Broadly Applicable Stereoselective Syntheses of Serrulatane, Amphilectane Diterpenes, and Their Diastereoisomeric Congeners Using Asymmetric Hydrovinylation for Absolute Stereochemical Control

Article abstract of DOI:10.1021/jacs.8b03549

A stereogenic center, placed at an exocyclic location next to a chiral carbon in a ring to which it is attached, is a ubiquitous structural motif seen in many bioactive natural products, including di- and triterpenes and steroids. Installation of these ce

Full text of DOI:10.1021/jacs.8b03549

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Article
Broadly Applicable Stereoselective Syntheses of Serrulatane,
Amphilectane Diterpenes and Their Diastereoisomeric Congeners
using Asymmetric Hydrovinylation for Absolute Stereochemical Control
Srinivasarao Tenneti, Souvagya Biswas, Glen Adam Cox, Daniel Mans, Hwan Jung Lim, and T. V. RajanBabu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b03549 • Publication Date (Web): 12 Jul 2018
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Broadly Applicable Stereoselective Syntheses of Serrulatane, Amphi-
lectane Diterpenes and Their Diastereoisomeric Congeners using
Asymmetric Hydrovinylation for Absolute Stereochemical Control
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Srinivasarao Tenneti,‡ Souvagya Biswas,‡,† Glen Adam Cox, ‡,† Daniel J. Mans, ‡,† Hwan Jung
Lim,† T. V. RajanBabu*
Department of Chemistry and Biochemistry, 100 West 18th Avenue, The Ohio State University, Columbus, Ohio 43210
United States
Supporting Information
ABSTRACT: A stereogenic center, placed at an exocyclic location next to a chiral carbon in a ring to which it is attached, is a
ubiquitous structural motif seen in many bioactive natural products including di- and tri-terpenes and steroids. Installation of these
centers has been a long-standing problem in organic chemistry. Few classes of compounds illustrate this problem better than serru-
latanes and amphilectanes, which carry multiple methyl-bearing exocyclic chiral centers. Nickel-catalyzed asymmetric hydrovinyl-
ation (HV) of vinylarenes and 1,3-dienes such as 1-vinylcycloalkenes provide an exceptionally facile way of introducing these chi-
ral centers. This manuscript documents our efforts to demonstrate the generality of the asymmetric HV to access not only the natu-
ral products, but also their various diastereoisomeric derivatives. Key to success here is the availability of highly tunable phospho-
ramidite Ni(II)-complexes useful for overcoming the inherent selectivity of the chiral intermediates. The yields for HV reactions
are excellent, and selectivities are in the range of 92-99% for the desired isomers. Discovery of novel, configurationally fluxional,
yet sterically less demanding, 2,2’-biphenol-derived phosphoramidite Ni-complexes (fully characterized by X-ray) turned out to be
critical for success in several HV reactions. We also report, a less spectacular, yet equally important role of solvents in a metal-
ammonia reduction for the installation of a key benzylic chiral center. Starting with simple oxygenated styrene derivatives we it-
eratively install the various exocyclic chiral centers present in typical serrulatane [e.g., a (+)-p-benzoquinone natural product, elisa-
bethadione, nor-elisabethadione, helioporin D, a known advanced intermediate for the synthesis of colombiasin and elisapterosin]
and amphilectane [e.g., A-F, G-J and K,L- pseudopterosins] derivatives. Our attempts to synthesize a hither-to elusive target, elisa-
bethin A, led to a stereoselective, biomimetic route to pseudopterosin A-F aglycone.
INTRODUCTION
the source of more complex metabolites such as colombi-
asin A (12),12 elisapterosin B (13)13 and a key biogenic
precursor, elisabethin A.14
Serrulatanes and their annulated congeners amphilec-
tanes (Figure 1) are important classes of natural products
exhibiting diverse biological activities including anti-
inflammatory, analgesic, anti-tuberculosis and anti-malarial
properties.1 These compounds are derived from both plant2
and marine1j,3 sources and differ considerably in the con-
figuration of the stereogenic centers and the oxygenation
pattern around the carbon frame (1, 2), which is essentially
conserved through a family of compounds. Prototypical
examples include helioporins (e.g., 3),1k,4 seco-
pseudopterosin A (4),5 leubethanol (5),6 elisabethadione
(6a),7 a (+)-p-benzoquinone containing serrulatane (7),8
pseudopterosins (8, 9),1f,1j,9 pseudopteroxazole (10),1b,1i,10
and antimalarial amphilectane isonitrile 11.1e,11 One of the
most prolific sources of these compounds, West Indian and
Caribbean sea whip Pseudopterogorgia elisabethae is also
The relatively simple structures of many of these com-
pounds belie the synthetic challenges presented by the vari-
ations in the configurations of the stereogenic centers in
these molecules. These carbons are often placed at exocy-
clic locations next to a chiral carbon on a ring (highlighted
in Figure 1), with no obvious functional groups nearby ca-
pable of directing the installation of these centers. As ex-
emplified by the serrulatanes, seco-pseudopterosin A (4)
and leubethanol (5), there are variations in the configura-
tions at the key centers C1, C4 and C11 (serrulatane number-
ing). Leubethanol (5) has the same configuration of a C11-
epi diastereomer of enantiomeric seco-pseudopterosin
aglycone. Among pseudopteropsins, aglycone of the A-F
series (8a) bears an enantiomeric relation with the aglycone
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suggest that the biological activity of compounds with such
a motifs depends on the configuration of this exocyclic
3
3
1
6
1
H
4
10
5
9
18
17
4
9
8
7
O
O
8
11
12
11
12
10
5
O
Scheme 1. Nickel-Catalyzed Asymmetric Hydrovinyla-
tiona
7
13
14
6
13
14
19
15
15
a. Asymmetric hydrovinylation of vinylarenes
16
2
1
3a C11(S) helioporin B;
and ent-3a
3b C11(R) 11-epi-helioporin B
H
H
amphilectane
skeleton
serrulatane
skeleton
H
cat: [(allyl)Ni-L*]+ X–
H
+
9
Ar
(– 78 °C to 23 °C)
20
10
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Ar
(1 atm)
1
H
4
H
H
18
10
OH
O
OR
OSug
OH
vinylarenes
(L* = chiral ligand)
yield (90-99%)
enantioselectivity (ee >95%)
11
12
15
13
14
O
17
19
b. Asymmetric hydrovinylation of 1,3-dienes and ‘exo-cyclic’
stereo-control
16
H
5
4
6a R = H (+)-elisabethadione
6b R = Me (+)-O-methyl
elisabethadione
(–)-leubethanol
seco-pseudopterosin A
(S)
(R)
*
H
2
cat: [(allyl)Ni-L*]+ X–
1
OH
3
20
+
*
H
H
H
9
4
H
10
OR
OR
OR
O
18
17
(L* = chiral ligand)
11
8
*
5
(1 atm)
yield (>95%)
enantioselectivity (ee 99%)
(dr 30:1)
12
15
OR
7
13
O
OH
6
14
19
c. Asymmetric hydrovinylation for control of C20 configuration in steroids
16
OH
7
9a (R = H)
pseudopterosin G-J
aglycone
8a (R = H)
(+)-p-benzoquinone
pseudopterosin A-F
aglycone
serrulatane
OH
C20S
H
8b R = Me
9b R = Me
H
NC
(i)
H
H
H
H
H
H
H
H
H
OR
H
O
N
H
H
H
(ii)
OR
C20R
BnO
H
(i) ethylene, cat: [(allyl)Ni-L3]+ X–
(ii) ethylene, cat: [(allyl)Ni-ent-L1]+ X–
11
10
(ent-8a R = H)
pseudopterosin K-L
aglycone
amphilectane isonitrile-1
pseudopteroxazole
Me
Me
a See Figure 2 for structures of ligands
H
H
H
H
Me
Me
O
OH
Me
O
Ph
Ph
N
Ph
N
Me
Sc
Sc
O
O
OH
O
O
O
O
Me
Me
Me
Me
O
H
H
OH
H
Ra
Ra
P
N
P
Me
P
Me
Me
Me
O
Me
O
O
Sc
Sc
Sc
Ph
Ph
13
(-)-elisapterosin B
12
(+)-elisabethin A
(-)-colombiasin A
L1
L2
L3
Figure 1. Serrulatanes and Amphilectanes. For the sake of
uniformity in this manuscript serrulatane numbering is fol-
lowed.
O
Ph
OBn
O
O
OBn
PPh2
Ra
P
N
PPh2
O
P
Ph
of the K-L series. In pseudopterosins G-J (9) and, the po-
tent anti-tuberculotic pseudopteroxazole (10), the carbons
bearing the 1-(2-methylpropenyl) groups (C13) have con-
figurations opposite to that of pseudopterosins A-F.
