Biomimetically Inspired Total Synthesis and Structure Activity Relationships of 1-O-Methyllateriflorone. 6π Electrocyclizations in Organic Synthesis

Article abstract of DOI:10.1021/ja040037+

The total synthesis of 1-O-methyllateriflorone (2) is described. The construction of the cage-like domain of the molecule involved a biomimetic Claisen/Diels-Alder cascade, whereas the novel spiroxalactone framework was generated by an intramolecular Mich

Full text of DOI:10.1021/ja040037+

Published on Web 04/09/2004
Biomimetically Inspired Total Synthesis and Structure Activity
Relationships of 1-O-Methyllateriflorone. 6π
Electrocyclizations in Organic Synthesis
K. C. Nicolaou,* Pradip K. Sasmal, and Hao Xu
Contribution from the Department of Chemistry and The Skaggs Institute for Chemical Biology,
The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, and
Department of Chemistry and Biochemistry, UniVersity of California, San Diego,
9500 Gilman DriVe, La Jolla, California 92093
Received February 2, 2004; Revised Manuscript Received February 25, 2004; E-mail: kcn@scripps.edu
Abstract: The total synthesis of 1-O-methyllateriflorone (2) is described. The construction of the cage-like
domain of the molecule involved a biomimetic Claisen/Diels-Alder cascade, whereas the novel spiroxa-
lactone framework was generated by an intramolecular Michael reaction within precursor 16a involving the
carboxylate residue as the nucleophile. This finding might bear on the biosynthetic pathway by which nature
forms lateriflorone. Described herein is also an interesting cascade sequence involving facile 6π
electrocyclizations which leads to complex benzopyran systems. The biological evaluation of a small library
of lateriflorone analogues and related systems establishing the first SAR within this class of compounds is
also included. Among the most active compounds against tumor cells are 2, 16b, 56, 58, and 59.
scortechinone B (12).7 Among all, lateriflorone (1), isolated from
the stem bark of Garcinia Lateriflora Bl (Guttiferae),2 is the
Introduction
The continuing phytochemical studies of Garcinia species
(belonging to the Guttiferae family of tropical plants) led to
the isolation of several xanthone-derived natural products, which
possess unusual molecular architectures and diverse biological
properties. Thus, some of these compounds exhibit noteworthy
cytotoxic and antibacterial properties, and the plant sources from
this family have been used by natives as folk medicines for
centuries.1 The signature structural motif of many of these
compounds is an intriguing 4-oxatricyclo[4.3.1.0]decan-2-one
scaffold attached onto a common xanthonoid ring system. Figure
1 displays a number of representative members of this class of
cage-like xanthonoids, including lateriflorone (1),2 morellin (3),3
desoxymorellin (4),3 morellic acid (5),3 bractatin (6),4 1-O-
methylbractatin (7),4 1-O-methylneobractatin (8),4 forbesione
(9),5 gaudichaudione H (10),6 scortechinone A (11),7 and
most interesting in that it possesses the additional complexity
of a unique spiroxalactone moiety, making its total synthesis
the ultimate challenge within this group of natural products.
Based on some scattered speculations, the biogenetic path-
way8 for the formation of the xanthonoid ring system of these
compounds might involve an intramolecular oxidative coupling
of benzephenone or benzophenone-like intermediates, which,
in turn, are formed by the condensation of shikimate and acetate-
derived moieties. In case of lateriflorone (1), it is hypothesized2
that the unique spiroxalactone could be formed either by an
oxidative cyclization of 13 (Scheme 1) or by the spiroketaliza-
tion between the two fragments 14 and 15. In the later case,
the C7-keto functionality of 14 could react with the C7-hydroxyl
group of 15 to form a hemiketal, which could subsequently
undergo lactonization in a Michael fashion to generate the novel
spiroxalactone system. Lateriflorone (1) exhibits potent cyto-
toxicity against the P388 cancer cells (ED50 5.4 µg/mL). Like
with all other xanthonoids of this family, the mechanism of
action of this compound is not known, although it is assumed
that the intriguing cage domain of the molecule plays a role in
their biological action. In this Article, we describe full details
of our investigations in this area which culminated to the total
synthesis of 1-O-methyllateriflorone (2), the application of 6π
electrocyclizations in the synthesis of novel benzopyran systems,
and the synthesis of several lateriflorone analogues and precur-
sors and their biological evaluation.
(1) Perry, L. M.; Metzger, J. Medicinal Plants of East and Southeast Asia:
Attributed Properties and Uses; The MIT Press: Cambridge, MA, 1980;
p 175.
(2) Kosela, S.; Cao, S.-G.; Wu, X.-H.; Vittal, J. J.; Sukri, T.; Masdianto; Goh,
S.-H.; Sim, K.-Y. Tetrahedron Lett. 1999, 40, 157-160.
