Highly Selective Synthesis of Halomon, Plocamenone, and Isoplocamenone

Article abstract of DOI:10.1021/jacs.5b08398

Over 160 chiral vicinal bromochlorinated natural products have been identified; however, a lack of synthetic methods for the selective incorporation of halogens into organic molecules has hindered their synthesis. Here we disclose the first total synthesis and structural confirmation of isoplocamenone and plocamenone, as well as the first selective and scalable synthesis of the preclinical anticancer natural product halomon. The synthesis of these inter-halogenated compounds has been enabled by our recently developed chemo-, regio-, and enantioselective dihalogenation reaction.

Full text of DOI:10.1021/jacs.5b08398

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Communication
Highly Selective Synthesis of Halomon, Plocamenone, and Isoplocamenone
Cyril Bucher, Richard M. Deans, and Noah Z. Burns
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b08398 • Publication Date (Web): 23 Sep 2015
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Highly Selective Synthesis of Halomon, Plocamenone, and
Isoplocamenone
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Cyril Bucher, Richard M. Deans, and Noah Z. Burns*
Department of Chemistry, Stanford University, Stanford, California 94305
Supporting Information Placeholder
to isolate sufficient material from natural sources have
failed,3a,h likely due to local and seasonal variations in
terpene content.3g,h Although no comprehensive study on
the mechanism of action has been reported, insight is
gained by the discovery that halomon inhibits DNA me-
thyltransferase-1,4 an important target for cancer re-
search and therapy.5 Surprisingly, based on computa-
tional analysis of its cytotoxicity profile, researchers
have concluded that the activity of 1 is unlikely to stem
from it acting as a non-specific alkylating agent.3b,6 Ex-
perimental investigations into the validity of this state-
ment have not been conducted.
ABSTRACT: Over 160 chiral vicinal bromochlorinated
natural products have been identified, however a lack of
synthetic methods for the selective incorporation of hal-
ogens into organic molecules has hindered their synthe-
sis. Here we disclose the first total synthesis and struc-
tural confirmation of isoplocamenone and plocamenone,
as well as the first selective and scaleable synthesis of
the preclinical anticancer natural product halomon. The
synthesis of these interhalogenated compounds has been
enabled by our recently developed chemo-, regio-, and
enantioselective dihalogenation reaction.
FIGURE 1. Structures of halomon, plocamenone, and
isoplocamenone and our approach to such motifs.
Over the course of the past few decades, a plethora of
halogenated natural products have been isolated, primar-
ily from marine sources.1a–c Roughly 240 contain chiral
vicinal dihalide motifs, with the majority (ca. 70%) be-
ing bromochlorinated terpenes.1d Many of these
interhalogenated compounds are reported to possess
promising biological activity including unique cytotoxi-
city profiles. Additionally, such molecules pose exquisite
challenges to selective synthesis and structural charac-
terization. This is highlighted by the lack of strategies
that provide stereocontrolled access to relevant halogen-
ated motifs and by the repeated misassignment of such
natural products.
Me
Br
O
Me
Cl
Cl
Cl Me
Me
Cl
Cl
Br
(+)-1: halomon
Cl
Br
(E)-2: plocamenone
• Preclinical candidate
• No reliable sources
• No selective syntheses
• Repeatedly misassigned
• Absolute configuration unassigned
• No reported syntheses
Me
Cl
Cl Me
Cl
O
Br
1
(Z)-2: isoplocamenone
(from X-ray data2b
)
The most-studied molecule of this class, halomon (1,
Fig. 1), was originally isolated in 1975 from the red al-
gae Portieria hornemannii.2a Full structural data as well
as relative and absolute stereochemical assignments
were presented seventeen years later by the National
Cancer Institute upon its reisolation and crystallization.
