Total synthesis of 1-O-methyllateriflorone

Article abstract of DOI:10.1002/anie.200351805

The unique spiroxalactone framework of lateriflorone (1) consists of a prenylated dihydrobenzoquinone moiety and a trioxatetracyclotetradecane system. A tandem Claisen rearrangement/Diels-Alder cascade was the key step in the synthesis of the complex tetr

Full text of DOI:10.1002/anie.200351805

Angewandte
Chemie
Natural Product Synthesis
easier bridge to forge between the two domains of the
molecules. The retrosynthetic analysis began with the dis-
connection of the spiroxalactone moiety by rupturing its
Total Synthesis of 1-O-Methyllateriflorone**
ꢀ
ethereal C O bond, thus unraveling prenylated quinone 3 as a
possible precursor (Scheme 1). The next rational disconnec-
tions, namely retro-aromatization of 3 and disassembly of its
precursor 4 at the ester bond led to fragments 5 and 6 as
suitable starting materials. Given our previous studies on
forbesione,[2,3] a naturally occurring substance related to the
present target, the cage ring system 6[4] can be traced to the
benzenoid compound 7. The coupling partner 5 can be
obtained from a simple benzene derivative.
K. C. Nicolaou,* Pradip K. Sasmal, Hao Xu,
Kenji Namoto, and Andreas RitzØn
With its unique spiroxalactone framework carrying a prenyl-
ated dihydrobenzoquinone moiety and
a
trioxatetra-
cyclo[7.4.1.02,7.02,11]tetradecane system, lateriflorone (1) rep-
resents an unusual synthetic challenge. Reported in 1999, this
novel natural product[1] was isolated from the stem bark of
Garcinia Lateriflora Bl (Guttiferae) collected from Indonesia,
and it exhibits potent cytotoxicity against the P388 cancer cell
line (ED50 = 5.4 mgmLꢀ1). Its seemingly fragile structure was
secured by spectroscopic and X-ray crystallographic analysis.
The secret of its stability, particularly at the spiroxalactone–
dihydroquinone junction, is probably due to the syn arrange-
ment between the C2’ proton and the C3’ ester grouping
which locks the leaving group in place, avoiding the b-
elimination pathway that may lead to its rupture. The
intriguing structural features of lateriflorone, coupled with
its biological activity, prompted us to seek a possible pathway
for its construction in the laboratory. Herein we report our
findings thus far in this project, including the first total
synthesis of 1-O-methyllateriflorone (2).
Scheme 1. Retrosynthetic analysis of lateriflorone (1).
We planned our synthesis of 1-O-methyllateriflorone (2)
based on the expectation that the ester bond would be the
The required prenylated 2,2’-dimethybenzopyran frag-
ment 5 was synthesized as summarized in Scheme 2. Thus, 2,3-
dihydroxybenzaldehyde (8) was selectively benzylated at the
3-position according to a literature procedure[5] to afford
compound 9, which was converted into bromophenol 10 in
61% overall yield by the following sequence: a) bromination
para to the phenolic group; b) protection as a MOM ether,
c) oxidation with m-CPBA; and d) cleavage of the resulting
formate ester with NaHCO3 (for abbreviations of reagents
and protecting groups, see legends in schemes). Protection of
the phenolic group in 10 as a TIPS ether to form 11 proceeded
smoothly under standard conditions (TIPSCl, imid, 96%).
Boronation of 11 required premixing of the substrate with
B(OiPr)3 prior to addition of tBuLi in Et2O at ꢀ788C. The
resulting borate derivative was then oxidized with H2O2 under
basic conditions (NaOH), and the resulting phenolic product
was methylated to afford 12 in 76% overall yield from 11.
[*] Prof. Dr. K. C. Nicolaou, Dr. P. K. Sasmal, H. Xu, Dr. K. Namoto,
Dr. A. RitzØn
Department of Chemistry and
The Skaggs Institute for Chemical Biology
The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, CA92037 (USA)
Fax: (+1)858-784-2469
E-mail: kcn@scripps.edu
and
Department of Chemistry and Biochemistry
University of California, San Diego
9500 Gilman Drive, La Jolla, CA92093 (USA)
[**] We thank Dr. D H. Huang and Dr. G. Siuzdak for NMR
spectroscopic and mass spectrometric assistance, respectively, and
Dr. R. K. Chadha for X-ray crystallographic analysis. Financial
support for this work was provided by The Skaggs Institute for
Chemical Biology and the National Institutes of Health (USA).
