Ethylene in organic synthesis. repetitive hydrovinylation of alkenes for highly enantioselective syntheses of pseudopterosins

Article abstract of DOI:10.1021/ja201321v

In this report we highlight the significant potential of ethylene as a reagent for the introduction of a vinyl group with excellent stereoselectivity at three different stages in the synthesis of a broad class of natural products, best exemplified by synt

Full text of DOI:10.1021/ja201321v

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Ethylene in Organic Synthesis. Repetitive Hydrovinylation of Alkenes
for Highly Enantioselective Syntheses of Pseudopterosins
Daniel J. Mans, G. Adam Cox, and T. V. RajanBabu*
Department of Chemistry, The Ohio State University, 100 West 18th Avenue, Columbus, Ohio 43210, United States
S Supporting Information
b
ABSTRACT: In this report we highlight the significant
potential of ethylene as a reagent for the introduction of a
vinyl group with excellent stereoselectivity at three different
stages in the synthesis of a broad class of natural products,
best exemplified by syntheses of pseudopterosins. The late-
stage applications of the asymmetric hydrovinylation reac-
tion further illustrate the compatibility of the catalyst with
complex functional groups. We also show that, depending
on the choice of the catalyst, it is possible to either enhance
or even completely reverse the inherent diastereoselectivity
in the reactions of advanced chiral intermediates. This
should enable the synthesis of diastereomeric analogs of
several classes of medicinally relevant compounds that are
not readily accessible by the existing methods, which depend
on ‘substrate control’ for the installation of many of the
chiral centers, especially in molecules of this class.
Figure 1. Structures of pseudopterosins and related compounds.
catalyst system be compatible with a substrate with several Lewis
basic centers? Perhaps more importantly, is it possible to enhance or
even override, by ligand tuning, any inherent diastereoselectivity
dictated by the resident chirality already present in an advanced
intermediate? It can be convincingly argued that, even in the most
developed catalyzed reactions, absolute control of diastereoselectivity
in reactions of chiral substrates can be a more formidable challenge
than achieving useful levels of asymmetric induction in a prochiral
substrate. In the event, we have completed a highly stereoselective
total synthesis of the aglycone of pseudopterosins GꢀJ. Since an
advanced enantiopure intermediate synthesized during this study
has already been converted into pseudopterosins AꢀF aglycone,3
this report also represents a formal stereoselective synthesis of this
molecule and its enantiomer, pseudopterosins KꢀL aglycone.
Among the sequence of reactions employed, the asymmetric
hydrovinylation was used three times with excellent yield and stereo-
selectivity (yields/selectivity as expressed in enantiomeric or diaste-
reomeric ratio: 99%/er = 98.2; 92%/dr = 92:8, and 99%/dr > 99:1).
We also show that the configuration of the asymmetric centers can be
independently controlled by the judicious choice of catalysts and/or reaction
conditions. This report discloses the details of this study.
thylene is one of the most abundantly available feedstocks,
providing up to 30% of all petroleum-based commodity
E
chemicals, yet its applications in complex organic synthesis are just
beginning to emerge.1 Among the handful of catalyzed asymmetric
CꢀC bond-forming reactions that use a feedstock carbon source is
the asymmetric hydrovinylation (HV), a reaction in which ethylene
is added, as a vinyl group and a hydrogen, to common organic
precursors such as an activated olefin, a 1,3-diene, or a strained
alkene, to produce an enantiomerically pure product (eq 1).2
While contemplating applications of this reaction in complex
molecule synthesis, we envisioned that three of the four chiral centers
(each marked with an asterisk in 1, Figure 1) of pseudopterosin
aglycones could be installed independently by repeated use of the
asymmetric hydrovinylation reaction. Any synthesis of the core
skeleton might also provide facile entry into other more complex
molecules shown in Figure 1. Late-stage applications of the asym-
metric hydrovinylation in such complex settings would rigorously
test the limits of this reaction in two important ways: will the Ni(II)-
West Indian and Caribbean sea whip Pseudopterogorgia elisa-
bethae has been a rich source of biologically active compounds of
varying structural complexity.4 These include (Figure 1) anti-
inflammatory pseudopterosins,5a and compounds with signifi-
cant antimycobacterial properties such as pseudopteroxazole,5b
Received: February 11, 2011
Published: March 30, 2011
r
2011 American Chemical Society
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Scheme 1
colombiasin A,5c elisapterosin B5d and a key biogenic precursor,
elisabethin A.5e Even in cases where the structures are not very
complex, the major challenge associated with the synthesis of these
compounds has been the control of the stereocenters at locations
with no neighboring controlling functionalities. An exocyclic methyl-
bearing carbon such as C3 or C7 in pseudopterosins is a very
common structural motif in many of these structures, and a chain
carrying this carbon is often attached at a stereogenic center in a ring.