(3) (a) Rao, B. S. J. Chem. Soc. C 1937, 853-857. (b) Kartha, G.;
Ramachandran, G. N.; Bhat, H. B.; Nair, P. M.; Raghavan, V. K. V.;
Venkataraman, K. Tetrahedron Lett. 1963, 4, 459-472. (c) Ollis, W. D.;
Ramsay, M. V. J.; Sutherland, I. O.; Mongkolsuk, S. Tetrahedron 1965,
21, 1453. (d) Karanjgaonkar, C. G.; Nair, P. M.; Venkataraman, K.
Tetrahedron Lett. 1966, 7, 687-691. (e) Bhat, H. B.; Nair, P. M.;
Venkataraman, K. Indian J. Chem. 1964, 2, 402.
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Sevenet, T. J. Nat. Prod. 2000, 63, 441-446.
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Synop. 1996, 392-393.
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J. T.; Goh, S. H. Tetrahedron 1998, 54, 10915-10924. For related
gaudichaudiones, see: (b) Cao, S.-G.; Wu, X.-H.; Sim, K.-Y.; Tan, B. K.
H.; Pereira, J. T.; Wong, W. H.; Hew, N. F.; Goh, S. H. Tetrahedron Lett.
1998, 39, 3353-3356. (c) Wu, X.-H.; Tan, B. K. H.; Cao, S.-G.; Sim,
K.-Y.; Goh, S. H. Nat. Prod. Lett. 2000, 14, 453-458.
(7) Rukachaisirikul, V.; Kaewnok, W.; Koysomboon, S.; Phongpaichit, S.;
Taylor, W. C. Tetrahedron 2000, 56, 8539-8543.
(8) (a) Bennett, G. J.; Lee, H.-H. J. Chem. Soc., Chem. Commun. 1988, 619-
620. (b) Roberts, J. C. Chem. ReV. 1961, 61, 591-605. (c) Carpenter, I.;
Locksley, H. D.; Scheinmann, F. Phytochemistry 1969, 8, 2013-2026.
9
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J. AM. CHEM. SOC. 2004, 126, 5493-5501
5493

A R T I C L E S
Nicolaou et al.
Scheme 2. Retrosynthetic Analysis of Lateriflorone (1)
Figure 1. Selected natural products from the Garcinia family of plants.
Scheme 1. Proposed Biosynthesis of Lateriflorone (1)
the easiest to form in the molecule, but, most significantly, such
disconnections would lead to a convergent strategy in the
synthetic direction. Scheme 2 depicts the logic of the initial
retrosynthetic analysis of 1. Thus, rupturing bond a generates
quinone-ether carboxylic acid 16a. Intramolecular conjugate
addition (path a) of the carboxyl group onto the closest enone
carbon atom may be expected to lead to 1 - granted with an
unknown stereochemical outcome. Alternatively, cleavage of
the ether C-O bond of the spiroketal system leads to quinone-
ester 16b, whose similar intramolecular collapse (path b) may
form the target molecule, again with the uncertainty of the
stereochemical outcome at the two generated centers looming
over the ring closure. In contemplating the choice between the
two paths (a and b), the ease of construction of the required
precursor (16a or 16b) favored path b, because forming an ester
bond was considered so much easier than casting an ether
linkage as needed for path a. Having defined 16b as the next
target, its quinone moiety was then retrosynthetically trans-
formed into the benzenoid system 17 whose disconnection at
the ester bond led to fragments 18 and 19a. Our previous study
with forbesione (9)10 pointed to the cascade approach to the
cage intermediate 19a from the aromatic system 20a via one
Claisen rearrangements and one Diels-Alder reaction (intramo-
lecular) as shown in Scheme 2.
Results and Discussion
1. Retrosynthetic Analysis. Inspection of the structure of
lateriflorone (1)9 leads to the identification of the spirolactone-
ketal moiety as the most appropriate strategic site for retrosyn-
thetic disconnection. Not only are the two C-O bonds among
(9) (a) For a preliminary communication, see: Nicolaou, K. C.; Sasmal, P.
K.; Xu, H.; Namoto, K.; Ritzen, A. Angew. Chem., Int. Ed. 2003, 42, 4225-
4229. (b) For the synthesis of seco-lateriflorone, see: Tisdale, E. J.; Vong,
B. J.; Li, H.; Kim, S. H.; Chowdhury, C.; Theodorakis, E. A. Tetrahedron
2003, 59, 6873-6887.
