A boron-based synthesis of the natural product (+)-trans- dihydrolycoricidine

Article abstract of DOI:10.1002/anie.201007135

Diastereoselective diboration results in the highly selective 1,4-dihydroxylation of chiral cyclohexadienes (see scheme). Together with the catalytic enantioselective conjugate allylboration, the diene diboration facilitates the asymmetric synthesis of the cytotoxic agent (+)-trans- dihydrolycoricidine (1). pin=pinacol. Copyright

Full text of DOI:10.1002/anie.201007135

DOI: 10.1002/anie.201007135
Natural Products
A Boron-Based Synthesis of the Natural Product (+)-trans-
Dihydrolycoricidine**
Sarah L. Poe and James P. Morken*
The members of the Amaryllidaceae family of natural
products (Figure 1) have long been recognized for their
medicinal properties.[1] In particular, many members of this
small subgroup of isocarbostyrils exhibit unusually high levels
of in vitro and in vivo antitumor and antiviral activity.[2]
ples of diastereoselective diboration as a method to control
the oxygenation pattern in the target molecule.
We envisioned an approach to the isocarbostyrils that
centers on the diastereoselective 1,4-dioxygenation of cyclo-
hexadiene 6 (Scheme 1), a compound that is readily available
in enantiomerically pure form by a sequence employing an
Scheme 1. Singlet-oxygen cycloaddition of chiral cyclohexadiene 6.
Figure 1. Representative Amaryllidaceae isocarbostyrils.
asymmetric conjugate allylation that was developed in our
laboratory.[10] A preliminary attempt at the stereoselective
dioxygenation of 6 employed a singlet oxygen cycloaddition
as a method to establish the required functional group
pattern.[11] While this transformation occurred in acceptable
yield, the complete lack of stereocontrol in this reaction (1:1
diastereomer ratio) suggested that other methods for this
dioxygenation would be required.[12]
Despite their potential for clinical use many of these
compounds are found in low natural abundance; whereas
narciclasine (1) is available in practical quantities,[1a,3] the
limited availability of lycoricidine (2), pancratistatin (3), and
other derivatives poses one limitation to their development as
viable therapeutic agents. Unsurprisingly, the limited avail-
ability of these isocarbostyrils, as well as their interesting
frameworks, have made these attractive and relevant targets
for organic synthesis, and many successful strategies for the
construction of 1, 2, and 3 have been described.[4] In contrast,
the syntheses of the natural products trans-dihydronarcicla-
sine (4)[5] and trans-dihydrolycoricidine (5)[6] have not been
explored as extensively even though they demonstrate potent
cytotoxicities.[7] To date, three syntheses of (+)-5 have been
reported in the literature[8] and a third report describes the
synthesis of the nonnatural enantiomer (À)-5.[9] Given their
promising biological activity and their interesting structures,
we have been attracted to the isocarbostyrils as synthetic
targets and herein describe the preparation of 5 by a route
that employs enantioselective conjugate allylation to control
the absolute configuration. We also describe the first exam-
Recent studies in our laboratory have focused on the
development of a platinum-catalyzed enantioselective 1,4-
diboration of 1,3-dienes as a method for 1,4-dioxygenation of
these substrates.[13] In a related vein, we considered that a
diastereoselective version of this reaction might be useful for
the elaboration of complex diene substrates and enable the
synthesis of the highly hydroxylated core of the isocarbosty-
rils such as 1–5. Initially, the diboration of 5-phenyl-1,3-
cyclohexadiene using bis(pinacolato)diboron (B2(pin)2) and
catalytic amounts of [Pt(dba)3] and PCy3 was examined
(Table 1, entry 1). The reaction proceeded for 14 hours at
608C and was then subjected to an oxidative work-up with
NaOH and H2O2. This 1,4-dihydroxylation occurred with
excellent yield and greater than 20:1 diastereoselectivity
(Table 1, entry 1). Examination of other substrates revealed
that high levels of stereocontrol and good reaction yields are a
general feature of these reactions. Similar to examples with
aryl-substituted substrates, alkyl substituents also provide
high levels of stereocontrol. X-ray analysis of both aryl- and
alkyl-substituted reaction products indicated that the dibora-
tion occurs with anti stereoselection as might be anticipated
from the steric influence of the aryl and alkyl groups on the
substrate.[14] Lastly, the diboration of a-phellandrene (entry 5)
was examined. The [4+2] singlet-oxygen cycloaddition with
this substrate has been the subject of numerous studies and is
notoriously nonselective.[15] However, diene diboration
[*] Dr. S. L. Poe, Prof. Dr. J. P. Morken
Department of Chemistry, Boston College
Chestnut Hill, MA 02467 (USA)
Fax: (+1)617-552-2705
E-mail: morken@bc.edu
[**] We are grateful to the NIH (NIGMS GM-59417 and GM-64451) for
financial support of this work.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201007135.