In this study, 1 produced “one of the most extreme cases
of differential cytotoxicity”2b in the NCI-60 human tu-
mor cell line screen. Preliminary in vivo studies were so
encouraging that the compound was selected by the NCI
for preclinical drug development, but was dropped ex-
plicitly due to lack of sufficient material.3a Despite in-
tense interest in 1 from the scientific community,3 efforts
Selective di- and interhalogenation as direct access to relevant motifs:
X
Cl
Me
Me Cl
OH
Me
OH
chiral
OH
OH
catalyst
X
Me
X
X
Cl
OH
OH
X = Br or Cl
Cl
Two non-selective total syntheses of halomon have
been reported by Mioskowsky and Hirama.7 Both efforts
afford halomon as mixtures of all possible diastereo- and
enantiomers and rely on silica gel chromatography and
two consecutive semi-preparative HPLC separations
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with achiral followed by chiral columns to afford pure and elimination may be responsible for this isomeriza-
1
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(+)-1 in undisclosed amounts. Hirama reported a dis-
crepancy in optical rotation between synthetic and natu-
ral material, leading them to posit the originally isolated
halomon may have been impure. While this could call
into question the original NCI-60 screen, subsequent
NCI-60 screens with halomon from different sources
have revealed similar cytotoxicity profiles.7g,h,i
tion of the trisubstituted olefin.
In its most recent isolation and structural report,11
isoplocamenone was reported to be unstable, but no
mention of decomposition products was made. In light
of the apparent isomerization during the α-
methylenation, we suspected that isoplocamenone could
possibly convert into its double bond isomer ploca-
menone. Indeed, when irradiated with a flood lamp for
five days, a pure sample of isoplocamenone was found
In addition to providing material for biological evalua-
tion, total synthesis is an invaluable tool for the structur-
al assignment of natural produts.8 Noncrystalline linear
polyhalogenated terpenes are notoriously difficult to
characterize, as illustrated by numerous NMR studies
relying on comparison to synthetic halogenated model
systems for structure elucidation.2a,9 For example, the
cytotoxic agent plocamenone (E)-2 has been repeatedly
misassigned in the literature,9b,10 with the closest pro-
posed structure being the (Z)-isomer.10b More recently,
Urban isolated and characterized both double bond iso-
mers from Plocamium angustum and assigned the previ-
ously isolated compound, plocamenone, as the (E)-
isomer ((E)-2). The minor isomer, termed isoploca-
menone ((Z)-2) was reportedly prone to decomposi-
tion.11
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to isomerize to
a
3:1 mixture of ploca-
menone/isoplocamenone.16b These syntheses have also
established the absolute configuration of the natural
products as the shown enantiomers.17
SCHEME 1. Synthesis of (–)-plocamenone and (–)-
isoplocamenone.
A recent advance made in this laboratory allows for
the chemo-, regio-, and enantioselecive bromochlorina-
tion, dibromination, and dichlorination of allylic alco-
hols (Fig. 1, bottom).12 Here, this method is used strate-
gically to achieve the first total syntheses, structural con-
firmation, and determination of the natural enantiomer
of isoplocamenone and plocamenone. Further, we report
the first total synthesis of (+)-halomon with essentially
complete stereocontrol.
Selective syntheses of (–)-plocamenone and (–
)-isoplocamenone
Reagents and conditions: a. NBS (1.05 equiv), ClTi(Oi-
Pr)3 (1.10 equiv), 20 mol % (S,R)-3, hexanes, –20 °C, 64%;
b. Dess–Martin periodinane (DMP) (1.5 equiv), NaHCO3
(10.0 equiv), CH2Cl2, r.t.; c. diethyl (1-chloro-2-
oxobutyl)phosphonate (6) (2.0 equiv), sodium hexamethyl-
disilazide (NaHMDS) (1.4 equiv), THF, –78 °C to 0 °C,
70% from 5; d. trimethylsilyl trifluoromethanesulfonate
(TMSOTf) (2.0 equiv), N,N-diisopropylethylamine (3.0
equiv), CH2Cl2, –78 °C to r.t.; 8 (5.0 equiv), –78 °C to r.t.;
e. iodomethane (5.0 equiv), N,N-diisopropylethylamine
(3.6 equiv), THF, r.t., 54% from 7; f. floodlamp, Et2O, 5
days, r.t.