L7
L6
L4
L5
Figure 2. Ligands for asymmetric hydrovinylation
The exocyclic methyl-bearing carbon such as C1 or C11
(1 in Figure 1) is a very common structural motif in many
of these structures, and a chain carrying this carbon is often
attached to a stereogenic center in a ring and installation of
such centers has been a long-standing problem in organic
synthesis.15 There are ample examples in the literature to
methyl-bearing carbon, such as seen in C20(S) vs. C20(R)-
vitamin-D analogs. While such effects have been extensi-
vely investigated in the steroid series with the C20-epimeric
analogs16 and the anti-tumor glycosides such as OSW-1,17
only limited studies have been undertaken in serrulatanes or
amphilectanes.1d,1g,6a,9c,18 Almost invariably biological
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installation of C1
stereoselective
reduction (C4)
installation of C11
1
1
1
*
*
*
*
4
*
OR1
OR2
OR1
OR2
OR1
OR2
OR1
OR2
OR1
OR2
AHV
AHV
serrulatanes
*
11
H
X
*
X
X
X
X
OH
7
8
18
14
16
17
15
9
installation of C13
H
1
*
1
1
intramolecular
Diesl-Alder
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*
*
4
H
colombiasin A
4
*
O
OR1
OR2
OR1
AHV
amphilectanes
11
*
elisapteropsin B
*
11
*
O
OR2
*
OR2
13
R
R
19
20
Asymmetric hydrovinylation (AHV): carbons from ethylene marked red
21
Figure 3. A general approach to serrulatanes and amphilectanes
studies in these molecules have concentrated on the periph-
eral appendages and seldom involved configurational
changes in the carbon frame.1c This might be due to a
dearth of facile methods for the preparation of the requisite
diastereoisomeric congeners.19 In a notable example, Ag-
garwal et al have reported the syntheses of all diastere-
omers of a serrulatane, erogorgiaene, using stoichiometric
chiral born reagents to introduce the chiral appendage.19b
Any general synthetic approach to these molecules should
address the installation of these centers independent of one
another if a broadly applicable strategy for syntheses of
diastereomers of these natural products is the goal. It can
be reasonably argued that the absolute control of diastere-
oselectivity in catalytic reactions of chiral substrates can be
a more formidable problem than achieving useful levels of
asymmetric induction with a prochiral substrate. For this
to be successful, the catalyst design must be sufficiently
flexible to overcome the inherent diastereoselectivity dic-
tated by the resident chirality of the substrate. Even though
several creative solutions to tackle this so-called ‘exocyclic
stereochemistry’ problem have been advanced, broadly
applicable methods that use easily accessible precursors are
still needed.15 We believe that the asymmetric hydrovinyla-
tion of vinylarenes (Scheme 1, a)20 and of 1,3-dienes
(Scheme 1, b, c)21 provide an especially attractive oppor-
tunity to fill this gap in the synthesis of serrulatanes and
amphilectanes and here we document the full details of our
work in the area. In addition to the enantioselective total or
formal syntheses of several natural products, we describe
how reagent control maybe exercised for the preparation of
selected congeners with high diastereoselectivity.19b
one at a time in a catalytic asymmetric hydrovinylation
reaction (e.g., 14 –> 15; 16 –> 17; 20 –>21), fully recog-
nizing that such an approach is likely to be longer in terms
of step count,22 but will offer unprecedented opportunities
in reagent-controlled installation of these centers. Such a
strategy would also have advantages over diastereoselec-
tive synthesis starting from chiral pool precursors, which
possess one or two of the chiral centers in the target.9d As
examples of the early such syntheses of pseudopterosins23
and other related compounds10,24 amply illustrate, the stere-
ochemical challenges are addressed to varying degree of
success via diastereoselective transformations. This ap-
proach always depends on the availability of both enantio-
mers of the starting material, and, may involve difficult and
sometimes circuitous skeletal transformations to reach the
final target. In addition, substrate control for the syntheses
of different diastereomers of a final product comes with its
own challenges as alluded to earlier. We hoped that the
outstanding flexibility in the design of ligands for nickel in
the asymmetric hydrovinylation reaction would allow in-
stallation of the C1 and C11 centers of serrulatanes, and, also
the additional chiral center C13 (serrulatane numbering, see
Figure 1) present in some of the amphilectanes.
In order to provide a proper perspective of our synthet-
ic efforts, which put this work in the context of complete
stereocontrol, we have added an extensive Table in the
Supporting Information (Table S1, pp. S39-S50), which
compares various approaches to key compounds among
these classes of compounds. This table provides the step
count, overall yield, how the stereochemical issues were
addressed, and limitations and advantages of various ap-
proaches.
RESULTS AND DISCUSSION
A General Strategy for the Synthesis of Serrulatanes
Our synthesis will start from the vinylarene 14, which
upon Ni-catalyzed asymmetric hydrovinylation would give
15, from which a second hydrovinylation substrate 16 will
be synthesized in preparation for the installation of the chi-
ral center at C11. The power of the asymmetric hydrovinyl-
ation to overcome the inherent stereochemical preference
and Amphilectanes.
In order to maximize the flexibility in the synthesis we
plan to start with a prochiral starting material, a vinylarene
(e.g., 14 in Figure 3), and install the stereogenic centers
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of a substrate will be tested in this reaction. We hoped that
2,3-dimethoxytoluene can be achieved. We also investi-
the highly tunable phosphoramidite and other ligands (Fig-
ure 2) we developed20b,25 would help address this issue.
Moving forward, there was some uncertainty about how we
might install the C4 configuration, even though earlier we
had shown in model systems (Scheme 1, b and c) hydrobo-
ration followed by catalytic heterogeneous (Pd/C) or ho-
mogeneous Ir-catalyzed directed hydrogenation using
Crabtree’s catalyst26 would result in high diastereoselectivi-
ty at the ring carbon in some model systems.21a,27 Single
electron-transfer reductions have also been shown to have
modest control in the installation of benzylic configuration
in related systems.28 The generic structure represented by
the alcohol 18 is a key compound in our plans since it sets
the stage for further elaboration into serrulatanes and am-
philectanes including several more complex members of
the family. An appropriately functionalized serrulatane
1,4-quinone-diene such as 19 has been converted into co-
lombiasin A (12) and elisapterosin B (13) in one or two
steps. Thus the preparation of this compound (19) or one
of its precursors would represent formal stereoselective
total syntheses of these compounds, but with unprecedent-
ed control over selectivity in the installation of the various
chiral centers.
gated other routes30 involving an aryl iodide31 and a modi-
fied Stille coupling.32 The aryl iodide is a versatile inter-
mediate and could be used to prepare the styrene 23 via Cu-
catalyzed cyanation, DIBAL reduction and Wittig reaction.
Styrene 25 was prepared in an easily scalable 5 step-
process from 2,6-dimethoxytoluene (Scheme 2, c), adapted
and modified from recipes in the literature.33
9
Even though we have had extensive experience with
asymmetric hydrovinylation reactions including that of 4-
methoxystyrene20b it became apparent that further optimiza-
tion of the ligand system would be needed as we looked at
even more electron-rich styrenes. For example, we found
that 2,3-dimethoxy-4-methylstyrene (23), a key precursor
for several diterpenes targets, while giving excellent yields,
gave enantioselectivity of only ~ 90% ee under the standard
conditions using the original Feringa ligand, L1. However,
nickel complex of a modified ligand L2 gave a quantitative
yield of the product (27) with exceptionally high enantiose-
lectivity (>99% ee) in a highly reproducible reaction that
could be performed on large scale (Scheme 3, b).34
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Scheme 2. Synthesis of Vinylarenes
a. Synthesis of 2,3-dimethoxystyrene (22)
Synthesis and Asymmetric Hydrovinylation of
Alkoxystyrene Precursors
O
[Ph3P-CH3]+ Br–, KHMDS, THF,
rt to reflux 16 h
OMe
OMe
OMe
OMe
Most of the serrulatane and amphilectane diterpenes
are characterized by varying levels of oxidation, and dense
functionality around the aromatic ring. We chose two of
the most oxygenated vinylarene precursors (23 and 25) in
addition to 4-methoxystyrene and 2,3-dimethoxystyrene
(22) as prototypes to initiate hydrovinylation studies. Since
the corresponding aromatic units are present in several of
these diterpenes, we expect a synthetic sequence that works
in these systems should be broadly applicable. These elec-
tron-rich aromatic rings can also be used to prepare more
oxidized compounds such as the 1,4- or 1,2-quinones.