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Table 1: Dioxygenation of 1,3-dienes through diboration/oxidation.[a]
Entry
1
Substrate
Product
Yield [%][b]
d.r.[c]
86
>20:1
2
3
71
93
>20:1
>20:1
4
69
87
>20:1
>20:1
5[d]
Scheme 2. Synthesis of 13. cod=1,5-cyclooctadiene, DCE=dichloro-
ethane, Mes=2,4,6-trimethylphenyl, Tf=trifluoromethanesulfonyl,
THF=tetrahydrofuran, TIPS=triisopropylsilyl.
[a] Reactions were conducted with exclusion of moisture and under a
nitrogen atmosphere. [b] The yield is of the isolated product and is an
average of at least two experiments. [c] Diastereoselectivity was
determined by 1H NMR analysis (400 MHz); for >20:1, the minor
diastereomer was not detected. [d] To achieve optimal yield with this
substrate, the [Pt(dba)3] and PCy3 were premixed at RT for 1 h. Cy=
cyclohexyl, dba=dibenzylideneacetone, pin=pinacol, TBS=tert-butyl-
dimethylsilyl.
diastereoselection to provide diol 11 in 83% yield. Notably, in
comparison to the simple phenyl-derived substrate (entry 1,
Table 1), this example shows that diene 6 is processed
efficiently and without interference from the Lewis basic
functionality in the substrate.
Substitution at position C4a of 11 with retention of
configuration was required to transform the existing hydroxy
group into an amine. We anticipated that the steric hindrance
provided by the aryl group should enable the selective
protection of the C2-hydroxy group, and leave the C4a-
hydroxy group free for subsequent activation in preparation
for allylic substitution. After surveying reaction conditions, it
was found that this protection was best accomplished by the
treatment of 11 with TIPSOTf (1.1 equiv) at room temper-
ature, to provide 12 in 68% yield (Scheme 2). The remaining
allylic alcohol at position C4a was then derivatized as the
ethyl carbonate, to give 13.
A palladium-catalyzed allylic substitution of 13 was used
for the amination of C4a. The choice of the nucleophile was
critical with basic nucleophiles resulting in elimination of the
intermediate p-allyl compound. The use of an azide anion,
however, was found to provide an optimal solution and
allowed conversion of the methyl carbonate into the allylic
azide 14. Azide 14 was converted into the corresponding
carbamate 15 in 73% yield by using a Staudinger reaction
with subsequent addition of ethyl chloroformate (Scheme 3).
occurs with excellent regio- and diastereoselectivity, cleanly
delivering the 1,4-dihydroxylation product in excellent yield.
The outcome with this substrate suggests that substituents on
the diene do not necessarily interfere with the reaction and
can provide products with enhanced substitution.
