Enantioselective divergent syntheses of several polyhalogenated plocamium monoterpenes and evaluation of their selectivity for solid tumors

Article abstract of DOI:10.1002/anie.201407726

The family of polyhalogenated monoterpenes from Plocamium counts over a hundred known members. Using glyceraldehyde acetonide as a chiral-pool precursor, an enantioselective and divergent strategy was developed that provides a blueprint for the synthesis of many of the small yet complex acyclic members of this family. The broad applicability of this approach is demonstrated with the short, eight-step synthesis of four natural products and three analogues. These syntheses are the first of any members of the acyclic polyhalogenated Plocamium monoterpenes and permitted the evaluation of their selectivity against a range of tumor cell lines. Glyceraldehyde acetonide serves as a chiral glyoxal equivalent and a linchpin for the enantioselective synthesis of several acyclic polyhalogenated monoterpenes from the red algae Plocamium. Several of these compounds demonstrate selective toxicity towards solid-tumor cell lines over leukemia cell lines, as well as low-micromolar cytotoxicity towards the HCT-116 human colon carcinoma cell line.

Full text of DOI:10.1002/anie.201407726

Angewandte
Chemie
DOI: 10.1002/anie.201407726
Natural Product Synthesis
Hot Paper
Enantioselective Divergent Syntheses of Several Polyhalogenated
Plocamium Monoterpenes and Evaluation of Their Selectivity for Solid
Tumors**
Carl V. Vogel, Halina Pietraszkiewicz, Omar M. Sabry, William H. Gerwick,
Frederick A. Valeriote, and Christopher D. Vanderwal*
Abstract: The family of polyhalogenated monoterpenes from
Plocamium counts over a hundred known members. Using
glyceraldehyde acetonide as a chiral-pool precursor, an
enantioselective and divergent strategy was developed that
provides a blueprint for the synthesis of many of the small yet
complex acyclic members of this family. The broad applic-
ability of this approach is demonstrated with the short, eight-
step synthesis of four natural products and three analogues.
These syntheses are the first of any members of the acyclic
polyhalogenated Plocamium monoterpenes and permitted the
evaluation of their selectivity against a range of tumor cell lines.
I
n 1973, Faulkner reported the discovery of (3R,4S,7S)-3,7-
dimethyl-1,8,8-tribromo-3,4,7-trichloro-(1E,5E)-octadiene
(1, Figure 1) from the digestive glands of the sea hare Aplysia
californica as the first in a series of polyhalogenated mono-
terpenes.[1] Shortly thereafter, it became clear that these types
of secondary metabolites were the products of red algae from
the genus Plocamium, a major food source for the sea hares.[2]
In the time since, over a hundred highly halogenated
monoterpenes, both cyclic and acyclic, have been isolated
Figure 1. Representative acyclic polyhalogenated monoterpenes from
Plocamium and the related natural product halomon with its biogene-
sis from myrcene. A, B, X, Y=Cl, Br, or H.
from many different Plocamium species and from various
locations.[3]
The family of acyclic polyhalogenated monoterpenes
gained some renown in the 1990s with the discovery that
halomon (2) had a unique profile of cytotoxicity when tested
against the NCI 60-cell line. It demonstrated particular
selectivity for cell lines that are typically resistant to chemo-
therapy (renal, brain, colon, and non-small-cell lung cancer),
with less efficacy towards leukemia and melanoma lines.[4,5]
Isolated from the red alga Portieria hornemannii, this com-
pound was the subject of preclinical development at the NCI.
The biogenesis of halomon from myrcene (3) is easily
explained by sequential bromochlorination of each alkene
followed by a single elimination of HBr (3!2). This
hypothesis was used as an inspiration for the exceptional
three-step synthesis of racemic halomon by Hirama and co-
workers.[6] The biogenesis of many of the Plocamium mono-
terpenes (including 1) is not so easily explained,[3] and
a straightforward laboratory conversion of an acyclic mono-
terpene feedstock into these targets is not likely.