(10) For the total synthesis of 1-O-methyl forbesione, see: Nicolaou, K. C.; Li,
J. Angew. Chem., Int. Ed. 2001, 40, 4264-4268.
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5494 J. AM. CHEM. SOC. VOL. 126, NO. 17, 2004

Total Synthesis of 1-O-Methyllateriflorone
A R T I C L E S
Scheme 3. Construction of Benzopyran Fragment 18a
2. Construction of the Benzopyran Domain. The synthesis
of the required prenylated 2,2′-dimethybenzopyran fragment 18
is summarized in Scheme 3. Thus, the known compound 2111
was smoothly and selectively brominated at the para position
with bromine in the presence of NaOAc to afford p-bromophen-
ol 22 (92% yield) whose exposure to MOMCl-Et3N led to
MOM ether 23 (93% yield). Dakin oxidation (m-CPBA) of
aldehyde 23 followed by in situ cleavage of the intermediate
formate ester with NaHCO3 furnished the new bromophenol
24 in 71% overall yield, which was protected as a TIPS ether
by treatment with TIPSCl in the presence of imidazole, leading
to compound 25 in 96% yield. Combining bromide 25 with
B(OiPr)3 in ether followed by sequential addition of BuLi at
t
-78 °C and NaOH-H2O2 at 0 °C furnished phenol 26 (86%
yield) via the corresponding borate derivative.12 The phenol (26)
was then methylated (K2CO3-MeI) to afford methoxy com-
pound 27 in 88% yield. Subsequent hydrogenolysis at the benzyl
group in 27 (H2, 10% Pd(OH)2/C) afforded phenolic compound
28 in quantitative yield. Propargylation13 of 28 using in situ
generated HCtCC(Me)2OCOCF3 in the presence of DBU and
catalytic amounts of CuCl2 afforded propargylic ether 29 in 76%
yield (90% yield based on 84% conversion). Compound 29
underwent Claisen rearrangement14 in refluxing xylene to furnish
benzopyran system 30. Removal of the solvent followed by
treatment of the crude product with TBAF in THF gave
desilylated product 31 in 93% overall yield from 29. Finally, a
second propargylation employing the same reaction conditions
as mentioned above afforded benzopyran system 32 in 80%
yield (91% based on 88% conversion). Selective reduction (H2)
of the acetylenic moiety in 32 in the presence of Lindlar catalyst
generated the corresponding olefin (33) in 95% yield. A second
Claisen rearrangement under thermal conditions (DMF, 120 °C)
converted 33 to the targeted benzopyran fragment 18 in 70%
yield.
3. Construction of the Caged Domain and Coupling of
the Two Fragments. The sequence devised and executed for
the synthesis of the initially designed precursor 20a is shown
in Scheme 4. Thus, commercially available 2,3,4-trihydroxy-
benzaldehyde (34) was perbenzylated with BnBr in the presence
of K2CO3 and catalytic amounts of KI in DMF, generating the
known aldehyde 3515 in 85% yield. Selective debenzylation of
the phenolic group adjacent to the aldehyde moiety was achieved
by the action of MgBr2‚Et2O in ether, leading to o-hydroxy-
benzaldehyde derivative 36 in 83% yield. Bromination with
molecular bromine in acetic acid of the later compound (36)
resulted in the formation of p-bromophenol 37 in 89% yield.
NaBH4 reduction of aldehyde 37 afforded diol 38 (91% yield),
which was subjected to acetonide formation, furnishing ketal
39 in 95% yield. This bromo compound (39) was then converted
to phenolic substrate 40 in 90% overall yield following the
standard protocol mentioned above via the borate intermediate.
Thus, lithium-halogen exchange (nBuLi), borate formation
a (a) Br2 (1.1 equiv), NaOAc (1.2 equiv), AcOH, 25 °C, 2 h, 92%; (b)
Et3N (5.0 equiv), 4-DMAP (0.1 equiv), MOMCl (3.0 equiv), 25 °C, 16 h,
93%; (c) m-CPBA (1.1 equiv), 0 f 25 °C, CH2Cl2, 6 h; then saturated
aqueous NaHCO3, 16 h, 71%; (d) TIPSCl (1.5 equiv), imid (2.0 equiv),
DMF, 25 °C, 2 h, 96%; (e) premix 25 and B(OiPr)3 (2.2 equiv) in ether;
then tBuLi (2.2 equiv) at -78 °C, 2 h, -78 f 0 °C, 1 h; then MeOH, 10%
aqueous NaOH (4.8 equiv), H2O2 (5.0 equiv), 0 °C, 0.5 h, 86%; (f) K2CO3
(10 equiv), MeI (10 equiv), acetone, 25 °C, 16 h, 88%; (g) 10% Pd(OH)2/C
(10 wt %), H2 (1 atm), EtOAc/EtOH (1:1), 25 °C, 0.5 h, 100%; (h) propargyl
alcohol (1.3 equiv), DBU (1.5 equiv), TFAA (1.2 equiv), MeCN, 0 °C, 0.5
h; DBU (1.35 equiv), CuCl2 (0.01 equiv), 10 min; then TFA propargyl
ester was added, 4 h, 0 °C, 76% (90% based on 84% conversion); (i) xylene,
140 °C, 0.5 h; (j) TBAF (1.5 equiv), THF, 0 °C, 5 min, 93% for two steps;
(k) propargyl alcohol (1.3 equiv), DBU (1.5 equiv), TFAA (1.2 equiv),
MeCN, 0 °C, 0.5 h; DBU (1.35 equiv), CuCl2 (0.01 equiv), 10 min; then
TFA propargyl ester was added, 4 h, 0 °C, 80% (91% based on 88%
conversion); (l) Lindlar catalyst (10 wt %), H2 (1 atm), quinoline (3.0 equiv),
EtOAc, 25 °C, 2 h, 95%; (m) DMF, 120 °C, 1 h, 70%. Bn ) benzyl,
4-DMAP ) 4-(dimethylamino)pyridine, MOM ) methoxymethyl, m-CPBA
) m-chloroperbenzoic acid, TIPS ) triisopropylsilyl, imid ) imidazole,
DBU ) 1,8-diazabicyclo[5.4.0]undec-7-ene, TFAA ) trifluoracetic anhy-
dride, TBAF ) tetra-n-butylammonium fluoride.