Even though several creative solutions to tackle this so-called
‘exocyclic stereochemistry’ problem have been advanced, no broadly
applicable method that uses an easily accessible precursor has
emerged.6a,b In pseudopterosins there is the additional challenge of
stereoselectively introducing the 2-methylpropenyl group at the C1
carbon. An examination of the various published procedures3,7ꢀ10 for
the syntheses of pseudopterosins exposes the limitations of the
current methodology to address the synthetic problems associated
with the installation of these chiral centers. The best stereoselective
syntheses solve these problems by starting with naturally occurring
monoterpenes which already possess one or two of the chiral centers
of the final products and installing the others via diastereoselective
transformations, with varying degrees of success. Such approaches
always depend on the availability of both enantiomers of the starting
materials and, often, involve difficult skeletal modifications to reach
the eventual target. For example, in earlier work (ꢀ)-limonene7,8 and
(þ)-menthol9 served as the starting materials for the syntheses of the
aglycone of pseudopterosins AꢀF (1). Kocienski later reported10a
the use of (ꢀ)-citronellal and (ꢀ)-isopulegol for the syntheses of
both pseudopterosin AꢀF and the enantiomeric pseudopterosin
KꢀL(3) aglycones. While the Kocienski approach is better in overall
stereoselectivity, his scheme, like the previous syntheses, also relies
on a cumbersome aromatic annulation, which consumes several
avoidable steps if one were to start with a more logical aromatic
precursor. Because of the ‘substrate-control’ nature of the key
reactions by which the chiral centers are introduced, all of these
syntheses have serious limitations if stereoisomeric congeners of these
compounds are needed. Asymmetric hydrovinylation allows a high
degree of reagent control in the installation of three of the four chiral
centers of the pseudopterosin core. Since both enantiomers of the
ligands are readily available, either enantiomer of the natural product
may be synthesized from the same prochiral precursor.
Enantioselective Synthesis of Pseudopterosin Core. In our
synthesis we targeted the tricyclic ketone 16 as a common key
intermediate from which the aglycones of all pseudopterosins
can be synthesized. The synthesis (Scheme 1)11 started with an
exceptionally efficient Ni-catalyzed asymmetric hydrovinylation
of 2,3-dimethoxy-4-methylstyrene (6) using the ligand L1, which
was chosen from a collection of ligands we prepared for
optimization of the hydrovinylation reaction.12 This reaction
gives a quantitative yield of 7, which incorporates the correct
configuration (S) at the C7 center for the pseudopterosin AꢀJ
series. This compound was converted into the ketone 10 in a
series of simple steps, starting with the hydroboration/oxidation
of 7,13 iodide formation, and displacement with CNꢀ resulting in
the chain-extended product 9. The cyanide 9 was hydrolyzed to
an acid and subsequently converted into an acid chloride, which
was cyclized under FriedelꢀCrafts conditions to form 10. The
diene 11 was synthesized in 86% yield from 10 via a Stille
reaction14 of a vinyltriflate generated in situ from the ketone. The
compound 11 is set up for the installation of the chiral center at
C3 via a second hydrovinylation, this time that of a 1,3-diene. Even
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Scheme 2. Stereoselective Synthesis of Pseudopterosin AꢀF
configurations at the various chiral centers. As described below the
intermediate 16 is useful for stereoselective syntheses of aglycones of
pseudopterosin AꢀF and GꢀJ.
Aglycone
Stereoselective Installation of the C1 Side Chain of Pseu-
dopterosins GꢀJ via Asymmetric Hydrovinylation. While the
synthesis of pseudopterosin AꢀF aglycone with the C1-isobutenyl
group in the more stable quasi-axial orientation is quite straightfor-
ward as previously reported3,9,18 (Scheme 2), approach to the C1-
epimeric GꢀJ aglycone is less apparent. Again we find that hydro-
vinylation provides a very attractive solution for the installation of the
last of the stereogenic centers in pseudopterosins GꢀJ. The requisite
substrate for this process was readily synthesized from the ketone 16
as shown in Scheme 3. Sodium borohydride reduction of 16 gave a
mixture of alcohols (1:1), which was quantitatively converted into
the tetrahydrophenalene 17 upon treatment with camphor sulfonic
acid in CH2Cl2. Hydrovinylation of 17 with Ni(allyl)(L2)/NaBARF
gave 18 in nearly quantitative yield with complete stereoselectivity
(dr >99.5:0.5). Conversion of the vinyl group into the aldehyde and a
subsequent Wittig reaction proceeded without incident giving the
pseudopterosin GꢀJ aglycone dimethyl ether 2B. Depending on the
reaction conditions, varying amounts (up to 13%) of isomerization of
the intermediate aldehyde was observed during the Wittig reaction,
giving the aglycone dimethyl ether of pseudopterosin AꢀF as a
byproduct. Incidentally, a more direct route involving Ru-catalyzed
cross-metathesis,19 in spite of considerable effort, only gave unac-
ceptable (<10%) yields.