[*] C. V. Vogel, Prof. C. D. Vanderwal
1102 Natural Sciences II, Department of Chemistry
University of California, Irvine
Irvine, CA 92697 (USA)
E-mail: cdv@uci.edu
H. Pietraszkiewicz, Dr. F. A. Valeriote
Division of Hematology and Oncology
Department of Internal Medicine, Henry Ford Hospital
Detroit, MI 48202 (USA)
Prof. W. H. Gerwick
Center for Marine Biotechnology and Biomedicine, Scripps
Institution of Oceanography, University of California, San Diego
La Jolla, CA 92093 (USA)
O. M. Sabry[+]
College of Pharmacy, Oregon State University
Corvallis, OR 97331 (USA)
[+] Current address: College of Pharmacy, Cairo University
Cairo, 11562 (Egypt)
[**] This work was supported by the NIH (R01 GM086483 to C.D.V., F31
CA174176 to C.V.V., and R01 CA100851 to W.H.G. and F.A.V.) and by
the UC Cancer Research Coordinating Committee (to C.D.V.). We
thank Dr. John Greaves for support with mass spectrometry and Dr.
Joseph Ziller and Jordan Corbey for assistance with X-ray crystal-
lography.
Syntheses of the acyclic polyhalogenated Plocamium
monoterpenes have not yet been described,[7,8] in spite of
their reported anticancer and antimalarial activities.[9,10]
Previously unpublished work from two of our laboratories
established that isomeric compounds 4 and 5[2] are selectively
cytotoxic to several solid tumor cell lines,[11] as defined by the
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201407726.
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selectivity, with the eventual goal of performing mechanism-
of-action and pharmacological studies on the most promising
candidates. Herein, we describe a simple strategy for the
enantioselective and divergent synthesis of many of these
natural products from glyceraldehyde acetonide, with proof-
of-principle execution resulting in access to four different
natural products and three analogues.
In considering a synthesis of compounds of type 4 and 5,
we recognized multiple challenges in spite of the small
molecular size of the targets. First, the vicinal secondary and
tertiary chloride-bearing centers at the C3 and C4 positions,
which are present in both the syn and anti diastereomeric
forms within this family of natural products,[2,3,10] are both
allylic and might cause undesired reactivity. Second, the
ꢀ
extensive halogenation on either side of the “central” C5 C6
alkene appears to necessitate a convergent approach; how-
ever, the method chosen to unite two precursor fragments
must be tolerant of the potentially reactive halogen atoms.
Third, as we wanted to access tens or hundreds of milligrams
of many different natural (and unnatural) polyhalogenated
Plocamium monoterpenes for biological evaluation, we
placed a premium on the development of a short and scalable,
yet divergent sequence that could effectively provide access
to dozens of different targets. The culmination of our work to
address these challenges is the flexible approach shown in
Scheme 1, which permits access to both enantiomeric series,
both diastereomeric forms of the C3/C4 vicinal dichloride,
and a wide range of halogen substitutions at the C1, C8, and
C10 positions. It features the non-obvious use of glyceralde-
hyde acetonide as the source of the C4 and C5 carbon atoms,
as a formal “chiral glyoxal” equivalent that permits the
stereocontrolled introduction of the C3 and C4 chlorine-
bearing stereogenic centers, and as a linchpin for the entire
synthesis.
Scheme 1. Divergent synthesis plan for the Plocamium monoterpenes.