(72%)
22
b. Synthesis of 2,3-dimethoxy-4-methylstyrene (23)
1. t-BuLi, THF, TMEDA, rt, 18 h
OMe
OMe
OMe
ZnCl2/THF, (–78 °C) to (–60 °C)
OMe
2. Pd(Ph3P)4 (cat.), vinyl bromide
(35%)
23
1. t-BuLi, TMEDA, hexanes, 16 h
2. DMF, 0 °C - rt, 1h
OMe
OMe
OMe
We examined a number of options for the syntheses of
the styrenes and the most scalable routes are shown in
Scheme 2. All these compounds are commercially availa-
ble, yet somewhat expensive (especially 23 and 25). We
chose to prepare them. While the synthesis of 22 is quite
straightforward, starting from 2,3-dimethoxybenzaldehyde,
the other two are more involved.
3. [Ph3P-CH3]+ Br–, KHMDS, THF,
OMe
rt to reflux, 16 h
23
(68%)
c. Synthesis of 2,3,5-trimethoxy-4-methylstyrene (25)
1. DMF, POCl3 (0 °C to 110 °C)
2. m-CPBA, CH2Cl2, then
KOH/MeOH
Several syntheses of 2,3-dimethoxy-4-methylstyrene
(23) have been described in the literature,29 but none con-
venient for large-scale preparation. We investigated two
new routes (Scheme 2, b). The one-pot, 2-step process
involves formation of the aryl zinc reagent followed by
Negishi coupling which proceeds in a modest 35% yield.
The other route proceeding through an intermediate alde-
hyde was reported to give poor yields for the Wittig reac-
tion.29 However, we find that using KHMDS as the base
and conducting the reaction at slightly elevated tempera-
tures acceptable yields (over all 68%) in two steps from
OMe
OMe
MeO
OMe
MeO
3. MgCl2, [HC(O)H]n, Et3N, CH3CN
4. MeI, K2CO3
5. [Ph3P-CH3]+ Br–, n-BuLi,
THF, 0 °C
24
25
(42%)
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Scheme 3. Asymmetric Hydrovinylation of mono-, di-,
fluxional, which suggested that upon complex formation
and tri-Methoxystyrenesa
2
3
with nickel, the pendant chiral α-methylbenzyl amine must
impart conformational rigidity to the catalytically active
complex. This has indeed been confirmed by obtaining a
solid-state structure of the complex L3(allyl)Ni(Br) (29,
Scheme 4). Further temperature-dependent NMR studies
of the preformed complex (29) showed no fluxional behav-
ior, thus suggesting that even in solution the active com-
plex retains its axial chirality. Note that the axial configu-
ration of the biphenyl moiety in this complex is the same as
what was found in the (R)-2,2’-binaphthol-derived com-
plexes used in Schemes 3 a, b, and c, all resulting in (S)-
configuration of the product. Further support comes from
the HV reaction with the enantiomeric catalyst, ent-
L3(allyl)NiX, which, as expected, gives the opposite enan-
tiomer of the product. This catalyst was also used to pre-
pare 11-epi-34 from diene 33 (Scheme 6).
4
5
6
7
8
9
a
ethylene (1 atm)
[(allyl)Ni-L]+ [BARF]– (0.7 mol%)
– 78 oC, CH2Cl2, 1 h
OMe
OMe
26
yield (%)
ee (%)
95
ligand
L1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
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54
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57
58
59
60
99
99
99
98
L2
95
L3
b
OMe
OMe
OMe
OMe
ethylene (1 atm)
[(allyl)Ni-L2]+ [BARF]– (1.4 mol%)
– 80 oC, CH2Cl2, 2 h
(5 mmol scale)
Scheme 4. A Biphenol-Derived Catalyst for Asymmet-
ric Hydrovinylation of Methoxystyrenes
yield 99%
ee >99%
23
27
Br
c
Br
COD
rt
L3, toluene
OMe
OMe
OMe
Ni
[L3]Ni(allyl)(Br)
ethylene (1 atm)
+ Ni(COD)2
Ni
Br
[(allyl)Ni-L3]+ [BARF]– (1 mol%)
CH2Cl2
29
MeO
OMe
MeO
(5.9 mmol scale)
25
28
cat
L1
L2
L3
mol%
temp time (h) yield %ee
5
5
1
–50
–50
–60
5
100
70
87
74
96
[L3]Ni(allyl)(Br) (29)
18
20
• Recrystallize from benzene/CH2Cl2
by slow diffusion of hexane
99
a See Figure 2 for the structures of ligands
A Diversion. A Fluxional Ligand and Induced Confor-
mational Rigidity in the Catalyst
Diene Precursor (33) for Installation of the Stereocenter
at C11
Further optimization was also needed for the styrene
25, which reacted surprisingly slowly with catalysts bear-
ing ligands L1 and L2 giving only modest selectivities
(Scheme 3, c). However, a complex bearing a sterically
less encumbered biphenyl backbone (L3) was found to give
excellent yield and enantioselectivity (96% ee) for the
asymmetric hydrovinylation reaction of this substrate
(Scheme 3, c). Note that the reaction was carried out at a
lower temperature (–60 oC) with no substantial loss of
yield. The discovery of a simpler (and cheaper) ligand (L3)
had further implications beyond the first hydrovinylation of
a demanding vinylarene. For example, as documented lat-
er, the nickel complex derived from this ligand (L3) was
even more critical in the subsequent hydrovinylation of the
1,3-diene (33) that was used to install the C11 stereocenters
in serrulatane intermediates (Scheme 6).
We reasoned that a second hydrovinylation of an appro-
priately substituted diene would give unprecedented oppor-
tunities to control the configuration of C11. A route to such
a compound (33) from the hydrovinylation product 28 is
shown in Scheme 5. The alkene 28 undergoes highly regi-
oselective hydroboration with 9-BBN followed by oxida-
tion of the resulting borane with H2O2 give 30 from which
the nitrile 31 is readily prepared in nearly quantitative yield
in two steps. Hydrolysis of this nitrile to the acid, the cor-
responding acid chloride (with oxalyl chloride), followed
by intramolecular Friedel-Crafts reaction proceeds in excel-
lent yield (90% in 3 steps) to give the ketone 32. Addition
of vinylmagnesium bromide followed by a surprisingly
facile acid-catalyzed dehydration with anhydrous camphor-
sulfonic acid give an excellent yield of the key diene 33 (a
substrate without the C5-methoxy group gives very low
yields of the diene, see later in Scheme 13).
We were surprised by these results since it appears that
the axially chiral (and more expensive) 1,1’-binaphthalene-
2,2’-dioxy backbone (e.g., as in L1 and L2) is not needed
for the phosphoramidite ligands to give high asymmetric
induction in the hydrovinylation reactions. From tempera-
ture dependent NMR studies, the ligand L3 itself appeared
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5
6
7
8
Scheme 5. A Diene Substrate for Installation of C11
Stereocenter
The asymmetric hydrovinylation of the 1,3-diene 33
posed considerable challenges since none of the most
commonly used phosphoramidite ligands derived from
binaphthols including the hugely successful ligands L1 and
L2 (Scheme 3)35 gave good yields at low temperatures. At
elevated temperatures, not unexpectedly, low enantioselec-
tivities were obtained. However, the ligand L3 (Scheme 4)
with the biphenyl backbone gave excellent yield (98%) and
diastereoselectivity (99:1) in the formation of the 1,2-
adduct (34, Scheme 6) with the indicated (S) configuration
at C11, commonly found in most serrulatanes and amphilec-
tanes. The diastereoselectivity in the reaction was initially
confirmed by the absence of signals corresponding to a
C1(S )
1
HO
1. 9-BBN, THF, rt, 3 h
OMe
OMe
OMe
2. NaOH, H2O2, 0 °C - rt
MeO
MeO
OMe
(>99%)
9
30
28
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1. Ph3P, Imidazole,
THF, I2, 0 °C - rt
2. NaCN, DMSO,
60 °C
(>98%)
1
1
diastereomer in the H or 13C spectra and subsequently by
1
NC
1. NaOH, H2O, MeOH
2. (COCl)2, CH2Cl2, 0 °C
3. AlCl3, 0 °C, 0.5 h
separation on a CSP GC column.30 The configurations of
the newly created stereocenter C11 (S) was initially assigned
based on precedents, but later confirmed by comparison of
full spectroscopic and chiroptical properties of advanced
intermediates and natural products derived from 36a with
those of known compounds in the literature (vide infra).
OMe
OMe
OMe
OMe
O
MeO
MeO
(90%)
31
32
1. vinylmagnesium bromide,
THF, 0 °C, 2 h
2. CSA, CH2Cl2, rt, 1 h
(80%)
We have since carried out this hydrovinylation using
the enantiomeric ligand ent-L3, which most gratifyingly
gave the expected product 11-epi-34 in excellent yield
(98%) and diastereoselectivity (>98:2).30 This product has
the C1(S):C11(R) configuration (11-epi-34, Scheme 6).