Scheme 3. Stereoselective Synthesis of Pseudopterosin GꢀJ
Aglycone via Installation of the C1 Side Chain Using Asym-
metric Hydrovinylation
In conclusion, we demonstrate the utility of ethylene for highly
enantioselective syntheses of aglycones of all known pseudop-
terosins. This approach provides unprecedented flexibility with
regard to the preparation of other diastereomeric analogs of these
molecules. In addition, the stereochemical features associated
with some of the advanced intermediates (e.g., alcohol 14a) are
common to a number of important diterpenes including
pseudopteroxazole,5b,20 colombiasin A,5c,21 elisabethin A,5e,22a
elisapterosin B,5d,22b and helioporins.23 With the stereochemical
issues largely resolved, it should now be possible to design
expeditious entry into these molecules and their congeners. Such
studies are currently in progress.
though the starting material is a nearly enantiopure diene, the
resident chirality (at the benzylic position, C7) in the molecule has
little influence on the stereoselectivity of the second hydrovinylation.
Indeed, the reaction using an achiral ligand L3 shows only a slight
preference [C3(S):C3(R) = 59:41] for the desired compound 12a.
However, this preference for 12a can be reinforced and a dr of 92:8
(12a:12b) can be obtained with the use of the phosphoramidite L2
in the Ni-catalyzed asymmetric hydrovinylation reaction. In a power-
ful demonstration of the versatility of asymmetric catalysis, it can be
shown that an enantiomeric catalyst generated from the ligand ent-
L2 overcame the inherent preference for the C3(S) isomer and gave
a ratio of 3:97 for 12a:12b, with C3(R) predominating. Thus, the
configuration of the C3 and C7 centers can be controlled indepen-
dently, an option not available in any of the previous syntheses of
these molecules or its congeners. The ensuing installation of the
correct configuration at C4 turned out to be a challenge. After much
experimentation, the correct C4(R)-center (dr: >20:1) was estab-
lished by a lithium/NH3 reduction15 of a primary alcohol that was
prepared from the alkene 12a by a hydroboration/oxidation proce-
dure. Various directed hydrogenations of 12a or 13 using either
Rh(I) or Ir(I), including Crabtree16 or Pfaltz17 hydrogenation
catalysts, were either sluggish or led to mixtures of products.
Incidentally, catalytic hydrogenation using Pd/C/H2 gave the C4
epimeric compound 14b as the major product (14a:14b = 1:13),
once again demonstrating the flexibility of a reagent-based strategy
for the control of stereoselectivity. The alcohol 14a was readily
converted into the tricyclic ketone 16 in a series of high-yielding
reactions (Swern oxidation to an aldehyde, 15, LindgenꢀKrausꢀ
Pinnick oxidation to an acid, acid chloride formation with oxalyl
chloride, and, finally, intramolecular FriedelꢀCrafts cyclization).
This sequence involved just one chromatography to purify the final
product 16. Recrystallization of the crude product gave an overall
yield of 47% of a highly crystalline tricyclic ketone from the alcohol
14a as a single diastereomer. The solid-state structure of this ketone as
revealed by X-ray crystallographic analysis confirmed the correct
’ ASSOCIATED CONTENT
S
Supporting Information. Full experimental details for
b
the preparation of the intermediates and hydrovinylation reac-
tions, spectroscopic and chromatographic data for characteriza-
tion of all compounds, Crystallographic Information File for the
ketone 16. This material is available free of charge via the Internet
at http://pubs.acs.org
’ AUTHOR INFORMATION
Corresponding Author
rajanbabu.1@osu.edu
’ ACKNOWLEDGMENT
Financial assistance for this research by NIH (General Medical
Sciences, R01 GM075107) and a fellowship provided by the
Chemistry-Biology Interface Training Program (NIH) to G.A.C.
are gratefully acknowledged. We thank Dr. A. Zhang for several
initial experiments and Dr. Judith Gallucci for determination of
the crystal structure of 16, shown in Scheme 1.
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