Colored regions are diversifiable. A, B, X, Y=Cl, Br, or H.
disk diffusion assay pioneered by Valeriote and co-workers.[12]
Our goal in this work was to generate many more compounds
of this series (the natural variability is shown by general
structure 6). We targeted a significant array of natural and
unnatural analogues for further testing of activity and
Mannitol diacetonide (7; Scheme 2a) has previously been
converted into allylic alcohol 8 by oxidative cleavage to
Scheme 2. a) General sequence for the synthesis of polyhalogenated monoterpenes. *: Olefination product 13b is contaminated by about 10% of
the elimination product (conjugated trienone). b) Examples of five completed targets, with yields for the final olefination steps. Geometrical
isomers 15/16 and 17/18 were completely separated by HPLC. TFAA=trifluoroacetic anhydride.
2
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glyceraldehyde acetonide, stereoselective olefination, and
ester reduction.[13] Dichlorination of the free allylic alcohol 8,
although highly diastereoselective, was plagued with com-
petitive oxidation to an enal[14] that resisted chlorination; this
undesired reactivity could not be prevented by tuning of the
reaction conditions. Therefore, a one-pot sequence of in situ
trifluoroacetylation, dichlorination, and deacylation was
developed, which afforded higher overall yields and high
selectivity (> 10:1 d.r.). It is likely that the minimization of
1,3-allylic (A1,3) strain[15] in substrate 8 and its trifluoroacety-
lated derivative is important, and although the outcome
mirrors the studies of Chamberlin and Hehre on the
iodofunctionalization of allylic alcohols,[16,17] the mechanism
underlying stereocontrol is not completely understood. X-ray
crystallographic analysis on a mesylated derivative of alcohol
9[18] enabled the unequivocal assignment of the absolute and
relative configuration for compounds produced by this
synthetic route.
Oxidation of alcohol 9 to aldehyde 10 was followed by
methylenation or bromomethylenation to afford products
11a or 11b, respectively. Direct oxidative cleavage of the
dioxolane produced sensitive aldehydes 12a/12b in high yield.
Olefination of these products was plagued by b-elimination
under many conditions examined; however, the use of NaH in
toluene with the Horner–Wadsworth–Emmons reagent
shown provided enones 13a/13b in good yields with high
levels of stereocontrol. Finally, methylenation or chlorome-
thylenation provided targets 14–18 in the yields shown in
Scheme 2b. The chloromethylenation products were obtained
as mixtures at the newly formed alkenes, but they could be
separated easily by preparative HPLC.[19] Compounds 14–16
and 18 are known natural products,[2,3,10] but 17 has not yet
been reported.
lished by X-ray crystallographic analysis of the corresponding
aldehyde obtained by oxidation.[23] Dichloroalcohol 20 was
converted into 21 and 22 by similar reactions to those shown
in Scheme 2.[23,24] The final products thus produced are in the
unnatural enantiomeric series because we used the same
enantiomer of glyceraldehyde acetonide as we did for 14–18.
Clearly, natural products in both diastereomeric series, as well
as in both enantiomeric forms, are available by this route,
because glyceraldehyde acetonide is readily available in both
mirror-image forms. Each of the target molecules (14–18, 21,
and 22) was obtained in only six steps from allylic alcohols 8
or 19 (eight steps from inexpensive commercially available
mannitol derivative 7). Although some of the steps proceeded
in only moderate yields, and the chemistry is “classical”, these
small but complex molecules have never been synthesized
before, and the sequence is direct enough to procure plenty of
material for biological evaluation.[25]
Stereocontrolled access to the chloride-bearing stereo-
genic centers at the C3 and C4 positions of the Plocamium
monoterpenes would not be easily accomplished by other
existing methods. The two best currently available methods to
obtain vicinal dichlorides in enantioenriched form—the
asymmetric dichlorination of allylic alcohols put forth by
the Nicolaou group[26] and the stereospecific deoxydichlori-
nation of epoxides developed by the Yoshimitsu group[27]—do
not appear to tolerate the formation of tertiary chlorides, such
as that at the C3 position. Moreover, the ready availability of
substrate 8 and the utility of the dioxolane for more than just
the control of diastereoselectivity in the dichlorination (see
below) is particularly attractive.
