Stereocomplementary routes to hydroxylated nitrogen heterocycles: Total syntheses of casuarine, Australine, and 7-epi-Australine

Article abstract of DOI:10.1002/chem.201301320

Addition of lithiated 1-benzyloxyallene to a D-arabinose-derived cyclic nitrone occurred with perfect diastereoselectivity furnishing a bicyclic 1,2-oxazine derivative, which is an excellent precursor for pyrrolizidine alkaloids hydroxylated at C-7 with o

Full text of DOI:10.1002/chem.201301320

FULL PAPER
Alkaloids
C. Parmeggiani, F. Cardona, L. Giusti,
H.-U. Reissig,* A. Goti* . . . . &&&& — &&&&
Ring size matters! Complete control of
the configuration at C-7 of polyhy-
droxy pyrrolizidine alkaloids has been
achieved by carrying out addition reac-
tions to an endocyclic double bond in
a six-membered 1,2-oxazine adduct, or
after ring contraction to a five-mem-
bered pyrrolidine (see scheme). Versa-
tility and reliability of the strategy
allowed high yield syntheses of both
casuarine and australine.
Stereocomplementary Routes to
Hydroxylated Nitrogen Heterocycles:
Total Syntheses of Casuarine,
Australine, and 7-epi-Australine
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DOI: 10.1002/chem.201301320
Stereocomplementary Routes to Hydroxylated Nitrogen Heterocycles: Total
Syntheses of Casuarine, Australine, and 7-epi-Australine
Camilla Parmeggiani,[a, b, c] Francesca Cardona,[a] Leonardo Giusti,[a, b]
Hans-Ulrich Reissig,*[b] and Andrea Goti*[a]
Abstract: Addition of lithiated 1-ben-
zyloxyallene to a d-arabinose-derived
cyclic nitrone occurred with perfect di-
astereoselectivity furnishing a bicyclic
1,2-oxazine derivative, which is an ex-
cellent precursor for pyrrolizidine alka-
loids hydroxylated at C-7 with optional
configuration at this stereogenic center.
tions occurring complementarily at the
bottom or top face of the endocyclic
australine as examples of the two
classes of diversely configured 7-hy-
droxypyrrolizidine alkaloids. An alter-
native synthesis of australine and two
strategies for the preparation of 7-epi-
australine are also reported, which
demonstrate that the stereoselectivity
of hydride reduction of an exocyclic
À
C C double bond in six- and five-
membered B rings, respectively. Ap-
plicability of these stereodivergent
routes to obtain polyhydroxy pyrrolizi-
dine alkaloids is demonstrated by the
efficient syntheses of casuarine and
À
À
Depending on the stage of the N O
C O double bond is independent of
bond cleavage and ring re-closure, 7-
hydroxypyrrolizidines with 7R or 7S
configuration were obtained, as a result
of completely selective addition reac-
the ring size, occurring preferentially
from the top face either in a six- or
five-membered ring.
Keywords: alkaloids · allenes · ni-
trones · nucleophilic attack · stereo-
selectivity
Introduction
logues, mainly by the use of chiral cyclic nitrones as inter-
mediates for 1,3-dipolar cycloadditions[2d] and nucleophilic
additions of organometallic reagents.[3,4,5,6] In the field of
pyrrolizidine alkaloids, we have recently succeeded in syn-
thesizing casuarine (1) and its 6-O-glucosyl conjugate,[7] and
uniflorine (2),[8] as well as a number of unnatural relatives,[9]
by cycloaddition of a suitably designed dipolarophile to d-
arabinose-derived nitrone 3 (Scheme 1) and related carbo-
Iminosugars (polyhydroxypiperidines and pyrrolidines) and
related bicyclic compounds belonging to the privileged
classes of indolizidines, pyrrolizidines, and nortropanes have
recently emerged as potential therapeutic agents towards a
large variety of diseases (diabetes, cancer, viral and bacterial
infections, lysosomal storage diseases) in view of their well-
established bioactivity as inhibitors of glycosyl hydrolases.[1]
This interesting behavior has stimulated intense synthetic
activity in the last decades to access natural products be-
longing to these classes and their unnatural congeners for
structure/activity relationship studies.[2] In this context, we
have addressed the synthesis of natural products and ana-
[a] Dr. C. Parmeggiani, Dr. F. Cardona, L. Giusti, Prof. A. Goti
Department of Chemistry “Ugo Schiff”, associated with
ICCOM-CNR, University of Florence
Via della Lastruccia 3-13
50019 Sesto Fiorentino (FI) (Italy)
Fax : (+39)0554573531
Scheme 1. Synthetic strategies to polyhydroxylated pyrrolizidine alkaloids
E-mail: andrea.goti@unifi.it
from carbohydrate-derived cyclic nitrone 3.
[b] Dr. C. Parmeggiani, L. Giusti, Prof. H.-U. Reissig
Institut fꢁr Chemie und Biochemie, Freie Universitꢂt Berlin
Takustrasse 3, 14195 Berlin (Germany)
hydrate-derived nitrones.[7,10,11] While this manuscript was in
preparation, Py and co-workers reported a synthesis of aus-
traline (7a-epi-alexine) (4)[12] based on their SmI2-mediated
reductive coupling of nitrones with acrylates[13] by starting
with the same precursor 3 (Scheme 1). One of the most
challenging points of both of these synthetic strategies
rested in placing the hydroxyl substituent at C-7 of the pyr-
E-mail: hreissig@chemie.fu-berlin.de
[c] Dr. C. Parmeggiani
Current address: CNR-INO
U.O.S. Sesto Fiorentino (LENS)
Via Nello Carrara 1
50019 Sesto Fiorentino (FI) (Italy)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201301320.
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Total Syntheses of Casuarine, Australine, and 7-epi-Australine
FULL PAPER
rolizidine ring, which was achieved by silicon to oxygen re-
placement with a Tamao–Fleming reaction.[7,12] Interestingly,
diastereomeric b-C-silyl acrylates, Z and E, respectively,
were necessary to achieve the opposite configuration re-
quired at C-7 of the target alkaloids 1 and 4 (Scheme 1).
We show herein that addition of the organolithium deriva-
tive 6 to nitrone 3 is a very straightforward key reaction to
directly install the hydroxy group at C-7 of the polyhydroxy-
pyrrolizidine skeleton and that the diastereofacial prefer-
ence for addition to the endocyclic double bond can be com-
pletely controlled by the size of ring B of the bicyclic inter-
mediate. The power of this strategy is exemplified by the
short and efficient syntheses of australine[19,20] and casuar-
ine.[21]
Results and Discussion
Placing a hydroxyl group at C-7 of a pyrrolizidine is not a
trivial task unless it is already part of a starting material
from the chiral pool as a carbohydrate. As mentioned
before, ours and Pyꢃs group have both managed to accom-
plish this aim by a Tamao–Fleming reaction.[7,12] Other re-
searchers have devised different routes; for example, Fleet,
Yu and co-workers achieved this purpose by introducing a
dithiane heterocycle that was then deprotected to a carbonyl
and reduced;[4g] Pyne and co-workers introduced the oxygen
atom at C-7 by oxidation of an endocyclic double bond
through dihydroxylation or epoxidation followed by hydrol-
ysis or reduction;[14] Huang and co-workers also employed a
dihydroxylation of a double bond installed in turn by a sele-
nylation/elimination procedure.[15] However, all these proce-
dures suffer from some drawbacks, requiring several distinct
synthetic steps and/or the use of expensive or unpleasant
stoichiometric reagents. In addition to the length of these
approaches, the key transformations do not always give
good yields of products or display complete regio- and/or
stereoselectivity. Moreover, they did not allow for control of
the stereoselectivity for installing each one of the two possi-
ble configurations at the newly created C-7 stereocenter, a
highly desirable target. We envisaged that nucleophilic addi-
tion of an appropriate lithiated 1-alkoxyallene derivative 6
to the same nitrone 3, according to a well-established meth-
odology developed by one of the groups,[16] would allow a
more direct access to 7-hydroxypyrrolizidines (Scheme 2).
Even more importantly, the intermediate adduct 5 might
The addition of lithiated 1-benzyloxyallene (6) to nitrone
3 occurred successfully with exclusive trans stereoselectivity
(with respect to the vicinal benzyloxy group at C-3 of the ni-
trone), as expected on the basis of previous findings collect-
ed by us and other groups on related nucleophilic addi-
tions,[3,4,22] which were established to be efficiently control-
led by steric and stereoelectronic effects.[23] Contrary to the
only precedent additions of a lithiated alkoxyallene to relat-
ed tartaric or malic acid derived nitrones,[3a] the primary
adduct 7 was barely detectable and chromatography aimed
to its isolation led to extensive decomposition. Extraction of
the reaction mixture with dichloromethane immediately
after quenching proved to be advantageous. After drying
with Na2SO4 and storage in CH2Cl2 solution for three days a
complete cyclization to 8 was observed. Albeit it was report-
ed earlier that related hydroxylamines may cyclize to two
isomeric bicyclic adducts, that is, either a pyrrolo-1,2-oxazine
or a pyrrolizidine N-oxide, in a concentration dependent
manner,[3a] only adduct 8 was obtained in our case, with no
trace of the pyrrolizidine N-oxide
9 being detected
(Scheme 3), even when increasing the concentration of the
solution. However, the 1,2-oxazine ring of 8 could be con-
verted into a pyrrolidine ring as well (see below).
Scheme 3. Stereoselective addition of lithiated 1-benzyloxyallene (6) to
nitrone 3.
Firstly, an addition to the C–C double bond of 1,2-oxazine
8 was studied. On the basis of the previous study[3a] it was
anticipated that additions would occur with efficient regio-
and stereocontrol. Indeed, hydroboration/oxidation of 8 fol-
lowing the established protocol[24] occurred with complete
regio- and stereoselectivity in quantitative yield (Scheme 4).