With an effective strategy for the diastereoselective
dihydroxylation of cyclohexadiene substrates in place, efforts
toward the construction of trans-dihydrolycoricidine were
initiated. As depicted in Scheme 2, enantioselective conjugate
allylation of dialkylidene ketone 7 (derived from the corre-
sponding cinnamic acid in two steps) furnished allylated
product 8 in 74% yield and 92% ee, as previously described
for the enantiomer of 8.[10a] Ring-closing metathesis employ-
ing the second-generation Hoveyda–Grubbs catalyst[16] pro-
vided enone 9 (81% yield), which was subjected to a Luche
reduction to afford allylic alcohol 10 in 98% yield. Treatment
of 10 with 2,4-dinitrobenzenesulfenyl chloride effected an
allylic transposition and a subsequent sulfoxide elimination to
provide enantioenriched diene 6.[17] As anticipated, the
diboration/oxidation of 6 occurred with excellent levels of
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with [Pt(dba)3] (11.2 mg, 0.013 mmol, 0.03 equiv), tricyclohexylphos-
phine (6.9 mg, 0.025 mmol, 0.06 equiv), and toluene (4.1 mL). After
stirring the reaction mixture in the dry box for 5 min, diene 6
(82.2 mg, 0.41 mmol, 1 equiv) and B2(pin)2 (109.5 mg, 0.43 mmol,
1.05 equiv) were added. The vial was sealed with a polypropylene cap,
removed from the dry box, and the reaction mixture was stirred at
608C for 14 h. The reaction mixture was cooled to 08C and then THF
(4.5 mL), 3m aqueous sodium hydroxide (3.0 mL), and 30% aqueous
hydrogen peroxide (1.5 mL) were added. The reaction mixture was
stirred under ambient atmosphere while slowly warming to RT over
4 h. The reaction mixture was cooled to 08C and saturated aqueous
sodium thiosulfate (10 mL) was added. The reaction mixture was
diluted with EtOAc and the layers were separated. The aqueous layer
was extracted with EtOAc (4 ꢀ 20 mL). The combined organic layers
were dried over sodium sulfate, filtered, and concentrated under
reduced pressure. The crude material was purified by silica gel
chromatography (50–70% EtOAc in hexanes) to afford (1S,4S,5R)-5-
(benzo[d][1,3]dioxol-5-yl)cyclohex-2-ene-1,4-diol as a white solid
(80.0 mg, 83%).
Received: November 12, 2010
Published online: March 31, 2011
Scheme 3. Completion of the synthesis of (+)-trans-dihydrolycoricidine.
DMAP=4-dimethylaminopyridine, NMO=N-methylmorpholine N-
oxide, TBAF=tetra-n-butylammonium fluoride.
Keywords: allylation · asymmetric synthesis · natural products ·
.
oxidation
In an effort to convert 15 into a derived cyclic lactam, the
substrate was subjected to the Banwell-modified Bischler–
Napieralski reaction conditions,[18] however, only decomposi-
tion products were observed. This problem was remedied by
using a strategy similar to that used by Kadas and co-
workers;[7b] first 15 was subjected to an OsO4-catalyzed
dihydroxylation to afford a single diastereomer of the diol,
which was acylated with Ac2O. This alternative substrate for
the ring closure (16) was treated with Tf2O and DMAP (5:3)
to afford the desired lactam 17 in 54% yield. Removal of the
acetate and TIPS protecting groups with methanolic NaOH
and TBAF, respectively, provided (+)-trans-dihydrolycorici-
dine (5). By NMR analysis, the synthetic material was found
to be identical to the natural product. Moreover, HPLC
analysis of the enantiomerically enriched material, in com-
parison to the racemic material, showed the synthetic
material to have retained the 92% ee from the initial
conjugate allylation step.
In conclusion, we have completed the synthesis of the
natural product (+)-trans-dihydrolycoricidine (5) by a route
that relies on enantioselective conjugate allylation and
diastereoselective diboration to establish the absolute and
relative stereochemistry. This represents the first reported
application of both of these methodologies in natural product
synthesis. Modification of the dialkylidine ketone substrate in
the conjugate allylation should allow for a similar synthesis of
trans-dihydronarciclasine (4). Furthermore, the diastereo-
selective diboration described in this paper promises con-
venient access to highly versatile 1,4-diols for a variety of
other applications and examination of this reaction in the
synthesis of other natural products will be the subject of
future studies.
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