Total syntheses of the tylophora alkaloids cryptopleurine, (-)-antofine, (-)-tylophorine, and (-)-ficuseptine C

Article abstract of DOI:10.1002/chem.200600592

A concise, efficient and modular approach to the tylophora alkaloids is described, a family of potent cytotoxic agents that are equally effective against drug sensitive and multidrug resistant cancer cell lines. The advantages of the chosen route are illustrated by the total syntheses of the phenanthroquinolizidine cryptopleurine (1) and the phenanthroindolizidines (-)-antofine (2), (-)-tylophorine (3), and their only recently isolated congener (-)-ficuseptine C (4). The key steps consist in a Suzuki cross-coupling between a (commercial) boronic acid and a simple aryl-l,2-dihalide followed by elaboration of the resulting products into the corresponding 2-alkynyl-biphenyl derivatives 27, 33, 41 and 46. The latter undergo PtCl₂-catalyzed cycloisomerizations with formation of the functionalized phenanthrenes 28, 34, 42 and 47, which were transformed into the targeted alkaloids by a deprotection/Pictet-Spengler annulation tandem. Due to the flexibility and robust character of this approach, it might enable a systematic exploration of the pharmacological profile of this promising class of bioactive natural products.

Full text of DOI:10.1002/chem.200600592

DOI: 10.1002/chem.200600592
Total Syntheses of the Tylophora Alkaloids Cryptopleurine, (ꢀ)-Antofine,
(ꢀ)-Tylophorine, and( ꢀ)-Ficuseptine C
[a]
Alois Fürstner* andJason W. J. Kennedy
Abstract: A concise, efficient and mod-
ular approach to the tylophora alka-
loids is described, a family of potent
cytotoxic agents that are equally effec-
tive against drug sensitive and multi-
drug resistant cancer cell lines. The ad-
vantages of the chosen route are illus-
trated by the total syntheses of the
phenanthroquinolizidine cryptopleur-
ine (1) and the phenanthroindolizidines
(ꢀ)-antofine (2), (ꢀ)-tylophorine (3),
and their only recently isolated conge-
ner (ꢀ)-ficuseptine C (4). The key
steps consist in a Suzuki cross-coupling
between a (commercial) boronic acid
and a simple aryl-1,2-dihalide followed
by elaboration of the resulting products
into the corresponding 2-alkynyl-bi-
phenyl derivatives 27, 33, 41 and 46.
The latter undergo PtCl2-catalyzed cy-
cloisomerizations with formation of the
functionalized phenanthrenes 28, 34, 42
and 47, which were transformed into
the targeted alkaloids by a deprotec-
tion/Pictet–Spengler
annulation
tandem. Due to the flexibility and
robust character of this approach, it
might enable a systematic exploration
of the pharmacological profile of this
promising class of bioactive natural
products.
Keywords: alkaloids
· anti-cancer
agents · cross-coupling · phenan-
threnes · platinum
Introduction
ing anti-inflammatory, antihistaminic, antiasthmatic, and im-
munomodulatory effects.[4]
Since the first isolation of tylophorine in 1935 from the per-
ennial climbing plant Tylophora indica (previously T. asth-
matica) native to the plains, hills and forests of southern and
eastern India,[1] the class of “tylophora alkaloids” produced
by various plants of the Asclepiadaceae family has grown
considerably,[2] presently encompassing close to 100 structur-
ally related phenanthroindolizidines and phenanthroquinoli-
zidines together with their seco-derivatives and N-oxides.[3]
As can be seen from the representative examples depicted
in Scheme 1, the defining feature of these pentacyclic natu-
ral products is the presence of a highly oxygenated phenan-
threne ring fused to a saturated N-heterocycle.
The main interest in alkaloids of this type lies in their di-
verse and potent pharmacological and medicinal proper-
ties.[4] The producing plant T. indica has been used for cen-
turies in Ayurvedic medicine for the treatment of various
ailments of the respiratory tract such as allergies and
asthma. Current research supports this traditional use, find-
ing that tylophora extracts may have health benefits includ-
[a]Prof. A. Fürstner, Dr. J. W. J. Kennedy
Max-Planck-Institut für Kohlenforschung
45470 Mülheim/Ruhr (Germany)
Fax : (+49)208-306-2994
Scheme 1. Representative tylophora alkaloids.
E-mail: fuerstner@mpi-muelheim.mpg.de
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Most promising, however, are the remarkable cytotoxic
activities of many compounds of this series.[2,5,6] Prototype
members such as antofine (2) are not only distinguished by
IC50 values in the low nanomolar range, but were also found
to be equally effective against drug-sensitive as well as mul-
tidrug-resistant (MDR) human cancer cell lines.[6] This re-
markable profile suggests that phenanthroindolizidines
might be poor substrates for the glycoprotein efflux pump
responsible for the MDR phenotype, thus emphasizing a po-
tential role as therapeutic leads in the quest for more effec-
tive anti-cancer agents.
This method tolerates many functional groups and is par-
ticularly well suited for the preparation of phenanthrenes
and heterocyclic analogues thereof (Scheme 2).[11] Since the
required biphenyl substrates are readily available, for exam-
Unfortunately, early clinical trials with tylocrebrine (5)
had to be stopped due to serious side effects on the central
nervous system manifested as ataxia and disorientation.[7]
However, it was recently suggested that the use of more
polar analogues might allow one to uncouple cyto- and
CNS-toxicity, as such derivatives should be less prone to
pass the blood/brain barrier; moreover, tissue specific drug
delivery techniques can also be envisaged.[6] Therefore it
seems appropriate to re-investigate this class of alkaloids
both from the medicinal as well as chemical point of view.
To this end, a synthetic route is desirable that allows for an
efficient fusion of their conserved pyrrolidine- or piperidine
parts[8] with a large variety of backbone architectures of dif-
ferent polarity by chemically robust and reliable transforma-
tions; ideally, such an approach should be amenable to com-
binatorial techniques. Although the tylophora alkaloids
served as prominent targets in the past,[3] the described ap-
proaches, though elegant and creative, do not fully meet
modern standards in terms of the desirable structural modu-
larity. Most notably, systematic variations of the oxygenation
pattern of the phenanthrene entity are difficult to achieve
by many of the established routes.
Scheme 2. Formation of (functionalized) polycyclic arenes by metal-cata-
lyzed cycloisomerization. This method is equally applicable to the prepa-
ration of condensed heteroaromatic skeletons if the phenyl rings in the
substrate are replaced by heteroarene moieties.
ple, by standard cross-coupling techniques, this method
opens access to a host of product structures and has already
borne scrutiny in the realm of natural product synthesis.[11,12]
In the present context, this transformation allows decon-
volution of the target alkaloids into simple building blocks
as shown in Scheme 3. After a Pictet–Spengler transform en-
coding the final annulation,[13] retrosynthetic cleavage at the
C14/C14a bond dissects the key intermediate A into a suita-
bly protected aminoalcohol derivative B and a 10-halophe-
nanthrene C (X=halogen) which derives from a haloalkyne
of type D by the metal-catalyzed cycloisomerization refer-
red to above. Alternatively, the heterocycle might already
be in place during the formation of the phenanthrene back-
bone by cycloisomerization of alkyne F, which in turn
should be accessible by cross-coupling between precursors
of type G and H, or B (or E)and D (X = H), respectively.
Although this analysis promises a considerable degree of
flexibility, several conceivable routes were dismissed during
our exploratory studies. Specifically, we were unable to con-
vert the proline-derived iodide 9 into an organometallic re-
agent suitable for cross-coupling with a halophenanthrene of
type C (Scheme 4). Although b-aminosubstituted organozinc
reagents are well known in the literature and have been suc-
cessfully employed in Negishi cross-coupling reactions,[14,15]
attempted insertion of activated zinc dust into 9 led only to
reductive ring opening with formation of 10.[16] Likewise,
several attempts to form compounds of type F by alkylation
of the acetylenic nucleophiles 13–15 with one of the prolinol
derivatives 9, 11 or 12 under various conditions essentially
met with failure.
As part of our investigations into the synthesis[9] and eval-
uation[10] of bioactive natural products of different origin
and structure, we set out to develop an access route to the
tylophora alkaloids that is both efficient and flexible. As
will be outlined below, recourse to modern cross-coupling
techniques and metal catalyzed cycloisomerization reactions
allows for the preparation of a set of representative mem-
bers of this family from simple and, in part, even commercial
building blocks. Since alterations of the required components
are trivial while maintaining a conserved synthesis blueprint,
this methodology might enable optimization of the pharma-
cological profiles of these potent cytotoxic agents by more
systematic modifications of their basic skeletons.
Results andDiscussion
Therefore we focused our efforts on the assembly route
envisaging cross-coupling of a biphenyl H with an alkyne G
carrying the intact pyrrolidine (n=1) or piperidine ring (n=
2) to be incorporated into the final target. Gratifyingly, this
sequence proved to be effective as evident from the total
syntheses of cryptopleurine (1), (ꢀ)-antofine (2), (ꢀ)-tylo-
phorine (3), and their only recently discovered congener
(ꢀ)-ficuseptine C (4) that are outlined below.
Strategic considerations and exploratory studies: Recent in-
vestigations from this laboratory have shown that exposure
of biaryl derivatives bearing an alkyne unit on one of their
ortho-positions to catalytic amounts of carbophilic Lewis
acids such as PtCl2, AuCl, AuCl3, or InCl3 engenders an
efficient cycloisomerization with formation of polycyclic
(hetero)arenes.[11]
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A. Fürstner and J. W. J. Kennedy
In order to be competitive, any new synthesis of 1 must
therefore not only be highly productive but should also be
more flexible by design than its ancestors. To this end
(Scheme 5), compound 16 was brominated on a large scale
to give dihalide 17 as a single isomer in virtually quantita-
tive yield. As expected, this compound underwent a selec-
tive Suzuki coupling[19] with the commercial boronic acid 18
ꢀ
at the more reactive C I bond, which was best performed
under conditions previously optimized in this laboratory for
similar purposes.[20] The resulting bromide 19, however,
turned out to be insufficiently reactive for the envisaged So-
nogashira-type coupling[21] (see below) and had to be trans-
formed into iodide 20 via lithiation followed by quench with
elemental iodine. An aromatic Finkelstein reaction as re-
cently described by Buchwald et al.[22] is also able to bring
about this transformation in satisfactory yield, but the reac-
tion time was found to be impractically long.
Scheme 3. Retrosynthetic analysis of phenanthroindolizidine- (n=1) and
phenanthroquinolizidine (n=2) alkaloids.
Scheme 5. a) Br2, HOAc, 99%; b) [(dppf)PdCl2](5 mol%), LiCl,
Na2CO3, DME/H2O, 70%; c) n-BuLi, THF, ꢀ788C, then I2, 1 h, 82%; or:
NaI, CuI, dimethylethylene diamine, 1,4-dioxane, 1158C, 7 d, 75%.
The preparation of the required coupling partner 25 start-
ed with the hydrogenation of pyridylacetate 21 over PtO2 as
the precatalyst,[23] followed by Boc protection of the result-
ing piperidine 22 to give the b-aminoester derivative 23
(Scheme 6). A very effective one-pot, two-step sequence[24]
then converted this material to the required alkyne 25 by in-
itial Dibal-H reduction followed by treatment of the corre-
sponding aldehyde with the Ohira–Bestmann reagent
24.[25,26]
The next step in the assembly process was the coupling of
the two fragments in hand via a Sonogashira-type reac-
Scheme 4. a) Zn dust (activated with 1,2-dibromoethane and TMSCl),
DMF.