(11) Parker, K. A.; Georges, A. T. Org. Lett. 2000, 2, 497-499.
(12) Luszniak, M. C.; Topiwala, U. P.; Whiting, D. A. J. Chem. Res., Miniprint
1998, 7, 1401-1417.
(13) Godfrey, J. D., Jr.; Mueller, R. H.; Sedergran, T. C.; Soundararajan, N.;
Colandrea, V. J. Tetraheron Lett. 1994, 35, 6405-6408.
(14) (a) Quillinan, A. J.; Scheinmann, F. J. Chem. Soc., Perkin Trans. 1 1972,
1382-1387. (b) Subramanian, R. S.; Balasubramanian, K. K. Tetrahedron
Lett. 1988, 29, 6797-6800. (c) Joshi, S. C.; Trivedi, K. N. Tetrahedron
1992, 48, 563-570. (d) Yamaguchi, S.; Ishibashi, M.; Akasaka, K.;
Yokoyama, H.; Miyazawa, M.; Hirai, Y. Tetrahedron Lett. 2001, 42, 1091-
1093.
[B(OMe)3], and oxidation with alkaline (NaOH) hydrogen
peroxide resulted in 40 whose phenolic group was protected as
(15) Hegedues, B.; Krasso, A. F. HelV. Chim. Acta 1970, 53, 959-963.
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A R T I C L E S
Nicolaou et al.
Scheme 4. Construction of Intermediate 20a
Scheme 5. First Attempt To Prepare the Cage-like Domain of
Laterifloronea
a (a) K2CO3 (5.0 equiv), BnBr (5.0 equiv), KI (0.1 equiv), DMF, 25 °C,
24 h, 85%; (b) MgBr2‚OEt2 (1.1 equiv), ether, 25 °C, 10 h, 83%; (c) Br2
(1.1 equiv), NaOAc (1.15 equiv), AcOH, 25 °C, 2 h, 89%; (d) NaBH4 (1.5
equiv), EtOH, 0 f 25 °C, 0.5 h, 91%; (e) 2,2-dimethoxypropane (5.0 equiv),
p-TsOH (0.01 equiv), CH2Cl2, 1 h, 95%; (f) nBuLi (1.1 equiv), ether, -78
°C, 2 h; then B(OMe)3 (3.0 equiv), 1 h, -78 f 0 °C; then 10% aqueous
NaOH (4.8 equiv), H2O2 (5.0 equiv), 0 °C, 0.5 h, 90%; (g) SEMCl (1.5
equiv), (iPr)2 NEt (2.0 equiv), CH2Cl2, 0 f 25 °C, 2h, 70%; (h) 10% Pd/C
(10 wt %), H2 (1 atm), EtOAc, 25 °C, 45 min, 95%; (i) tBuOK (2.2 equiv),
THF, 0 °C; then concentrated and suspended in MeCN; then 18-Crown-6
(2.2 equiv), 15 min, bromoisobutyraldehyde (5.0 equiv), 0 f 25 °C, 1 h,
70%; (j) CH3P+Ph3Br- (3.0 equiv), NaHMDS (3.0 equiv), THF, 0 °C, 1 h,
75%; (k) tBuOK (1.1 equiv), THF, 0 °C; then concentrated and suspended
in MeCN; then 18-Crown-6 (1.1 equiv), 15 min, bromoisobutyraldehyde
(5.0 equiv), 0 f 25 °C, 1 h, 75%; (l) CH3P+Ph3Br- (2.0 equiv), NaHMDS
(2.0 equiv), THF, 0 °C, 1 h, 75%. Ts ) p-toluenesulfonyl, HMDS )
hexamethyldisilazane.
a (a) DMF, 120 °C, 2 h, 19a (65%) and 19a′ (30%); (b) nPrSH (9.0
equiv), Yb(OTf)3 (0.1 equiv), CH2Cl2, 25 °C, 1.5 h, 84%.