We began our syntheses of plocamenone and
isoplocamenone with (S,R)-Schiff base 3-catalyzed bro-
mochlorination12b of known allylic alcohol 4 (Scheme
1), which can be synthesized in one step from commer-
cially available isoprene oxide.13 Absolute configuration
was assigned through X-ray crystallographic analysis
(see Supporting Information). The resulting alcohol 5
was then oxidized with Dess–Martin periodinane and
subjected to Horner–Wadsworth–Emmons olefination
with 614 to yield ketone 7 in a 13:1 ratio of double bond
isomers (see Supporting Information for nOe structural
assignment). Treatment with Eschenmoser’s chloride
salt (8) and subsequent activation with iodomethane and
elimination15 yielded a separable 1:2 mixture of ploca-
menone ((E)-2) and isoplocamenone ((Z)-2).16a The use
of Eschenmoser’s iodide salt produced a significantly
messier reaction mixture but showed no signs of double
bond isomerization. This leads us to surmise that conju-
gate addition of chloride followed by C–C bond rotation
Selective synthesis of (+)-halomon
Our highly selective route to halomon starts with
known allylic alcohol 9,18 which was bromochlorinated
according to reported conditions12b with (R,S)-Schiff
base 3 to provide 10 in 90% ee on multigram scale
(Scheme 2). It was found that the resulting bromochlo-
roalcohol could be deoxygenated in nearly quantitative
yield via activation as the trifluoromethanesulfonate es-
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Journal of the American Chemical Society
ter followed by treatment with L-selectride.19 The result-
ferrocenecarboxylate derivative 14a (Scheme 3, top).
1
ing bromochlorinated myrcene derivative 11 was taken
on without purification and subjected to a formal 1,4-
bromohydration sequence,20 which occurs via dibromide
13 in moderate overall yield but excellent selectivity for
the trans double bond isomer 12 which is readily isola-
ble in pure form. Several aspects of this sequence are of
note. The initial 1,4-dibromination to 13 is highly selec-
tive for the E-isomer, presumably due to dibromination
occuring on the s-trans conformational isomer of 11.
Bromide displacement with acetate occurs with high
selectivity for the less-hindered terminal allylic site, but
at high conversion subsequent displacement of the se-
cond allylic bromide occurs, prompting us to stop this
reaction prior to full conversion. In our hands, direct
bromoacetylation of 11 with acetyl hypobromite gave
mixtures of 1,4- and 1,2-bromoacetylated products.
We have identified this derivatization as being particu-
larly valuable in cases where common benzoate and sul-
fonate derivatives fail to induce adequate crystallinity.
Alcohol 14 was then converted to the primary trifluoro-
methanesulfonate ester and selectively eliminated with
aqueous hydroxide in the presence of five alkyl halides
to afford (+)-halomon (1). The route thus developed has
allowed for the synthesis of 400 mg of pure (+)-1. In
initial biological activity investigations (K562 human
leukemia), we have repeatedly measured 50% growth
inhibitory concentrations of 1.3–2.3 ꢀm, closely match-
ing the originally reported 1.2 ꢀm.2b We also have used
this chemistry to synthesize unnatural enantiomer (–)-1
demonstrating the power of the developed dihalogena-
tion reaction in this context.21 The stage is now set for
the synthesis of other unnatural stereoisomers as well as
analogues for structure–activity relationship and target-
identification studies.22
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SCHEME 2. Synthesis of (+)-halomon.
Our first strategy toward a selective synthesis of
halomon involved attempted double bromochlorination
of bis-allylic alcohol 15 (Scheme 3, bottom). Likely due
to poor solubility of the substrate in the reaction solvent,
the diastereoselectivity of the reaction was found to be
poor. Whereas a 20 mol % ligand loading afforded a 1:1
mixture of diastereomers, the best result was obtained
with 100 mol %, giving a meager ratio of 3:1 favoring
the desired diastereomer 16 (confirmed via X-ray crys-
tallographic analysis, Scheme 3). The identity of the
minor diastereomer was not unambiguously determined.
Scheme 3. Stereochemical confirmation of 14 and a
first generation approach to halomon.