1
4
OMe
11
MeO
5
OMe
33
Scheme 7. Reduction of C3-C4 Double Bond and the
Configuration of C4
Scheme 6. Asymmetric Hydrovinylation of a 1,3-Diene
1
1
3
4
1
S
4
S
9-BBN, THF, rt , 2 h
H2O2/OH, 0 °C – rt
OMe
OMe
OMe
OMe
4
OMe
OMe
ethylene (1 atm)
11
S
11
11
S
[(allyl)Ni(L3)]+ [BARF]–
(5 mol%)
CH2Cl2, –7 °C, 20 h
O
5
O
5
(96%)
O
5
Me
34
OH Me
1
Me
35a
4
OMe
OMe
34 (98% yield, dr 99:1)
condition a: NH3:dioxane (20:1)
11
Na, – 60 °C, 5-10 min
MeO
5
1
OR
S
4
condition b: Pd/C/H2, MeOH
OMe
ethylene (1 atm)
33
11
R
1S
[(allyl)Ni(ent-L3)]+ [BARF]–
(5 mol%)
3
O
5
OMe
H
4R
H
OMe
OMe
OMe
OMe
DMP, NaHCO3, CH2Cl2
Me
CH2Cl2, –7 °C, 20 h
11S
0 °C - rt, 2.5 h
O
11-epi-34 (98% yield, dr 99:1)
O
5
O
(73%)
OH Me
H
Me
36d
[73%,
dr 99:1 (CSP GC)]
• Low temperature gave incomplete conversion
• Complexes of ligands L1 and L2 (Scheme 3) gave unacceptable
yield/selectivity
condition a: 36a [83%, dr C4(R:S) > 85:15
• after column chromatography > 97:3 (CSP GC)
condition b: 4-epi-36a [99%, dr C4(R:S) 1:99]
• Authentic diasteromeric mixture (1S,11S)/(1S,11R) was prepared
via complex of ligand L6
Ph
Ph
The hydrovinylation product 34 was subjected to hy-
OBn
O
O
O
droboration using 9-BBN followed by oxidation to get the
primary alcohol 35a, which serves as a suitable precursor
for 36a [C4-(R)] and its diastereomer 4-epi-36a [i.e., C4-
(S)] (Scheme 7). While the former is important for majori-
ty of naturally occurring diterpenes of these classes, any
broadly applicable methodology should be able to install
the latter configuration as well, since biologically active
serrulatanes with both C4 configuration are known.36 Table
1 summarizes results of various hydrogenation and metal-
P
N
P
N
O
PPh2
Ph
Ph
L3
ent-L3
L6
Asymmetric Hydrovinylation of Diene 33 and Installa-
tion of Stereocenters C4 and C11. Making either the
C11(S)- or the C11 (R)-diastereomer
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ammonia reduction experiments directed towards this goal.
Initial attempts to effect the diastereoselective conver-
2
3
4
5
In addition to the alcohol 35a, corresponding TBDMS
(35b) and TBDPS ethers (35c), the aldehyde 35d and Wit-
tig product of the aldehyde 35e were included in these at-
tempts to control the configuration of C4 (Scheme 8).
sion of 35a to 36a started with simple catalytic reduction of
the double bond using 5% Pd/C and hydrogen in methanol.
This reaction gave in quantitative yield of a single diastere-
omer which was subsequently identified (see later) as the
C4 (S)-derivative, 4-epi-36a [C4(S)] (Table 1, entry 1).
6
7
Scheme 8. Reduction of C3-C4 Double Bond
For the preparation of the diastereomer with the C4-(R)
configuration, which turned out to be more challenging, we
resorted to metal/liquid ammonia reduction of 35a at low
temperature. Even though we found this reaction to be
capricious in the beginning, running the reaction at low
8
9
1
1
3
3
4
Pd/C (cat.)
or
metal/NH3
H
4
OMe
OMe
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
OMe
OMe
*
11
11
(see Table 1)
R
O
5
R
O 5
o
Me
temperature (-78 C) and for brief periods (~5 min) using
Me
C4 (R/S)
lithium in liquid ammonia in THF (v/v 20:1) gave accepta-
ble yields of the product, but with only a modest diastere-
oselectivity of 63:37 in favor of the desired (R)-isomer
(Table 1, entry 2). Adding varying amounts of external
protic sources such as ethanol or i-propanol to the
THF/ammonia solution, or, carrying out the reaction in
diethyl ether or dioxane in place of THF as a solvent only
marginally improved the selectivity (entries 3-5). Careful
maintenance of the reaction in anhydrous ammonia:1,4-
36a R = CH2OH
35a R = CH2OH
36b R = CH2OTBDMS
36c R = CH2OTBDPS
36d R = -C(=O)H
35b R = CH2OTBDMS
35c R = CH2OTBDPS
35d R = -C(=O)H
36e R = -C(H)=CH2
35e R = -C(H)=CH2
Table 1. Reduction of C3~C4 Double Bond. Setting the
Configuration of C4
o
dioxane mixture (20:1) at -60 C and use of sodium gave
entry substrate
conditions
product
yield (%)
36a, >99
C4 (R):
C4 (S)
0:100
the best and reproducible results giving yields above 80%
and diastereomeric ratios consistently above 85:15 in favor
of the desired isomer (entry 6). However, the diastere-
omers were readily separable by chromatography and pure
C4(R)-can be isolated in high yield and diastereoselectivity,
dr >97:3). The hydroxypropyl side-chain is important for
the formation of the C4(R)-diastereomer in the metal-
ammonia reduction, as is clear from the similar reaction of
the protected derivatives, the corresponding silyl ethers 35b
and 35c. Both these compounds yielded the respective
C4(S)-diastereomer as the major product (entries 7 and 8).
The aldehyde 35d gave a R:S ratio of 58:42 and, the alkene
35e, a ratio 0:100. Incidentally, all isomeric ratios were
determined as the corresponding aldehydes (36d) since
these show base-line separation on a chiral stationary phase
1
2
35a
35a
H2, Pd/C, EtOH, rt
36a, 78
36a, 78
63:37
70:30
Li, NH3:THF (20:1), -
78 oC, 5 min
3
4
35a
35a
Li, NH3:THF (20:1), -
78 oC, EtOH or i-
PrOH, 5 min
36a, 78
70:30
Li, NH3:Et2O (20:1), -
78 oC, EtOH or i-
PrOH, 5 min
5
6
35a
35a
35b
35c
36a, 80
36a, 83
36b, 61b
36c, 66b
36d, 76
36e, 58e
70:30
>85:15a
3:97
Li, NH3:1,4-dioxane
(20:1), -78 oC, 5 min
1
GC column.30 The ratios were further confirmed by H
Na, NH3:1,4-dioxane
(20:1), -60 oC, <5 min
NMR spectroscopy.
Scheme 9. Origin of Stereoselectivity in the Reduction
of C3-C4 Double Bond
7
Li, NH3:THF (20:1), -
78 oC, 5 min
8
8:92
Li, NH3:THF (20:1), -
78 oC, 5 min
Li/NH3, (R = CH2OH, intra-
molecular (α) delivery of H)
Me
R
α
36-C4(R)
36-C4(S)
MeO
Me
H
H
9
35dc
35ed
58:42
0:100
Li, NH3:THF (20:1), -
78 oC, 5 min
Li, NH3, (R = CH2O{Si} or C(H)=CH2
β-delivery of H (more exposed face)
Me
RO
OR
OR Pd/C/H2 (R = CH2OH)
10
Li, NH3:THF (20:1), -
78 oC, 5 min
35
It is tempting to propose a model for these reduction
reactions. If one assumes a favorable conformation for the
side-chain in 35 based on 1,3-allylic strain (Scheme 9) the
top and the bottom-face of the molecule are clearly differ-
entiated with the bulky group blocking the approach from
below, unless the proton delivery is of an intramolecular
nature as in the Li/NH3 reduction of the hydroxyethyl-
bearing alcohol 35a. This model correctly predicts the ob-
a After purification by column chromatography >97:3. See
In two steps from
35a. Substrate made by DMP-oxidation (81%) of 35a.
Alkene 35e made from 35a by DMP oxidation followed by
b
Supporting Information for details.
c
d
e
Wittig reaction with Ph3P=CH2. Yield for 3 steps from
35a.
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served configuration of the products in the catalytic and
metal-liquid ammonia reductions.
quired latent functionality to prepare many of the naturally
occurring serrulatanes, amphilectanes, helioporins and re-
lated diterpenes. Two examples are shown in Scheme 10.
Thus DMP-oxidation of 36a furnishes an aldehyde 36d,
which is readily converted into the alkene 36e and subse-
quently to a primary alcohol 37.