Cryptopleurin: Isolated as early as 1948 from the bark of
the Australian laurel Cryptocarya pleurosperma,[17] crypto-
pleurine (1) constitutes the parent compound of the phenan-
throquinolizidine alkaloid family. 1 acts as a potent inhibitor
of protein biosynthesis and shows pronounced cytotoxicity
in the standard assays.[3,4] This particular alkaloid and sever-
al structural variants thereof were later also found in a vari-
ety of other plants belonging to the Lauraceae, Vitidaceae
and Urticaceae genera and served as prominent target for
many total syntheses campaigns in the past.[3,18]
Scheme 6. a) PtO2 (3 mol%), H2 (1 atm), EtOH, HCl, 79%; b) Boc2O,
Et3N, CH2Cl2, 94%; c) i) Dibal-H, CH2Cl2, ꢀ788C; ii) compound 24,
K2CO3, MeOH, 08C ! RT, 75 %.
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Alkaloids Natural Products
FULL PAPER
tion.[21] In the present case, however, this seemingly routine
transformation was very low yielding under a variety of ex-
perimental conditions and mainly led to competitive homo-
dimerization of alkyne 25. Gratifyingly though, recourse to
the “9-MeO-9-BBN variant” of the Suzuki reaction previ-
ously developed in this laboratory[27,28] opened a convenient
and high yielding access to the desired product 27. Rather
than generating the required borate nucleophile by reaction
of an organoborane substrate with a suitable base, the reac-
tive intermediate is formed from 9-MeO-9-BBN on treat-
ment with an organolithium or other polar organometallic
reagent R-M (Scheme 7). If the latter is an alkynylmetal
species, the resulting borate complex readily transfers its al-
kynyl substituent to aryl halides or triflates under palladium
catalysis.[27]
Figure 1. Molecular structure of phenanthrene 28 from single crystal X-
ray structure determination. Anisotropic displacement ellipsoids are
shown at the 50% probability level and hydrogen atoms have been omit-
ted for clarity.
Scheme 7. Preparation of the borate donor necessary for Suzuki cross-
coupling reactions either via the conventional route or by the “9-MeO-9-
BBN” variant.
This methodology was easily implemented as shown in
Scheme 8. Thus, deprotonation of 25 with n-BuLi in THF at
ꢀ408C gave an alkynyllithium reagent that was trapped
with 9-MeO-9-BBN to give borate 26, which then reacted
smoothly with iodide 20 in the presence of [(dppf)PdCl2]
(5 mol%) to give product 27 in 82% yield. Exposure of this
compound to catalytic amounts of PtCl2 in toluene at 608C
engendered a cycloisomerization[11] with formation of phen-
anthrene 28 which could be isolated in almost quantitative
yield. In this transformation, the chosen dilution was found
to be key to success: while all reactions performed at c=
0.05m gave excellent and well reproducible results, attempt-
ed cycloisomerizations in 0.2m solution were much lower
yielding (35–50%), most likely due to competing oligomeri-
zations of the substrate. The constitution of phenanthrene
28 as the key intermediate of this route to crytopleurine
could be confirmed by X-ray structure analysis (Figure 1).
The total synthesis then ended with a one-pot tandem de-
protection/cyclization process, converting compound 28 into
cryptopleurine (1) in 67% yield. In this sequence, the depro-
tection step occurred rapidly, while the Pictet–Spengler cyc-
lization[13] turned out to be rate determining. Although this
latter transformation followed previous procedures, slight
modifications in the work-up had a beneficial effect on the
yield and purity of the final product (cf. Experimental Sec-
tion).
Scheme 8. a) n-BuLi, THF, ꢀ408C, then 9-MeO-9-BBN, RT; b) iodide
20, [(dppf)PdCl2](5 mol%), THF, reflux, 82%; c) PtCl (20 mol%), tol-
2
uene (0.05m), 608C, 3 h, 97%; d) aq. HCHO, HCl/EtOH, 808C, 67%.
become evident from its ready adaptation to the total syn-
theses of three related phenanthroindolizidine derivatives.
Although this exploratory study afforded racemic 1, it can
be adapted to the preparation of optically active crypto-
pleurine as well;[26] all three companion syntheses described
below bear witness for this notion. Moreover, (ꢁ)-1 can be
easily resolved by chiral HPLC.
(ꢀ)-Antofine: Since cryptopleurine (1) and antofine (2)
share a common phenanthrene skeleton, it was obvious to
divert the route leading to 1 to the preparation of this latter
target.[29] Antofine is known as an exceptionally potent cyto-
toxic agent that is active against human drug sensitive and
multidrug resistant cancer cell lines alike.[3–6] For its synthe-
sis, it sufficed to replace alkyne 25 bearing a piperidine ring
In summary, cryptopleurine (1) as a prototype phenan-
throquinolizidine alkaloid was prepared from three cheap
and commercial starting materials by a high yielding and
scalable route comprising only six steps in the longest linear
sequence. The modular character of this approach will
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A. Fürstner and J. W. J. Kennedy
by the formally ring contracted analogue 32, for which an
effective preparation had to be developed.
As already mentioned above, attempts to obtain this com-
pound by alkynylation of prolinol derivatives 9, 11 or 12
were unrewarding (Scheme 4). Therefore, an alternative
route starting from a homoproline derivative as the sub-
strate was pursued that is summarized in Scheme 9. Al-
Scheme 10. a) i) n-BuLi, THF, ꢀ408C, then 9-MeO-9-BBN, RT; ii) iodide
20, [(dppf)PdCl2](5 mol%), THF, reflux, 58%; b) PtCl (20 mol%), tolu-
2
ene (0.01m), 60–808C, 3 h, 72%; c) aq. HCHO, HCl/EtOH, 808C, 91%
(ee > 98%, chiral HPLC).
Scheme 9. a) 'Tetra-n-propylammonium perruthenate (TPAP) (5 mol%),
N-morpholine-N-oxide (NMO), CH2Cl2, 82%; b) Ph3P=CH2, THF, 61%;
c) i) 9-BBN, THF; ii) NaBO3·4H2O, H2O, 88%; d) TPAP (5 mol%),
NMO, CH2Cl2, 73%; e) Bestmann–Ohira reagent 24, K2CO3, MeOH,
55% (ee > 99.5, chiral GC).
(ꢀ)-Tylophorine: The preparation of (ꢀ)-tylophorine (3) as
the parent compound of the phenanthroindolizidine
series[1,35] used the same pyrrolidine building block 32 as our
synthesis of (ꢀ)-antofine but required a more highly oxy-
genated biphenyl derivative as the coupling partner.
This building block was prepared by regioselective iodina-
tion of veratrole 35[36] followed by bromination of the result-
ing product 36 under standard conditions (Scheme 11). Al-
though this compound contained some dibromide contami-
nant that could not be separated at this stage, it was amena-
ble to a subsequent Suzuki reaction with the commercial
boronic acid 38 under the previously optimized condi-
tions[11,20] to give analytically pure biaryl 39. Iodine for bro-
mine exchange (39 ! 40) followed by a second Suzuki
cross-coupling, now via the 9-MeO-9-BBN variant,[27] al-
lowed for attachment of the alkyne entity, which set the
stage for the platinum-catalyzed cylcoisomerization[11] of 41
with formation of the functionalized phenanthrene 42. This
key intermediate was then converted into (ꢀ)-tylophorine
(3) by the established deprotection/cyclization tandem. As
in the previous cases, the spectral characteristics as well as
the optical rotation of the synthetic sample were in excellent
agreement with the literature data.[13c]
though homoproline itself is commercially available, this
particular b-amino acid is rather expensive and only offered
as the undesired S isomer. Likewise, several literature pro-
cedures for the one-carbon homologation of proline to ho-
moproline were dismissed for practicality reasons and/or be-
cause they were plagued by impractically low yields.[30]
The slightly longer but robust alternative depicted in
Scheme 9, however, reliably provided the required alkyne
32 in optically pure form (ee > 99.5%).[31] Specifically, oxi-
dation of N-Boc-prolinol 29[32] with the tetra-n-propylammo-
nium perruthenate (TPAP) cat./N-methylmorpholine-N-
oxide (NMO) couple[33] followed by Wittig olefination of the
resulting aldehyde furnished alkene 30 which was subjected
to hydroboration/oxidation to give alcohol 31. TPAP oxida-
tion of this alcohol and reaction of the resulting aldehyde
with the Ohira/Bestmann reagent 24[25] delivered the desired
alkyne 32 in good overall yield.[34]
With building block 32 in optically active form in hand,
the preparation of (ꢀ)-antofine (2) could be easily complet-
ed (Scheme 10). Thus, 9-MeO-9-BBN mediated cross-cou-
pling[27] of 32 with iodide 20 already used in the cryptopleur-
ine series followed by platinum-catalyzed rearrangement[11]
of the resulting alkynylated biphenyl derivative 33 furnished
the desired phenanthrene 34. Cleavage of the Boc group fol-
lowed by Pictet–Spengler cyclization[13] could again be per-
formed as a one-pot operation which furnished antofine (2)
in high yield. Not only did the analytical and spectroscopic
data of our samples match those of the natural product re-
ported in the literature,[29] but the synthetic material was
also found to be optically pure within the limits of detection
(> 98%, HPLC). This result shows that pre-existing chiral
centers are not compromised in any step of the chosen se-
quence.
(ꢀ)-Ficuseptine C: The leaves of the subtropic tree Ficus
septica Burm. f. (Moraceae), which grows abundantly in
Taiwan, are widely used in traditional Chinese medicine for
their purgative and emetic effects to treat colds, fevers and
infective diseases. A recent search for the bioactive compo-
nents showed that the methanol extract also exhibits potent
cytotoxic properties due to the presence of a cocktail of var-
ious phenanthroindolizidine alkaloids.[37] In addition to sev-
eral known members of this series (including tylophorine
(3), tylocrebrine (5) and antofine-N-oxide (7)), 8 new alka-
loids of this type have been isolated and characterized; un-
fortunately, however, some of them were obtained in minute
amounts only, thus making a detailed assessment of their bi-
ological properties impossible; (ꢀ)-ficuseptine C (4) belongs
to this group (only 1 mg of product was isolated from
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Scheme 12. a) Boronic acid 43, [(dppf)PdCl2](5 mol%), LiCl, Na 2CO3,
DME/H2O, 80 8C, 41%; b) n-BuLi, THF, ꢀ788C, then I2, ꢀ788C ! RT,
77%; c) i) alkyne 32, n-BuLi, THF, ꢀ408C, ii) 9-MeO-9-BBN, RT; iii)
iodide 45, [(dppf)PdCl2](5 mol%), THF, reflux, 59%; d) PtCl
2
(20 mol%), toluene (0.05m), 60–808C, 56%; e) aq. HCHO, HCl/EtOH,
808C, 62% (ee > 98%, chiral HPLC).