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DOI: 10.1002/anie.200351805
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propargylic ether 13 in 76% overall yield. Heating of the
latter compound in refluxing xylene induced a Claisen
rearrangement,[7] furnishing, after desilylation with TBAF,
benzopyran derivative 14 in 93% overall yield. Finally, a
second propargyl ether was introduced in 14; selective
reduction (H2, Lindlar catalyst) of the acetylenic group to
the corresponding olefin and Claisen rearrangement under
thermal conditions provided the targeted prenylated benzo-
pyran segment 5 in 53% overall yield.
The sequence devised and executed for the synthesis of
precursor 7 is shown in Scheme 3. Thus, 2,3,4-trihydroxybenz-
aldehyde (15) was perbenzylated (K2CO3, BnBr, KI) and then
selectively debenzylated at the position adjacent to the
aldehyde group by the action of MgBr2·Et2O. Subsequent
para bromination (Br2, NaOAc) and reduction of the
aldehyde with NaBH4 afforded dihydroxy compound 16 in
57% overall yield. Acetonide formation (Me2C(OMe)2,
TsOH) followed by lithium–halogen exchange (nBuLi),
borate formation (B(OMe)3), and oxidation (H2O2, NaOH)
led to phenolic substrate 17 in 86% overall yield. Methylation
of 17 followed by hydrogenolysis of its benzyl ethers led to
dihydroxy derivative 18 in 97% overall yield. The dipotas-
sium salt of 18, generated by addition of KOtBu, was
suspended in acetonitrile and treated with bromoisobutyr-
aldehyde in the presence of 18[crown]-6 to afford a mixture of
regioisomeric lactols 19a,b (ca. 1:1, 70% yield), which
reacted with methylene phosphorane (MeP+Ph3Brꢀ,
NaHMDS) to provide olefins 20a,b (ca. 1:1, 75% yield).
Reiteration of the last two steps furnished, via 21a,b, the
required dialkene 7 in 60% overall yield.
Upon heating in DMF at 1208C, the methoxy derivative 7
entered into the expected Claisen rearrangement/Diels–
Alder cascade[3,8] leading through the indicated intermediate
products to 6 and 6’ in 47 and 42% yields, respectively
(Scheme 4). X-ray crystallographic analysis of 6’[9] (see
ORTEP drawing, Scheme 4) revealed its structure, and, by
extension, that of 6; both structures 6 and 6’ were also
supported by NOE studies (see Scheme 4). Selective removal
of the acetonide group from 6 (TsOH, MeOH), followed by a
two-step oxidation protocol (1) DMP, 2) NaClO2), led to
hydroxy carboxylic acid 22 in 91% overall yield. An
analogous sequence to that shown in Schemes 3 and 4 was
originally employed to construct the dihydroxy acid 22a.
Attempted coupling of this fragment, 22a), with the phenolic
domain 5 (see Scheme 2), however, proved futile, presumably
as a result of complications instigated by the free hydroxy
group adjacent to the ketone moiety. Thus, this problem led to
the targeting and adoption of the methoxy counterpart of this
compound, substrate 22, for our subsequent studies. The
coupling of 22 with benzopyran system 5 (see Scheme 2) was
smoothly realized under the influence of EDC and 4-DMAP
(64% yield) to furnish the required advanced intermediate 4
as shown in Scheme 4.