Careful analysis of the NMR spectroscopic data showed
that the diastereoisomer 10 was formed exclusively, which
Scheme 2. Retrosynthetic analysis for casuarine (1) and australine (4).
give the opportunity to access both classes of pyrrolizidine
derivatives belonging to the casuarine (1)[17] or the austral-
ine (4)[18] classes, with opposite configuration at C-7, de-
pending on the diastereofacial preference of addition to the
double bond (Scheme 2).
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H.-U. Reissig, A. Goti et al.
events, that is, operating the ring-opening/cyclization steps
before the addition reaction, would switch the diastereofa-
cial preference for the addition, thus providing access to the
australine class of alkaloids possessing the opposite configu-
ration at C-7.
The pyrrolo-1,2-oxazine 8 was first subjected to a chemo-
À
selective reduction of the N O bond to pyrrolidine 14,
[27]
which was successful with both [Mo(CO)6]/NaBH4
and
SmI2,[24,25,28] with the latter reagent being more satisfactory
(Scheme 5).
Scheme 4. Hydroboration of bicyclic 1,2-oxazine derivative 8 and synthe-
sis of casuarine (1).
indicated a preferential addition to the Si face, anti to the
bridgehead hydrogen atom. This approach installed, there-
fore, the correct configuration required for casuarine (1) at
the two newly created stereogenic centers. Indeed, casuarine
was easily obtained by reductive ring opening of 10 with Zn/
H+ or SmI2,[24,25] followed by cyclization of 11 with an
excess of MsCl to pyrrolizidine 12 and final reductive steps
for demesylation to 13 with LiAlH4 and deprotection by Pd/
C-catalyzed hydrogenation. The resulting product displayed
physical and spectroscopic data in good agreement with
those reported in the literature.[21] This accomplished the
most straightforward and high yielding total synthesis of cas-
uarine reported to date, with an 84% overall yield of the al-
kaloid and six steps from nitrone 3 (ten steps, 47% from
commercially available tribenzyl-protected d-arabinose).
The same synthetic sequence had been preliminarly car-
ried out by starting with the parent 1-methoxyallene as a
model substrate. Essentially analogous results have been ob-
tained (see Supporting Information) for the preparation of
the corresponding products 8–13 with a methoxy instead of
a benzyloxy group at C-4 (dihydro-1,2-oxazines) or C-7 (pyr-
rolizidines). Of course, final hydrogenation of the pyrrolizi-
dine corresponding to 13 furnished the methylated analogue
7-O-methylcasuarine (1b, see the Supporting Information).
Interestingly, bioassays of this compound towards a set of 12
commercial glycosidases showed that it behaved similarly to
casuarine itself, displaying good and selective inhibition of
amyloglucosidase from Aspergillus niger (97% inhibition at
1 mm, IC50 =9.7 mm).[26]
Scheme 5. Ring contraction of bicyclic 1,2-oxazine 8 to pyrrolizidine 15
and synthesis of australine (4).
Pyrrolidine 14 smoothly cyclized after mesylation to quan-
titatively afford pyrrolizidine 15. Hydrogenation of 15 over
Pd/C occurred quantitatively, but furnished a mixture of the
desired australine (4) and its 7-oxo relative 16 in an approxi-
mately 3:1 ratio. Formation of this mixture indicates that de-
benzylation of the hydroxy group at C-7 competes with hy-
drogenation of the double bond in 15: when debenzylation
occurs first, the resulting enol readily isomerizes to its keto
tautomer, which is inert to hydrogenation under these condi-
tions.[29] Attempted selective debenzylation to 16 with BCl3
led to a complex mixture of products. However, only aus-
traline (4) was isolated in good yield (87%) when the reac-
tion mixture resulting from work up of the hydrogenation
step was treated directly with NaBH4 in methanol. This
result derives from complete stereoselectivity in the hydro-
genation of the double bond of 15 and in the hydride reduc-
tion of the carbonyl group of 16, with reagents always ap-
proaching from the upper convex face of the pyrrolizidine
ring as anticipated. NMR spectroscopic data and optical ro-
tation of the synthesized alkaloid were in good agreement
with those previously reported for australine.[18] Thus, we
completed this novel total synthesis of australine in four
steps from nitrone 3 with 59% overall yield (eight steps,
33% from commercial tribenzyl protected d-arabinose),
which compares very well with the previously reported syn-
theses.[19]
The stereoselectivity of the key addition to 8, occurring
from the bottom face, may be attributed to a preferential
conformation of the six-membered ring, in which the top
face is more encumbered. In other words, a pyrrolo-1,2-oxa-
zine bicyclic system does not present a pronounced convex
face, contrary to a ring-contracted pyrrolizidine heterocycle.
We reasoned therefore that, inverting the order of the
Prompted by the observed complete stereoselectivity in
the hydride reduction of ketone 16, yet another approach
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Total Syntheses of Casuarine, Australine, and 7-epi-Australine
FULL PAPER
has been envisaged aiming at an alternative synthesis of aus-
traline. We expected that the benzyl enol ether in 8 might
undergo acid-catalyzed hydrolysis to the ketone 17, which
would be reduced to the corresponding secondary alcohol.
We speculated that hydride reagents would attack from the
same face as for ketone 16, as a consequence of the shift of
the double bond from the endo (in 8) to the exo position
which should give a chair conformation in which equatorial
attack to C-4 would be favored.
borohydride gave a low yield of a 4:1 diastereomeric mix-
ture of alcohols 18, with the major alcohol 18a deriving
from hydride attack syn to the bridgehead hydrogen atom
as anticipated. Structural assignment of 18a,b was based on
analysis of the coupling constants, as well as on subsequent
synthetic elaboration (see below). Increase of the reagent
bulkiness by use of l-selectride in THF at À758C allowed
complete control of diastereoselectivity, affording alcohol
18a exclusively in a satisfactory 86% yield. Benzylation of
the free hydroxyl group of 18a followed by cleavage of the
Hydrolysis of 8 to the ketone 17 was challenging.[30] A set
of different solvents (methanol, acetonitrile, dioxane) in a
mixture with H2O were tested, as well as different strong
protic acids (HCl, HClO4) at different concentrations. None
of the conditions employed allowed clean and complete con-
version to the ketone. Concentration of the acid had to be
kept low to avoid decomposition; consequently, long reac-
tion times were required and it was found convenient to
stop the reaction before complete consumption of the start-
ing material. Moreover, the dimethyl ketal of 17 (in
CH3OH) and a mixed benzyl methyl ketal were detected be-
sides the desired product and unreacted starting material.
After extensive experimentation, dioxane/water and HCl
were selected as the most satisfactory reaction mixture,
which at least did not form ketal byproducts. Also in this
case, however, complete conversion of the enol ether 8 was
not achieved. The advancement of the reaction had to be
À
N O bond with SmI2 and re-closure to a pyrrolizidine upon
mesylation furnished the tetra-O-benzylated australine pre-
cursor 20 in 55% overall yield. The final deprotection by hy-
drogenation with Pd/C furnished the natural alkaloid 4 in
73% yield in high purity.
The second strategy also gave access to intermediates
which may be useful for achieving complementary targets.
As an example, we envisaged that the alcohol 18b would
serve as a suitable precursor of 7-epi-australine (7,7a-di-epi-
alexine), a tetrahydroxylated pyrrolizidine yet unidentified
from natural samples.[31] This compound has been previously
synthesized[34] for structural correlation to isolated natural
products[31] and was found to be a weak inhibitor of several
glycosidases.[33b] The result described above for the reduc-
tion of ketone 17 with NaBH4 discouraged us to test other
reducing agents for the selective synthesis of 18b. Alterna-
tively, inversion of configuration at C-4 from alcohol 18a
through a Mitsunobu reaction was deemed a better solution.
Indeed, treatment of 18a under Mitsunobu conditions with
p-nitrobenzoic acid afforded ester 21, which was hydrolyzed
to alcohol 18b under basic conditions (Scheme 7). This alco-
1
monitored by H NMR spectroscopy and the reaction was
stopped at about 80% conversion; moreover, in our hands
the reaction suffered from scarce reproducibility. Under the
optimized conditions, a 75% yield of the desired ketone 17
was isolated from the reaction mixture by flash column
chromatography (Scheme 6). Reduction of 17 with sodium
Scheme 7. Synthesis of 7-epi-australine (22) by starting from precursors
18a or 12.
hol, through the same transformations reported above for
its diastereoisomer 18a (Scheme 6), should afford 7-epi-aus-
traline. However, it was simultaneously evaluated to access
7-epi-australine via intermediates obtained in the strategy il-
lustrated in Scheme 4, which is fairly more efficient and reli-
able. Unfortunately, attempted protodeboration of the
borane obtained by hydroboration of adduct 8 was unsuc-
cessful. Then, we turned our attention to the mesylate 12,
which should undergo a reductive deoxygenation as previ-
ously observed for a related compound in our synthesis of
Scheme 6. Acid-catalyzed hydrolysis of benzyl enol ether 8 and synthesis
of australine (4).