Scheme 11. a) I2, HgO, CH2Cl2, 97%; b) Br2, HOAc, 67%; c) boronic
acid 38, [(dppf)PdCl2](5 mol%), LiCl, Na 2CO3, DME/H2O, 80 8C, 59%;
d) n-BuLi, THF, ꢀ788C, then I2, ꢀ788C ! RT, 54%; e) i) alkyne 32, n-
BuLi, THF, ꢀ408C, ii) 9-MeO-9-BBN, RT; iii) iodide 40, [(dppf)PdCl2]
(5 mol%), THF, reflux, 64%; f) PtCl2 (20 mol%), toluene (0.05m), 60–
808C, 56%; g) aq. HCHO, HCl/EtOH, 808C, 48 % (ee > 98%, chiral
HPLC).
purity and integrity of our synthetic material. The original
spectra of 4, kindly provided by Professor Wu (Taiwan),
matched our spectra; however, they also suggested that con-
taminants from the extraction process had remained in the
original sample which might explain the differences in ap-
pearance and [a]D. We therefore believe that the analytical
and spectroscopic data recorded for synthetic (ꢀ)-4, as com-
piled in the Experimental Section, represent the correct ref-
erence data set for (ꢀ)-ficuseptine C. Biochemical evalua-
tions of this compound and its congeners will be disclosed in
due course.
46.5 kg of plant material).[37] Due to the close structural rela-
tionship with the other alkaloids discussed herein, we set
out to prepare meaningful quantities of this compound in
order to confirm its structure and to enable a preliminary
biochemical and biological profiling.
In view of the flexibility of our assembly process, this goal
was easily attained as summarized in Scheme 12. Thus, it
sufficed to engage boronic acid 43 in the Suzuki reaction
with iodide 17 to give biphenyl 44 in an unoptimized 41%
yield. Metal–halogen exchange followed by addition of I2 af-
forded iodide 45 ready for cross-coupling with alkyne 32 via
the 9-MeO-9-BBN-based methodology described above.[27]
Subsequent cycloisomerization of the resulting product 46
with the aid of PtCl2 in toluene[11] gave the somewhat labile
phenanthrene 47 which was converted into the targeted al-
kaloid 4 by the usual deprotection/cyclization protocol.
Synthetic (ꢀ)-ficuseptine C was a beige solid rather than
a colorless gum as described in the literature;[37] moreover,
its specific optical rotation deviated significantly from that
of the isolated natural product (cf. Experimental Section).
Worried about these discrepancies, a very detailed spectro-
scopic analysis of the compound was carried out which un-
ambiguously proved the proposed constitution as well as
Conclusion
This report describes the establishment of a concise, effi-
cient and modular synthetic route to typlophora alkaloids.
The versatility and flexibility of the method was demonstrat-
ed by the preparation of four representative members be-
longing to the phenanthroquinolizidine as well as the phe-
nanthroindolizidine series. These examples illustrate that
modification of the substitution pattern around the phenan-
threne ring as well as of the heterocyclic segments are easily
accommodated due to the flexibility inherent to the underly-
ing synthesis blueprint. Key transformations include palladi-
um catalyzed cross-coupling reactions for the formation of
the biphenyl scaffold as well as for the introduction of the
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A. Fürstner and J. W. J. Kennedy
22 mmol), degassed aq. Na2CO3 (2m, 17 mL, 34 mmol), and [(dppf)PdCl2]
(234 mg, 0.287 mmol) in DME (50 mL) was stirred at 808C for 21 h. The
mixture was cooled to ambient temperature, diluted with aq. NH4Cl
(50 mL) and extracted with tert-butyl methyl ether (4”25 mL). The com-
bined organic layers were washed with brine (50 mL) and dried over
Na2SO4. Evaporation of the solvents afforded the crude product as a
dark oil which was purified by flash chromatography (20% tert-butyl
methyl ether in hexanes) to give biaryl 19 as a colorless oil which slowly
solidified over time (1.40 g, 70%). M.p. 56–588C; 1H NMR (400 MHz,
CDCl3): d=7.53 (d, J=8.8 Hz, 1H), 7.01–6.90 (m, 3H), 6.89 (d, J=
3.1 Hz, 1H), 6.76 (dd, J=8.8, 3.1 Hz, 1H), 3.93 (s, 3H), 3.90 (s, 3H), 3.81
(s, 3H); 13C NMR (100 MHz, CDCl3): d=158.9, 148.7, 148.4, 143.2, 133.9,
133.7, 121.6, 116.9, 114.4, 113.3, 113.0, 110.8, 56.0, 55.9, 55.6; IR (film):
n˜ =3068, 2935, 1604, 1255, 1028, 808 cmꢀ1; MS (EI): m/z (%): 324 (100)
alkynyl substituent at one of the ortho-positions. The relia-
bility of these methods and the ready availability of a host
of suitable building blocks suggest that systematic explora-
tions of pertinent structure/activity relationships as well as a
fine tuning of the physico-chemical properties of the result-
ing products should be fairly straightforward. This modular
character might enable an optimization of the pharmacolog-
ical profile of these highly cytotoxic alkaloids. Moreover,
the success of this total synthesis campaign also attests to
the maturity of the PtCl2-catalyzed cycloisomerization reac-
tion leading to substituted phenanthrene derivatives and
(heterocyclic) analogues thereof.[11,12] Further applications of
this and related methodologies to natural product synthesis
together with a first round of biological evaluations is pres-
ently ongoing and will be reported in the near future.
[M
N
N
200 (45); HRMS (EI): m/z: calcd for C15H1579BrO3: 322.020470; found:
322.020279 [M +]; elemental analysis calcd (%) for C15H15BrO3: C 55.75,
H 4.68; found: C 55.86, H 4.61.
2-Iodo-3’,4’,5-trimethoxybiphenyl (20): A solution of bromide 19 (249 mg,
0.770 mmol) in THF (1 mL) at ꢀ788C was treated slowly with n-BuLi
(1.64m in hexanes, 0.50 mL, 0.82 mmol). The resulting bright yellow solu-
tion was stirred at ꢀ788C for 5 min and then treated with a solution of I2
(274 mg, 1.08 mmol) in THF (1 mL). The resulting dark slurry was stirred
at ꢀ788C for 15 min and then at ambient temperature for 1 h. The reac-
tion was quenched with aq. sat. NH4Cl (5 mL) and enough water to dis-
solve the resulting precipitate. The layers were separated and the aque-
ous phase was extracted with tert-butyl methyl ether (4”5 mL). The com-
bined organic extracts were washed with 5% aq. Na2S2O3 (2”5 mL) and
brine (10 mL), before they were dried (Na2SO4) and evaporated to a
yellow oil (268 mg, 94%) which eventually solidified. This compound was
pure enough to use in the subsequent step. The product could be further
purified by flash chromatography (1% EtOAc in toluene) to give prod-
uct 20 as a colorless oil which slowly solidified over time (235 mg, 82%).
M.p. 76–788C. 1H NMR (400 MHz, CDCl3): d=7.79 (d, J=8.7 Hz, 1H),
6.90 (m, 4H), 6.63 (dd, J=8.7, 3.0 Hz, 1H), 3.92 (s, 3H), 3.91 (s, 3H),
3.80 (s, 3H); 13C NMR (100 MHz, CDCl3): d=159.8, 148.7, 148.3, 147.3,
140.0, 136.9, 121.5, 116.2, 115.0, 113.0, 110.7, 87.6, 56.0, 55.9, 55.5; IR
(film): n˜ =3054, 2937, 1603, 1231, 1019, 803 cmꢀ1; MS (EI): m/z (%): 370
(100) [M +], 355 (7), 327 (6), 243 (2), 200 (8); HRMS (EI): m/z: calcd for
C15H15IO3: 370.006592; found: 370.006188; elemental analysis calcd (%)
for C15H15IO3: C 48.67, H 4.08; found: C 48.81, H 4.14.
Experimental Section
General methods: All reactions were carried out under Ar in flame-dried
glassware. The solvents used were purified by distillation over the drying
agents indicated and were transferred under Ar: THF, Et2O, DME (Mg/
anthracene), CH2Cl2, 1,2-dichloroethane (P4O10), MeCN, Et3N, NMP
(CaH2), MeOH, iPrOH (Mg), hexane, benzene, toluene (Na/K). Flash
chromatography: Merck silica gel 60 (230–400 mesh); where indicated,
flash chromatography was performed with the aid of a Combiflash Com-
panion apparatus using pre-packed RediSep columns. NMR: Spectra
were recorded on a Bruker DPX 300 or AV 400 spectrometer in the sol-
vents indicated; chemical shifts (d) are given in ppm relative to TMS,
coupling constants (J) in Hz. The solvent signals were used as references
and the chemical shifts converted to the TMS scale (CDCl3: dC
77.0 ppm; residual CHCl3 in CDCl3: dH 7.24 ppm; CD2Cl2: dC
ꢂ
ꢂ
ꢂ
ꢂ
53.8 ppm; residual CH2Cl2 in CD2Cl2: dH 5.32 ppm). Where indicated,
the signal assignments are unambiguous; the numbering scheme is arbi-
trary and is shown in the inserts. The assignments are based upon 1D and
2D spectra recorded using the following pulse sequences from the
Bruker standard pulse program library: DEPT; COSY (cosygs and co-
sydqtp); HSQC (invietgssi) optimized for 1J
A
(ꢁ)-Ethyl (piperidin-2-yl)acetate (22): A solution of pyridine 21 (1.02 g,
6.14 mmol) in aq. HCl (6m, 2 mL) and EtOH (10 mL) was treated with
PtO2 (42 mg, 0.19 mmol) and stirred under an atmosphere of H2 (1 bar)
for 20 h. The mixture was filtered through a plug of Celite with EtOH
and the filtrate was evaporated. The resulting colorless oil was treated
with NH4OH (14m, 1.5 mL) and brine (8.5 mL) and extracted with tert-
butyl methyl ether (5”10 mL). The combined extracts were dried
(MgSO4) and evaporated to a colorless oil (832 mg, 79%) which could be
further purified by Kugelrohr distillation (2008C, 0.1 Torr). 1H NMR
(400 MHz, CDCl3): d=4.14 (q, J=7.2 Hz, 2H), 3.04 (m, 1H), 2.91 (dddd,
J=10.7, 7.9, 5.5, 2.6 Hz, 1H), 2.66 (m, 1H), 2.36 (m, 1H), 2.34 (d, J=
2.3 Hz, 1H), 2.03 (brs, 1H), 1.78 (m, 1H), 1.60 (m, 2H), 1.39 (m, 2H),
1.25 (t, J=7.1 Hz, 3H), 1.17 (m, 1H); 13C NMR (100 MHz, CDCl3): d=
172.4, 60.4, 53.4, 46.9, 41.8, 32.7, 26.1, 24.7, 14.3; IR (film): n˜ =3304, 2932,
1733, 1176 cmꢀ1; MS (EI): m/z (%): 171 (4) [M +], 142 (6), 84 (100);
HRMS (EI): m/z: calcd for C9H17NO2: 171.125927; found: 171.126149.
(inv4gslplrnd) for correlations via nJ
AHCTREUNG
using an MLEV17 mixing time of 120 ms. IR: Nicolet FT-7199 spectrom-
eter, wavenumbers (n˜) in cmꢀ1. MS (EI): Finnigan MAT 8200 (70 eV),
ESI-MS: Finnigan MAT 95, accurate mass determinations: Bruker
APEX III FT-MS (7 T magnet). Melting points: Büchi melting point ap-
paratus B-540 (corrected). Elemental analyses: H. Kolbe, Mülheim/Ruhr.
Unless stated otherwise, all commercially available compounds (Fluka,
Lancaster, Aldrich) were used as received.