Scheme 2. Synthesis of prenylated 2,2’-dimethylbenzopyran fragment
5: a) NaH (2.5 equiv), BnBr (1.0 equiv), THF, 258C, 48 h, 72%; b) Br2
(1.1 equiv), NaOAc (1.2 equiv), AcOH, 258C, 2 h; c) Et3N (5.0 equiv),
4-DMAP (0.1 equiv), MOMCl (3.0 equiv), 258C, 16 h; d) m-CPBA(1.1
equiv), 0!258C, CH2Cl2, 6 h; e) aqueous saturated NaHCO3, 16 h,
61% for four steps; f) TIPSCl (1.5 equiv), imid (2.0 equiv), DMF, 258C,
2 h, 96%; g) premix 11 and B(OiPr)3 (2.2 equiv) in diethyl ether; then
tBuLi (2.2 equiv) at ꢀ788C, 2 h, ꢀ78!08C, 1 h; then MeOH, aque-
ous NaOH (10%; 4.8 equiv), H2O2 (5.0 equiv), 08C, 30 min, 86%;
h) K2CO3 (10 equiv), MeI (10 equiv), acetone, 258C, 16 h, 88%;
i) Pd(OH)2/C (10 wt%; 10%), H2 (1 atm), EtOAc/EtOH (1:1), 258C,
30 min, 100%; j) propargyl alcohol (1.3 equiv), DBU (1.5 equiv), TFAA
(1.2 equiv), MeCN, 08C, 30 min; DBU (1.35 equiv), CuCl2 (0.01%
equiv), 10 min; then TFApropargyl ester, 4 h, 0 8C, 76% (90% based
on 84% conversion); k) xylene, 1408C, 30 min; l) TBAF (1.5 equiv),
THF, 08C, 5 min, 93% for two steps; m) propargyl alcohol (1.3 equiv),
DBU (1.5 equiv), TFAA (1.2 equiv), MeCN, 08C, 30 min; DBU
(1.35 equiv), CuCl2 (0.01% equiv), 10 min; then TFApropargyl ester,
4 h, 08C, 80% (90% based on 86% conversion); n) Lindlar catalyst
(10 wt%), H2 (1 atm), EtOAc, quinoline (3 equiv), 258C, 2 h, 95%;
o) DMF, 1208C, 1 h, 70%. Bn=benzyl, 4-DMAP=4-dimethylaminopyr-
idine, MOM=methoxymethyl, m-CPBA=m-chloroperbenzoic acid,
TIPS=triisopropylsilyl, imid=imidazole, DMF=N,N-dimethylforma-
mide, DBU=1,8-diazabicyclo[5.4.0]undec-7-ene, TFAA=trifluoracetic
anhydride, TBAF=tetra-n-butylammonium fluoride.
Having assembled the entire lateriflorone carbon skeleton
as expressed in compound 4, its MOM group was selectively
cleaved upon exposure to acidic conditions (HCl, MeOH/
Et2O) leading to a rapidly and spontaneously equilibrating
mixture of phenolic esters 23a,b (ca. 1:1, 96% yield)
(Scheme 4). Oxidation of this mixture under a variety of
Hydrogenolysis of the benzyl group in this new product
[6]
ꢁ
followed by reaction with CH CC(Me)2OCOCF3 in the
presence of DBU and CuCl2 resulted in the formation of
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Chemie
conditions[10] did not lead directly to the desired lateri-
florone molecular framework, but rather to an array of
other products, among which the most interesting were
those shown in Scheme 5. Thus, exposure of 23a,b to
PhI(OCOCF3)2 in CH2Cl2 led to benzoquinone 3 (Table
1) in 43% yield. Attempts to cyclize this substance under
Table 1: Selected data for compounds 2, 3, and 25.