Br
O
Me
O
Cl
Cl
Cl
DMAP
Me
O
14
+
Br
14a
Cl
Fe
Fe
Reagents and conditions: a. NBS (1.05 equiv), ClTi(Oi-
Pr)3 (1.10 equiv), 20 mol % (R,S)-3, hexanes, –20 °C, 73%;
b. triflic anhydride (1.2 equiv), 2,6-lutidine (1.5 equiv),
CH2Cl2, –78 °C; c. L-selectride (2.2 equiv), THF, –78 °C,
crude 95% from 10; d. Br2, K2CO3, hexanes, –78 °C; e.
Lithium acetate (1 equiv), DMF, 0 °C; f. K2CO3 (1 equiv),
methanol, 0 °C to r.t., 39% 12 + 22% 13; g. t-BuOCl (1.5
equiv), ClTi(Oi-Pr)3 (1.10 equiv), 30 mol % (S,R)-3, hex-
anes, –20 °C, 82%; h. triflic anhydride (1.2 equiv), 2,6-
lutidine (1.5 equiv), CH2Cl2, –78 °C; i. sodium hydroxide,
H2O, THF, 0 °C to r.t., 69% from 14.
(X-ray)
(X-ray)
Br
Cl
(R,S)-3 (20 mol %)
NBS, ClTi(Oi-Pr)3
Me
Cl Me
HO
OH
HO
OH
hexanes, –20 °C
(50%, 1:1 dr)
Br
16 (desired diast.)
15
Bromohydrin 12 was then subjected to dichlorination
conditions12b with (S,R)-Schiff base 3 to give alcohol 14
in >20:1 diastereomeric ratio. In the absence of chiral
ligand an inseperable 1:1 mixture of dichloride dia-
stereomers was obtained. Other dichlorination condi-
tions such as Et4NCl3 also resulted in no diastereoselec-
tivity. At this point, the absolute and relative configura-
tion was confirmed by X-ray crystal structure analysis of
The chemo-, enantio-, and regioselective di- and
interhalogenation developed in this laboratory has prov-
en to be an invaluable tool for the synthesis of stereo-
complex polyhalogenated natural products. It has ena-
bled the first total synthesis of isoplocamenone and
plocamenone, as well as the first selective and scaleable
total synthesis of halomon. The syntheses have made
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(6) Paull, K. D.; Shoemaker, R. H.; Hodes, L.; Monks, A.; Scu-
diem, D. A.; Rubinstein, L.; Plowman, J.; Boyd, M. R. J. Natl. Can-
cer Inst. 1989, 81, 1088–1092.
possible the structural confirmation of isoplocamenone
and plocamenone, the determination of their natural en-
antiomers, and the finding of an interesting photoisomer-
ization between the two compounds. In addition, the
synthesis reported here proved to be a reliable source of
pure (+)-halomon, allowing a total of more than 400 mg
to have been synthesized to date. This material will be
used in future studies toward answering important ques-
tions pertinent to the mechanism of action of halomon.
1
2
3
4
5
6
7
8
(7) (a) Schlama, T.; Baati, R.; Gouverneur, V.; Valleix, A.; Falck,
J. R.; Mioskowski, C. Angew. Chem. Int. Ed. 1998, 37, 2085–2087.
(b) Sotokawa, T.; Noda, T.; Pi, S.; Hirama, M. Angew. Chem. Int. Ed.
2000, 39, 3430–3432. (c) Hirama, M.; Togawa, N. JP3589592, 1999.
For studies towards the synthesis of 1, see: (d) Braddock, D. C.; Gao,
A. X.; White, A. J. P.; Whyte, M. Chem. Commun. 2014, 50, 13725–
13728. Also see: (e) Boyes, A. L.; Wild, M. Tetrahedron Lett. 1998,
39, 6725–6728. (f) For the first syntheses of acyclic polyhalogenated
Plocamium monoterpenes, see Ref. 3g. (g) Data obtained directly
from the NCI-60 database via: CellMiner Database Version 1.6.1.
http://discover.nci.nih.gov/cellminer (accessed August 18, 2015). (h)
Reinhold, W. C.; Sunshine, M.; Liu, H.; Varma, S.; Kohn, K. W.;
Morris, J.; Doroshow, J.; Pommier Y. Cancer Res. 2012, 72, 3499–
3511. (i) See Supporting Information for halomon NCI-60 data.