Key Intermediate Alcohol 36a and the Synthesis of (+)-
Elisabethadione (6a), (+)-O-Methyl Elisabethadione
(6b) and a (+)-p-Benzoquinone Serrulatane (7)
The enantiomerically pure alcohol 36a (>98% ee) has
the correct configuration at C1, C4 and C11 and has the re-
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 10. Formal Syntheses of (+)-Elisabethadione (6) and (+)-p-Benzoquinone Serrulatane (7)
[Ph3PMe]+ Br_, n-BuLi,
9-BBN (2 equiv.)
THF, rt, 3 h
H
H
H
OMe
OMe
OMe
OMe
OMe
OMe
THF, 0 °C, 1 h
O
30% H2O2, 10 °C
(90%)
O
O
O
H
Me
Me
(81%)
Me
HO
37
36e [dr ~ 99:1 (CSP-GC)]
36d [dr ~ 99:1 (CSP-GC)]
H
H
H
H
O
OH
OMe
O
5 steps
OMe
OMe
6 steps
Davies et al (47%)7b, 8
Malkov et al (21%) 37
Davies et al (41%)8
O
O
OMe
O
OR
O
Me
Me
HO
36e
OH
37
6 R = H (+)-elisabethadione
6a R = Me (+)-O-methyl
elisabethadione
7 a (+)-p-benzoquinone
serrulatane
The alkene 36e has been converted into a -p-
One further application of the aldehyde 36d is for the
synthesis of nor-elisabethadione (Scheme 11), whose me-
thyl ether is a minor natural product isolated from Pseu-
dopterogorgia elisabethae.7b
benzoquinone natural product (+)-7 by Davies.8 Likewise
the alcohol 37 is a key intermediate for the synthesis of (+)-
elisabethadione. Davies synthesis of 37 in 10 steps (~ 26%
yield) starting from 2,6-dimethoxytoluene relies on a com-
bined C-H activation/Cope rearrangement in a key selectiv-
ity-determining step that gives 42% absolute yield of the
desired precursor in 92% ee. Because of the high stereo-
specificity associated with the individual steps in the simul-
taneous generation of the 3 chiral enters, there are neces-
sarily some limitations in this otherwise astonishingly effi-
cient route for the synthesis of other diastereomers of this
natural product.
Yet another recent synthesis of 37 (in over all yield of
~ 9% from 1,3,4-trimethoxybenzene)37,19b involves a cata-
lytic asymmetric crotylation of a suitable aldehyde (97%
ee) to install the first asymmetric center followed by anion-
ic oxy-Cope rearrangement to install the other two centers.
The limitation of this method is the modest diastereoselec-
tivity of the oxy-Cope reaction (3:1) which necessitates a
chiral stationary phase LC separation of the diastereomers.
Other methods that rely on [3,3]-sigmatropic rearrange-
ments also have similar limitations when it comes to the
synthesis of specific diastereomers of the natural
products.19 By contrast the hydrovinylation approach (~ 15
steps from the starting vinylarene, ~ 28% yield, >98% ee),
though longer, provides excellent stereocontrol at every
stereogenic center.
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Scheme 11. Synthesis of nor-Elisabethadione
Scheme 12. Formal Total Syntheses of (-)-Colombiasin
A and (-)-Elisapteropsin B
MgBr
H
H
4
OMe
OMe
A
OMe
ceric ammonium nitrate
CH3CN:H2O (1:1),
5
6
H
H
OMe
OMe
O
HO
O
O
O
OMe THF, rt, 10 min
(92%)
0 °C, 10 min
HO
Me
O
O
OMe
H
Me
7
8
9
(68%)
Me
36a
OR
43a R = H (Mulzer)38
38 (dr ~ 1:1)
36d
43b R = (i-Pr)3Si (Rychnovsky)39
CSA, CH3CN
rt, 30 min
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(96%)
DMP, CH2Cl2,
0 °C to rt, 3 h,
(64%)
drops of H2O
H
H
OH(Me)
OMe
OMe
NaSEt, DMF
100 °C, 12 h
H
H
O
PPh3
O
O
OMe(H)
O
(65%)
THF, 0 °C to rt
<10%
O
OMe
Me
Me
O
OMe
O
40 (2:1 mixture)
39
45 (E:Z mixture)
44
(46%,
1. CAN/CH3CN/H2O
2. LiI, lutidine, 80 °C, 3 h
2 steps)
H
B
H
H
PPh3
OMe
OMe
OMe
THF, rt, 2 h
(64%)
O
O
O
OMe
X
O
Me
H
Me
O
OH
44a
36d (Scheme 7)
41
nor-elisabethadione
oxidation
TMSI/CHCl3
rt/ 1.5 h
45
H
OMe
OMe
H
1. H2O
O
2. DMP, CH2Cl2
0 oC to rt, 2h
O
Intermediates for the Syntheses of (–)-Colombiasin A
and (–)-Elisapterosin B
O
OMe
RO
Me
O
Me
46a R = TMS
46b R = H
44
Alcohol 36a, available in enantiomerically pure form
via the asymmetric hydrovinylation route from 2,3,5-
trimethoxy-4-methylstyrene in 12 steps (45-52%) is a valu-
able precursor for the synthesis of (-)-elisapterosin and (-)-
colombiasin. For example, we find that 36a is readily oxi-
dized to a quinone-alcohol 43a in modest yield (68%) upon
brief exposure to ceric ammonium nitrate in aqueous ace-
tonitrile. The structure of 43a was confirmed by compari-
son of 1H and 13C NMR spectrum with a racemic variant of
this compound that has been prepared by Mulzer38 in 10
7 steps
1 steps
2 steps
(–)-elisapteropsin B
(–)-colombiasin A
(–)-elisapteropsin B
(–)-colombiasin A
43b
(Rychnovsky 39
45
9 steps
)
alluded to earlier, our route has sufficient flexibility to
make any of the 8 diastereomers of the precursor alcohol
43a, and thus it should be possible to prepare the corre-
sponding to colombiasin and elisapterosin diastereomers.
steps
from
2,5-dihydroxy-4-methoxy-3-methylbenza-
Incidentally, we found that the alcohol 43a could be
readily oxidized in a respectable 64% yield to an aldehyde
44, which we were able to transform directly into 45, a key
diene in only low (<10%) yield in spite of considerable
effort (Scheme 12). The diene 45 is only one step from (–)-
elisapterosin (41%) and 2 steps from (–)-colombiasin
(61%) by previously established routes.39 The alcohol 36a
could also be oxidized by DMP to the aldehyde 36d
(Scheme 7), and subsequently transformed into 46, by
treatment with TMSI in CHCl3. Oxidation of 46 with DMP
also gave the quinone aldehyde 44. Even though 36d un-
dergoes a facile Wittig reaction to give 44a, this compound
could not be transformed into the key quinone-diene 45.
ldehyde in ~22% yield. The corresponding tri-i-
propylsilylether 43b has been converted into colombiasin
(12) and elisapterosin (13) by Rychnovsky39, thus estab-
lishing formal syntheses of these two natural products. As
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Total Syntheses of Aglycones of Pseudopterosins A-F,
Pseudopterosins G-J and Pseudopterosins K-L
POCl3, pyridine, rt; 5 equiv. Burgess reagent, CH2Cl2, 40
oC, methyl xanthate pyrolysis) gave either mixtures of
products or unacceptable yields. Acceptable yield of the
diene 50 was obtained by Stille reaction of the vinyltriflate
prepared from the ketone 48 using Commin’s reagent.40
From a practical perspective we realized that these reac-
tions can be carried out in a single pot from 48 giving 86%
yield of the diene 50.
We have previously communicated our preliminary re-
sults on enantioselective syntheses of the aglycone of pseu-
dopterosins G-J (Figure 1) using the asymmetric hydrovi-
nylation at 3 different stages, to control the configurations
of the carbons C1, C11 and C13 (to be consistent across this
article, we use the serrulatane skeletal numbering also for
the pseudopterosins, which traditionally follows a different
convention). Highlights of this synthesis and further details
of key steps are included here for the sake of completion
and to document the additional experiments that enabled
the control diastereoselectivity at C1, C4, C11 and C13. We
also disclose a new biomimetic synthesis of pseu-
dopterosins A-F aglycone (Scheme 19).
9
Hydrovinylation of the diene 50 was initially attempt-
ed using achiral hemilabile phosphine ligands L6 and L7
(see Figure 2 for structures of the ligands) to probe the pre-
ferred diastereoselectivity of the chiral precursor in the
hydrovinylation reaction (Scheme 14, Table 2). Several
key features of this reaction became immediately apparent
in these early studies. The diene substrate was significantly
less reactive vis-à-vis the vinylarenes, requiring tempera-
tures > – 10 oC as compared to – 70 oC for the vinylarenes.