75% yield). The phenolic group within 44 was alkylated with
bromoisobutyraldehyde under the same reaction conditions as
mentioned above to afford regioisomeric aldehydes 45a and 45b
in 75% combined yield. A second Wittig reaction on the latter
mixture then furnished the required di-olefin 20a in 75% yield.
Having constructed the aromatic precursor 20a, we then
proceeded to the next stage which aimed at the rearrangement
of this substrate to the desired cage-like intermediate via the
projected Claisen/Diels-Alder cascade.10,17 Thus, heating 20a
in DMF at 120 °C for 2 h led to the expected product 19a (65%
yield) and its regioisomer 19a′ (30% yield), presumably via the
shown intermediates (see Scheme 5). The structures of these
products were based on both spectroscopic and X-ray crystal-
lographic techniques (see ORTEP drawing18 of 19a′, Scheme
5). Attempts to selectively remove the acetonide group from
19a, however, were unsuccessful; instead, the various conditions
tried led to unwanted products, including triol 46 (44% yield)
and rearranged triol 46′ (40% yield), both of which were
a SEM ether (SEMCl, Et3N) to afford 41 (70% yield).
Subsequent hydrogenolysis of the benzyl groups (H2, 10% Pd/
C, 95% yield) in 41 led to the formation of dihydroxy compound
42. The di-potassium salt of 42, generated by addition of
KOtBu, was then suspended in acetonitrile and reacted with
bromoisobutyraldehyde16 in the presense of 18-Crown-6 to
afford an unseparable mixture of regioisomeric lactols (43a:
43b, ca. 1.7:1 ratio,70% yield) which reacted with methylene
phosphorane (generated from MeP+Ph3Br- and NaHMDS),
leading to olefins 44a:44b (ca. 1.7:1 ratio of the regioisomers,
(17) (a) Quillinan, A. J.; Scheinmann, F. Chem. Commun. 1971, 966-967. (b)
Tisdale, E. J.; Chowdhury, C. Vong, B. G.; Li, H.; Theodorakis, E. A.
Org. Lett. 2002, 4, 909-912.
(18) See the Supporting Information for crystallographic data of compounds
19a′, 46′, 49b, 19b′, 17, 58, and 2.
(16) Beckwith, A. L. J.; Thomas, C. B. J. Chem. Soc., Perkin Trans. 2 1972,
861.
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5496 J. AM. CHEM. SOC. VOL. 126, NO. 17, 2004

Total Synthesis of 1-O-Methyllateriflorone
A R T I C L E S
Scheme 6. Construction of Key Building Block 20ba
the latter compound was debenzylated (H2, 10% Pd/C, 98%
yield), leading to bis-phenol 48. This compound was found to
be quite sensitive on standing and was, therefore, taken
immediately to the next step which involved generation of the
di-potassium salt (KOtBu-18-Crown-6) followed by quenching
with bromoisobutyraldehyde to afford a mixture of regioisomeric
lactols (49a:49b, ca. 1:1 ratio, 70% yield). These two lactols
were separated by chromatography, allowing the X-ray crystal-
lographic analysis18 of the one that crystallized (49b) from its
ether-hexane solution (see ORTEP drawing of 49b, Scheme
6). Each of the two lactols (49a and 49b) was subjected to Wittig
olefination (Ph3PdCH2) to afford the corresponding phenolic
olefin (50a and 50b) in 70% yield. Reiteration of the last two-
step sequence furnished the targeted di-olefin 20b, via 51a and
51b (60% overall yield).
Upon heating in DMF at 120 °C for 1 h, the methoxy
derivative 20b entered into the expected Claisen Diels-Alder
cascade channel, leading to the indicated intermediate products
19b and 19b′ in 47% and 42% yields, respectively (see Scheme
7). An X-ray crystallographic analysis18 of 19b′ revealed its
structure, and by extension that of 19b. Both structures 19b
and 19b′ were also supported by nOe studies. Selective removal
of the acetonide group from 19b was achieved by treatment of
20b with catalytic amounts of p-TsOH in methanol, furnishing
diol 52 in 98% yield. A two-step oxidation protocol (DMP;21
NaClO222) then was employed to convert diol 52 to the required
hydroxy carboxylic acid 54 in 93% overall yield via intermediate
aldehyde 53. The crucial coupling of carboxylic acid 54 with
phenol 18 (see Scheme 3) was brought about by EDC and
4-DMAP, leading to advanced intermediate ester 17 in 64%
yield. Crystalline 17 yielded to X-ray crystallographic analysis
(see ORTEP drawing of 17, Scheme 7).