Cryptopleurine series
3-Iodo-4-bromoanisole (17): Br2 (2.8 mL, 54 mmol) was added dropwise
to a solution of 3-iodoanisole (16; 10.01 g, 42.79 mmol) in glacial HOAc
(65 mL) and the resulting orange mixture was stirred at ambient temper-
ature for 26 h. For work up, the solution was diluted with water (250 mL)
and extracted with hexanes (5”50 mL). The combined orange extracts
were washed with aq. Na2S2O3 (5%, 3”25 mL) and brine (50 mL), dried
(Na2SO4), and concentrated to an orange oil (13.32 g). Kugelrohr distilla-
tion (2508C, 0.1 Torr) gave product 17 as a pale brown oil (13.24 g,
99%). 1H NMR (400 MHz, CDCl3): d=7.46 (d, J=8.8 Hz, 1H), 7.38 (d,
J=2.8 Hz, 1H), 6.76 (dd, J=8.8 Hz, 2.8 Hz, 1H), 3.76 (s, 3H); 13C NMR
(100 MHz, CDCl3): d=158.8, 132.6, 125.5, 120.3, 116.0, 101.1, 55.7; IR
(ꢁ)-Ethyl (N-tert-butoxycarbonylpiperidin-2-yl)acetate (23): A solution
of piperidine 22 (2.70 g, 15.8 mmol) and NEt3 (4.5 mL, 32 mmol) in
CH2Cl2 (25 mL) at 08C was treated with Boc2O (3.40 g, 15.6 mmol) and
the resulting mixture was stirred for 18 h. The reaction was successively
washed with aq. HCl (1m, 3”20 mL), aq. sat. NaHCO3 (25 mL) and
brine (25 mL), dried (Na2SO4) and evaporated, and the residue was puri-
fied by Kugelrohr distillation (2008C, 0.1 Torr) to yield product 23 as a
colorless oil (4.02 g, 94%). 1H NMR (400 MHz, CDCl3, rotamers): d=
4.70 (m, 1H), 4.11 (q, J=7.1 Hz, 2H), 3.99 (m, 1H), 2.78 (m, 1H), 2.55
(m, 2H), 1.7–1.4 (m, 6H), 1.45 (s, 9H), 1.25 (t, J=7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=171.4, 154.7, 79.5, 60.4, 48.1, 39.2, 35.4, 28.4, 28.2,
(film): n˜ =3082, 2934, 1580, 1460, 1284, 1228, 1034, 833, 802, 602 cmꢀ1
;
MS (EI): m/z (%): 314 (98) [M
A
ACHTREUNG
297 (9), 271 (8), 269 (8), 172 (17), 170 (17), 63 (42); HRMS (EI): m/z:
calcd for C7H6I79BrO: 311.864688; found: 311.864329 [M +].
2-Bromo-3’,4’,5-trimethoxybiphenyl (19): A mixture of aryl iodide 17
(1.94 g, 6.20 mmol), boronic acid 18 (1.22 g, 6.70 mmol), LiCl (0.92 g,
7404
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 7398 – 7410

Alkaloids Natural Products
FULL PAPER
25.3, 18.9, 14.2; IR (film): n˜ =2936, 1737, 1692, 1412, 1392, 1366, 1273,
1161 cmꢀ1; MS (EI): m/z (%): 271 (4) [M +], 215 (5), 170 (40), 128 (45),
84 (100), 57 (57), 41 (14); HRMS: m/z: calcd for C14H25NO4+Na:
294.167578; found: 294.167311.
1.61 (m, 4H), 1.52–1.40 (m, 2H), 1.26 (brs, 9H); 13C NMR (100 MHz,
CDCl3): d=157.9, 155.1, 149.7, 148.8, 130.6, 130.5, 129.6, 127.2, 126.0,
125.8, 124.8, 115.3, 105.8, 103.9, 79.0, 56.4, 56.1, 55.6, 50.2, 39.6, 34.0, 29.7,
28.2, 25.6, 18.9; IR (film): n˜ =2937, 1673, 1620, 1607, 1413, 1363, 1160,
1030, 835 cmꢀ1; MS (EI): m/z (%): 465 (18) [M +], 282 (21), 281 (39), 184
(18), 128 (100), 84 (34), 57 (14); HRMS: m/z: calcd for C28H35NO5 +Na:
488.240742; found: 488.240956; elemental analysis calcd (%) for
C28H35NO5: C 72.23, H 7.58, N 3.01; found: C 72.25, H 7.67, N 2.89.
(ꢁ)-N-tert-Butoxycarbonyl-2-propargylpiperidine (25):
A solution of
compound 23 (2.04 g, 7.52 mmol) in CH2Cl2 (15 mL) at ꢀ788C was treat-
ed slowly with Dibal-H (1m in hexanes, 8.4 mL, 8.4 mmol). After TLC
showed that the ester had been consumed (~4 h), the reaction was
quenched with MeOH (5 mL) and warmed to 08C. This mixture was
treated first with a solution of the Bestmann–Ohira reagent 24 (1.45 g,
7.56 mmol) in MeOH (10 mL) and then with K2CO3 (2.02 g, 14.6 mmol),
stirred for 30 min at 08C and then overnight at ambient temperature.
After 19 h the yellow slurry was treated with saturated Rochelle salt solu-
tion (50 mL) and stirred until all solids had dissolved (~30 min). The
aqueous phase was repeatedly extracted with tert-butyl methyl ether (6”
15 mL), the combined extracts were washed with brine (50 mL), dried
(Na2SO4) and evaporated to a yellow oil. Flash chromatography of this
residue (10% tert-butyl methyl ether in hexanes) gave product 25 as a
white solid (1.27 g, 75%). M.p. 52–548C; 1H NMR (400 MHz, CDCl3):
d=4.41 (m, 1H), 3.99 (m, 1H), 2.73 (m, 1H), 2.44 (m, 2H), 1.95 (t, J=
2.6 Hz, 1H), 1.86 (m, 1H), 1.60–1.41 (m, 5H), 1.46 (s, 9H); 13C NMR
(100 MHz, CDCl3): d=154.9, 81.6, 79.5, 69.9, 49.6, 39.1, 28.5, 26.8, 25.2,
19.6, 18.7; IR (film): n˜ = 3248, 2942, 1680, 1157 cmꢀ1; MS (EI): m/z (%):
223 (1) [M +], 184 (15), 128 (100), 84 (88), 57 (68); HRMS: m/z: calcd
for C13H21NO2+Na: 246.146444; found: 246.146246; elemental analysis
calcd (%) for C13H21NO2: C 69.92, H 9.48; found: C 69.92, H 9.44.
Representative procedure for the deprotection/Pictet–Spengler cycliza-
tion tandem: (ꢁ)-cryptopleurine (1): A solution of phenanthrene 28
(75 mg, 0.16 mmol) in EtOH (5 mL) was treated with aqueous HCHO
(37% w/w, 1.0 mL, 12 mmol) and HCl (12m, 0.15 mL, 1.8 mmol), and the
resulting mixture was stirred at 808C in the dark for 4 d. The solvents
were evaporated and the residue was dissolved in NaOH (6m, 5 mL) and
extracted with CH2Cl2 (4”5 mL). The combined extracts were successive-
ly washed with water (6”5 mL) and brine (5 mL), dried (Na2SO4), and
evaporated to give a light brown solid which was further purified by flash
chromatography (Combiflash Companion, 0!15% EtOH in CH2Cl2) to
give cryptopleurine (1) as a yellow-green powder (41 mg, 67%). The
enantiomers can be separated by chiral HPLC (Chiralpak AD-H
(250 mm”4.6 mm), n-heptane/isopropanol 4:1, 0.5 mLminꢀ1, 42.52 min,
48.27 min). 1H NMR (400 MHz, CDCl3): d=7.88 (s, 1H), 7.87 (d, J=
2.6 Hz, 1H), 7.76 (d, J=9.0 Hz, 1H), 7.22 (s, 1H), 7.18 (dd, J=9.0,
2.6 Hz, 1H), 4.42 (d, J=15.5 Hz, 1H), 4.08 (s, 3H), 4.04 (s, 3H), 4.00 (s,
3H), 3.61 (d, J=15.5 Hz, 1H), 3.26 (d, J=11.0 Hz, 1H), 3.05 (dd, J=
16.5, 3.1 Hz, 1H), 2.87 (dd, J=16.0, 10.5 Hz, 1H), 2.38 (m, 1H), 2.29 (m,
1H), 2.02 (dd, J=12.9, 2.5 Hz, 1H), 1.88 (d, J=12.6 Hz, 1H), 1.81 (m,
2H), 1.55 (m, 1H), 1.43 (m, 1H); 13C NMR (100 MHz, CDCl3): d=157.5,
149.5, 148.4, 130.2, 126.5, 125.4, 124.4, 124.1, 123.7, 123.5, 114.9, 104.8,
104.00, 103.96, 57.6, 56.2, 56.05, 55.96, 55.5, 34.6, 33.7, 25.9, 24.3; IR
(film): n˜ =2929, 1610, 1256, 1041 cmꢀ1; MS (EI): m/z (%): 377 (32) [M +],
294 (100), 279 (4), 189 (6); HRMS: m/z: calcd for C24H28NO3:
378.206370; found: 378.206195.
Representative procedure for cross-coupling via the 9-MeO-9-BBN var-
iant of the Suzuki reaction: (ꢁ)-N-tert-butoxycarbonyl-2-[3-(3’,4’,5-trime-
thoxybiphenyl-2-yl)-prop-2-ynyl]piperidine (27): A solution of alkyne 25
(42 mg, 0.19 mmol) in THF (1.6 mL) at ꢀ408C was treated with n-BuLi
(1.69m in hexanes, 110 mL, 0.186 mmol) and stirred for 40 min. To this
solution was added 9-MeO-9-BBN (37 mg, 0.24 mmol) and the resulting
solution was stirred at ambient temperature for 1 h. Iodide 20 (49 mg,
0.13 mmol) and [(dppf)PdCl2](6 mg, 0.007 mmol) were then added, and
the resulting dark mixture was stirred at 808C for 21 h. The mixture was
cooled to ambient temperature before it was diluted with aq. sat. NH4Cl
(5 mL) and extracted with tert-butyl methyl ether (4”5 mL). The com-
bined organic phases were washed with brine (10 mL), dried over
Na2SO4, and evaporated to give the crude product as an orange oil which
was purified by flash chromatography (Combiflash Companion, 0!30%
tert-butyl methyl ether in hexanes) to give product 27 as a colorless oil
(50 mg, 82%). 1H NMR (400 MHz, CDCl3): d=7.42 (d, J=8.5 Hz, 1H),
7.13 (m, 1H), 7.11 (dd, J=8.2, 2.0 Hz, 1H), 6.91 (d, J=8.2 Hz, 1H), 6.87
(d, J=2.6 Hz, 1H), 6.79 (dd, J=8.6, 2.7 Hz, 1H), 4.32 (brs, 1H), 3.96 (m,
1H), 3.92 (s, 3H), 3.91 (s, 3H), 3.83 (s, 3H), 2.69 (m, 1H), 2.61 (ABX,
Antofine series
(R)-N-(tert-Butoxycarbonyl)-2-ethenylpyrrolidine (30):[38] A solution of
Boc-prolinol 29 (7.44 g, 36.95 mmol)[32] and NMO (6.57 g, 56.07 mmol) in
CH2Cl2 (75 mL) was treated with powdered molecular sieves (3 Š,
19.2 g) and then with TPAP (649 mg, 1.85 mmol),[33] resulting in a brief
exothermic reaction. The dark mixture was stirred at ambient tempera-
ture for 3.5 h and then filtered through a silica gel column with tert-butyl
methyl ether. Evaporation of the filtrate afforded (R)-N-(tert-butoxycar-
bonyl)-prolinal as a colorless oil (6.06 g, 82%) which was used without
further purification. Characteristic data:[39]1 H NMR (400 MHz, CDCl3,
rotamers): d=9.56 (m) and 9.46 (d, J=2.9 Hz) (1H), 4.20 and 4.06 (m,
1H), 3.50 (m, 2H), 2.2–1.6 (m, 4H), 1.49 and 1.44 (s, 9H); 13C NMR
(100 MHz, CDCl3): d=200.7, 200.4, 155.0, 154.0, 80.7, 80.2, 65.1, 64.9,
46.9, 46.8, 28.4, 28.3, 28.0, 26.8, 24.7, 24.0; IR (film): n˜ =2977, 1735, 1687,
1389, 1159, 1118 cmꢀ1; MS (EI): m/z (%): 170 (14) [M +ꢀCHO], 126
(12), 114 (50), 70 (94), 57 (100), 41 (23), 29 (15); HRMS: m/z: calcd for
C10H18NO3: 200.128669; found: 200.128424.