2: Rf =0.19 (silica gel, EtOAc/hexanes 3:7); m.p.=173–1748C (Et2O/
hexane, uncorrected); 1H NMR (600 MHz, CDCl3): d=7.50 (s, 1H), 6.49
(d, J=9.8 Hz, 1H), 5.78 (d, J=9.8 Hz, 1H), 5.32 (br t, J=7.0 Hz, 1H),
4.66 (br t, J=7.0 Hz, 1H), 3.53 (s, 3H), 3.20 (dd, J=8.3, 3.1 Hz, 1H)
2.83 (m, 1H), 2.79 (m, 1H), 2.56 (m, 1H), 2.39 (dd, J=14.5, 7.0 Hz,
1H), 2.16 (d, J=13.0 Hz, 1H), 1.89 (d, J=9.9 Hz, 1H), 1.69 (s, 3H),
1.68 (s, 3H), 1.60 (dd, J=13.0, 9.9 Hz, 1H), 1.56 (s, 3H), 1.55 (s, 3H),
1.48 (s, 3H), 1.45 (s, 3H), 1.16 ppm (s, 3H), 1.14 ppm (s, 3H); 13C NMR
(150 MHz, CDCl3): d=200.7, 189.0, 186.7, 158.0, 150.9, 139.0, 136.5,
133.6, 134.0, 125.2, 123.0, 121.6, 116.0, 115.4, 101.3, 85.6, 84.7, 84.0,
82.8, 81.3, 57.4, 54.1, 48.6, 31.9, 30.0, 29.1, 28.3, 28.2, 27.8, 25.9, 25.8,
21.6, 18.1, 17.9 ppm; HRMS (MALDI): calcd for C34H40O9Na+: 615.2564
[M+Na+], found 615.2549
3: Rf =0.32 (silica gel, EtOAc/hexanes 3:7); 1H NMR (600 MHz, CDCl3):
d=7.50 (s, 1H), 6.45 (d, J=10.1 Hz, 1H), 5.63 (d, J=10.1 Hz, 1H), 5.43
(s, 1H, OH, D2O exchangeable), 4.99 (br t, J=7.5 Hz, 1H), 4.84 (br t,
J=7.2 Hz, 1H), 3.57 (s, 3H), 3.09–3.17 (m, 2H), 2.68 (dd, J=14.0, 6.9
Hz, 1H), 2.61 (dd, J=14.0, 7.9 Hz, 1H), 2.37 (d, J=13.0 Hz, 1H), 2.35
(d, J=10.1 Hz, 1H), 1.69 (s, 3H), 1.68 (dd, J=13.0, 10.1, Hz, 1H), 1.67
(s, 3H), 1.61 (s, 3H), 1.60 (s, 3H), 1.59 (s, 3H), 1.51 (s, 3H), 1.50 (s,
3H), 1.27 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=202.8, 182.8,
174.7, 162.5, 149.7, 146.7, 144.2, 135.6, 135.4, 135.3, 130.6, 128.7, 118.4,
117.2, 116.1, 115.0, 84.6, 84.2, 83.5, 82.7, 81.2, 54.0, 50.1, 31.4, 30.1,
29.2, 28.54, 28.53, 28.3, 26.1, 25.9, 23.5, 18.1, 17.9 ppm; HRMS
(MALDI): calcd for C34H40O9Na+: 615.2564 [M+Na+], found 615.2594
25: Rf =0.24 (silica gel, EtOAc/hexanes 3:7); m.p.=1548C (Et2O/
hexane, uncorrected); 1H NMR (500 MHz, CDCl3): d=7.47 (s, 1H), 6.25
(d, J=10.0 Hz, 1H), 5.84 (d, J=10.0 Hz, 1H), 5.24 (br t, J=6.5 Hz, 1H),
4.75 (br t, J=8.0 Hz, 1H), 3.60 (s, 3H), 3.53 (s, 3H), 3.24 (dd, J=15.0,
8.0 Hz, 1H), 2.99 (dd, J=15.0, 6.5 Hz, 1H), 2.84 (dd, J=13.5, 8.0 Hz,
1H), 2.40 (dd, J=13.5, 6.0 Hz, 1H), 2.13 (d, J=13.0 Hz, 1H), 2.08 (d,
J=9.5 Hz, 1H), 1.75 (dd, J=13.0, 9.5 Hz, 1H), 1.68 (s, 6H), 1.56 (s,
3H), 1.49 (s, 3H), 1.48 (s, 3H), 1.44 (s, 3H), 1.34 (s, 3H), 1.16 ppm (s,
3H); 13C NMR (125 MHz, CDCl3): d=201.5, 188.7, 159.0, 149.2, 140.4,
136.6, 136.1, 135.6, 132.6, 126.2, 124.7, 123.4, 121.7, 117.1, 116.2, 97.3,
85.2, 84.9, 84.0, 82.8, 78.0, 60.4, 54.0, 48.4, 31.9, 29.9, 28.3, 28.0, 27.7,
27.2, 26.0, 25.8, 24.5, 17.9, 17.8 ppm; HRMS (MALDI): calcd for
C35H43O9: 607.2901 [M+H+], found 607.2886
Scheme 3. Synthesis of intermediate 7: a) K2CO3 (5.0 equiv), BnBr
(5.0 equiv), KI (0.1 equiv), DMF, 258C, 24 h, 85%; b) MgBr2·Et2O (1.1 equiv),
diethyl ether, 258C, 10 h, 83%; c) Br2 (1.1 equiv), NaOAc (1.15 equiv), AcOH,
258C, 2 h, 89%; d) NaBH4 (1.5 equiv), EtOH, 0!258C, 30 min, 91%; e) 2,2-
dimethoxypropane (5.0 equiv), TsOH (0.01 equiv), CH2Cl2, 1 h, 95%; f) nBuLi
(1.1 equiv), diethyl ether, ꢀ788C, 2 h; then B(OMe)3 (3.0 equiv), 1 h, ꢀ78!