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H.-U. Reissig, A. Goti et al.
hyacinthacine A2.[9a] Indeed, treatment of 12 with diisobuty-
laluminium hydride (DIBAL) in refluxing toluene for 2 h
led to the desired deoxygenation at C-6. As previously ob-
served on related benzyl-protected carbohydrate deriva-
tives,[35] DIBAL promoted the concomitant selective deben-
zylation of the hydroxy group at C-7, affording the tri-O-
benzylated 7-epi-australine 23 in reasonable yield
(Scheme 7). Final debenzylation with hydrogen over Pd/C
quantitatively provided the desired 7-epi-australine 22,
which displayed spectroscopic and physical data in good
agreement with the literature.[34] Subjected to inhibition
assays towards the same set of glycosidic enzymes, 7-epi-aus-
traline 22 showed a good inhibition of amyloglucosidase
from Aspergillus niger (95% inhibition at 1 mm, IC50 =
3.5 mm)[26] with a potency lower than that of casuarine, but
much higher (>1 order of magnitude) than that reported
earlier.[33b] It also showed significant inhibition (80% inhibi-
tion at 1 mm) of a-glucosidase from yeast, in good agree-
ment with the literature.[33b]
analysis on 0.25 mm silica gel plates (Merck F254). Column chromatogra-
phies were carried out on silica gel 60 (32–63 mm) or on silica gel (230–
400 mesh, Merck). Yields refer to spectroscopically and analytically pure
1
compounds unless otherwise stated. H NMR spectra were recorded on a
Varian Mercury-400, on a Varian INOVA 400, on Bruker (AC 250, WH
270, AC 500, AVIII), or JEOL (ECX 400, Eclipse 500) instruments at
258C. 13C NMR spectra were recorded on a Varian Gemini-200 or on a
Varian Gemini-300. Chemical shifts are reported relative to TMS (1H:
d=0.00 ppm) and CDCl3 (13C: d=77.0 ppm). Integrals are in accordance
with assignments, coupling constants are given in Hz. For detailed peak
assignments 2D spectra were measured (COSY, HMQC, HMBC,
NOESY, and NOE as necessary). IR spectra were recorded with a
Perkin–Elmer Spectrum BX FT-IR System spectrophotometer, with a
Nicolet 5 SXC FTIR spectrometer, or with a Nexus FTIR spectrometer
equipped with a Nicolet Smart DuraSample IR ATR. Mass spectra were
recorded on a QMD 1000 Carlo Erba instrument by direct inlet. HRMS
analyses were performed with a Varian Ionspec QFT-7 (ESI-FT ICRMS)
instrument. Elemental analyses were performed with a Perkin–Elmer
2400 analyzer or with CHN-Analyzer 2400 (Perkin–Elmer), Vario EL, or
Vario EL III. Optical rotation measurements were performed on a
JASCO DIP-370 polarimeter.
(4aS,5R,6R,7R)-4,5,6-Tris(benzyloxy)-7-[(benzyloxy)methyl]-4a,5,6,7-tet-
rahydro-2H-pyrroloACHTUNGNRTE[NUG 1,2-b]-1,2-oxazine (8): A solution of nBuLi in
hexane (1.6m, 3.30 mL, 5.28 mmol) was added at À408C to a stirred solu-
tion of 1-benzyloxyallene[5d] (815 mg, 5.58 mmol) in dry THF (20 mL)
under an argon atmosphere. The mixture was stirred at À408C for
10 min, and then a solution of nitrone 3[10] (1.27 g, 3.00 mmol) in dry
THF (15 mL) was added at À788C. The mixture was stirred at À788C for
2 h. TLC control (CH2Cl2/AcOEt 8:1) showed the disappearance of the
starting material (Rf =0.11) and the appearance of a new product (Rf =
0.82), and then H2O (30 mL) was added dropwise and the mixture was
warmed up to RT. The mixture was extracted with dichloromethane (3ꢄ
20 mL) and the combined organic layers were dried over anhydrous
Na2SO4, filtered, and stirred at RT for 3 d. Evaporation under reduced
pressure and purification of the residue by flash column chromatography
on silica gel (hexane/AcOEt 4:1) afforded pure 8 (1.67 g, 2.97 mmol,
99%) as a yellow oil. Rf =0.26 (hexane/AcOEt 4:1); [a]2D0 =À21 (c=1.4
in CHCl3); 1H NMR (500 MHz, CDCl3): d=7.46–7.25 (m, 20H; Ar-H),
4.93–4.87 (m, 3H, H-3; Bn-H), 4.74–4.53 (m, 6H; Bn-H), 4.51–4.49 (m,
Conclusion
We have developed an efficient and straightforward strategy
for accessing the 7-hydroxy pyrrolizidine skeleton and have
proved that control of the configuration at C-7 can be ach-
ieved by carrying out additions to the endocyclic C–C
double bond either to the initial 6-membered 1,2-oxazine
adduct, or after ring contraction to a five-membered dihy-
dropyrrole. In contrast, the stereoselectivity of the hydride
reduction of an exocyclic C–O double bond preferentially
occurred from the top face in six- and five-membered het-
erocycles. These results represent a considerable improve-
ment and extension of the methodology based on addition
of organometallic reagents to chiral cyclic nitrones for ac-
cessing alkaloid-like pyrrolizidine heterocycles by: 1) allow-
ing direct placement of a protected hydroxyl substituent at
C-7 without the need of additional synthetic elaborations,
2) providing efficient access to both 7R and 7S-configured
compounds (with the additional option of stereocontrol at
C-6) as a result of completely stereocontrolled addition re-
actions that occur with opposite preference depending on
the size of ring B. Versatility and reliability of the strategy
were demonstrated by high-yield syntheses of both casuar-
ine and australine as examples of the two classes of 7-hy-
droxypyrrolizidine alkaloids. In particular, the high efficacy
of our casuarine synthesis, with an overall yield doubled
compared to the best previously published total syntheses,[21]
should facilitate further biological investigations and lead to
possible applications in view of its excellent inhibition of
human digestive glycosidase enzymes.[7]
2H, H-5; Ha-2), 4.42 (dd, 2J
A
E
3
3
4.23 (t, J
(H,H)=4.2 Hz, 1H; H-6), 3.97 (d, J
3.78–3.74 (m, 2H; H-7, Ha-8), 3.66 ppm (dd, 2J(H,H)=11.3, 2J
ACTHNUTRGENNUG ACHTUNGTRENNUNG(H,H)=
7.7 Hz, 1H; Hb-8); 13C NMR (125 MHz, CDCl3): d=151.2 (s, C-4),
À
138.4–136.9 (s, 4C; Ar-C), 128.7–127.7 (d, 16C; Ar C), 93.0 (d, C-3), 87.9
(d, C-5), 86.3 (d, C-6), 73.6, 72.4, 72.1 (t, Bn-C), 69.6 (t, C-8), 69.4 (t, Bn-
C), 68.3 (d, C-7), 66.3 (d, C-4a), 63.6 ppm (t, C-2); IR (KBr): n˜ =3029,
2897, 1673, 1496, 1453, 1361, 1349, 1216, 1199, 1074, 732, 694 cmÀ1
;
HRMS (ESI): m/z: calcd for C36H37NO5 +H+: 564.2705 [M+H+]; found:
564.2742; elemental analysis calcd (%) for C36H37NO5: C 76.71, H 6.62, N
2.48; found: C 76.76, H 6.58, N 2.50.
(3S,4S,4aS,5R,6R,7R)-4,5,6-Tris(benzyloxy)-7-[(benzyloxy)methyl]hexa-
hydro-2H-pyrroloACTHNUTRGNEUNG[1,2-b]-1,2-oxazin-3-ol (10): A solution of BH3·THF in
THF (1m, 2.92 mL, 2.92 mmol) was added at À308C to a stirred solution
of 8 (410 mg, 0.73 mmol) in dry THF (15 mL) under an argon atmos-
phere. The solution was stirred at À308C for 5 min and then at RT for
2 h. TLC control (hexane/AcOEt 2:1) showed the disappearance of the
starting material (Rf =0.35) and the appearance of a new product (Rf =
0.63), then a 2n solution of NaOH (4.38 mL) and 35% H2O2 (1.46 mL)
were added dropwise at À108C and the mixture was stirred for 15 h at
RT. After this time, a saturated aqueous solution of Na2S2O3 (5 mL) was
added dropwise and the mixture was stirred for 10 min and then extract-
ed with Et2O (3ꢄ20 mL). The combined organic layers were dried over
anhydrous Na2SO4, filtered, and evaporated under reduced pressure. Pu-
rification of the residue by flash column chromatography on silica gel
(hexane/AcOEt 2:1) afforded pure 10 (425 mg, 0.73 mmol, 100%) as a
colorless oil. Rf =0.16 (hexane/AcOEt 2:1); [a]2D0 =À26 (c=0.41 in
CHCl3); 1H NMR (500 MHz, CDCl3): d=7.38–7.21 (m, 20H; Ar-H),
Experimental Section
General methods: Commercial reagents were used as received. All reac-
tions were carried out under magnetic stirring and monitored by TLC
4.70–4.44 (m, 8H; Bn-H), 4.31–4.25 (m, 1H; H-5), 4.06 (t, 3J
2.8 Hz, 1H; H-6), 4.03 (d, 3J
(H,H)=3.3 Hz, 1H; Ha-2), 3.77–3.69 (m,
ACHTUNGTRENNUNG(H,H)=
ACHTUNGTRENNUNG
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ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
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Total Syntheses of Casuarine, Australine, and 7-epi-Australine
FULL PAPER
3
4H; Hb-2, H-3, H-7, Ha-8), 3.59 (t, J
G
ACHTUNGTRENNUNG
3
3
2J
(H,H)=8.9, J
(H,H)=7.4 Hz, 1H; Hb-8), 3.35 (t, J
A
E
ACHTUNGTRENNUNG
H-4a), 2.39 ppm (brs, 1H, OH); 13C NMR (125 MHz, CDCl3): d=138.3,
138.2, 138.0, 137.9 (s; Ar-C), 128.6–127.8 (d, 16C; Ar-C), 85.4 (d; C-6),
84.7 (d; C-5), 76.9 (d; C-4), 73.6, 73.1, 71.9, 71.7 (t; Bn-C), 69.0 (d; C-3),
68.9, 68.8 (t; C-2, C-8), 67.9 ppm (d, 2C; C-7, C-4a); IR (KBr): n˜ =3432,
3029, 2910, 2864, 1495, 1453, 1362, 1206, 1093, 750, 734 cmÀ1; HRMS
(ESI): m/z: calcd for C36H39NO6 +H+: 582.2811 [M+H+]; found:
582.2861; elemental analysis calcd (%) for C36H39NO6: C 74.33, H 6.76, N
2.41; found: C 74.17, H 6.98, N 2.42.