Ligand L7, which we found41 to be an exceptional ligand
for the nickel-catalyzed hydrovinylation of vinylarenes,
was ineffective for the hydrovinylation of the 1,3-diene. In
sharp contrast, nickel complex of ligand L6 gave quantita-
tive yield of the product 50 in a diastereomeric ratio of
59:41 [C11(S):C11(R)]. Unlike in the hydrovinylation of a
vinylarene with this ligand,41 no isomerization of the pri-
mary product was observed even at higher temperatures.
Among chiral ligands, L1 gave the best selectivity (Scheme
13, Table 2, entries 1 and 2).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The synthesis (Scheme 13) starts with the hydrovinyla-
tion product 27, which can be prepared on multi-gram scale
using the ligand L2 (Scheme 3, b). This product was con-
verted into the ketone 48, a potential precursor for a diene
substrate 50 for a second hydrovinylation via a series of
high-yielding reactions (Scheme 13). While the conversion
of the HV product 27 to the ketone 48 proceeds without
event, all direct routes to convert the ketone to the diene 50
gave only modest yields (Scheme 13). For example, addi-
tion of vinyl magnesium bromide followed by acid-
catalyzed dehydration under a variety of conditions (0.2
equiv. CSA, CHCl3, rt, 3 h; 3 equiv. CSA, THF, 40 h;
Scheme 13. Intermediates for Psuedopterosin Aglycones. Stereocontrol at C and C
1
11
1. 9-BBN, then H2O2, NaOH
2. I2, imidazole, PPh3
1. NaOH followed by H+
X
OMe
OMe
OMe
OMe
OMe
OMe
O
2. (COCl)2, CH2Cl2
then AlCl3 0 °C to rt
3. NaCN/DMSO/60 °C
MgBr
, ether, 0 °C-rt
(~ 96% for 3 steps)
(97 %)
48
47a X = I
27
47b X = CN
(83%)
1. KHMDS, THF, PhNTf2
2. Pd2(dba)3,CHCl3 (cat.)
HO
OMe
OMe
Ph3As, LiCl, Bu3Sn(vinyl)
1
1
(86%)
(17-40) %
4
OMe
49
OMe
11S
11
dehydration
low yields
(see text)
9-BBN, H2O2, NaOH
(94%)
AHV, conditions a, b, c
OMe
OMe
OMe
OMe
51
+
OH
52-C11 (S)
1
4
50
OMe
OMe
11R
condition a: [(allyl)Ni(L1)]+ [BARF]– (0.025 equiv. cat., 0 °C): 51-C11(S):51-C11(R) = 92:8
condition b: [(allyl)Ni(ent)-L1]+ [BARF]– (0.025 equiv. cat., 0 °C): 51-C11(S):51-C11(R) = 3:97
condition c: [(allyl)Ni(L6)]+ [BARF]– (0.025 equiv. cat., 0 °C): 51-C11(S):51-C11(R) = 59:41
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Scheme 14. Diastereoselective Asymmetric Hydrovi-
nylation of Diene 50. Ligand Effects (Table 2)
Table 3. Reduction of Alcohol 52-C11(S) for Installation
of C4 Configurationa
selectivityb
53-C4(R):
53-C4(S)
1
1
4
5
ethylene (1 atm)
[(allyl)NiBr]2 (2.5 mol%)
Ligand (5 mol%)
S
S
entry
1
conditions
Ir+(COD)(PCy3)(py) PF6
4
4
OMe
OMe
OMe
OMe
11
6
11
-
NaBARF (5 mol%)
CH2Cl2, 0 °C, 4 h
5
17:83c
7
8
9
5
(5 mol%), THF, H2 (50 psi), 21 h
Rh+(dppe)(COD) SbF6 – (5 mol%, H2
(19 psi), THF, rt, 20 h
50
(> 90% yield)
51
2
3
4
no reaction
7:93
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 2. Hydrovinylation of Diene 50. Ligand Effectsa
H2, Pd/C, EtOH, rt, 15 h
51-C (S):51-C (R)c
entry
ligandb
conv.c
SmI2 (2,5 equiv.), MeOH (50 equiv.),
THF, -78 oC, 15 min.
11
11
no reaction
1
2
3
4
5
6
L1
ent-L1
L2
>99
>99d
62
92:8
3:97
82:12
60:40
59:41
-
SmI2 (2 equiv.), MeOH (4 equiv.),
THF, rt, 20 h
5
6
no reaction
67:33
Li (10 equiv.), NH3:THF (3:5),
-78 oC, 15 min, MeOH or NH4Cl
L4
46
Li (10 equiv.), NH3:THF (5:1),
-78 oC, 15 min, MeOH or NH4Cl
L6
>95
0
7
80:20
L7
Li (15 equiv.), dry NH3:THF (20:1),
-78 oC, 15 min., then MeOH
a
8
97:3
See Supporting Information for details including CSP GC
b
traces showing diastereomeric ratios (dr).
See Figure 2
Li (10 equiv.), NH3:THF (5:1),
-78 oC, 15 min, MeOH or NH4Cl
for structures of ligands. c Determined by CSP GC. d ~ 2%
isomerization of 1-alkene.
9d
20:80d
a See Supporting Information for details. bDetermined by NMR
c
d
and GC.
Conversion 68%.
Tri-isopropylsilyl ether of 52-
Having established the C1 and C11 configuration, we
turned our attention to the C4 center. Based on our previ-
ous experience,25a we had hoped to employ hydroxyl-
directed Rh- or Ir-catalyzed hydrogenation to effect this
stereoselective transformation. Accordingly, the alcohol
52-C11(S) was prepared from 51-C11(S) via hydroboration
and oxidation (94% yield, Scheme 13). The alcohol was
subjected to hydrogenation and other reduction conditions
(Scheme 15) listed in Table 3. Crabtree’s catalyst26 gave
an exceptionally clean product in modest yield under con-
ditions shown (entry 1). The product 53 is formed in a
diastereomeric ratio (R:S) of 17:83 at C4. A cationic Rh
complex (entry 2) known to effect such directed hydrogen-
conditions42 was unreactive under a variety of reaction.
Reduction under heterogeneous conditions using Pd/C in
ethanol gave a quantitative yield of 53-C4(S) product in
excellent diastereoselectivity (entry 3, dr = 93:7).
C11(S) was used as starting material.
Electron-transfer reductions showed more promise for
the formation of the desired C4-(R)-isomer. Especially
useful are the reductions using lithium and liquid ammonia,
which gave the C4-(R) as the major product. Optimization
of the reaction indicate that brief reaction times and a large
THF:NH3 ratios help improve the selectivity (entries 6-8).
Thus using 20:1 ratio of THF and NH3 up to 97% of the C4-
(R)- product can be realized. The importance of the free –
OH group in the Li/liquid-ammonia reactions is again re-
vealed by the reaction of the tri-isopropylsilyl ether of 52,
which gave mostly the (S)-isomer. Incidentally, SmI2
known to effect such reductions of styryl alkenes,28a failed
to react with this substrate (entries 4 and 5).
Key Intermediates for Synthesis of Helioporins, seco-
Pseudopterosins and Aglycones of Pseudopterosins.
Confirmation of Configurations of C1, C4 and C11.
Scheme 15. Intermediates for Pseudopterosins and He-
lioporins. Stereocontrol at C4 (Table 3)
Inspection of the structures of helioporins (Figure 1, 3)
and seco-pseudopterosins (4) reveal that alcohol 53-C4(R)
and other intermediates in Scheme 16, could be converted
into these molecules through very straight forward and reli-
able functional group transformations. An example of the
use of 53-C4(R) for the synthesis of a known helioporin D
1
1
H
H
4
4
4
OMe
OMe
OMe
OMe
OMe
OMe
Table 3
11
11
+
OR
OR
OR
1
precursor (56),28a is shown in Scheme 16. The H and 13C
R = H 52-C11(S)
R = (i-Pr)3Si
R = H 53-C4(R)
R = H 53-C4(S)
chemical shifts in this series of compounds are extremely
sensitive to the configuration of the stereogenic centers
28a,43 and this conversion for the first time established abso-
lute configuration of all such centers in the molecule.
High-yield conversions of the dimethoxy-compounds to the
naturally occurring methylenedioxy derivatives of heli-
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2
3
4
5
6
7
8
oporins and seco-pseudopterosins are well-documented in
Synthesis of amphilectanes from the precursor alcohol
the literature. Applications of either of the nearly enanti-
opure 53-C4(R) or the corresponding 53-C4(S) derivatives
for the synthesis of a myriad of diastereomeric congeners
of these natural products are obvious upon reflection.
53 would involve further annulation of a third ring and ste-
reoselective incorporation of the C13 side-chain. Details of
these transformations44 in the context of pseudopterosin G-
J aglycone are shown in Scheme 17, along with the solid-
state structure of an intermediate ketone 57, which further
confirms the configurations of all the newly created stereo-
genic centers.