08C; then aqueous NaOH (10%; 4.8 equiv), H2O2 (5.0 equiv), 08C, 30 min,
90%; g) K2CO3 (5.0 equiv), MeI (10.0 equiv), DMF, 0!258C, 16 h, 99%;
h) Pd/C (10 wt%; 10%), H2 (1 atm), EtOAc, 258C, 45 min, 98%; i) tBuOK
(2.2 equiv), THF, 08C; then concentrated and suspended in MeCN; then
18[crown]-6 (2.2 equiv), 15 min, bromoisobutyraldehyde (5.0 equiv), 0!
258C, 1 h, 70%; j) CH3P+Ph3Brꢀ (3.0 equiv), NaHMDS (3.0 equiv), THF, 08C,
1 h, 75%; k) tBuOK (1.1 equiv), THF, 08C; then concentrated and suspended
in MeCN; then 18[crown]-6 (1.1 equiv), 15 min, bromoisobutyraldehyde
(5.0 equiv), 0!258C, 1 h, 75%; l) CH3P+Ph3Brꢀ (2.0 equiv), NaHMDS
(2.0 equiv), THF, 08C, 1 h, 80%. Ts=p-toluenesulfonyl, HMDS=hexamethyl-
disilazane.
a variety of conditions failed to produce the desired
lateriflorone skeleton, leading instead to a number of
other compounds whose description will have to await
the full account of this work.
Having failed to construct the desired 1-O-methyl-
lateriflorone (2) from quinone 3, we then proceeded to
investigate the possibility of casting this structural motif
from 23a,b via benzoquinone monoketal 24. To this end,
23a,b was exposed to PhI(OCOCF3)2 in MeOH/CH2Cl2
(1:1), which led to the formation of 24 (60% yield)
through the participation of a molecule of methanol.
Upon subsequent treatment with PPTS in refluxing
benzene under azeotropic conditions, 24 led to 25
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(Table 1) in 69% yield, together with
quinone 3, which was obtained in 11%
yield (Scheme 5). Pleasantly, com-
pound 25 crystallized as beautiful
yellow crystals whose X-ray crystallo-
graphic analysis[9] revealed its lateri-
florone-like molecular architecture,
including the correct stereochemistry
at C3’ (see ORTEP drawing, Scheme
5). However, an attempt to hydrolyze
the enol methyl ether within 25 under
acidic conditions (HCl (aq.)/THF) led
to red quinone ether carboxylic acid 3’
(80%), which after methylation with
diazomethane, afforded red quinone
methyl ester 26 (81%, Scheme 6). The
structurally intriguing isomeric qui-
nones 3 (Scheme 5) and 3’ (Scheme 6)
may well be related to biogenetic
precursors and/or in vivo degradation
products of lateriflorone. As such,
these novel compounds, 3 and 3’, may
exhibit biological activity, and so could
1,1’-O,O-dimethyllateriflorone (25).
At this juncture, we felt that ben-
zoquinone carboxylic acid 3’ presented
a new opportunity for a final attempt
to reach the lateriflorone framework.
Indeed, exposure of 3’ to PPTS in
refluxing benzene under anhydrous
conditions led, in 83% yield, to a
single yellow substance whose spectral
data strongly suggested the lateriflor-
one-like structure 2 (Scheme 6). Pleas-
ingly, X-ray crystallographic analysis[9]
of the crystalline 2 (Table 1) confirmed
its identity as 1-O-methyllateriflorone,
ending the quest for this highly unusual
molecular architecture. The com-
pletely stereoselective manner in
which both 3’ and 24 cyclize to the
corresponding lateriflorone frame-
works is noteworthy. It is not impos-
sible that both reactions are under
thermodynamic control, leading to the
natural stereochemistry, which may
represent the most stable configura-
tion of this system.