JAB =16.5 Hz, 1H), 2.44 (ABX, JAB =16.5 Hz, 1H); 1.70–1.22 (m, 6H),
1.42 (s, 9H); 13C NMR (100 MHz, CDCl3): d=159.2, 154.9, 148.6, 148.4,
145.0, 134.6, 133.6, 121.6, 114.8, 114.5, 112.8, 112.5, 110.8, 88.4, 81.6, 79.4,
56.0, 55.99, 55.4, 49.9, 39.2, 28.5, 26.6, 25.2, 20.7, 18.7; IR (film): n˜ =2933,
1685, 1602, 1407, 1364, 1251, 1160, 1028, 810 cmꢀ1; MS (EI): m/z (%): 465
(7) [M +], 281 (6), 184 (24), 128 (100), 84 (43), 57 (20); HRMS: m/z:
calcd for C28H35NO5 +Na: 488.240743; found: 488.240514; elemental
analysis calcd (%) for C28H35NO5: C 72.23, H 7.58, N 3.01; found: C
72.30, H 7.48, N 2.94.
A yellow solution of Ph3P=CH2 (2.28 g, 8.23 mmol) in THF (5 mL) was
treated with a solution of the crude prolinal described above (1.51 g,
7.57 mmol) in THF (10 mL). After stirring for 3 h, the reaction mixture
was absorbed onto silica gel and purified by flash chromatography (10%
tert-butyl methyl ether in hexanes) to give compound 30 as a colorless oil
Representative procedure for the PtCl2-catalyzedcycloisomerization re-
action: Preparation of (ꢁ)-N-tert-butoxycarbonyl-2-[(2,3,6-trimethoxy-
phenanthren-10-yl)methyl]-piperidine (28): A solution of compound 27
(48 mg, 0.10 mmol) in toluene (2 mL) was treated with PtCl2 (5 mg,
0.02 mmol) and stirred at 608C for 3 h. The mixture was adsorbed on
silica gel and the product was purified by flash chromatography (Combi-
flash Companion, 0!25% tert-butyl methyl ether in hexanes) to give
phenanthrene 28 as a white powder (47 mg, 97%). The enantiomers can
be separated by chiral HPLC (Chiralpak AD-H (250 mm”4.6 mm), n-
heptane/isopropanol 4:1, 0.5 mLminꢀ1, 14.90 min, 20.29 min). M.p. 190–
1918C; 1H NMR (400 MHz, CDCl3): d=7.92 (s, 1H), 7.85–7.75 (brs,
1H), 7.84 (d, J=2.3 Hz, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.37 (s, 1H), 7.16
(dd, J=8.8, 2.4 Hz, 1H), 4.69 (m, 1H), 4.15 (brs, 3H), 4.11 (s, 3H), 4.06
(m, 1H), 4.00 (s, 3H), 3.23 (m, 2H), 3.08 (dt, J=13.2, 2.9 Hz, 1H), 1.90–
1
(907 mg, 61%). H NMR (400 MHz, CDCl3): d=5.76 (ddd, J=16.6, 10.6,
5.9 Hz, 1H), 5.05 (m, 2H), 4.30 (m, 1H), 3.39 (m, 2H), 2.01 (m, 1H),
1.84 (m, 2H), 1.69 (m, 1H), 1.45 (s, 9H); 13C NMR (100 MHz, CDCl3):
d=154.6, 138.9, 113.7, 79.1, 59.1, 46.3, 31.8, 28.5, 23.0; IR (film): n˜ =3083,
2975, 1697, 1643, 1394, 1171, 1114, 988, 914 cmꢀ1; MS (EI): m/z (%): 197
(6) [M +], 141 (56), 124 (15), 70 (17), 57 (100), 41 (29), 29 (13); HRMS:
m/z: calcd for C11H19NO2 +Na 220.130800; found: 220.130884.
(R)-N-(tert-Butoxycarbonyl)-2-(hydroxyethyl)-pyrrolidine (31): The solu-
tion of olefin 30 (907 mg, 4.60 mmol) in THF (9 mL) at 08C was treated
with 9-BBN dimer (866 mg, 3.52 mmol). After 1 h the mixture was al-
lowed to warm to ambient temperature and stirring was continued for
5 h. Na2BO3·4H2O (3.22 g, 20.9 mmol) and water (10 mL) were then
added, and the resulting mixture was allowed to stir at ambient tempera-
Chem. Eur. J. 2006, 12, 7398 – 7410
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7405

A. Fürstner and J. W. J. Kennedy
ture for 18 h. For work up, the mixture was diluted with water (75 mL)
and extracted with tert-butyl methyl ether (5”20 mL). The combined or-
ganic layers were washed with brine (25 mL), dried (Na2SO4), and evapo-
rated and the residue was purified by flash chromatography (Combiflash
Companion, 0!50% tert-butyl methyl ether in hexanes) to give product
31 as a colorless oil (868 mg, 88%).[40]1 H NMR (400 MHz, CDCl3, ro-
tamers): d=4.13 (m, 1H), 3.59 (m, 2H), 3.33 (m, 2H), 2.93 (brs, 1H),
1.97 (m, 1H), 1.88 (m, 2H), 1.65 (m, 2H), 1.50–1.31 (m, 1H), 1.47 (s,
9H); 13C NMR (100 MHz, CDCl3): d=79.9, 59.3, 53.6, 46.4, 38.4, 31.2,
28.5, 23.5; MS (EI): m/z (%): 215 (4) [M +], 170 (14), 142 (11), 114 (86),
70 (100), 57 (100), 41 (29), 29 (17); HRMS: m/z: calcd for C11H21NO3 +
Na: 238.141361; found: 238.141392.
158.8, 154.0, 148.1, 147.9, 144.6, 134.2, 133.2, 121.1, 114.5, 114.2, 113.9,
112.4, 112.1, 110.4, 88.3, 87.9, 81.1, 80.8, 79.0, 78.7, 55.9, 55.6, 55.0, 46.6,
46.3, 30.2, 29.4, 28.2, 24.7, 24.0, 23.2, 22.4; IR (film): n˜ =2969, 1690, 1603,
1393, 1365, 1254, 1167, 1029 cmꢀ1; MS (EI): m/z (%): 451 (23) [M +], 378
(8), 282 (16), 281 (12), 170 (30), 114 (100), 70 (74), 57 (35), 41 (5);
HRMS: m/z: calcd for C27H33NO5 +Na: 474.225096; found: 474.225134;
elemental analysis calcd (%) for C27H33NO5: C 71.82, H 7.37, N 3.10;
found: C 71.88, H 7.43, N 2.96.
(R)-N-(tert-Butoxycarbonyl)-2-[(2,3,6-trimethoxyphenanthren-10-yl)-
methyl]-pyrrolidine (34): Prepared according to the representative proce-
dure for the cycloisomerization described above, upon treatment of a sol-
ution of substrate 33 (194 mg, 0.430 mmol) with PtCl2 (30 mg, 0.11 mmol)
in toluene (43 mL) at 608C for 1 h and then at 808C for 3 h. Flash chro-
matography (Combiflash Companion, 0!30% tert-butyl methyl ether in
hexanes) of the crude product gave phenanthrene 34 as an oil which
slowly solidified upon standing (141 mg, 72%). Chiral HPLC analysis
(Chiralcel OD-H (250 mm”4.6 mm), n-heptane/isopropanol 98:2,
0.5 mLminꢀ1, 28.07 min (R isomer), 33.85 min (S isomer)) showed that
(R)-N-(tert-Butoxycarbonyl)-2-propargylpyrrolidine (32): A mixture of
homoprolinol 31 (2.62 g, 12.2 mmol), NMO (2.16 g, 18.5 mmol), and pow-
dered molecular sieves (3 Š, 7.61 g) in CH2Cl2 (25 mL) was treated at
08C with TPAP (227 mg, 0.646 mmol).[33] The resulting dark mixture was
stirred at this temperature for 30 min and then at ambient temperature
for 2 h. The mixture was filtered through a short silica gel column with
tert-butyl methyl ether. The filtrates were evaporated to give crude (R)-
N-(tert-butoxycarbonyl)-2-(2-oxoethyl)-pyrrolidine as an oil (1.91 g,
73%)[41] which was used in the next step without further purification.
Characteristic data: 1H NMR (400 MHz, CDCl3, rotamers): d=9.77 (t,
J=2.0 Hz, 1H), 4.25 (m, 1H), 3.36 (m, 2H), 2.86 (m, 1H), 2.47 (ddd, J=
16.2, 7.5, 1.7 Hz, 1H), 2.11 (m, 1H), 1.85 (m, 2H), 1.66 (m, 1H), 1.44 (s,
9H); 13C NMR (100 MHz, CDCl3): d=201.0, 154.4, 79.8, 52.4, 49.2, 46.4,
31.7, 28.5, 23.4; IR (film): n˜ =2973, 1690, 1393, 1169 cmꢀ1; MS (EI): m/z
(%): 213 (0.5) [M +], 212 (0.5), 185 (10), 114 (34), 70 (56), 57 (100), 41
(34), 29 (10); HRMS: m/z: calcd for C11H19NO3 +Na: 236.125712; found:
236.125605.
the product had an enantiomeric excess of
> 98%. M.p. 99–1018C;
1
[a]2D0 =ꢀ72.1 (c 1.07, CH2Cl2); H NMR (400 MHz, CDCl3, rotamers): d=
8.32 (brs, 1H), 7.91 (s, 1H), 7.84 (d, J=2.3 Hz, 1H), 7.72 (d, J=8.7 Hz,
1H), 7.38 (s, 1H), 7.16 (dd, J=8.7, 2.3 Hz, 1H), 4.26 (m, 1H), 4.20 (brs,
3H), 4.11 (s, 3H), 4.01 (s, 3H), 3.90 (m, 1H), 3.48 (m, 1H), 3.35 (m, 1H),
2.62 (m, 1H), 2.00 (m, 1H), 1.82 (m, 2H), 1.66 (m, 1H), 1.49 (s, 9H);
13C NMR (100 MHz, CDCl3): d=157.8, 154.7, 149.8, 148.8, 131.0, 130.6,
129.6, 127.3, 126.0, 125.8, 124.6, 115.3, 106.8, 103.9, 103.5, 79.0, 57.3, 56.7,
56.0, 55.6, 46.8, 38.5, 29.1, 28.6, 23.4; IR (film): n˜ =2927, 1684, 1609, 1394,
1260, 1160, 1029, 799 cmꢀ1; MS (EI): m/z (%): 451 (37) [M +], 378 (7),
282 (33), 281 (77), 170 (18), 114 (100), 70 (72), 57 (52), 41(14); HRMS:
m/z: calcd for C27H33NO5 +Na: 474.225093; found: 474.224895; elemental
analysis calcd (%) for C27H33NO5: C 71.82, H 7.37, N 3.10; found: C
71.68, H 7.32, N 3.15.