Scheme 16. Syntheses of Helioporin D and Confirma-
tion of Configurations of C1, C4 and C11
9
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
H
H
4
1. Ph3P, midazole, THF
I2, 0 °C - rt, 1.5 h
OMe
OMe
OMe
OMe
11
2. NaCN, DMSO
60 °C, 15 h
CN
OH
53-C4(R)
54
1. DIBAL-H/hexane
– 78 °C -rt, workup
[(i-Pr)PPh3]+ I –, KHMDS, rt
H
H
O
OR
OR
OMe
OMe
+ aldehyde 0 °C - rt, 20 h
(57% from 53)
H
55
56a R = Me
(ref 43)
= CH2, helioporin D
56b R R
56c R, R = H, H seco-pseudoptrosin A (ref 5)
Scheme 17. Synthesis of Ketone 57, a Precursor for Aglycones of Pseudopterosin A-F
1. DMSO, oxalyl chloride, CH2Cl2 (-78 °C),
add alcohol 53, then Et3N, rt
2. remove low boilers, THF, t-BuOH,
2,3-dimethyl-2-butene, NaClO2,
NaH2PO4, H2O, 1 h
1
H
H
4
OMe
OMe
OMe
OMe
11
3. oxalyl chloride (excess), CH2Cl2, 0 °C - rt, 1 h
4. 0 °C, AlCl3, CH2Cl2
OH
53-C4(R)
O
57
Corey et al 23b
• no purification of intermediates (47% in 4 steps)
pseudopterosin A-F
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Scheme 18. Installation of Stereocenter at C13. Pseudopterosin Aglycones G-J
2
3
4
5
6
7
8
9
1. O3/CH2Cl2,
then Me2S
2. [i-PrPPh3]+ Br–,
KHMDS
H
H
OMe
OMe
H
ethylene (1 atm)
[(allyl)Ni(L1)]+ [BARF]–
H
1.NaBH4/EtOH
2. H+/CH2Cl2
OMe
OMe
OMe
OMe
OMe
OMe
(2 mol% cat.)
CH2Cl2, rt, 2.5 h
R
(99%)
(57%; dr 87:13)
cross-metathesis
O
(99%; dr 99:1)
9b R = Me (0%)
59
58
57
(Grubbs Gen II catalyst)
60 R = H (81%)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
H
H
1. KHMDS, THF,
PhNTf2
H
H
1. Li/NH3/THF
-78 °C, 15 min
OR
OR
OR
OR
OMe
OMe
OMe
OMe
+
SnBu3
2.
2. NaSEt, DMF
150 °C, 2 h
(63)
OTf
61
LiCl, AsPh3
.
62
9
8
Pd2dba3 CHCl3
(5 mol%)
R = Me 8b:9b = 1:2 (80%)
pseudopterosin A-F (8a)
pseudopterosin G-J (9a)
NaSEt, DMF
150 °C, 2 h
R = H
(74%)
(60%)
The ketone 57 is a key intermediate that has been
near perfect selectivity for the major S isomer (entry 4).
Disappointingly, the enantiomeric catalyst with ent-L1,
failed to overcome the inherent preference of the substrate
for the formation of the C13(S)-isomer, and in a sluggish
reaction yielded only this product (entry 5). During these
transformed into pseudopterosins A-F aglycone.23b Since
using the enantiomeric of ligands in the key steps in our
synthesis ent-57 can be prepared, this also is a formal syn-
thesis of the corresponding enantiomeric compounds, agly-
cones of pseudopterosins K-L (ent-8a, Figure 1).
Table 4. Diastereoselective Hydrovinylation of 58. In-
stallation of Stereocenter at C13
As compared to the pseudopterosins A-F, there has on-
ly been a limited effort towards enantioselective synthesis
of the pseudopterosins G-J.19,23d,45 A recent45 highly inno-
vative 11-step enantioselective synthesis (dr in a key step
5:1:1 in favor of the desired major isomer, overall yield ~
1%) relies on two high pressure cycloadditions (19 kbar) of
modest yields (~ 15% and 82%).19b
entry
1
liganda
conditionsb
conv.
39
dr (C13,
S:R)c
99:1
L6 (achiral)d
catalyst (0.05
equiv.), rt, 10 h
2
L1 (RaScSc)
60
only S
catalyst (0.2
equiv.), 0 oC, 15
min.
We wondered whether the vinylarene 58 (Scheme 18)
derived from the key enantiomerically pure ketone inter-
mediate 57could serve as a precursor for pseudopterosin G-
J aglycone. Using the asymmetric hydrovinylation of this
alkene to install a vinyl group at the C13 position appeared
especially attractive since there exists the possibility of
reagent control to make both the C13(R)- and C13(S)-
diastereomers. Accordingly, 58 was prepared by reduction
of the ketone 57 with NaBH4 in ethanol followed by acid-
catalyzed dehydration (Scheme 18). The asymmetric hy-
drovinylations of this substrate under a variety of condi-
tions were tried and the results are documented in Table 4.
3
4
L1 (RaScSc)
L1 (RaScSc)
100
100
42
only S
only S
only S
only S
only S
only S
catalyst (0.2
equiv.), rt, 2.5 h
catalyst (0.02
equiv.), rt, 2.5 h
5
ent-L1
catalyst (0.05
equiv.), rt, 10 h
(SaRcRc)
6
L3 (ScSc)
L4 (ScSc)
55
catalyst (0.2
equiv.), rt, 1 h
7
32
catalyst (0.2
equiv.), rt, 1 h
8e
L1 (RaScSc)
65e
catalyst (0.2
equiv.), oC, 15
min.
The results suggest that the substrate 58 is much less
reactive than simple vinylarenes (entries 1, 2 and 6) and the
reaction requires higher temperatures (rt) and concentra-
tions of the catalyst. Even the catalyst carrying the an achi-
ral ligand L6 (2-benzyloxyphenyl)diphenylphosphine) gave
exceptionally high diastereoselectivity for the formation of
the C13(S)-isomer, thus displaying total substrate control in
this reaction (entry 1). Complexes of ligand L1 appears to
be more active and the reaction can be performed at rt with
See Figure 3 for structures of ligands. b Conditions: ethylene (1
a
atm.), [(allyl)NiBr]2 (0.x equiv.), L (2x equiv.), NaBARF (x
c
d
equiv.), CH2Cl2. Determined by CSP GC and NMR.
(2-
e
Benzyloxyphenyl)diphenylphosphine. A mixture of 58 and C4-
epi-58 (65:35) was used. Only 58 was converted into the product.
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8
investigations we also recognized that a diastereomeric
In an attempt to effect abiomimetic spiroannulation as
mixture of alkenes 58 and C4-epi-58 (65:35) underwent
highly selective hydrovinylation of the former, leaving be-
hind the unreacted epimeric isomer (entry 8). Completion
of the synthesis of pseudopterosin G-J aglycone involves
the installation of the 2-methyl-1-propenyl side-chain. In
principle, cross-metathesis to exchange the methylidene in
59 with isopropylidene (59 –> 9b) is an ideal way to com-
plete the synthesis and we invested significant effort to-
wards this goal.30a However, all attempts to effect this
transformation failed, even though we found that using
Grubbs 2nd generation catalyst46 or Grubbs-Hoveyda 2nd
generation catalyst47 and 2-methyl-2-butene the corre-
sponding ethylidene compound 60 could be prepared in
81% yield.
shown in Scheme 19 (67 –> 68) we treated 38 with boron
trihalides and TMSI.50 While no products resembling the
elisabethane skeleton (68) were formed, we were pleasantly
surprised to find, in the TMSI reaction, a 65% yield of a
partially methylated aglycone of pseudopterosin A-F (69).
This molecule has been described in the literature during
the original isolation studies51 and is a suitably protected
derivative for the synthesis of pseudopterosin A-F by sub-
sequent glycosylation.23b Further confirmation of the struc-
ture comes from the conversion of 69 to a dimethyl deriva-
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
tive 8b, whose H and 13C spectra match with those of au-
thentic compounds described in the literature.28a,52 A pos-
sible mechanism for this transformation is also shown in
Scheme 19, and, may resemble the biosynthesis of pseu-
dopterosins. Indeed a C5-oxygenated analog structurally
related to 71 has been identified as a natural product and as
a possible biogenetic precursor of pseudopterosins.7a
Finally, the synthesis of 9b was accomplished in 2
steps by ozonolyis of the isolated double bond in 59 fol-
lowed by Wittig reaction of the resulting aldehyde in a
combined yield 57% (Scheme 18). Even though the alde-
hyde is formed with no erosion of stereoselectivity, the
accompanying Wittig reaction causes some isomerization
and the final product is contaminated with up to 13% of the
C13-epimer, which, corresponds to the pseudopterosin A-F
series. The compounds in these two series are easily dis-
tinguished by the chemical shift of alkene H and the ben-
zylic hydrogens.30a
A less selective, yet operationally simpler route to the
aglycones of both series of pseudopterosins (A-F and G-J)
is also shown in Scheme 18. In this route, the ketone 57 is
converted to a diene 62 via vinyl triflate (61) formation and
a subsequent Stille coupling with 1-(tri-n-butylstannyl)-2-
methylpropene (63). The conjugated alkene is reduced
under Li/NH3 conditions to give a mixture of 8b and 9b in
a ratio of 1:2 in an overall yield of 80%. For identification
purposes, the two dimethyl ether derivatives were convert-
ed into the aglycones of pseudopterosins A-F and G-J (60%
combined yield) by treatment with NaSEt in DMF at 150
oC for 2 h.