ACHTUNGTRENNUNG
CDCl3): d=138.4, 138.2, 138.0, 137.5 (s, Ar-C), 128.6–127.7 (d, 16C; Ar-
C), 85.9 (d; C-7), 85.8 (d; C-1), 85.3 (d; C-2), 85.3 (d; C-6), 73.5, 72.8 (t;
Bn-C), 72.5 (t; C-8), 72.4, 72.1 (t; Bn-C), 68.2 (d; C-3), 57.2 (t; C-5),
38.6 ppm (q, CH3); IR (CDCl3): n˜ =3029, 2893, 2863, 1342, 1175, 1090,
1071, 750, 696 cmÀ1; HRMS (ESI): m/z: calcd for C37H41NO7S+H+:
644.2637 [M+H+]; found: 644.2678; elemental analysis calcd (%) for
C37H41NO7S: C 69.03, H 6.42, N 2.18; found: C 69.50, H 6.03, N 2.60.
(1R,2R,3R,6S,7S,7aR)-1,2,7-Tris(benzyloxy)-3-[(benzyloxy)methyl]hexa-
ACHTUNGTRENNUNG(2’S,3’S)-3’-(Benzyloxy)-3’-{(2R,3R,4R,5R)-3,4-bis(benzyloxy)-5-[(benzy-
hydro-1H-pyrrolizin-6-ol (13):
A solution of LiAlH4 in THF (1m,
loxy)- methyl]pyrrolidin-2-yl}-propan-1’,2’-diol (11):
0.88 mL, 0.88 mmol) was added to a stirred solution of 12 (140 mg,
0.22 mmol) in dry THF (4 mL) at 08C under an argon atmosphere. The
solution was stirred at reflux for 2 h. TLC control (hexane/AcOEt 1:1)
showed the disappearance of the starting material (Rf =0.44) and the ap-
pearance of a new product (Rf =0.16). Then, a saturated aqueous solution
of Na2SO4 (0.7 mL) was added and the mixture was filtered over Celite
and evaporated under reduced pressure. Purification of the residue by
flash column chromatography on silica gel (hexane/AcOEt 1:3) afforded
pure 13 (106 mg, 0.19 mmol, 85%) as a colorless oil. Rf =0.43 (hexane/
AcOEt 1:3); [a]2D0 =À7 (c=0.14 in CHCl3); 1H NMR (500 MHz, CDCl3):
d=7.36–7.25 (m, 20H; Ar-H), 4.60–4.48 (m, 8H; Bn-H), 4.26 (q, 3J-
Procedure A: Zn dust (100 mg, 1.53 mmol) was added to a stirred solu-
tion of 10 (166 mg, 0.30 mmol) in 9:1 acetic acid/H2O (3 mL) at RT. The
mixture was heated at 658C for 5 h. TLC control (petroleum ether/
AcOEt 1:1) showed the disappearance of the starting material (Rf =0.41)
and the appearance of a new product (Rf =0.00). The mixture was cooled
to RT and a saturated aqueous solution of NaHCO3 was added until a
basic pH was reached. The mixture was extracted with AcOEt (3ꢄ
20 mL) and the combined organic layers were dried over anhydrous
Na2SO4, filtered, and evaporated under reduced pressure. Purification of
the residue by flash column chromatography on silica gel (AcOEt/
CH3OH 40:1) afforded pure 11 (146 mg, 0.25 mmol, 83%) as an orange
oil.
3
3
A
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
Procedure B:[24a] Sm powder (232 mg, 1.54 mmol) was added to a stirred
solution of 1,2-diiodoethane (376 mg, 1.33 mmol) in dry THF (9 mL) at
RT under an argon atmosphere. The solution was stirred at RT for 2 h,
and then a solution of 10 (216 mg, 0.37 mmol) in dry THF (9 mL) was
added and the mixture was stirred at RT for a further 2 h. TLC control
(hexane/AcOEt 1:1) showed the disappearance of the starting material
(Rf =0.55) and the appearance of a new product (Rf =0.02). At this
point, a saturated aqueous solution of NaHCO3 (6.5 mL) was added and
the mixture was extracted with Et2O (3ꢄ20 mL). The combined organic
layers were dried over anhydrous Na2SO4, filtered, and evaporated under
reduced pressure. Purification of the residue by flash column chromatog-
raphy on silica gel (CH2Cl2/CH3OH 20:1) afforded pure 11 (216 mg,
0.37 mmol, 100%) as an orange oil. Rf =0.69 (AcOEt/CH3OH 40:1); Rf =
0.38 (CH2Cl2/CH3OH 20:1); [a]2D0 =À7 (c=0.49 in CHCl3); 1H NMR
(500 MHz, CDCl3): d=7.37–7.22 (m, 20H; Ar-H), 4.66 (d, J=11.4 Hz,
1H; Bn-H), 4.54–4.42 (m, 7H; Bn-H), 4.05–4.01 (m, 2H; H-3, H-2’), 3.98
G
ACHTUNGTRENNUNG
d=138.5, 138.3, 138.2, 137.8 (s; Ar-C), 128.6–127.6 (d, 16C; Ar-C), 88.6
(d; C-7), 86.5 (d; C-1), 85.7 (d; C-2), 77.6 (d; C-6), 73.6 (d; C-7a), 73.4,
72.4 (t; Bn-C), 72.2 (t; C-8), 71.8, 71.1 (t; Bn-C), 70.3 (d; C-3), 61.1 ppm
(t; C-5); HRMS (ESI): m/z: calcd for C36H39NO5 +H+: 566.2901 [M+H+
]; found: 566.2904; elemental analysis calcd (%) for C36H39NO5: C 76.43,
H 6.95, N 2.48; found: C 75.79, H 7.00, N 2.43.
(1R,2R,3R,6S,7S,7aR)-3-(Hydroxymethyl)hexahydro-1H-pyrrolizine-
1,2,6,7-tetrol (Casuarine) (1): Conc. HCl (4 drops) and 10% Pd/C
(34 mg) were added to a stirred solution of 13 (57 mg, 0.10 mmol) in
CH3OH (10 mL). The suspension was stirred under a H2 atmosphere for
15 h, and then filtered through Celite and washed with CH3OH. Evapora-
tion under reduced pressure afforded a viscous oil that was transferred to
a column of DOWEX 50WX8 and washed with CH3OH (20 mL) and
H2O (20 mL) to remove nonamine-containing products and then with
7% NH4OH (30 mL) to elute casuarine (1). Evaporation of the solvent
afforded casuarine (1) as a white solid (21 mg, 0.10 mmol, 100%) with
physical and spectroscopic data in good agreement with those reported in
the literature.[21] [a]D20 = +13.6 (c=0.66 in CH3OH) (lit. [a]2D0 = +14 (c=
(dd, 3J(H,H)=5.7, 3J(H,H)=2.7 Hz, 1H; H-4), 3.78 (d, 3J
ACHTUNGTRENNUNG ACHTUNGTRENNUNG ACTUHNGTRENNNGU
2H; Ha,b-1’), 3.68 (dd, 3J(H,H)=9.5, 3J
ACTHNUGTRENNUGN ACHTUNGTRENNNUG
3.56 (m, 1H; H-2), 3.56 (d, 3J
A
3
3J
(H,H)=10.0, J
E
d=138.2, 138.1, 137.9, 137.8 (s; Ar-C), 128.6–127.8 (d, 16C; Ar-C), 86.9
(d; C-3), 88.8 (d; C-4), 76.4 (d; C-3’), 73.3, 72.9 (t; Bn-C), 72.2 (d; C-2’),
72.1, 71.5 (t; Bn-C), 68.7 (t; C-6), 64.4 (d; C-2), 63.4 (t; C-1’), 62.4 ppm
0.52 in H2O));[7] 1H NMR (500 MHz, D2O): d=4.20–4.17 (m, 2H; H-6,
3
H-7), 4.14 (t, J
G
3.60 (dd, 2J
(H,H)=11.8, 3J
ACHUTGTNRENNUG CAHTUNGTRENNUNG
(d; C-5); IR (KBr): n˜ =3312, 3029, 2862, 1495, 1452, 1070, 695 cmÀ1
;
T
G
ACHTUNGTRENNUNG
HRMS (ESI): m/z: calcd for C36H41NO6 +H+: 584.2967 [M+H+]; found:
584.3011; elemental analysis calcd (%) for C36H41NO6: C 74.04, H 7.08, N
2.40; found: C 73.61, H 7.01, N 2.33.
AHCTUNGTRENNUNG
G
ACHTUNGTRENNUNG
d=79.3 (d; C-7), 78.2 (d; C-1), 77.9 (d; C-6), 77.1 (d; C-2), 72.7 (d; C-
(1R,2R,3R,6S,7S,7aS)-1,2,7-Tris(benzyloxy)-3-[(benzyloxy)methyl]hexa-
hydro-1H-pyrrolizin-6-yl methanesulfonate (12): Triethylamine (108 mL,
0.78 mmol) and MsCl (44 mL, 0.57 mmol) were added to a stirred solution
of 11 (151 mg, 0.26 mmol) in dry CH2Cl2 (20 mL) at RT under an argon
atmosphere. The solution was stirred at RT for 1.5 h. TLC control
(CH2Cl2/CH3OH 9:1) showed the disappearance of the starting material
7a), 70.5 (d; C-3), 62.7 (t; C-8), 58.6 ppm (t; C-5).