A
solution of the crude homoprolinal described above (588 mg,
2.76 mmol) and the Bestmann–Ohira reagent 24 (551 mg, 2.86 mmol)[25]
in MeOH (15 mL) at 08C was treated with K2CO3 (895 mg, 6.48 mmol)
and the resulting mixture was allowed to slowly reach ambient tempera-
ture. After stirring for 20 h, the reaction was quenched with aq. NH4Cl
(75 mL) and water (10 mL) and extracted with tert-butyl methyl ether
(5”15 mL). The combined extracts were washed with brine (25 mL),
dried (Na2SO4), and evaporated. Flash chromatography of the residue
(10% tert-butyl methyl ether in hexanes) gave alkyne 32 as a colorless oil
which slowly solidified upon standing (317 mg, 55%). Chiral GC analysis
(BGB-176SE/SE-52 column (30 m”0.25 mm, 0.25 mm stationary phase
thickness), injection at 2208C, 1408C isothermal, FID detection at 3208C,
0.7 bar H2, tR =33.1 min (R), tR =34.4 min (S)) showed that the product
had an enantiomeric excess of > 99.5%. M.p. 52–548C; [a]2D0 =+73.5 (c
1.03, CH2Cl2); 1H NMR (400 MHz, CDCl3, rotamers): d=3.89 (m, 1H),
3.37 (m, 2H), 2.59 (m, 1H), 2.38 (m, 1H), 2.10–1.92 (m, 4H), 1.90–1.70
(m, 1H), 1.47 (s, 9H); 13C NMR (100 MHz, CDCl3): d=154.4, 81.7, 79.4,
69.6, 56.1, 46.9, 30.7, 29.8, 28.6, 23.2; IR (film): n˜ =3243, 2969, 1678, 1396.
1171 cmꢀ1; MS (EI): m/z (%): 209 (0.4) [M +], 170 (19), 114 (67), 70
(100), 57 (88), 41 (23), 29 (11); HRMS: m/z: calcd for C12H19NO2 +Na:
232.130794; found: 232.130771; elemental analysis calcd (%) for
C12H19NO2: C 68.87, H 9.15, N 6.69; found: C 68.81, H 9.22, N 6.58.
(ꢀ)-Antofine (2): A solution of phenanthrene 34 (122 mg, 0.271 mmol) in
EtOH (12 mL) was treated with aqueous HCHO (37% w/w, 2.2 mL,
27 mmol) and HCl (12m, 0.4 mL, 5 mmol) and the resulting mixture was
stirred at 808C in the dark for 43 h. The solvents were evaporated and
the residue was taken up in NaOH (6m, 5 mL) and extracted with
CH2Cl2 (4”5 mL). The combined extracts were washed with water (4”
5 mL) and brine (10 mL), dried (Na2SO4), and concentrated to give the
title compound as a powder (90 mg, 0.25 mmol, 91%). Chiral HPLC
analysis (Chiralpak AD-H (250 mm”4.6 mm), n-heptane/isopropanol
4:1, 0.5 mLminꢀ1, 33.39 min (S isomer), 49.72 min (R isomer)) showed
that the product had an enantiomeric excess of > 98%. [a]2D0 =ꢀ113.4 (c
1.23, CHCl3); 1H NMR (400 MHz, CDCl3): d=7.93 (s, 1H), 7.92 (d, J=
2.6 Hz, 1H), 7.83 (d, J=9.0 Hz, 1H), 7.32 (s, 1H), 7.22 (dd, J=9.0,
2.6 Hz, 1H), 4.71 (d, J=14.8 Hz, 1H), 4.12 (s, 3H), 4.08 (s, 3H), 4.03 (s,
3H), 3.72 (d, J=15.0 Hz, 1H), 3.47 (m, 1H), 3.37 (dd, J=15.8, 2.4 Hz,
1H), 2.92 (m, 1H), 2.47 (m, 2H), 2.26 (m, 1H), 2.05 (m, 1H), 1.92 (m,
1H), 1.78 (m, 1H); 13C NMR (100 MHz, CDCl3): d=157.6, 149.5, 148.5,
130.3, 127.0, 126.3, 125.5, 124.3, 124.1, 123.6, 115.0, 104.7, 104.0, 103.9,
60.3, 56.1, 55.9, 55.6, 55.1, 53.7, 33.5, 31.3, 21.6; IR (film): n˜ =2913, 1614,
1510, 1205, 1032, 840, 830, 808, 780 cmꢀ1; MS (EI): m/z (%): 363 (28)
[M +], 294 (100), 279 (7), 251 (5); HRMS: m/z: calcd for C23H26NO3:
364.190721; found: 364.190408.
(R)-N-(tert-Butoxycarbonyl)-2-[3-(3’,4’,5-trimethoxybiphenyl-2-yl)-prop-
2-ynyl]-pyrrolidine (33): Prepared according to the representative proce-
dure for the 9-MeO-9-BBN mediated coupling process described above,
using alkyne (R)-32 (279 mg, 1.33 mmol) in THF (3 mL), n-BuLi (1.45m
in hexanes, 0.92 mL, 1.33 mmol), 9-MeO-9-BBN (220 mg, 1.45 mmol),
iodide 20 (400 mg, 1.08 mmol), and [(dppf)PdCl2](47 mg, 0.058 mmol).
Flash chromatography of the crude product (Combiflash Companion,
0!25% tert-butyl methyl ether in hexanes) afforded product 33 as a col-
orless syrup (284 mg, 0.629 mmol, 58%). Chiral HPLC analysis (Chiralcel
Tylophorine series
1,2-Dimethoxy-4-iodobenzene (36):[36] A purple solution of veratrole 35
(2.10 g, 15.23 mmol) and iodine (4.23 g, 16.7 mmol) in CH2Cl2 (60 mL)
was treated with red HgO (3.58 g, 16.5 mmol). After stirring for 5 h, the
mixture was filtered through Celite and the filtrate was washed with aq.
Na2S2O3 (5% w/w, 4”15 mL) and brine (50 mL) before being dried
(Na2SO4) and concentrated to a reddish oil which could be used without
further purification (3.90 g, 97%). 1H NMR (400 MHz, CDCl3): d=7.22
(dd, J=8.5, 2.1 Hz, 1H), 7.12 (d, J=2.1 Hz, 1H), 6.62 (d, J=8.4 Hz, 1H),
3.86 (s, 3H), 3.85 (s, 3H); 13C NMR (100 MHz, CDCl3): d=149.8, 149.2,
129.8, 120.4, 113.2, 82.3, 56.1, 55.9; IR (film): n˜ =3076, 2999, 1583, 1501,
1250, 839, 798, 762 cmꢀ1; MS (EI): m/z (%): 264 (100) [M +], 249 (28),
221 (8), 94 (26); HRMS (EI): m/z: calcd for C8H9IO2: 263.964730; found:
263.964440.
OJ (250 mm”4.6 mm), n-heptane/isopropanol 9:1, 0.5 mLminꢀ1
,
18.38 min (R isomer), 48.27 min (S isomer)) showed that the product had
1
an enantiomeric excess of > 98%. [a]2D0 +45.6 (c 1.19, CH2Cl2); H NMR
(400 MHz, CDCl3, rotamers): d=7.42 (d, J=8.5 Hz, 1H), 7.14 (m, 1H),
7.11 (dd, J=8.2, 1.7 Hz, 1H), 6.92 (d, J=8.2 Hz, 1H), 6.88 (d, J=2.6 Hz,
1H), 6.70 (dd, J=8.5, 2.5 Hz, 1H), 3.92 (s, 3H), 3.91 (s, 3H), 3.82 (s,
3H), 3.78 (m, 1H), 3.4–3.3 (m, 2H), 2.8–2.6 (m, 1H), 2.44 (m, 1H), 1.9–
1.6 (m, 4H), 1.45 (s, 9H); 13C NMR (100 MHz, CDCl3, rotamers): d=
7406
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 7398 – 7410

Alkaloids Natural Products
FULL PAPER
2-Bromo-3’,4,4’,5-tetramethoxybiphenyl (39): A solution of iodoveratrole
36 (3.90 g, 14.8 mmol) in HOAc (4 mL) was treated dropwise with a solu-
tion of bromine (1.0 mL, 19 mmol) in HOAc (5 mL). After stirring for
3 h, the dark mixture was diluted with water (50 mL) and extracted with
tert-butyl methyl ether (4”15 mL). The combined organic layers were
washed with aq. sat. NaHCO3 (25 mL), aq. Na2S2O3 (10%, 6”10 mL)
and brine (25 mL), before being dried (Na2SO4) and evaporated. Recrys-
tallization of the crude product from ethanol afforded reddish-white crys-
tals of 1-iodo-2-bromo-4,5-dimethoxybenzene (37) (3.37 g, 67%) which
were contaminated with ~15% of a dibromide. This product was used in
the next step without further purification. Characteristic data: 1H NMR
(400 MHz, CDCl3): d=7.22 (s, 1H), 7.07 (s, 1H), 3.85 (s, 3H), 3.84 (s,
3H).
30.6, 29.7, 28.6, 25.0, 24.3, 23.5, 22.9; IR (film): n˜ =2931, 1687, 1602, 1503,
1391, 1364, 1250, 1027, 858 cmꢀ1; MS (EI): m/z (%): 481 (24) [M +], 408
(5), 312 (12), 311 (6), 280 (15), 170 (16), 114 (100), 70 (92), 57 (48), 41
(7); HRMS: m/z: calcd for C28H35NO6 +Na 504.235655; found:
504.235686.