(8) Nicolaou, K. C.; Snyder, S. A. Angew. Chem. Int. Ed. 2005, 44,
1012–1044.
(9) (a) Crews, P.; Naylor, S.; Hanke, F. J.; Hogue, E. R.; Kno, E.;
Braslau, R. J. Org. Chem. 1984, 49, 1371–1377. (b) Naylor, S.; Ma-
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Sims, J. J. Tetrahedron Lett. 1984, 25, 153–156.
9
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ASSOCIATED CONTENT
Supporting Information. Experimental procedures, char-
acterizations, and spectral data. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
nburns@stanford.edu
Funding Sources
This work was supported by generous funds from Stanford
University and the National Institutes of Health (R01
GM114061 & R01 GM087934).
(11) Timmers, M. A.; Dias, D. A.; Urban, S. Mar. Drugs 2012, 10,
2089-2102.
ACKNOWLEDGMENT
(12) (a) Hu, D. X.; Shibuya, G. M.; Burns, N. Z. J. Am. Chem. Soc.
2013, 135, 12960–12963. (b) Hu, D. X.; Seidl, F. J.; Bucher, C.;
Burns, N. Z. J. Am. Chem. Soc. 2015, 137, 3795–3798.
(13) Mandal, A. K.; Schneekloth, J. S.; Kuramoji, K.; Crews, C. M.
Org. Lett. 2006, 8, 427–430.
(14) Prévost, S.; Gauthier, S.; Caño do Andrade, M. C.; Mordant,
C.; Touati, A. R.; Lesot, P.; Savignac, P.; Ayad, T.; Phansavath, P.;
Ratovelomanana-Vidal, V.; Genêt, J.-P.Tetrahedron: Asymmetry
2010, 21, 1436–1446.
(15) (a) Schreiber, J.; Maag, H.; Hashimoto, N.; Eschenmosher, A.
Angew. Chem. Int. Ed. 1971, 10, 330–331. (b) Danishefsky, S.; Kita-
hara, T.; McKee, R.; Schuda, P. F. J. Am. Chem. Soc. 1976, 98, 6715–
6717.
(16) (a) Conducting the α-methylenation in the dark yielded the
same 1:2 mixture of double bond isomers. (b) Irradiation for 12 hours
produced a 2:1 plocamenone/isoplocamenone ratio.
(17) Natural (E)-2: [α]D = –14.3° (c = 0.8) from Ref. 10a; synthetic
(E)-2: [α]D = –15.6° (c = 0.5, CHCl3) .
(18) Wender, P. A.; Croatt, M. P.; Witulski, B. Tetrahedron 2006,
62, 7505–7511.
(19) For the reduction of alkyl sulfonates with lithium triethyl-
borohydride, see: (a) Krishnamurthy, S.; Brown, H. C. J. Org. Chem.
1976, 41, 3064–3066. (b) Krishnamurthy, S. J. Organomet. Chem.
1978, 156, 171–181. For utility in synthesis, see: (c) Hua, D. H.; Si-
nai-Zingde, G.; Venkataraman, S. J. Am. Chem. Soc. 1985, 107,
4088–4090.
We are grateful to Dr. A. Oliver (University of Notre
Dame) for X-ray crystallographic analysis and Dr. S. Lynch
(Stanford University) for assistance with NMR spectrosco-
py.
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(20) Conditions adapted from: Doi, N.; Seko, S.; Kimura, K.;
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(21) Both enantiomers of synthetic halomon were analyzed by re-
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(Ref. 7b) and found to be of >99% ee (see Supporting Information).
(22) For example, silyl protection of 10 has allowed for the synthe-
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(4) Andrianasolo, E. H.; France, D.; Cornell-Kennon, S.; Gerwick,
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