AHCTUNGTERG(NNUN 2’E)-3’-(Benzyloxy)-3’-{(3R,4R,5R)-3,4-bis(benzyloxy)-5-[(benzyloxy)-
methyl]-pyrrolidin-2-yl}prop-2’-en-1’-ol (14):
Procedure A:[27] [Mo(CO)6] (111 mg, 0.42 mmol) was added at RT to a
stirred solution of 8 (153 mg, 0.27 mmol) in 7:1 CH3CN/H2O (4 mL);
then, after 5 min, NaBH4 (5.2 mg, 0.14 mmol) was added at RT and the
mixture was heated at reflux for 3 h. TLC control (petroleum ether/
AcOEt 1:1) showed the disappearance of the starting material (Rf =0.60)
and the appearance of a new product (Rf =0.07). The mixture was cooled
to RT and filtered over Celite and then evaporated under reduced pres-
sure. Purification of the residue by flash column chromatography on
silica gel (petroleum ether/AcOEt 2:3) afforded pure 14 (70 mg,
0.12 mmol, 46%) as a colorless oil.
(Rf =0.54) and the appearance of
a new product (Rf =0.88). Water
(5.0 mL) was added and the mixture was extracted with CH2Cl2 (3ꢄ
20 mL). The combined organic layers were dried over anhydrous MgSO4,
filtered, and evaporated under reduced pressure. Purification of the resi-
due by flash column chromatography on silica gel (hexane/AcOEt 1:1)
afforded pure 12 (167 mg, 0.26 mmol, 100%) as a colorless oil. Rf =0.54
(hexane/AcOEt 1:1); [a]D20 =À7 (c=1.3 in CHCl3); 1H NMR (500 MHz,
CDCl3): d=7.38–7.25 (m, 20H; Ar-H), 5.17 (dt, 3J
N
ACHTUNGTRNE(NUNG H,H)=
E
Procedure B:[28] SmI2 in THF (0.1m, 9.9 mL, 0.99 mmol) was added to 8
(155 mg, 0.27 mmol) under a nitrogen atmosphere at RT and the mixture
was stirred for 2.5 h until disappearance of the starting material was ob-
A
ACHTUNGTRENNUNG
A
U
ACHTUNGTRENNUNG
Chem. Eur. J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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H.-U. Reissig, A. Goti et al.
served as above. Then a saturated aqueous solution of NaHCO3 (4.5 mL)
was added and the mixture was extracted with Et2O (3ꢄ10 mL). The
combined organic layers were dried over anhydrous Na2SO4, filtered, and
evaporated under reduced pressure. Purification of the residue by flash
column chromatography on silica gel (petroleum ether/AcOEt 1:4) af-
forded pure 14 (104 mg, 0.18 mmol, 68%) as a colorless oil. Rf =0.07 (pe-
troleum ether/AcOEt 1:1); [a]2D0 = +15 (c=1.0 in CHCl3); 1H NMR
(4aS,5R,6R,7R)-5,6-Bis(benzyloxy)-7-(benzyloxymethyl)hexahydro-4H-
pyrroloACHTNUTRGENN[UG 1,2-b]ACHUTNGTREN[NUGN 1,2]oxazin-4-one (17): Concentrated HCl (0.2 mL) was
added to a stirred solution of 8 (1.12 g, 1.98 mmol) in water/dioxane (1:3,
200 mL). The solution was stirred for 78 h at RT. TLC control (hexane/
AcOEt 2:1) showed the disappearance of the starting material (Rf =0.64)
and the appearance of a new compound (Rf =0.55). A saturated aqueous
solution of NaHCO3 (20 mL) was added and the mixture was evaporated
under reduced pressure and extracted with CH2Cl2 (3ꢄ20 mL). The com-
bined organic layers were dried over anhydrous Na2SO4, filtered, and
evaporated under reduced pressure. Purification of the residue by flash
column chromatography on silica gel (hexane/AcOEt 1:4) afforded start-
ing material 8 (232 mg, 0.411 mmol, 21% yield) and pure 17 (705 mg,
1.49 mmol, 75% yield) as an orange oil. Rf =0.21 (hexane/AcOEt 1:4);
[a]2D0 =À41 (c=1.0 in CHCl3); 1H NMR (700 MHz, CDCl3): d=7.38–7.26
(m, 15H; Ar-H), 4.63–4.49 (m, 7H; Bn-H, H-5), 4.25 (m, 2H; Ha,b-2),
(400 MHz, CDCl3): d=7.34–7.22 (m, 20H; Ar-H), 5.13 (t, 3J
8.0 Hz, 1H; H-2’), 4.75, 4.72 (AB system, J(H,H)=11.5 Hz, 2H; Bn-H),
ACHTUNGTRNE(NUNG H,H)=
AHCTUNGTRENNUNG
4.59–4.48 (m, 6H; Bn-H), 4.18–3.39 (m, 5H; Ha-1’, Hb-1’, H-2, H-3, H-
4), 3.56–3.49 (m, 2H; Ha-6, H-b-6), 3.49–3.42 ppm (m, 1H; H-5);
13C NMR (50 MHz, CDCl3): d=156.7 (s, C-3’), 138.0, 137.4, 136.4 (s, 4C;
Ar-C), 128.4–127.5 (d, 20C; Ar-C), 101.4 (d; C-2’), 87.1 (d; C-3), 86.6 (d;
C-4), 73.4, 72.6, 72.1 (t; Bn-C), 71.4 (t; C-6), 69.4 (t; Bn-C), 61.7 (d; C-5),
60.2 (d; C-2), 57.2 ppm (t; C-1’); IR (CDCl3): n˜ =3450, 3350, 3066, 3031,
2932, 2867, 2243, 1654, 1495, 1454, 1362, 1220, 1094, 1076 cmÀ1; MS
(ESI): m/z: 588.43 (100) [M+Na+], 566.45 (88) [M+H+]; elemental anal-
ysis calcd (%) for C36H39NO5: C 76.43, H 6.95, N 2.48; found: C 76.00, H
7.47, N 2.94.
4.12 (dd, 3J
8.4 Hz, 1H; H-4a), 3.72 (td, 3J
3.58 (dd, 2J(H,H)=9.8, 3J(H,H)=5.5 Hz, 1H; Ha-8), 3.50 (dd, 2J
9.8, 3J(H,H)=6.6 Hz, 1H; Hb-8), 2.63 (dt, 2J(H,H)=16.3, 3J
ACHTUNGTRENNUNG
G
R
ACHTUNGTRENNUNG(H,H)=
G
ACHTUNGTRENNUNG
E
ACHTUNGTRENNUNG
N
U
(1R,2R,3R,7aS)-1,2,7-Tris(benzyloxy)-3-[(benzyloxy)methyl]-2,3,5,7a-tet-
rahydro-1H-pyrrolizine (15): Triethylamine (0.3 mL, 2.01 mmol) and
MsCl (0.08 mL, 1.00 mmol) were added to a stirred solution of 14
(380 mg, 0.67 mmol) in dry CH2Cl2 (25 mL) under a nitrogen atmosphere
at RT and the mixture was stirred at RT for 15 h. Then, H2O (20 mL)
was added and the mixture was extracted with CH2Cl2 (3ꢄ20 mL). The
collected organic layers were dried over Na2SO4, filtered, and then
evaporated under reduced pressure. Purification of the residue by flash
column chromatography on silica gel (petroleum ether/AcOEt 3:1) af-
forded pure 15 (367 mg, 0.67 mmol, 100%) as a pale-yellow oil. Rf =0.57
(petroleum ether/AcOEt 1:1); [a]2D0 =À18 (c=0.63 in CHCl3); 1H NMR
(400 MHz, CDCl3): d=7.30–7.12 (m, 20H; Ar-H), 4.81 (AB system, 2J-
Ha-3); 13C NMR (175 MHz, CDCl3): d=204.1 (s; C-4), 137.8, 137.7, 137.0
(s; Ar-C), 128.4–127.7 (d, 15C; Ar-C), 86.2 (d; C-6), 85.6 (d; C-5), 76.9
(d; C-4a), 73.4, 72.2, 71.9 (t; Bn-C), 71.2 (d; C-7), 68.9 (t; C-8), 66.2 (t;
À1
À
C-2), 37.8 ppm (t, C-3); IR (CHCl3): n˜ =2957 (str. C H), 1699 cm (str.
C=O); HRMS (ESI): m/z: calcd for C29H31NO5 +H+ 474.2280 [M+H+];
found 474.2288; elemental analysis calcd (%) for C29H31NO5: C 73.55, H
6.60, N 2.96; found: C 73.58, H 6.64, N 2.96.
(4S,4aR,5R,6R,7R)-5,6-bis(Benzyloxy)-7-[(benzyloxy)methyl]hexahydro-
2H-pyrroloACHTUGTNRENNUG[1,2-b]ACHTUNGTRENNUNG
(2.7 mL, 2.7 mmol) was added to
a
1.49 mmol) in dry THF (15 mL) at À758C under an argon atmosphere.