(R)-N-(tert-Butoxycarbonyl)-2-[(2,3,6,7-tetramethoxy-phenanthren-10-
yl)methyl]-pyrrolidine (42): A solution of alkyne 41 (35 mg, 0.073 mmol)
in toluene (1.5 mL) was treated with PtCl2 (4 mg, 0.02 mmol) and the re-
sulting mixture was stirred at 608C for 2 h and then at 808C for 1 h. The
mixture was then absorbed onto silica gel and eluted through a pad of
silica gel (10% EtOAc in toluene) to give phenanthrene 42 as an oil
1
(20 mg, 56%). [a]2D0 =ꢀ11.3 (c 0.99, CH2Cl2); H NMR (400 MHz, CDCl3,
rotamers): d=8.31 (brs, 1H), 7.82 (brs, 1H), 7.78 (s, 1H), 7.37 (s, 1H),
7.17 (s, 1H), 4.21–3.90 (m, 2H), 4.21 (brs, 3H), 4.13 (s, 3H), 4.11 (s, 3H),
4.03 (s, 3H), 3.49 (m, 1H), 3.33 + 2.99 (m, 1H), 2.60 (m, 1H), 2.02 (m,
1H), 1.84 (m, 2H), 1.62 (m, 1H), 1.52 (brs, 9H); 13C NMR (100 MHz,
CDCl3): d=154.7, 149.1, 149.0, 148.9, 148.7, 131.8, 126.24, 126.16, 125.3,
124.7, 123.9, 107.9, 106.8, 102.9, 79.0, 57.4, 56.7, 56.2, 56.0, 55.9, 46.9, 38.6,
29.1, 28.6, 23.5; IR (film): n˜ =2932, 1685, 1619, 1396, 1253, 1150 cmꢀ1; MS
(EI): m/z (%): 481 (40) [M +], 408 (6), 312 (32), 311 (72), 170 (16), 114
(100), 70 (71), 57 (40), 41 (6); HRMS: m/z: calcd for C28H35NO6 +Na:
504.235659; found: 504.235438.
A
mixture of crude iodide 37 (689 g, 2.01 mmol), boronic acid 38
(396 mg, 2.18 mmol), LiCl (256 mg, 6.04 mmol), degassed aq. Na2CO3
(2m, 5.0 mL, 10 mmol), and [(dppf)PdCl2](89 mg, 0.11 mmol) in DME
(15 mL) was stirred at 808C for 16 h. The mixture was cooled to ambient
temperature, diluted with aq. NH4Cl (50 mL) and extracted with tert-
butyl methyl ether (4”25 mL). The combined organic layers were
washed with brine (50 mL) and dried over Na2SO4. Evaporation of the
solvents afforded the crude product as a dark oil which was purified by
flash chromatography (Combiflash Companion, 0!25% tert-butyl
methyl ether in hexanes) to give biaryl 39 as a colorless oil which slowly
solidified upon standing (423 mg, 59%). The analytical data for this com-
(ꢀ)-Tylophorine (3): Prepared according to the representative procedure
for the deprotection/Pictet–Spengler tandem, using phenanthrene 42
(17 mg, 0.035 mmol), aq. HCHO (37% w/w, 0.30 mL, 3.7 mmol) and HCl
(12m, 50 mL, 0.60 mmol) in EtOH (1.5 mL). Reaction time: 23 h; the
crude product was purified by flash chromatography (10% EtOH in
CH2Cl2) to give tylophorine as a pale brown powder (6.5 mg, 48%).
[a]2D0 =ꢀ77.6 (c 0.65, CHCl3); 1H NMR (300 MHz, CDCl3): d=7.84 (s,
1H), 7.83 (s, 1H), 7.32 (s, 1H), 7.17 (s, 1H), 4.64 (d, J=14.7 Hz, 1H),
4.11 (m, 6H), 4.06 (s, 3H), 4.05 (s, 3H), 3.68 (d, J=15.9 Hz, 1H), 3.48
(m, 1H), 3.38 (dd, J=16.6, 2.9 Hz, 1H), 2.92 (m, 1H), 2.50 (m, 2H), 2.24
(m, 1H), 1.99 (m, 2H), 1.77 (m, 1H); 13C NMR (75 MHz, CDCl3): d=
148.8, 148.6, 148.5, 126.4, 126.1, 125.9, 124.4, 123.7, 123.5, 104.1, 103.6,
103.5, 103.3, 60.3, 56.1, 56.0, 55.9, 55.2, 54.1, 33.8, 31.3, 21.7; IR (film):
n˜ =2830, 1618, 1512, 1244, 1207, 1148, 1017, 841 cmꢀ1; MS (EI): m/z (%):
393 (27) [M +], 324 (100), 309 (7), 162 (8); HRMS (ES, m/z) calcd for
C24H28NO4: 394.201282; found: 394.201207.
1
pound matched the published data.[42] M.p. 84–858C; H NMR (400 MHz,
CDCl3): d=7.12 (s, 1H), 6.95–6.93 (m, 3H), 6.84 (s, 1H), 3.93 (s, 3H),
3.91 (m, 6H), 3.88 (s, 3H); 13C NMR (100 MHz, CDCl3): d=148.6, 148.4,
148.2, 134.6, 133.8, 121.8, 115.8, 114.0, 113.1, 112.7, 110.7, 56.2, 56.1, 56.0,
55.9; IR (KBr): 3057, 2936, 1600, 1499, 1248, 1027 cmꢀ1; MS (EI): m/z
(%): 354 (99) [M
U
G
375.020257; found: 375.020196.
2-Iodo-3’,4,4’,5-tetramethoxybiphenyl (40):
A solution of bromide 39
(199 mg, 0.564 mmol) in THF (5 mL) at ꢀ788C was treated with n-BuLi
(1.6m in hexanes, 0.45 mL, 0.72 mmol) and stirred for 45 min. The result-
ing dark yellow solution was treated with a solution of I2 (212 mg,
0.835 mmol) in THF (2.5 mL), stirred at ꢀ788C for a further 5 min, and
then stirred at ambient temperature for 45 min. The resulting dark solu-
tion was quenched with aq. sat. NH4Cl (5 mL) and extracted with tert-
butyl methyl ether (4”5 mL). The combined organic layers were washed
with brine (10 mL), dried (Na2SO4), and concentrated to a yellow oil
(192 mg) which was purified by flash chromatography (Combiflash Com-
panion, 0!30% tert-butyl methyl ether/hexane) to give product 40 as an
oil which solidified over time (123 mg, 54%). 1H NMR (400 MHz,
CDCl3): d=7.33 (s, 1H), 6.93–6.86 (m, 3H), 6.84 (s, 1H), 3.93 (s, 3H),
3.92 (s, 3H), 3.90 (s, 3H), 3.86 (s, 3H); 13C NMR (100 MHz, CDCl3): d=
149.1, 148.6, 148.4, 148.2, 139.1, 137.0, 121.7, 121.6, 113.1, 113.0, 110.6,
86.8, 56.3, 56.00, 55.99, 55.9; IR (film): n˜ =2933, 1593, 1495, 1244,
1025 cmꢀ1; MS (EI): m/z (%): 400 (100) [M +], 385 (9), 357 (5), 273 (1),
215 (8); HRMS: m/z: calcd for C16H17IO4 +Na: 423.006375; found:
423.006276.
Ficuseptine C series
2-Bromo-3’,4’-methylenedioxy-5-methoxybiphenyl (44):
A mixture of
iodide 17 (630 mg, 2.01 mmol), boronic acid 43 (352 mg, 2.12 mmol), LiCl
(322 mg, 7.60 mmol), degassed aq. Na2CO3 (2m, 4 mL, 8 mmol), and
[(dppf)PdCl2](84 mg, 0.103 mmol) in DME (15 mL) was stirred at 80 8C
for 20 h. The mixture was cooled to ambient temperature, diluted with
aq. NH4Cl (50 mL) and extracted with tert-butyl methyl ether (4”
25 mL). The combined organic layers were washed with brine (50 mL)
and dried over Na2SO4. Evaporation of the solvents afforded the crude
product as a dark oil which was purified by flash chromatography (Com-
biflash Companion, 0!5% tert-butyl methyl ether in hexanes) to give
biaryl 44 as a light yellow oil (278 mg, 45%) which was further purified
by Kugelrohr distillation (2508C, 0.1 Torr) to give the product as a color-
less oil (251 mg, 41%). 1H NMR (400 MHz, CDCl3): d=7.48 (d, J=
8.8 Hz, 1H), 6.89 (m, 1H), 6.83 (m, 3H), 6.72 (dd, J=8.8, 3.1 Hz, 1H),
5.97 (s, 2H), 3.76 (s, 3H); 13C NMR (100 MHz, CDCl3): d=158.7, 147.13,
147.11, 142.9, 134.9, 133.6, 122.8, 116.8, 114.5, 113.2, 110.0, 107.9, 101.2,
55.4; IR (film): n˜ =3002, 2892, 1590, 1566, 1463, 1226, 1026, 804 cmꢀ1; MS
(R)-N-(tert-Butoxycarbonyl)-2-[3-(3’,4,4’,5-tetramethoxy-biphenyl-2-yl)-
prop-2-ynyl]-pyrrolidine (41): Prepared according to the representative
procedure for the 9-MeO-9-BBN mediated coupling outlined above,
using alkyne (R)-32 (93 mg, 0.45 mmol) in THF (1 mL), n-BuLi (1.6m in
hexanes, 0.26 mL, 0.42 mmol), 9-MeO-9-BBN (82 mg, 0.54 mmol), iodide
(EI): m/z (%): 308 (99) [M
N
N
40 (123 mg, 0.307 mmol, added as
a solution in 2 mL THF), and
(7), 126 (25); HRMS (EI): m/z: calcd for C14H1179BrO3: 305.989169;
found: 305.989001; elemental analysis calcd (%) for C14H1179BrO3: C
54.75, H 3.61; found: C 54.76, H 3.57.
[(dppf)PdCl2](14 mg, 0.018 mmol). Work up after 20 h gave the crude
product as a dark oil which was purified by flash chromatography (Com-
biflash Companion, 0!50% tert-butyl methyl ether in hexane) to give
product 41 as a syrup (35 mg, 64% based on recovered iodide 40 (51 mg,
42%)). [a]2D0 =+47.5 (c 1.32, CH2Cl2); 1H NMR (300 MHz, CDCl3): d=
7.13 (m, 1H), 7.07 (dd, J=8.2, 2.1 Hz, 1H), 6.98 (s, 1H), 6.91 (d, J=
7.8 Hz, 1H), 6.82 (s, 1H), 3.92 (s, 3H), 3.91 (s, 3H), 3.90 (s, 3H), 3.89 (s,
3H), 3.80 (m, 1H), 3.40–3.22 (m, 2H), 2.91–2.62 (m, 1H), 2.44 (m, 1H),
1.90–1.60 (m, 4H), 1.44 (s, 9H); 13C NMR (100 MHz, CDCl3): d=154.5,
149.0, 148.3, 147.7, 137.2, 137.0, 133.7, 129.1, 121.5, 115.4, 113.8, 112.9,
112.4, 110.8, 88.7, 88.2, 81.7, 81.2, 79.5, 79.1, 56.3, 56.1, 56.0, 47.0, 46.7,
2-Iodo-3’,4’-methylenedioxy-5-methoxybiphenyl (45): A solution of bro-
mide 44 (251 mg, 0.743 mmol) in THF (8 mL) at ꢀ788C was treated with
n-BuLi (1.6m in hexanes, 0.56 mL, 0.90 mmol) and stirred for 15 min.
Solid I2 (270 mg, 1.06 mmol) was added to the bright yellow solution, and
the resulting dark mixture was stirred at ꢀ788C for 15 min and then at
ambient temperature for 1 h. The reaction was quenched with aq.