4. Final Stages of the Synthesis. Having constructed the ester
bridge between the two domains, the next task called for
oxidation of the molecule’s aromatic nucleus to a quinone and
ring closure to lateriflorone’s spirolactone skeleton. To this end,
compound 17 was exposed to the action of 0.25 N HCl in
MeOH:Et2O (1:1) solution, leading to a spontaneously equili-
brating mixture23 of phenolic esters (55a:55b, ca. 1:1, 96% yield)
(see Scheme 8). Careful separation of the two components of
this mixture by HPLC revealed the rapid equilibration of each
back to the original ca. 1:1 composition. It was, however,
decided to proceed to the next step in the hopes that at least
some of the desired oxidation product, or even the targeted
lateriflorone derivative, might result. Oxidation of this mixture
(55a:55b) under a variety of conditions24 did not lead, however,
to the desired outcome, but rather to an array of other products,
a (a) K2CO3 (5.0 equiv), MeI (10 equiv), DMF, 25 °C, 16 h, 99%; (b)
10% Pd/C (10 wt %), H2 (1 atm), EtOAc, 25 °C, 45 min, 98%; (c) tBuOK
(2.2 equiv), THF, 0 °C; then reaction mixture concentrated and suspended
in MeCN; then 18-Crown-6 (2.2 equiv), 15 min, bromoisobutyraldehyde
(5.0 equiv), 0 f 25 °C, 1 h, 70%; (d) CH3P+Ph3Br- (3.0 equiv), NaHMDS
(3.0 equiv), THF, 0 °C, 1 h, 75%; (e) tBuOK (1.1 equiv), THF, 0 °C; then
reaction mixture concentrated and suspended in MeCN; then 18-Crown-6
(1.1 equiv), 15 min, bromoisobutyraldehyde (5.0 equiv), 0 f 25 °C, 1 h,
75%; (f) CH3P+Ph3Br- (2.0 equiv), NaHMDS (2.0 equiv), THF, 0 °C, 1 h,
80%.
obtained upon exposure to nPrSH-Yb(OTf)3.19 Apparently, the
rearranged keto-triol 46′ is formed by the Lewis acid-induced
R-ketol rearrangement20 of the parent triol 46. Although these
two triols were chromatographically unseparable, the rearranged
compound (46′) crystallized preferentially from an ether/hexane
solution of the mixture, thus enabling its X-ray crystallographic
analysis18 (see ORTEP drawing of 46′, Scheme 5).
In the face of this rather unexpected circumstance, we decided
to target lateriflorone’s 1-O-methyl derivative (2) to avoid the
complications arising from the deacetonization step. We,
therefore, adopted the methoxy derivative 20b (Scheme 6) as
the substrate for the Claisen/Diels-Alder cascade sequence. Its
construction proceeded along lines similar to those already
described above for compound 20a and is summarized in
Scheme 6. Thus, phenolic compound 40 was methylated (K2-
CO3, MeI) to afford methoxy derivative 47 (99% yield), and
(21) (a) Dess, D. R.; Martin, J. C. J. Org. Chem. 1983, 48, 4155-4156. (b)
Meyer, S. D.; Schreiber, S. L. J. Org. Chem. 1994, 59, 7549-7552.
(22) (a) Lindgren, B. O.; Nilsson, T. Acta Chem. Scand. 1973, 27, 888. (b)
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G. A.; Roth, B. J. Org. Chem. 1980, 45, 4825-4830.
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benzenoid systems, see: (a) Varvoglis, A. Tetrahedron 1997, 53, 1179-
1255. (b) Kita, Y.; Tohma, H.; Kikuchi, K.; Inagaki, M.; Yahura, T. J.
Org. Chem. 1991, 56, 435-438. (c) Scheffler, G.; Seike, H.; Sorensen, E.
J. Angew. Chem., Int. Ed. 2000, 39, 4593-4596. (d) Pelter, A.; Ward, R.
S. Tetrahedron 2001, 57, 273-282. (e) Tohma, H.; Morioka, H.; Takizawa,
S.; Arisawa, M.; Kita, Y. Tetrahedron 2001, 57, 345-352. (f) Quideau,
S.; Pouyse´gu, L.; Oxoby, M.; Looney, M. A. Tetrahedron 2001, 57, 319-
329. (g) Canesi, S.; Belmont, P.; Bouchu, D.; Rousset, L.; Ciufolini, M.
A. Tetrahedron Lett. 2002, 43, 5193-5195.
(19) Nicolaou, K. C.; Veale, C. A.; Hwang, C.-K.; Hutchinson, J.; Prasad, C.
V. C.; Ogilvie, W. W. Angew. Chem., Int. Ed. Engl. 1991, 30, 299-303.
(20) Paquette, L. A.; Hofferberth, J. E. Org. React. 2003, 62, 477-567.
9
J. AM. CHEM. SOC. VOL. 126, NO. 17, 2004 5497

A R T I C L E S
Nicolaou et al.
Scheme 7. Synthesis of Advanced Intermediate 17a
Scheme 8. Oxidation of Phenols 55ab with Hypervalent Iodine
Reagentsa
a (a) 0.25 M HCl in MeOH:ether (1:1), 0 f 25 °C, 1 h, 96%; (b)
PhI(OCOCF3)2 (1.2 equiv), CH2Cl2, -78 f 25 °C, 2 h, 16b (43%) and 14
(16%); (c) PhI(OCOCF3)2 (1.2 equiv), CH2Cl2:MeOH (1:1), -78 f 25
°C, 2 h, 60%; (d) PhI(OAc)2 (1.2 equiv), pyridine (cat.), CF3CH2OH, -20
f 0 °C, 30 min, 15%.