Although the synthesis of a ten-carbon target by four
classical olefination reactions might seem far from ideal, this
approach permits maximum divergence both with respect to
constitution and configuration (Scheme 1) and suffers from
few non-productive operations. The biggest liability, at this
stage of development, is the lack of stereocontrol in the final
olefination step; this apparent problem is mitigated by the
fact that many of these natural products are found in both
The synthesis shown in Scheme 2 is highly divergent and
will provide access to many more naturally occurring
polyhalogenated natural products from Plocamium as well
as unnatural analogues. However, there remains another
important aspect of our design: The Z-isomer of allylic
alcohol 8 is also readily available (see 19, Scheme 3),[20–22] and
we have shown that it also undergoes stereocontrolled
dichlorination to procure the syn-configured C3/C4 dichlor-
ide 20. The relative configuration of product 20 was estab-
[2,3]
ꢀ
C7 C8 isomeric forms,
and that the isomers are readily
separable. Furthermore, in the context of compounds 4 and 5
at least, these isomers are known to readily equilibrate upon
exposure to minimally acidic medium.[19] Overall, the strate-
gic use of glyceraldehyde acetonide as a chiral glyoxal
equivalent is significant; it not only plays the role of a chiral
auxiliary to control the absolute configuration of the C3/C4
dichloride, it also serves as a truly effective linchpin for our
short synthesis by virtue of the one-step conversion of the
dioxolane into an aldehyde. At current count, we have made
four naturally occurring polyhalogenated Plocamium mono-
terpenes, one that is likely to be an as yet undiscovered
natural product, and two unnatural enantiomers, thereby
showcasing the generality of our approach.
Compounds 14–16 were subjected to the disk diffusion
assay, which provides an indication of the selectivity of
compounds for human solid-tumor cell lines compared with
the CCRF–CEM human leukemia cell line. These data were
compared with the data obtained for halomon (2) and
compound 4 using the same assay (Table 1).[11,28] All five
compounds exhibited selectivity for solid tumors, with some
Scheme 3. Synthesis of 3,4-syn Plocamium monoterpenes 21 and 22
through diastereocontrolled dichlorination of Z-allylic alcohol 19. See
the Supporting Information for details.
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[8] Significant work has been reported
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R. W. Geisser, E. M. Carreira,
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Compound H116 H125 MCF-7 LNCaP OVC-5 U251N MDA PANC-1 HepG2 IC50
[mgmLꢀ1
]
halomon (2)
4
14
15
16
?
?
?
?
?
?
?
?
?
?
?
?
?
?
?
?
?
?
?
?
?
?
?
?
?
0.37[c]
1.3
15
1.3
3.6
?
?
?
?
?
?
?
[a] H116: HCT-116 human colon carcinoma; H125: human non-small-cell lung carcinoma; MCF-7:
human breast adenocarcinoma; LNCaP: androgen-sensitive human prostate adenocarcinoma; OVC-5:
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carcinoma; PANC-1: human pancreatic carcinoma; HepG2: human hepatocellular carcinoma. [b] The
disk-diffusion soft-agar colony formation assay is used to identify compounds that are selective for solid-
tumor lines. The observation of a substantial difference in the zone of growth inhibition between solid-
tumor cell lines and leukemia cell lines indicates solid-tumor selectivity. See the Supporting Information
for raw data. [c] Insufficient amounts of halomon were available to determine its IC50 value against HCT-
116 cells in our laboratories; this value is taken from Ref. [4].
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for PANC-1, whereas all were selective for LNCaP, OVCAR-
5, and U251N tumor cells with respect to the leukemia cell
line. Of the three synthetic compounds evaluated, 15 proved
to be the most potent, with an IC50 value of 1.3 mgmLꢀ1
against the HCT-116 colon carcinoma cell line, and it
demonstrated similar activity to previously isolated com-
pound 4. This level of activity, coupled with the good
selectivity for solid tumors, is sufficient to warrant further
studies, including the development of a detailed SAR profile
for this class of compounds and the synthesis of more
bioavailable analogues. Our versatile synthesis is ideal to
fuel these studies.