Na2S2O3 (1m, 5 mL) and extracted with tert-butyl methyl ether (4”
5 mL). The combined organic phases were washed with water (5 mL) and
Chem. Eur. J. 2006, 12, 7398 – 7410
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7407

A. Fürstner and J. W. J. Kennedy
brine (5 mL) before they were dried (Na2SO4) and evaporated. Flash
Table 1. Tabular survey of the NMR spectroscopic data of ficuseptine C
(4). Unless stated otherwise, all assignments are unambiguous (cf. general
methods); numbering scheme as shown in the insert; the reported cou-
pling constants are not averaged.
chromatography (toluene/hexane 1:1) gave product 45 as a colorless oil
1
(220 mg, 77%). H NMR (400 MHz, CDCl3): d=7.78 (d, J=8.7 Hz, 1H),
6.87–6.85 (m, 2H), 6.82 (d, J=1.6 Hz, 1H), 6.78 (dd, J=7.9 Hz, 1.7 Hz,
1H), 6.63 (dd, J=8.7 Hz, 3.0 Hz, 1H), 6.02 (s, 2H), 3.79 (s, 3H);
13C NMR (100 MHz, CDCl3): d=159.7, 147.1, 147.07, 147.0, 139.9, 138.0,
122.8, 116.0, 115.1, 109.9, 107.9, 101.2, 87.5, 55.4; IR (film): n˜ =3002,
2889, 1584, 1225, 1036, 805 cmꢀ1; MS (EI): m/z (%): 354 (100) [M +], 212
(6), 197 (10), 169 (12), 139 (11), 126 (16); elemental analysis calcd (%)
for C14H11IO3: C 47.48, H 3.13; found: C 47.43, H 3.08.
(R)-N-(tert-Butoxycarbonyl)-2-[3-(3’,4’-methylenedioxy-5-methoxybi-
phenyl-2-yl)-prop-2-ynyl]-pyrrolidine (46): Prepared according to the re-
presentative procedure for the 9-MeO-9-BBN mediated cross-coupling,
using alkyne (R)-32 (156 mg, 0.745 mmol) and n-BuLi (1.6m in hexanes,
0.46 mL, 0.74 mmol) in THF (1.5 mL), 9-MeO-9-BBN (137 mg,
0.90 mmol), [(dppf)PdCl2](24 mg, 0.030 mmol), and iodide 45 (204 mg,
0.575 mmol, added as a solution in 4 mL THF). Work-up after 20 h as de-
scribed afforded a yellow oil which was purified by flash chromatography
(Combiflash Companion, 0!25% tert-butyl methyl ether in hexanes) to
give product 46 as a syrup (148 mg, 59%). [a]2D0 =+39.6 (c 1.15, CH2Cl2);
1H NMR (400 MHz, CDCl3, rotamers): d=7.41 (d, J=8.5 Hz, 1H), 7.08
(m, 1H), 7.02 (m, 1H), 6.85 (d, J=7.8 Hz, 1H), 6.83 (d, J=2.5 Hz, 1H),
6.79 (dd, J=8.4, 2.5 Hz, 1H), 6.00 (s, 2H), 3.90–3.81 (m, 1H), 3.83 (s,
3H), 3.4–3.2 (m, 2H), 2.9–2.6 (m, 1H), 2.46 (m, 1H), 1.84 (m, 3H), 1.67
(m, 1H), 1.46 (s, 9H); 13C NMR (75 MHz, CDCl3, rotamers): d=159.1,
154.4, 147.2, 147.0, 144.8, 134.8, 134.5, 122.7, 114.8, 114.4, 112.7, 109.9,
107.9, 101.0, 88.8, 88.5, 81.2, 81.0, 79.4, 79.2, 70.9, 56.3, 55.4, 47.0, 46.7,
32.1, 30.6, 29.8, 28.6, 26.3, 25.1, 24.4, 23.6, 22.9, 22.1; IR (film): n˜ =2926,
1688, 1600, 1391, 1364, 1237, 1038, 809 cmꢀ1; MS (EI): m/z (%): 435 (9)
[M +], 266 (11), 170 (27), 114 (100), 70 (77), 57 (51), 41 (8); HRMS: m/z:
calcd for C26H29NO5 +Na: 458.193790; found: 458.193851.
Position
13C NMR
1H NMR (400 MHz, CDCl3): d
(J in Hz)
G
ACHTREUNG
[D6]acetone CDCl3
1
2
3
4
4a
4b
5
6
7
102.0
149.0
148.1
102.1
126.0
131.5
104.8
158.8
117.1
125.0
124.8
128.0
54.5
101.5
147.8[a]
147.0[a]
101.1
125.0
130.4
104.0
157.5
115.8
124.2
124.1
126.7
53.8
7.34 (s)
7.92 (s)
7.80 (d, J=2.4 Hz)
7.16 (dd, J=2.4, 9.0 Hz)
7.76 (d, J=9.0 Hz)
8
8a
8b
9
4.64 (dd, J=< 1, 15.0 Hz)
3.64 (ddd, J=1.8, 2.4, 15.0 Hz)
3.43 (dt, J=2.0, 8.7 Hz)
11
12
55.6
22.2
55.1
21.6
(R)-N-(tert-Butoxycarbonyl)-2-[(2,3-methylenedioxy-6-methoxy-phe-
2.41 (q, J=9.0 Hz)
nanthren-10-yl)methyl]-pyrrolidine (47):
A solution of compound 46
2.00 (tdt, J=4.2, 8.7, 12.0 Hz)
1.88 (ddddd, J=2.3, 6.5, 9.0, 10.0,
12.0 Hz)
2.20 (dddd, J=4.2, 6.8, 10.0, 12.2 Hz)
1.72 (ddt, J=6.4, 9.6, 11.7 Hz)
2.43 (dddd, J=4.0, 7.0, 9.6, 10.4 Hz)
3.25 (ddd, J=1.6, 3.9, 16.0 Hz)
2.84 (dddd, J=1.6, 2.2, 10.4, 16.0 Hz)
(148 mg, 0.340 mmol) in toluene (7 mL) was treated with PtCl2 (19 mg,
0.71 mmol) and the resulting mixture was stirred at 608C for 2 h and
then at 808C for additional 20 h. The mixture was then passed through a
plug of silica (EtOAc), the filtrate was evaporated and the residue was
purified by flash chromatography (5!10% EtOAc in toluene) to give
phenanthrene 47 as a pale yellow powder (83 mg, 56%). M.p. 78–808C;
13
32.0
31.3
13a
14
61.1
34.7
60.2
34.0
1
[a]2D0 =ꢀ28.0 (c 1.06, CH2Cl2); H NMR (400 MHz, CDCl3, rotamers): d=
8.08 and 7.74 (brs, 1H), 7.97 (s, 1H), 7.78 (d, J=2.2 Hz, 1H), 7.71 (d, J=
8.9 Hz, 1H), 7.39 (s, 1H), 7.17 (dd, J=8.6, 2.2 Hz, 1H), 6.11 (s, 2H), 4.25
(m, 1H), 4.00 (s, 3H), 3.92–3.62 (m, 1H), 3.60–3.20 (m, 2H), 2.69 (dd,
J=13.5, 10.6 Hz, 1H), 2.11–1.91 (m, 1H), 1.90–1.70 (m, 2H), 1.70–1.40
(m, 1H), 1.57 (s, 9H); 13C NMR (100 MHz, CDCl3): d=158.0, 154.7,
148.0, 147.4, 131.2, 130.7, 130.6, 129.5, 128.2, 126.6, 126.2, 126.1, 126.0,
116.4, 103.6, 103.2, 102.8, 101.4, 101.2, 100.9, 80.1, 79.0, 57.2, 56.5, 55.4,
46.9, 46.6, 38.8, 38.0, 29.6, 28.8, 28.7, 23.5, 22.5; IR (CH2Cl2): n˜ =2971,
1682, 1614, 1473, 1392, 1231, 1038, 834 cmꢀ1; MS (EI): m/z (%): 435 (28)
[M +], 362 (7), 266 (28), 265 (72), 170 (21), 114 (100), 70 (78), 57 (49), 41
(8); HRMS: m/z: calcd for C26H29NO5 +Na 458.193794; found:
458.193680; elemental analysis calcd (%) for C26H29NO5: C 71.70, H 6.71,
N 3.22; found: C 71.63, H 6.66, N 3.24.
14a
14b
126.9
129.3
125.9
128.5
101.3
55.4
-OCH2O- 102.0
MeO- 55.8
6.07 (s, 2H)
3.97 (s, 3H)
[a]These assignments can be interchangeable.
tions, 2117 reflections with I>2s(I), structure solved by direct methods
and refined by full-matrix least-squares against F2 to R1 =0.062 [I>
2s(I)], wR2 =0.176, 313 parameters, H atoms riding, S=0.908, residual
electron density +0.2/ꢀ0.3 eŠ
CCDC-603030 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
ꢀ3
.
(ꢀ)-Ficuseptine C (4): Prepared according to the general procedure for
the deprotection/Pictet-Spengler tandem described above, using phenan-
threne 47 (79 mg, 0.181 mmol), aq. HCHO (37% w/w, 1.5 mL, 18 mmol)
and HCl (12m, 0.25 mL, 3.0 mmol) in EtOH (8.5 mL). Workup after 3 d
afforded the crude product as a brown powder which was purified by
flash chromatography (5% EtOH in CH2Cl2) to give ficuseptine C as a
beige powder (39 mg, 62%). M.p. 193–1958C (decomp); [a]2D5 =ꢀ26 (c
0.06, MeOH), ꢀ129.7 (c 1.05, CHCl3). For a compilation of the spectro-
scopic data, see Table 1.
Acknowledgements
X-ray crystal structure analysis of phenanthrene 28: C28H35NO5, Mr =
465.57, colorless plate, crystal size 0.08”0.02”0.02 mm, monoclinic,
space group P21/c, a=18.5321(10), b=6.2770(3), c=21.1387(13) Š, b=
Generous financial support by the MPG, the Chemical Genomics Center
(CGC), the Fonds der Chemischen Industrie, and the Canadian NSERC
(fellowship for J.K.) are gratefully acknowledged. We also thank Prof. T.-
S. Wu, National Research Institute of Chinese Medicine, Taiwan, for pro-
viding spectra of ficuseptine C, Mrs. P. Philipps for the expert spectro-
scopic analysis of this particular compound, Mrs. S. Holle for exploratory
94.466(3)8, V=2451.5(2) Š3, T=100 K, Z=4, 1calcd =1.261 gcmꢀ3
,
l=
Nonius KappaCCD diffractometer,
4.08<q<24.03, 19361 measured reflections, 3835 independent reflec-
0.71073 Š,
m ,
(MoKa)=0.086 mmꢀ1
A
7408
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 7398 – 7410

Alkaloids Natural Products
FULL PAPER
experiments and technical assistance, Mrs. A. Dreier and Dr. C. W. Leh-
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2703–2706; b) (+)-2: L. Faber, W. Wiegrebe, Helv. Chim. Acta 1973,
56, 2882–2884; c) L. Faber, W. Wiegrebe, Helv. Chim. Acta 1976, 59,
2201–2212; d) for a compilation of previous syntheses of antofine,
see ref. [3].
[30]a) J. R. Harrison, P. OꢂBrien, D. W. Porter, N. M. Smith, J. Chem.
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[31]For precedent see: I. T. Forbes, A. D. Gribble, WO02062788, 2002.
[32]A. F. Spatola, M. K. Anwer, A. L. Rockwell, L. M. Gierasch, J. Am.
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[42]J. L. Schulte, S. Laschat, Synthesis 1999, 475–478.
[33]S. V. Ley, J. Norman, W. P. Griffith, S. P. Marsden, Synthesis 1994,
639–666.
[34]It should also be mentioned that attempts to shorten this sequence
by converting the aldehyde derived from 29 directly into homoproli-
Received: April 28, 2006
Published online: July 31, 2006
7410
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