The described chemistry opens a
facile entry into the novel lateriflorone
molecular architecture and under-
scores the importance of careful strat-
egy design for its construction. Future
studies in the field will include further
Scheme 4. Construction of advanced intermediate 23a,b: a) DMF, 1208C, 1 h, 6’ (42%) and 6
(47%); b) TsOH (20 mol%), MeOH, 258C, 16 h, 98%; c) DMP (2.0 equiv), NaHCO3 (2.0 equiv),
CH2Cl2, 258C, 30 min, 93%; d) NaClO2 (6.0 equiv), NaH2PO4 (6.0 equiv), 2-methyl-2-butene
(75.0 equiv), THF/tBuOH/H2O (2:4:1), 30 min, 100%; e) EDC (1.5 equiv), 4-DMAP (1.5 equiv),
5 (2.0 equiv), CH2Cl2, 0!258C, 16 h, 64%; f) HCl (0.25m) in MeOH/Et2O (1:1), 0!258C, 1 h,
96%. DMP=Dess–Martin periodinane, EDC=1-ethyl-(3-dimethylaminopropyl)carbodiimide
hydrochloride.
methodological
explorations
and
chemical biology investigations with
the synthesized compounds.
Received: May 5, 2003 [Z51805]
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Scheme 6. Synthesis and ORTEP drawing of 1-O-methyllateriflorone (2):
a) aqueous HCl (1n), THF, 0!258C, 16 h, 80%; b) CH2N2, diethyl ether,
Scheme 5. Synthesis and ORTEP drawing of 1,1’-O,O-dimethyllateriflor-
one (25): a) PhI(OCOCF3)2 (1.2 equiv), CH2Cl2, ꢀ78!258C, 2 h, 43%;
b) PhI(OCOCF3)2 (1.2 equiv), CH2Cl2/MeOH (1:1), ꢀ78!258C, 2 h,
60%; c) PPTS (1.0 equiv), benzene, reflux, 4 h, 3 (11%) and 25 (69%).
PPTS=pyridinium p-toluenesulfonate.
08C, 30 min, 81%; c) PPTS (1.0 equiv), benzene, reflux, 4 h, 83%.
[5] K. A. Parker, A. T. Georges, Org. Lett. 2000, 2, 497 – 499.
[6] J. D. Godfrey, Jr., R. H. Mueller, T. C. Sedergran, N. Soundar-
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[7] A. J. Quillinan, F. Scheinmann, J. Chem. Soc. Perkin Trans. 1
1972, 1382 – 1387.
[8] CCDC-209801 (6’), CCDC-209802 (4), and CCDC-209803 (2)
contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge via www.ccdc.cam.
ac.uk/conts/retrieving.html (or from the Cambridge Crystallo-
graphic Data Centre, 12, Union Road, Cambridge CB21EZ,
UK; fax: (+ 44)1223-336-033; or deposit@ccdc.cam.ac.uk).
[9] A. J. Quillinan, F. Scheinmann, J. Chem. Soc. Chem. Commun.
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[10] For related applications of hypervalent iodine reagents to
dearomatize benzenoid systems, see: a) A. Varvoglis, Tetrahe-
dron 1997, 53, 1179 – 1255; b) Y. Kita, H. Tohma, K. Kikuchi, M.
Inagaki, T. Yahura, J. Org. Chem. 1991, 56, 435 – 438; c) G.
Scheffler, H. Seike, E. J. Sorensen, Angew. Chem. 2000, 112,
4785 – 4788; Angew. Chem. Int. Ed. 2000, 39, 4593 – 4596; d) A.
Pelter, R. S. Ward, Tetrahedron 2001, 57, 273 – 282; e) H. Tohma,
H. Morioka, S. Takizawa, M. Arisawa, Y. Kita, Tetrahedron 2001,
57, 345 – 352; f) S. Canesi, P. Belmont, D. Bouchu, L. Rousset,
M. A. Ciufolini, Tetrahedron Lett. 2002, 43, 5193 – 5195.
Keywords: cascade reactions · Claisen rearrangement ·
.
Diels–Alder reactions · electrocyclic reactions ·
natural products · quinones
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