After 3 h, a TLC control (hexane/AcOEt 2:1) showed the disappearance
of the starting material (Rf =0.55) and the appearance of a new com-
pound (Rf =0.19); then water (3 mL) was added and the temperature was
allowed to rise to RT. The mixture was extracted with Et2O (3ꢄ20 mL)
and the combined organic layers were dried over anhydrous Na2SO4, fil-
tered, and evaporated under reduced pressure. Purification of the residue
by flash column chromatography on silica gel (hexane/AcOEt 1:2) af-
forded the pure reduction product (616 mg, 1.29 mmol, 86% yield, dia-
ACHTUNGTRENNUNG
2
3
3.84 (m, 1H; Ha-5), 3.56 (dd, JACTHNUTRGENNG(U H,H)=9.7, JACHUTNGTREN(NNGU H,H)=3.9 Hz, 1H; Ha-8),
3.51–3.45 (m, 2H; Hb-8, Hb-5), 2.97–2.93 ppm (m, 1H, H-3); 13C NMR
(50 MHz, CDCl3): d=138.2–136.2 (s, 4C; Ar-C), 128.4–127.3 (d, 20C;
Ar-C), 100.9 (s; C-7), 91.7 (d; C-6), 85.2 (d; C-1), 84.3 (d; C-2), 73.4 (t;
Bn-C), 72.9 (d; C-7a), 72.6, 72.5, 71.9 (t; Bn-C), 71.1 (t; C-8), 68.9 (d; C-
3), 58.6 ppm (t; C-5); MS (ESI): m/z: 570.35 (95) [M+Na+], 548.40 (100)
[M+H+]; elemental analysis calcd (%) for C36H37NO4: C 78.95, H 6.81,
N 2.56; found: C 78.92, H 6.54, N 2.36.
stereomeric ratio (d.r.) >97:3) as a pale-yellow oil. Rf =0.19 (hexane/
1
AcOEt 2:1); [a] 20 =À16 (c=0.9 in CHCl3); H NMR (700 MHz, CDCl3):
D
d=7.37–7.24 (m, 15H; Ar-H), 4.65–4.43 (m, 6H; Bn-H), 4.39 (s, 1H; H-
(1R,2R,3R,7S,7aR)-3-(Hydroxymethylhexahydro-1H-pyrrolizine-1,2,7-
triol (Australine) (4): Conc. HCl (3 drops) and 10% Pd/C (50 mg) were
added to a stirred solution of 15 (111 mg, 0.20 mmol) in CH3OH (10 mL)
at RT under a nitrogen atmosphere. The mixture was stirred at RT under
H2 for 3 d. NMR spectroscopic control showed the disappearance of the
signals of the benzyl groups and the formation of two products identified
as 4 and 16 in an approximately 3:1 ratio. The mixture was filtered over
Celite and evaporated under reduced pressure, and then fresh CH3OH
(10 mL) and NaBH4 (30 mg) were added and the suspension was stirred
for 15 h. After addition of conc. HCl (4 drops), the mixture was filtered
over Celite and evaporated under reduced pressure. Then the crude
product was transferred to a column of DOWEX 50WX8 and washed
with CH3OH (20 mL) and H2O (20 mL) to remove nonamine-containing
products and then with 7% NH4OH (30 mL) to elute australine (4).
After evaporation, 4 was obtained (33 mg, 0.17 mmol, 87%) as a color-
less vitreous solid, with physical and spectroscopic data in good agree-
ment with those reported in the literature.[19] [a]D20 = +15 (c=0.62 in
CH3OH) (lit. [a]D20 = +17.1 (c=2.9 in CH3OH)];[12] 1H NMR (400 MHz,
5), 4.18 (s, 1H; H-4), 4.12–4.06 (m, 2H; Ha-2, H-6), 3.85–3.80 (m, 1H;
Hb-2), 3.73–3.66 (m, 2H; Ha-8, H-7), 3.56 (t, 2J(H,H)=3J
ACTHNUGTRENNUGN ACHTUNGTRENNNUG
1H; Hb-8), 3.38 (dd, 3J(H,H)=8.6, 3J
ACTHNUGTRENNUGN ACHTUNGTRENNNUG
(brs, 1H; OH), 1.85–1.74 ppm (m, 2H; Ha-3, Hb-3); 13C NMR
(175 MHz, CDCl3): d=138.0, 137.8, 137.7 (s; Ar-C), 128.5–127.7 (d, 15C;
Ar-C), 85.1 (d; C-6), 82.4 (d; C-5), 73.4, 72.3, 71.6 (t; Bn-C), 69.4 (d; C-
7), 68.1 (d; C-4a), 65.9 (t; C-2), 64.8 (d; C-4), 31.3ppm (t; C-3); IR
(CHCl3): n˜ =3521, 3064, 3032, 3011, 2981, 2952, 2918, 2866, 1494, 1451,
1361, 1258, 1094 cmÀ1; HRMS (ESI): m/z: calcd for C29H33NO5 +H+:
476.2436 [M+H+]; found: 476.2435; elemental analysis calcd (%) for
C29H33NO5: C 73.24, H 6.99, N 2.95; found: C 73.24, H 6.99, N 3.03.
(4S,4aR,5R,6R,7R)-4,5,6-Tris(benzyloxy)-7-[(benzyloxy)methyl]hexahy-
dro-2H-pyrroloACTHNUTRGNENGU[1,2-b]ACHTUNGTRNE[NUGN 1,2]oxazine (19): NaH (60% in mineral oil, 86 mg,
2.14 mmol), tetrabutylammonium iodide (TBAI) (44 mg, 0.119 mmol),
and benzyl bromide (305 mg, 1.78 mmol) were added to a stirred solution
of 18a (565 mg, 1.19 mmol) in dry THF (50 mL). The suspension was stir-
red at RT overnight under an argon atmosphere. TLC control (hexane/
AcOEt 2:1) showed the disappearance of the starting material (Rf =0.19)
and the appearance of a new compound (Rf =0.45). Then, a saturated
aqueous solution of NH4Cl (15 mL) was added. The mixture was extract-
ed with Et2O (3ꢄ20 mL) and the combined organic layers were dried
over anhydrous Na2SO4, filtered, and evaporated under reduced pressure.
Purification of the residue by flash column chromatography on silica gel
(hexane/AcOEt 1:3) afforded pure 19 (502 mg, 0.887 mmol, 74% yield)
as a pale-yellow oil. Rf =0.33 (hexane/AcOEt 1:3); [a]2D0 =À56 (c=1.1 in
CHCl3); 1H NMR (700 MHz, CDCl3): d=7.43–7.21 (m, 20H; Ar-H),
D2O): d=4.25 (dt, 3J
(H,H)=7.8 Hz, 1H; H-1), 3.78 (dd, 3J
H-2), 3.67 (dd, 2J(H,H)=11.7, 3J(H,H)=3.4 Hz, 1H; Ha-8), 3.50 (dd, 2J-
(H,H)=11.7, 3J
(H,H)=6.5 Hz, 1H; Hb-8), 3.11–3.03 (m, 2H; H-7a, Ha-
ACHTUNGTRENNUNG ACHTUNGTRENNUNG
(H,H)=4.4, 3J
A
R
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
5), 2.66–2.59 (m, 2H; H-3, Hb-5), 1.95–1.89 (m, 1H; Ha-6), 1.87–
1.77 ppm (m, 1H; Hb-6); 13C NMR (50 MHz, D2O): d=78.4 (d, C-2),
72.8 (d, C-1), 70.9 (d, C-7a), 70.5 (d, C-3), 69.3 (d, C-7), 61.7 (t, C-8), 51.8
(t, C-5), 35.0 ppm (t, C-6); MS (ESI): m/z: 212.17 (100) [M+Na+], 190.15
(36) [M+H+]; elemental analysis calcd (%) for C8H15NO4: C 50.78, H
7.99, N 7.40; found: C 50.87, H 7.82, N 7.20.
3
4.73–4.50 (m, 9H; Bn-H, H-5), 4.21–4.15 (m, 2H; Ha-2, H-6), 4.06 (dt, J-
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Total Syntheses of Casuarine, Australine, and 7-epi-Australine
FULL PAPER
A
E
(H,H)=12.0, 3J-
water (6 mL) was added and the mixture was extracted with Et2O (3ꢄ
5 mL). The combined organic layers were dried over anhydrous Na2SO4,
filtered, and evaporated under reduced pressure. Purification of the resi-
due by flash column chromatography on silica gel (hexane/AcOEt 1:3)
afforded pure 21 (28 mg, 0.05 mmol, 68% yield) as a pale yellow oil.
R
ACHTUNGTRENNUNG
E
R
(m, 1H; Hb-3); 13C NMR (175 MHz, CDCl3): d=138.5, 138.4, 138.2,
138.1 (s; Ar-C), 128.5–127.4 (d, 20C; Ar-C), 87.1 (d; C-6), 83.9 (d; C-5),
73.4, 72.6 (t; Bn-C), 71.6 (d, 1C; C-4, t, 1C; Bn-C), 70.6 (t; Bn-C), 70.0
(d; C-7), 68.5 (t; C-8), 67.3 (d; C-4a), 66.3 (t; C-2), 28.0 ppm (t; C-3)
ppm; IR (CHCl3): n˜ ~ =3066, 3034, 3007, 2928, 2863, 2252, 1496, 1453,
1356, 1101, 1028 cmÀ1; HRMS (ESI): m/z calcd for C36H39NO5 +H+:
566.2906 [M+H+]; found: 566.2889; elemental analysis calcd (%) for
C36H39NO5: C 76.43, H 6.95, N 2.48; found: C 76.18, H 6.64, N 2.65.