149b (16% yield) were obtained as the only characterizable
products from 55a:55b upon treatment with PhI(OCOCF3)2 in
CH2Cl2 (see Scheme 8).
The failure to obtain the lateriflorone structure directly from
the oxidation of 55a:55b did not end the chase for lateriflorone,
because the newly formed hydroxyquinone 16b held consider-
able promise as a potential precursor to the coveted architecture.
Toward this goal, several attempts were made, including
protocols involving acidic conditions (e.g., PPTS, p-TsOH, TFA,
amberlyst 15), basic conditions (e.g., Et3N, DBU, LiHMDS,
NaH), sealed tube high temperature (180 °C), and high pressure
(100 psi) treatment in xylene under microwave irradiation, as
well as silica supported (both acidic and basic) microwave
irradiation. In all cases, decomposition and/or recovery of
starting material was observed with no evidence of spiroxalac-
tone formation.
a (a) DMF, 120 °C, 1 h, 19b (47%) and 19b′ (42%); (b) p-TsOH (20
mol %), MeOH, 25 °C, 16 h, 98%; (c) DMP (2.0 equiv), NaHCO3 (2.0
equiv), CH2Cl2, 25 °C, 0.5 h, 93%; (d) NaClO2 (6.0 equiv), NaH2PO4 (6.0
equiv), 2-methyl-2-butene (75.0 equiv), THF:tBuOH:H2O (2:4:1), 0.5 h,
100%; (e) EDC (1.5 equiv), 4-DMAP (1.5 equiv), 18 (2.0 equiv), CH2Cl2,
0 to 25 °C, 16 h, 64%. DMP ) Dess-Martin periodinane, EDC ) 1-ethyl-
(3-dimethylaminopropyl)carbodiimide hydrochloride.
among which the most interesting are those shown in Scheme
8. Thus, exposure to PhI(OAc)2 in CF3CH2OH afforded a
complex mixture from which was isolated novel benzo-oxepene
ring system 57 (15% yield), presumably formed from 55b via
radical chemistry.25 On the other hand, reaction of 55a:55b with
PhI(OCOCF3)2 in MeOH:CH2Cl2 (1:1) led to benzoquinone
monoketal 56 (60% yield) through the participation of a
molecule of methanol.26 Hydroxyquinones 16b (43% yield) and
At this juncture, we reasoned that the poor nucleophilicity
of the tertiary hydroxyl group was responsible for the failure to
obtain the desired spiroxalactone moiety from hydroxyquinone
16b, and we proceeded to design a more electrophilic Michael
acceptor to enhance the chances for ring closure involving the
same tertiary hydroxyl group. Toward this purpose, hydroxy
dimethyl ketal 56 was treated with PPTS in refluxing benzene,
and, according to our expectation, spiroxalactone compound 58
(25) For a precedent of radical generation with PhI(OAc)2, see: Dorta, R. L.;
Francisco, C. G.; Herna´ndez, R.; Salazar, J. A.; Sua´rez, E. J. Chem. Res.,
Synop. 1990, 240-241.
(26) Corey, E. J.; Wu, L. I. J. Am. Chem. Soc. 1993, 115, 9327-9328.
9
5498 J. AM. CHEM. SOC. VOL. 126, NO. 17, 2004

Total Synthesis of 1-O-Methyllateriflorone
A R T I C L E S
Scheme 9. Synthesis of 1-O-Methyllateriflorone (2)a
a (a) PPTS (1.0 equiv), benzene, reflux, 4 h, 58 (69%) and 16b (11%); (b) 1 N aqueous HCl, THF, 0 f 25 °C, 16 h, 80%; (c) excess CH2N2, ether, 0
°C, 0.5 h, 81%; (d) PPTS (1.0 equiv), benzene, reflux, 4 h, 83%. PPTS ) pyridinium p-toluene sulfonate.
was formed in 69% yield, together with quinone 16b (11%
yield) (see Scheme 9). The latter compound might be formed
by simple rupture of the ketal moiety prior to cyclization.
Compound 58 crystallized in beautiful yellow crystals, whose
X-ray crystallographic analysis18 revealed its lateriflorone-like
molecular architecture, including the correct stereochemistry at
C-3′ (see ORTEP drawing, Scheme 9). From compound 58,
1-O-methyllateriflorone (2) was in sight, the two compounds
separated only by ketal hydrolysis. While mild acidic conditions
employing PPTS or TFA left 58 unchanged, an attempt to
hydrolyze the enol methyl ether within 58 employing aqueous
HCl in THF at room temperature led to red quinone ether
carboxylic acid 16a in 80% yield. This acid was derivatized
and characterized as its methyl ester 59, a red colored substance,
obtained in 81% yield upon methylation with diazomethane.