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[11] For the purpose of testing, compounds 4 and 5 were reisolated
from P. cartilagineum.
Received: July 29, 2014
[12] F. A. Valeriote, K. Tenney, J. Media, H. Pietraszkiewicz, M.
Edelstein, T. A. Johnson, T. Amagata, P. Crews, J. Exp. Ther.
Oncol. 2012, 10, 119 – 134.
Revised: August 20, 2014
Published online: && &&, &&&&
[13] H. Nemoto, A. Satoh, M. Ando, K. Fukumoto, J. Chem. Soc.
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36, 2342 – 2344; Angew. Chem. 1997, 109, 2440 – 2442.
Keywords: antitumor agents · chlorination · olefination ·
stereocontrol · total synthesis
.
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[17] In our early work towards the chlorosulfolipids, we found that Z-
allylic esters underwent diastereocontrolled dichlorination; see:
G. M. Shibuya, J. S. Kanady, C. D. Vanderwal, J. Am. Chem. Soc.
2008, 130, 12514 – 12518.
[18] See the Supporting Information for this X-ray crystal structure.
When the dichlorination reaction was performed on a multi-
gram scale, enough of the minor diastereomer was obtained for
X-ray crystallographic analysis of its mesylate. This structure can
also be found in the Supporting Information.
[1] a) D. J. Faulkner, M. O. Stallard, Tetrahedron Lett. 1973, 14,
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[19] Facile isomerization of the Z-isomer (5) to the E-isomer (4)
under mildly acidic conditions has been reported for very similar
systems in studies in the Gerwick laboratory; see: O. M. Sabry,
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4
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[20] Compound 19 is known, but has not been made with high
stereoselectivity; see: S. Takano, A. Kurotaki, M. Takahashi, K.
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4343 – 4346.
[22] We generated compound 19 through a reasonably Z-selective
(6:1) Horner–Wadsworth–Emmons olefination, which is much
more economical than the corresponding modified Still–Gennari
reaction. See the Supporting Information for details.
and 22, and the fact that in many cases both geometrical isomers
are isolated from the same source, it is reasonable to assume that
both 17 and ent-21 are natural products that have not yet been
described in the literature.
[25] For example, we have made ca. 40 mg of compound 15 by this
route, without any attempt to scale up the synthesis.
[26] K. C. Nicolaou, N. L. Simmons, Y. Ying, P. M. Heretsch, J. S.
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[28] A mixture of compounds 4 and 5 and each separate compound
were tested and showed similar selectivity to that shown for 4 in
Table 1. However, there was only enough material to do the
complete set of assays, including IC50 determination, for com-
pound 4.
[23] Please see the Supporting Information for details.
[24] The enantiomer of 21 has not yet been reported, but that of 22 is
known (see Ref. [2]). On the basis of the ready equilibration of
the “left-hand” trichloropropenyl moieties found in 15–18, 21,
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Communications
Natural Product Synthesis
C. V. Vogel, H. Pietraszkiewicz,
O. M. Sabry, W. H. Gerwick,
F. A. Valeriote,
C. D. Vanderwal*
&&&& — &&&&
Glyceraldehyde acetonide serves as
a chiral glyoxal equivalent and a linchpin
for the enantioselective synthesis of sev-
eral acyclic polyhalogenated monoter-
penes from the red algae Plocamium.
Several of these compounds demonstrate
selective toxicity towards solid-tumor cell
lines over leukemia cell lines, as well as
low-micromolar cytotoxicity towards the
HCT-116 human colon carcinoma cell
line.
Enantioselective Divergent Syntheses of
Several Polyhalogenated Plocamium
Monoterpenes and Evaluation of Their
Selectivity for Solid Tumors
6
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