsumoto, K.; White, S.; Olden, K. Cancer Res. 1986, 46, 5212. (c)
Ostrander, G. K.; Scribner, N. K.; Rohrschneider, L. R. Cancer Res. 1988,
48, 1091.
(2) (a) Gruters, R. A.; Neefjes, J. J.; Termette, M. de Goede, R. E. Y.
Tulp, A.; Huisman, H. G.; Miedema, F. Ploegh, H. L. Nature 1987, 330,
74. (b) Walker, B. D. Lowalski, M.; Goh, W. C.; Kozarsky, K.; Sodroski,
J. Proc. Natl. Acad. Sci. U.S.A. 1987, 84, 693. (c) Ratner, L. AIDS Res.
Hum. RetroViruses 1992, 8, 165.
(3) Nash, R. J.; Thomas, P. I.; Waigh, R. D.; Fleet, G. W. J.; Wormald,
M. R.; Lilley, P. M de Q.; Watkin,. D. J Tetrahedron Lett. 1994, 35, 7849.
(4) Bell, A. A.; Pickering, L.; Watson, A. A.; Nash, R. J.; Pan, Y. T.;
Elbein, A. D.; Fleet, G. W. J. Tetrahedron Lett. 1997, 38, 5869.
(5) Robins, D. J. Nat. Prod. Rep. 1990, 377.
(6) (a) Denmark, S. E.; Thorarensen, A. Chem. ReV. 1996, 96, 137. (b)
Denmark, S. E.; Thorarensen, A. J. Org. Chem. 1994, 59, 5672. (c)
Denmark, S. E.; Thorarensen, A. J. Am. Chem. Soc. 1996, 118, 8266. (d)
Denmark, S. E.; Thorarensen, A. J. Am. Chem. Soc. 1997, 119, 125. (e)
Denmark, S. E.; Herbert, B. J. Am. Chem. Soc. 1998, 120, 7357. (f)
Denmark, S. E.; Martinborough, E. A. J. Am. Chem. Soc. 1999, 121, 3048.
(7) Denmark, S. E.; Schnute, M. E. J. Org. Chem. 1994, 59, 4576.
(8) Denmark, S. E. Seierstad, M. J.; Herbert, B. J. Org. Chem. 1999,
64, 884.
10.1021/ol9909886 CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/23/1999

This synthetic design is outlined in Scheme 1. It is
expected that casuarine would be produced from nitroso
element a priori was uncertain. Additionally, the presence
of a C(5) benzoate group could exert considerable influence
on the reactive conformation of the nitronate. In fact, studies
on heavily substituted nitronates show a strong sensitivity
of facial approach to nitronate conformation.11
Scheme 1
Orienting experiments indicated that the acetoxy vinyl
ether 7a, the preferred bisalkoxy dienophile in previous
studies,7 was unsuitable for a productive cycloaddition with
nitroalkene 6.12 Instead, the more reactive benzoyloxy vinyl
ether 7b7 effectively produced the desired nitronate. Unfor-
tunately, the existing synthesis of the benzoate 7b gave a
very poor yield (17%),7 so a new route had to be developed
(Scheme 2). The chiral alkoxy aldehyde 87 was converted
Scheme 2
acetal 2 by N-O bond cleavage and N-alkylation followed
by Tamao-Fleming oxidation9 of the silyl moiety. Thus,
nitroso acetal 2 possesses all the required stereocenters and
functionality for the synthesis of (+)-casuarine. With the
exception of C(7) (nitroso acetal numbering), all the remain-
ing stereocenters are established in the tandem cycloaddition.
Ketone 3 was targeted as the key intermediate as it would
allow a substrate-controlled reduction for the creation of the
center at C(7) and would arise from a tandem inter [4 +
2]/inter [3 + 2] cycloaddition of simple components 6, 7,
and 4. Most importantly, a predictable stereochemical
outcome of these events is critical for the successful synthesis
of (+)-casuarine. [4 + 2] cycloaddition of nitroalkene 66b
and Z-acyloxy vinyl ether 77should provide nitronate 5. The
required C(4)/C(5) trans relationship was expected, given
the high exo selectivity which has been demonstrated
previously with this chiral vinyl ether.7 The desired approach
of the dipolarophile in the [3 + 2] cycloaddition for the
assembly of the nitroso acetal framework was more difficult
to predict. In cases where the C(4) benzoate and the C(6)
acetal center are positioned on the same side of the nitronate
ring, the approach of the dipolarophile is exclusively on the
side opposite these substituents.6b,e,8 This outcome has been
attributed to a cooperative effect between these two substit-
uents. However, in the absence of a C(4) substituent, the
C(6) acetal center alone can direct the facial attack of the
dipolarophile to the opposite side to a significant degree.10
Since the C(4) benzoate and the C(6) acetal center are on
opposite faces of the nitronate, the dominant controlling
to silyl enol ether 9 in 99% yield as a 10/1 (Z/E) mixture.