1H NMR (700 MHz, CDCl3): d=8.24–8.15 (m, 4H; Ar-H), 7.38–7.08 (m,
2
15H; Ar-H), 5.38–5.35 (m, 1H; H-4), 4.67 (d, J
N
H), 4.60 (m, 2H; Bn-H), 4.50 (d, 2J
2J(H,H)=12.0 Hz, 1H; Bn-H), 4.41 (d, 2J
4.26 (t, 3J
(H,H)=7.4 Hz, 1H; H-5), 4.16–4.09 (m, 2H; Ha-2, H-6), 3.99
(ddd, 2J(H,H)=11.3, 3J(H,H)=7.2, 3J
(H,H)=3.7 Hz, 1H; Hb-2), 3.77–
3.73 (m, 2H; H-7, Ha-8,), 3.58 (t, 2J(H,H)=3J
(H,H)=10.2 Hz, 1H; Hb-
8), 3.36 (dd, 3J(H,H)=8.8, 3J
(H,H)=6.0 Hz, 1H; H-4a), 2.14–2.09 (m,
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
A
R
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
1H; Ha-3), 1.82–1.75 ppm (m, 1H, Hb-3); 13C NMR (175 MHz, CDCl3):
d=164.0 (s; C=O), 150.4 (s; Ar-NO2), 138.0, 137.8, 137.7 (s; Ar-C), 135.6
(s; Ar-C), 131.0–123.4 (d, 19C; Ar-C), 85.1 (d, 2C; C-6, C-5), 73.5, 72.1,
71.8 (t; Bn-C), 70.3 (d; C-4), 69.2 (d; C-7), 68.0 (d; C-4a), 67.9 (t; C-8),
65.1 (t; C-2), 30.9 ppm (t, C-3); HRMS (ESI): m/z: calcd for
C36H36N2O8 +H+: 625.2544 [M+H+]; found: 625.2519.
(1R,2R,3R,7S,7aR)-1,2,7-Tris(benzyloxy)-3-[(benzyloxy)methyl]hexahy-
dro-1H-pyrrolizine (20): A solution of SmI2 in THF 0.13m (23.8 mL,
3.19 mmol) was added to a stirred solution of 19 (502 mg, 0.887 mmol) in
dry and degassed THF (15 mL) under an argon atmosphere. The solution
was stirred at RT overnight. TLC control (hexane/AcOEt 1:1) showed
the disappearance of the starting material (Rf =0.76) and the appearance
of a new compound (Rf =0.03). Then, a saturated aqueous solution of
NaHCO3 (4 mL) was added and the mixture was extracted with Et2O
(3ꢄ15 mL). The combined organic layers were dried over anhydrous
Na2SO4, filtered, and evaporated under reduced pressure. The crude
product obtained (489 mg) was dissolved in dry CH2Cl2 (25 mL) and
methanesulfonyl chloride (0.2 mL, 2.58 mmol) and triethylamine
(0.45 mL, 3.44 mmol) were added. The solution was stirred under an
argon atmosphere for 14 h. When TLC control (hexane/AcOEt 1:1)
showed the disappearance of the starting material (Rf =0.03) and the ap-
pearance of a new compound (Rf =0.35), water (10 mL) was added and
the mixture was extracted with CH2Cl2 (3ꢄ20 mL) and the combined or-
ganic layers were dried over anhydrous Na2SO4, filtered, and evaporated
under reduced pressure. Purification of the residue by flash column chro-
matography on silica gel (hexane/AcOEt 1:1, 1:3 then AcOEt) afforded
pure 20 (360 mg, 0.655 mmol, 74% yield) as a pale-yellow oil. Rf =0.35
(hexane/AcOEt 1:1); [a] 2D0 = +22 (c=0.92 in CHCl3); 1H NMR
(700 MHz, CDCl3): d=7.39–7.27 (m, 20H; Ar-H), 4.79–4.39 (m, 9H; Bn-
(4R,4aR,5R,6R,7R)-5,6-Bis(benzyloxy)-7-[(benzyloxy)methyl]hexahy-
dro-2H-pyrroloACTHNUTRGNENGU[1,2-b]ACHTUNGTNER[NUGN 1,2]oxazin-4-ol (18b): KOH (100 mg, 1.8 mmol)
was added to a stirred solution of 21 (28 mg, 0.05 mmol) in THF (5 mL).
After 3 h, a TLC control (hexane/AcOEt 2:1) showed the disappearance
of the starting material (Rf =0.54) and the appearance of a new com-
pound (Rf =0.19). Then, water (5 mL) was added. The mixture was ex-
tracted with Et2O (3ꢄ5 mL) and the combined organic layers were dried
over anhydrous Na2SO4, filtered, and evaporated under reduced pressure.
Purification of the residue by flash column chromatography on silica gel
(hexane/AcOEt 1:2) afforded pure 18b (15 mg, 0.03 mmol, 71% yield) as
a pale-yellow oil. Rf =0.19 (hexane/AcOEt 2:1); 1H NMR (700 MHz,
CDCl3): d=7.38–7.26 (m, 15H; Ar-H), 4.65 (d, 2J
Bn-H), 4.59 (m, 2H; Bn-H), 4.54 (m, 2H; Bn-H), 4.46 (d, 2J
12.2 Hz, 1H; Bn-H), 4.18 (dd, 3J(H,H)=8.2, 3J
(H,H)=3.2 Hz, 1H; H-5),
4.06 (dd, 3J(H,H)=3.2, 3J
(H,H)=2.5 Hz, 1H; H-6), 4.05–4.02 (m, 1H;
Ha-2), 3.95–3.91 (m, 1H; H-4), 3.88 (ddd, 2J(H,H)=11.5, 3J
(H,H)=7.2,
3J(H,H)=3.8 Hz, 1H; Hb-2), 3.72 (dd, 2J(H,H)=11.5, 3J
(H,H)=4.8 Hz,
1H; Ha-8), 3.68–3.65 (m, 1H; H-7), 3.52 (dd, 2J(H,H)=9.3, 3J
(H,H)=
7.7 Hz, 1H; Hb-8), 3.10 (dd, 3J(H,H)=8.2, 3J
(H,H)=6.1 Hz, 1H; H-4a)
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
A
R
ACHTUNGTRENNUNG
H, H-1), 4.21 (dd, 3J
(m, 1H; H-7), 3.67 (dd, J
3.56 (m, 2H; Hb-8, H-7a), 3.30 (m, 1H; Ha-5), 3.03 (m, 1H; H-3), 2.77
(ddd, 2J(H,H)=13.6, 3J(H,H)=10.5, 3J
(H,H)=6.0 Hz, 1H; Hb-5), 2.24–
ACHTUNGTRENNUNG ACHTUNGTREN(NNGU H,H)=7.2 Hz, 1H; H-2), 3.93–3.90
(H,H)=9.0, 3J
A
ACHTUNGTRENNUNG
2
3
ACHUTNGREN(NUG H,H)=9.8, JACHTUNGTERN(NUGN H,H)=3.1 Hz, 1H; Ha-8), 3.61–
A
ACHTUNGTRENNUNG
1.97–1.92 (m, 1H, Ha-3), 1.59–1.54 ppm (m, 1H, Hb-3); 13C NMR
(175 MHz, CDCl3): d=138.2, 138.1, 137.9 (s; Ar-C), 128.5–127.6 (d, 15C;
Ar-C), 85.5 (d; C-6), 85.0 (d; C-5), 73.5, 72.0, 71.7 (t; Bn-C), 70.3 (d; C-
7), 70.1 (d; C-4a), 68.1 (t; C-8), 67.0 (d; C-5), 66.3 (d, C-4), 65.4 (t; C-2),
31.2 ppm (t, C-3); HRMS (ESI): m/z: calcd for C29H33NO5 +H+:
476.2436 [M+H+]; found: 476.2434.
A
R
ACHTUNGTRENNUNG
2.20 (m, 1H; Ha-6), 1.90–1.84 ppm (m, 1H; Hb-6); 13C NMR (175 MHz,
CDCl3): d=138.6, 138.5, 138.4, 138, 3 (s; Ar-C), 128.4–127.4 (d, 20C; Ar-
C), 85.9 (d; C-2), 80.9 (d; C-1), 78.1 (d; C-7), 73.4, 72.8, 72.2 (t; Bn-C),
71.3 (t, 1C; C-8, d, 1C; C-7), 70.7 (t; Bn-C), 68.9 (d; C-3), 52.3 (t; C-5),
32.1 ppm (t; C-6); HRMS (ESI): m/z: calcd for C36H39NO4 +H+:
550.2957 [M+H+]; found: 550.2950; elemental analysis calcd (%) for
C36H39NO4: C 78.66, H 7.15, N 2.55; found: C 78.65, H 7.18, N 2.58.
(1R,2R,3R,7R,7aR)-1,2-Bis(benzyloxy)-3-[(benzyloxy)methyl]hexahy-
dro-1H-pyrrolizin-7-ol (23): DIBAL (2m sol. in toluene, 0.8 mL,
1.6 mmol) was added dropwise at 08C to a stirred solution of 12 (67 mg,
0.10 mmol) in dry toluene (4 mL) under an argon atmosphere and then
the resulting mixture was heated to reflux temperature. The mixture was
stirred at reflux temperature for 2 h. TLC analysis (hexane/AcOEt 1:1)
showed the disappearance of the starting material (Rf =0.64) and the ap-
pearance of a new product (Rf =0.00). The mixture was cooled to RT and
a saturated aqueous solution of Na2SO4 was added (0.42 mL) at 08C. The
mixture was filtered on Celite and evaporated under reduced pressure.
Purification of the residue by flash column chromatography on silica gel
(AcOEt) afforded pure 23 (24 mg, 0.05 mmol, 52%) as a colorless oil.
Rf =0.50 (AcOEt/MeOH 30:1); [a]2D0 =À27 (c=0.33 in CHCl3); 1H NMR
(500 MHz, CDCl3): d=7.36–7.25 (m, 15H; Ar-H), 4.70–4.48 (m, 6H; Bn-
(1R,2R,3R,7S,7aR)-3-(Hydroxymethylhexahydro-1H-pyrrolizine-1,2,7-
triol (australine) (4): Conc. HCl (4 drops) and 10% Pd/C (185 mg) were
added to
a stirred solution of 20 (175 mg, 0.318 mmol) in CH3OH
(15 mL). The suspension was stirred under H2 for 67 h and then filtered
through a pad of Celite and washed with CH3OH. Evaporation under re-
duced pressure afforded a viscous oil that was transferred to a column of
DOWEX 50WX200. The column was washed with CH3OH (20 mL) and
H2O (20 mL) to remove nonamine-containing products and then with
5% NH4OH (40 mL) to elute australine (4). Evaporation of the solvent
afforded australine 4 (44 mg, 0.232 mmol, 73%) as a yellowish solid, with
spectroscopic data identical to those given above. [a]2D1 = = +21 (c=2.2
in CH3OH).