An Unsuccessful Attempt to Synthesize Elisabethin A
Skeleton and a Surprising Stereoselective, Biomimetic
Route to Pseudopterosin A-F from the Allyl Alcohol 38
Elisabethin A (Figure 1), a possible biogentic precur-
sor of colombiasin and elisapterosin,14 remains an elusive
molecule despite several efforts to synthesize this com-
pound.24a,38,48 The allyl alcohol 38 (Scheme 11), which was
prepared as an intermediate for nor-elisabethadione, ap-
peared to be an attractive precursor for this compound.
We have explored the chemistry of this intermediate in an
attempt to synthesize the core skeleton of elisabethin A via
a spiroannulation shown in Scheme 19.49 While these at-
tempts have been unsuccessful for the preparation of the
elisabethin skeleton, the new chemistry that emerged re-
vealed a new route topseudopterosins.
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Scheme 19. An Approach to Elisabethin A Skeleton and an Unexpected Annulation for a New Stereoselective Synthe-
sis of Pseudopterosin A-F Aglycones
4
5
1
1
6
7
8
9
H
H
Demethylation
Cyclization
H
H
H
O
OH(Me)
OMe(H)
OMe
OMe
OH(Me)
OMe(H)
4
4
5
HO
ZO
BBr3, BCl3, TMSI
O
OH
O
O
5
..
O
Me Me
Me
X–
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Me
38 (Scheme 10)
elisabethin A
67
68
TMSI (2 equiv)
CHCl3, rt, 1 h
(65%)
A possible mechanism for the annulation (38 to 69)
1
1
CH3I, KH
DME, rt
H
H
1
1
OMe
OMe
OH
4
4
H
4
..
..
H
4
Iodide-mediated
reduction
O
OMe
5
(90%)
5
OMe
38
69
5
ZO
Me
Me
(H2O)
OMe
5
OMe
O
Me
Me
69 51
MeO
71
8b pseudopterosin A-F
dimethyl ether 28a,52
Me
70
has been converted into (–)-colombiasin and (–)-
elisapterosin; (v) cross-coupling (Stille reaction) route to
pseudopterosins A-F and G-J (Scheme 18) and (vi) explo-
ration (unsuccessful) of a spiroannulation strategy for the
synthesis of elisabethin A that led to an unexpected discov-
ery of a biomimetic route to pseudopterosin A-F (Scheme
19). In addition, several previously undisclosed details of
the syntheses of pseudopterosin G-J are discussed.
Overall yields of several of the key products from
commercially available starting materials are as follows:19a
36e (14 steps, 30.7%; previous best: 10 steps, 17%), 37 (15
steps, 27.8%; previous best: 8 steps 22.8%), 43a (13 steps
36%; previous best: 17 steps, 5%, racemic), helioporin D
(17 steps, 29.3%; previous: 17 steps, 25.5%), pseu-
dopterosin A-F aglycone (15 steps, 25.6%; previous: 20
steps, 13.5%), pseudopterosin G-J aglycone (20 steps,
13.6%; previous: 15 steps, 5.5%). Our yields are general-
ly higher than those reported for these compounds, even
with comparable or higher number of steps. However,
yield in a chemical synthesis is only one of the several cri-
teria for efficiency and practicality. Possibility of control-
ling the relative and absolute configurations of nearly all
the stereogenic centers adds further value to this approach.
CONCLUSIONS
Nickel-catalyzed asymmetric hydrovinylation (HV) of
vinylarenes and 1,3-dienes is a powerful carbon-carbon
bond-forming reaction, especially suited for the installation
of methyl-bearing stereogenic centers attached to an aro-
matic or cycloalkene ring. In the latter class of compounds,
the resident alkene provides further opportunities to control
the configuration at the carbon to which is attached the
methyl-bearing carbon. The resulting motif is ubiquitous
among many natural products, none exemplifying this bet-
ter than serrulatane and amphilectane diterpenes. In this
paper, we present several examples of how the HV reaction
can be used to synthesize different classes of serrulatanes
and amphilectanes (Figure 3). Because of the availability
of easily tunable ligands (Figure 2) that control these HV
reactions, high yields and excellent diastereoselectivities
can be achieved for disparate intermediates, which are oth-
erwise difficult to prepare because of strong inherent stere-
ochemical preferences of certain chiral precursors. This
provides unprecedented opportunities for obtaining ligand-
dependent selectivities for making diastereoisomeric con-
geners of biologically active compounds. Among the novel
aspects which have not been disclosed before include the
following: (i) stream-lined synthesis of highly oxygenated
styrene derivatives (e.g. Scheme 2); (ii) biphenyl-based
phosphoramidite-nickel complexes (Scheme 4) that are
crucial for the HV reactions of sterically encumbered sub-
strates (Scheme 6); (iii) optimization of metal-ammonia
reduction procedures to control C4-configuration (Tables 1
and 3); (iv) synthesis of enantiomerically pure intermediate
36a, which has been converted into (+)-elisabethadione and
a (+)- p-benzoquinone natural product 7, and, 43a which
ASSOCIATED CONTENT
SUPPORTING INFORMATION
Experimental procedures, syntheses and isolation of all
intermediates. Spectroscopic and gas chromatographic data
showing compositions of products under various reaction
conditions. Crystallographic Information Files (.cif) for
compound 29 whose structure was determined by X-ray
crystallography. This material is available free of charge
via the Internet at http://pubs.acs.org
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AUTHOR INFORMATION
Corresponding Author
9
* rajanbabu.1@osu.edu
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(a) Ata, A.; Kerr, R. G.; Moya, C. E.; Jacobs, R. S.
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ORCID
10484.
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T. V. RajanBabu: 0000-0001-8515-3740
(a) Look, S. A.; Fenical, W.; Matsumoto, G. K.; Clardy, J.
J. Org. Chem. 1986, 51, 5140-5145. (b) Ata, A.; Win, H. Y.; Holt,
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Notes
The authors declare no financial interest.
† Present Addresses
(10)
Yang, M.; Yang, X. W.; Sun, H. B.; Li, A. Angew. Chem.
Souvagya Biswas, The Dow Chemical Company, Midland,
MI
Glen Adam Cox, Lubrizol Corporation, Cleveland, OH
Daniel J. Mans, FDA, St. Louis, MO
Hwan Jung Lim, KRICT, Daejeon, Korea
Int. Ed. 2016, 55, 2851-2855.
(11)
Pronin, S. V.; Shenvi, R. A. J. Am. Chem. Soc. 2012, 134,
19604-19606. This paper describes an exceptionally innovative
Diels-Alder route to the amphilectane isonitrile 11. Even though it
leads to a recemic product, this synthesis repesents the shortest route
to date (9 steps, 6.4% yield, lowest dr of an intermediate 88:12) to a
complex amphilectane. See Supporting Information Table S1B for
details.
Author Contributions
‡These authors contributed equally.
(12)
(13)
Rodríguez, A. D.; Ramírez, C. Org. Lett. 2000, 2, 507-510.
Rodríguez, A. D.; Ramírez, C.; Rodríguez, II; Barnes, C. L.
ACKNOWLEDGMENTS
J. Org. Chem. 2000, 65, 1390-1398.
(14)
Rodríguez, A. D.; González, E.; Huang, S. D. J. Org.
Financial assistance for this research provided by the US
National Institutes of Health (R01 GM108762) is gratefully
acknowledged. We thank Dr. Judith Gallucci for determi-
nation of the solid-state structures of 29 and 57. We like to
thank two of the reviewers who suggested changes that
make this a more readable and useful publication.
Chem, 1998, 63, 7083-7091.
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(a) See Supporting Information for details. (b) A table
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H
Iterative asymmetric
hydrovinylation
OR1
OR1
OR2
5
6
7
8
[L*]Ni(II) X (cat.)
H
HO
X
OR2
X
R
Me
Serrulatanes
OR1
OR2
• Stereocontrol at
highlighted centers
• Red - carbons from
ethylene
• A biomimetic route to
psuedopterosin A-F
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Colombiasin
Elisapterosin
R3
Me
Amphilectanes C13 (R or S)
(e. g., Psedopterosins)
R4
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