O-Acylation with benzoyl fluoride and a catalytic amount
of TBAF (2 mol %)13 afforded the Z-vinyl ether in 81% yield
along with 6% of the undesired E-vinyl ether which was
easily separated by silica gel chromatography.
With an improved synthesis of the dienophile in hand, the
optimization of the [4 + 2] cycloaddition could be under-
taken. Combining the chiral vinyl ether (Z)-7b and the
nitroalkene in the presence of 2.5 equiv of SnCl4 provided
the nitronate 5 as a 4.8:1 mixture of diastereomers (vide infra)
(Scheme 3). We have discovered that quenching the reaction
with Et3N/MeOH at low temperature proved to be critical
to obtain the cycloadduct in a high yield. The standard
method for quenching the Lewis acid (NaOH/MeOH)
partially converted the nitronate (up to 29%) to oxime 10.
In fact, quenching with a slight excess of NaOH/MeOH led
to complete conversion of the nitronate to oxime 10 (Scheme
4).14 The [4 + 2] cycloaddition was judged to be high
yielding (81%) and occurred with modest facial selectivity
(11) Schnute, M. E. Ph.D. Thesis, University of Illinois, 1995.
(12) In CH2Cl2, extensive polymerization occurred and no nitronate was
detected. With toluene as the solvent, the nitronate was produced; however,
the yield of [4 + 2]/[3 + 2] was unsatisfactory (54%).
(13) Limat, D.; Schlosser, M. Tetrahedron 1995, 51, 5799.
(14) (a) Denmark, S. E.; Moon, Y.-C.; Cramer, C. J.; Dappen, M. S.;
Senanayake, C. B. Tetrahedron 1990, 46, 7373. (b) Colvin, E. W.;
Robertson, A. D.; Seebach, D.; Beck, A. K. J. Chem. Soc., Chem. Commun.
1981, 952.
(9) (a) Tamao, K.; Ishida, N.; Tanaka, T.; Kumada, M. Organometallics
1983, 2, 1694. (b) Tamao, K.; Ishida, N. J. Organomet. Chem. 1984, 269,
C37. (c) Fleming, I.; Henning, R.; Plaut, H. J. Chem. Soc., Chem. Commun.
1984, 29. (d) Fleming, I.; Henning, R.; Parker, D. C.; Plaut, H. E.;
Sanderson, P. E. J. J. Chem. Soc., Perkin Trans. 1 1984, 317.
(10) Denmark, S. E.; Hurd, A. R. J. Org. Chem. 1998, 63, 3045.
1312
Org. Lett., Vol. 1, No. 8, 1999

Scheme 3
(4.8:1) in view of the conversion of 5 to 10.15 Nitronate 5
the mesylate with Raney nickel in MeOH under 260 psi of
H2 provided crystalline pyrrolizidine 14 in 64% yield along
with a 99% recovery of the chiral auxiliary 15. The C(6)
benzoate suffered partial saponification under the reaction
conditions. Thus, to facilitate purification, K2CO3 was added
at the end of the reaction to effect complete removal of both
benzoate groups.
proved to be too unstable for isolation and purification and
was immediately treated with the â-silyl enone 48 to afford
a 45:7:3:2:1:1 mixture of nitroso acetals in 76% yield.16 The
major nitroso acetal was enriched to the extent of 41:0:0:2:
1:1 by preparative HPLC for an overall yield of 55%. Thus
four of the five stereocenters in (+)-casuarine were now set.
The completion of the synthesis required only the trans-
formation of the C(1) silyl group to the final hydroxyl
substituent and deprotection. This process began with deary-
lation of the silyl group with mercuric trifluoroacetate in
trifluoroacetic acid and acetic acid for 1 h, followed by room-
temperature oxidation (16 h) with peracetic acid to provide
(+)-casuarine.19 If the oxidation were conducted at higher
temperature (50 °C), a significant portion of N-oxide was
observed. Although this could be converted back to casuarine
by hydrogenation, failure to remove all the mercury by ion
exchange chromatography was known to complicate this
step.6e Under the current oxidation conditions less than 5%
N-oxide was detected by 1H NMR analysis. After ion
exchange chromatography, casuarine was isolated by crystal-
lization from EtOH. The N-oxide present in the mother liquor
was reduced (H2, MeOH, Pd/C, HOAc, 16 h) and following
ion exchange chromatography and crystallization provided
additional amounts of casuarine to bring the combined yield
to 84%.