H), 4.07 (dd, 3J
(H,H)=5.2, 3J(H,H)=4.0 Hz, 1H; H-7), 3.78 (t, 3J
H-1), 3.60–3.56 (m, 2H; Ha,b-8), 3.46 (dd, 3J(H,H)=5.9, 3J
3.5 Hz, 1H; H-7a), 3.15–3.10 (m, 1H; Ha-5), 2.79 (dt, 3J(H,H)=7.1, 3J-
(H,H)=3.6 Hz, 1H; H-3), 2.77–2.72 (m, 1H; Hb-5), 2.00–1.93 (m, 1H;
(H,H)=6.9, 3J
ACHUTGTNRENNUG CAHTUNGTRENNUNG
A
R
ACHTUNGTRENNUNG
(4R,4aR,5R,6R,7R)-5,6-Bis(benzyloxy)-7-[(benzyloxy)methyl]hexahy-
dro-2H-pyrroloACHTUNGTRENNUNG[1,2-b]ACHTUNGTRENNUNG[1,2]oxazin-4-yl-4-nitrobenzoate (21): A stirred sol-
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
ution of 18a (31 mg, 0.07 mmol), p-nitrobenzoic acid (27 mg, 0.16 mmol),
and PPh3 (80 mg, 0.31 mmol) in dry THF (10 mL) was cooled to 08C and
stirred for 5 min under an argon atmosphere. Then diethyl azodicarboxy-
late (DEAD) (48 mL, 0.31 mmol) was added dropwise and the tempera-
ture brought to RT. The solution was stirred at RT for 1 day. TLC control
(hexane/AcOEt 1:2) showed the disappearance of the starting material
(Rf =0.19) and the appearance of a new compound (Rf =0.54). Then,
AHCTUNGTRENNUNG
Ha-6), 1.91–1.86 ppm (m, 1H; Hb-6); 13C NMR (125 MHz, CDCl3): d=
138.3, 138.2, 138.1 (s; Ar-C), 128.5–127.8 (d, 12C; Ar-C), 86.4 (d; C-1),
84.1 (d; C-2), 83.4 (d; C-7), 73.3 (d; C-7a), 73.0, 71.9, 71.3 (t; Bn-C), 69.3
(d; C-3), 60.6 (t; C-8), 51.7 (t; C-5), 30.5 (t; C-6), 58.6 ppm (t; C-5); IR
(KBr): n˜ =3029, 2922, 2867, 1453, 1361, 1108, 734, 696 cmÀ1; HRMS
Chem. Eur. J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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H.-U. Reissig, A. Goti et al.
(ESI): m/z: calcd for C29H33NO4 +H+: 460.2443 [M+H+]; found:
460.2495.
8, 102–133; j) R. Lahiri, A. A. Ansari, Y. D. Vankar, Chem. Soc.
Rev. 2013, 42, 5102–5118.
[3] a) R. Pulz, S. Cicchi, A. Brandi, H.-U. Reissig, Eur. J. Org. Chem.
2003, 1153–1156; b) A. Goti, S. Cicchi, V. Mannucci, F. Cardona, F.
Guarna, P. Merino, T. Tejero, Org. Lett. 2003, 5, 4235–4238; c) F.
Cardona, G. Moreno, F. Guarna, P. Vogel, C. Schuetz, P. Merino, A.
Goti, J. Org. Chem. 2005, 70, 6552–6555; d) M. Marradi, S. Cicchi,
I. Delso, L. Rosi, T. Tejero, P. Merino, A. Goti, Tetrahedron Lett.
2005, 46, 1287–1290; e) P. Merino, I. Delso, T. Tejero, F. Cardona,
M. Marradi, E. Faggi, C. Parmeggiani, A. Goti, Eur. J. Org. Chem.
2008, 2929–2947; f) I. Delso, T. Tejero, A. Goti, P. Merino, Tetrahe-
dron 2010, 66, 1220–1227; g) I. Delso, T. Tejero, A. Goti, P. Merino,
J. Org. Chem. 2011, 76, 4139–4143.
[4] For contributions from other groups, see: a) R. Ballini, E. Marcanto-
ni, M. Petrini, J. Org. Chem. 1992, 57, 1316–1318; b) R. Giovannini,
E. Marcantoni, M. Petrini, J. Org. Chem. 1995, 60, 5706–5707; c) H.
Ohtake, Y. Imada, S.-I. Murahashi, Bull. Chem. Soc. Jpn. 1999, 72,
2737–2754; d) M. Lombardo, S. Fabbroni, C. Trombini, J. Org.
Chem. 2001, 66, 1264–1268; e) X.-G. Hu, Y.-M. Jia, J. Xiang, C.-Y.
Yu, Synlett 2010, 982–986; f) X.-G. Hu, B. Bartholomew, R. J. Nash,
F. X. Wilson, G. W. J. Fleet, S. Nakagawa, A. Kato, Y.-M. Jia, R. van
Well, C.-Y. Yu, Org. Lett. 2010, 12, 2562–2565; g) W. Zhang, K.
Sato, A. Kato, Y.-M. Jia, X.-G. Hu, F. X. Wilson, R. van Well, G.
Horne, G. W. J. Fleet, R. J. Nash, C.-Y. Yu, Org. Lett. 2011, 13,
4414–4417.
(1R,2R,3R,7R,7aR)-3-(Hydroxymethyl)hexahydro-1H-pyrrolizine-1,2,7-
triol (7-epi-australine, 22): Conc. HCl (4–5 drops) and 10% Pd/C
(104 mg) were added to a stirred solution of 23 (58 mg, 0.13 mmol) in
MeOH (6 mL),. The suspension was stirred under a hydrogen atmos-
phere overnight, and then filtered through Celite and washed several
times with MeOH. Evaporation under reduced pressure afforded a vis-
cous oil that was transferred to a column of DOWEX 50WX8 and then
washed with MeOH (20 mL) and H2O (20 mL) to remove nonamine-con-
taining products and then with 7% NH4OH (30 mL) to elute 7-epi-aus-
traline 22. Evaporation of the solvent under reduced pressure afforded
pure 22 (24 mg, 0.13 mmol, quantitative yield) as a yellow solid. M.p.
176–1778C (dec.); [a] 20 =À6 (c=0.49 in MeOH), lit. [a]D23 =-13.0 (c=
D
0.55 in H2O);[34a] 1H NMR (400 MHz, D2O): d=4.25 (dt, 3J
ACHTUNGTRENNUNG
G
3J
2J
A
E
N
N
ACHTUNGTRENNUNG
(H,H)=1.7 Hz, 1H; H-7a), 2.80 (ddd, 2J
A
ACHTUNGTRENNUNG
A
R
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
1H; Hb-6); 13C NMR (50 MHz, D2O): d=77.1 (d; C-1), 75.5 (d; C-2),
74.4 (d; C-7), 73.9 (d; C-7a), 68.2 (d; C-3), 61.5 (t; C-8), 51.8 (t; C-5),
31.3 ppm (t; C-6); IR (KBr): n˜ =3357, 3307, 3243, 2912, 1443, 1340, 1316,
1261, 1035, 978, 530 cmÀ1; HRMS (TOF): m/z: calcd for C8H15NO4 +H+:
190.1074 [M+H+]; found: 190.1087.
[5] For earlier work on acyclic carbohydrate derived nitrones, see for
example: a) A. Dondoni, S. Franco, F. L. Merchan, P. Merino, T.
Tejero, Tetrahedron Lett. 1993, 34, 5475–5478; b) A. Dondoni, F.
Junquera, S. Franco, F. L. Merchan, P. Merino, T. Tejero, V. Bertola-
si, Chem. Eur. J. 1995, 1, 505–520; c) W. Schade, H.-U. Reissig, Syn-
lett 1999, 632–634; d) M. Helms, W. Schade, R. Pulz, T. Watanabe,
A. Al-Harrasi, L. Fisera, I. Hlobilova, G. Zahn, H.-U. Reissig, Eur.
J. Org. Chem. 2005, 1003–1019.
Acknowledgements
[6] For a general review on nitrones, see: P. Merino, in Science of Syn-
thesis Vol. 27 (Eds: A. Padwa, D. Bellus), George Thieme: Stuttgart.
2004, pp. 511–584.
[7] F. Cardona, C. Parmeggiani, E. Faggi, C. Bonaccini, P. Gratteri, L.
Sim, T. M. Gloster, S. Roberts, G. J. Davies, D. R. Rose, A. Goti,
Chem. Eur. J. 2009, 15, 1627–1636.
We thank MIUR-Italy (PRIN 2008, 200824M2HX, and PRIN 2010–2011,
2010L9SH3K 006) and Ente Cassa di Risparmio di Firenze (CRF, 2009/
3141) for financial support. Support of the Berlin group by the Deutsche
Forschungsgemeinschaft and Bayer HealthCare is most gratefully ac-
knowledged. MIUR is also acknowledged for a doctoral grant to CP. The
DAAD is gratefully acknowledged for a research fellowship to LG. We
thank Dr. C. Bello, Universitꢅ de Lausanne, Switzerland, for the biologi-
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Total Syntheses of Casuarine, Australine, and 7-epi-Australine
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Received: April 8, 2013
Published online: && &&, 0000
Chem. Eur. J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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These are not the final page numbers!