Scheme 4
The final stereocenter was installed by a selective ketone
reduction. Treatment of keto nitroso acetal 3 with L-
Selectride led to 10:1 mixture of epimeric alcohols 12 in
87% yield.17 Additionally, the minor diastereomers present
in the starting ketone mixture were chromatographically
removed. The selectivity demonstrated in this reduction can
be rationalized by assuming a reactive conformation invoked
in the Cornforth model18 wherein the phenyldimethylsilyl
group provides the facial shielding to hydride attack. The
resulting alcohols were activated in near quantitative yield
with methanesulfonic anhydride in pyridine. Treatment of
All physical and spectral properties of synthetic (+)-
casuarine were obtained from an analytically pure sample
and are in agreement with the reported measurements of the
natural product. However, the optical rotation of synthetic
(+)-casuarine was low (+10.8° versus +16.9° (H2O, pH 8.4)
reported for the natural material). This discrepancy prompted
us to vouchsafe the enantiomeric purity of the synthetic
(15) Diastereomeric ratio was determined by NMR. The two major
diastereomers are assumed to be facial diastereomers. It is uncertain whether
the minor diastereomer is an oxime geometric isomer or an acetal epimer.
(16) Diastereomeric ratio was determined by chiral stationary phase
supercritical fluid chromatography (SFC).
(17) Diastereomeric ratio was determined by SFC.
(18) Cornforth, J. W.; Cornforth, R. H.; Mathew, K. K. J. Chem. Soc.
1959, 112.
(19) Kolb, H. C.; Ley, S. V.; Slawin, A. M. Z.; Williams, D. J. J. Chem.
Soc., Perkin Trans. 1 1992, 2735.
Org. Lett., Vol. 1, No. 8, 1999
1313

material by independently establishing the enantiomeric
composition of a late-stage synthetic intermediate. The 2,6,7-
trisbenzoate of pyrrolizidine 14 was determined to have an
enantiomeric excess of ca. 98% by chiral stationary phase
supercritical fluid chromatography (SFC).20 We thus con-
clude that the reported optical rotation for natural (+)-
casuarine is erroneously high.
and geometry, it is surprising that the face selectivity switches
by the simple substitution of the exo-oriented â substituent
from a carbomethoxy to a phenyldimethylsilyl. Examination
of molecular models indicates that the â face approach is
disfavored by a nonbonded steric interaction between the
axially oriented C(4) benzoate of the nitronate and the
phenyldimethylsilyl moiety of 4.
The stereochemical analysis of the key step in this
synthesis was complicated by the difficulty in establishing
the identity of the minor diastereomers in the product. The
[4 + 2] cycloaddition was deemed to occur in 81% yield
with 4.8:1 facial selectivity, as determined by its conversion
to the oximino ether 10. The selectivity in the [3 + 2]
cycloaddition step is less clear. In the worst instance, if all
the other diastereomers arose from the â face approach to
the nitronate, the [3 + 2] selectivity would be 3.2:1.
However, since this diastereomeric ratio must include the
[4 + 2] cycloaddition diastereomers (4.8:1), the [3 + 2] ratio
is probably closer to 9:1. The sense and magnitude of this
preference is astonishing because the selfsame nitronate
undergoes [3 + 2] cycloaddition with dimethyl maleate to
the extent of 3/1 faVoring the opposite face, Scheme 5.21
Assuming that both dipolarophiles react with similar timing
In summary, we have accomplished the first synthesis of
the (+)-casuarine in only eight steps from the chiral R-alkoxy
aldehyde 8 in 20% overall yield. Five of the six stereocenters
were created in the tandem cycloaddition, with the sixth
provided by a selective substrate-controlled ketone reduction.
The Lewis acid promoted [4 + 2] cycloaddition was
successfully applied with two highly oxygenated components
and would not have been viable without the improved
synthesis of the chiral acyloxy vinyl ether. The facial
selectivity in the [3 + 2] cycloaddition was found to be
suprisingly dependent upon the dipolarophile, apparently due
to nonbonded interactions with the â-silyl substituent. Further
studies with highly functionalized cycloaddition components
are in progress.
Acknowledgment. We gratefully acknowledge the gift
of natural (+)-casuarine from R. J. Nash (Aberystwyth).
Financial support was provided by the National Institutes of
Health (GM 30938). A.R.H. gratefully acknowledges the
University of Illinois for a Graduate Fellowship, Eastman
Chemical Company for an Eastman Summer Fellowship, and
Zeneca Pharmaceuticals for the Zeneca Graduate Fellowship
in Synthetic Organic Chemistry.
Scheme 5
Supporting Information Available: Preparation and full
1
characterization of (+)-casuarine and H NMR spectra of
both natural and synthetic (+)-casuarine. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL9909886
(20) Chiralcel OD column, 150 psi, 5.5 mL/min, 5% MeOH.
(21) The structural assignment of the vinyl silane cycloadduct (3) was
determined by conversion to the natural product. The structural assignment
of the dimethyl maleate cycloadduct (11) was determined by single-crystal
X-ray analysis.
1314
Org. Lett., Vol. 1, No. 8, 1999