Compound 16a presented yet another opportunity to effect
the long-sought ring closure to the lateriflorone framework, the
expectation being that acid treatment would initiate the required
conjugate addition. Indeed, exposure of 16a to PPTS in refluxing
benzene led to the formation of a single yellow substance whose
spectral data were consistent with the expected, lateriflorone-
like structure 2. Also, upon crystallizing fron an ether-hexane
9
J. AM. CHEM. SOC. VOL. 126, NO. 17, 2004 5499

A R T I C L E S
Nicolaou et al.
Scheme 10. Cascade Sequence Leading from Quinone 16b to
solution in beautiful yellow crystals, this compound yielded to
X-ray crystallographic analysis18 (see ORTEP drawing, Scheme
9), which confirmed beyond doubt its structure (2). Thus, the
quest for this unusual molecular architecture was complete.
Attempts to remove the methyl group from the C-20 oxygen
were not successful, presumably due to the inherent instability
of the labile R-ketol moiety, especially under the Lewis acid
conditions employed in the attempts.
Benzopyrans 63a-ca
The exclusively regio- and stereoselective manner by which
both substrates 16a and 56 cyclize under acid conditions to form
the spirolactone framework is noteworthy. In both cases, the
reaction may proceed under thermodynamic control, leading to
the natural stereochemistry at C-3′. In the case of 16a, the
cyclization leads to what might actually be the thermodynami-
cally most stable configuration at both C-2′ and C-3′, which
also happens to be the natural arrangement at those centers.
5. Synthetic Technology for the Construction of Benzopy-
rans via Facile 6π Electrocyclizations. From the several
attempts to accomplish the required ring closure to the spiro-
lactone fragments, the one involving Et3N led to the most
interesting results, even though it, too, like the others failed to
produce the desired outcome. Thus, exposure of 16b to Et3N
in CH2Cl2 at room temperature (the red solution turned
immediately to yellow) followed by concentration and chro-
matographic purification led to isolation of compounds 63a:
63b (30%, equilibrium mixture of regioisomers due to internal
acyl migration, yellow) and 63c (66%, colorless) (see Scheme
10). To explain the formation of these intriguing structures from
16b, we propose initial conjugation of 16b to its two geometrical
isomers 60-Z and 60-E, which then follow different reaction
paths, leading to the observed products via a series of bond
reorganizations, including a 6π electrocyclization14b,27(or a
conjugate addition, 62-Z f 63a and 61-E f 63c) as the key
ring-forming process.
The mild conditions and high yield associated with this
cascade sequence28 boded well for its further exploitation to
generate benzopyran-type29 compounds from the corresponding
quinonoid systems. As shown in Table 1, this entry into this
series of compounds (64 f 67a-c; 65 f 68a-c; and 66 f
69a-c) is quite general and holds promise for the construction
of a variety of natural-product-like structures.
6. Biological Investigations. The campaign toward lateri-
florone produced a number of key building blocks and advanced
intermediates which were considered worthy of biological
evaluation. Following the lead of the natural substance, we
proceeded to screen such compounds (see Table 2) as cytotoxic
agents against ovarian cancer cells 1A9 (parental), A2780, and
(27) (a) Bu¨chi, G.; Yang, N. C. J. Am. Chem. Soc. 1957, 79, 2318-2323. (b)
Becker, R. S.; Michl, J. J. Am. Chem. Soc. 1966, 88, 5931-5933. (c)
Rodr´ıguez-Otero, J. J. Org. Chem. 1999, 64, 6842-6848. (d) Li, C.;
Johnson, R. P.; Porco, J. A., Jr. J. Am. Chem. Soc. 2003, 125, 5095-5106.
(e) Malerich, J. P.; Trauner, D. J. Am. Chem. Soc. 2003, 125, 9554-9555.
(28) For recent reviews on cascade reactions in organic synthesis, see: (a)
Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.; Vassilikogiannakis, G. E.
Angew. Chem., Int. Ed. 2002, 41, 1668-1698. (b) Nicolaou, K. C.;
Montagnon, T.; Snyder, S. A. Chem. Commun. 2003, 551-564.
(29) For recent advances in benzopyran synthesis, see: (a) Nicolaou, K. C.;
Pfefferkorn, J. A.; Roecker, A. J.; Cao, G.-Q.; Barluenga, S.; Mitchell, H.
J. J. Am. Chem. Soc. 2000, 122, 9939-9953. (b) Nicolaou, K. C.;
Pfefferkorn, J. A.; Mitchell, H. J.; Roecker, A. J.; Barluenga, S.; Cao, G.-
Q.; Affleck, R. L.; Lillig, J. E. J. Am. Chem. Soc. 2000, 122, 9954-9967.
(c) Nicolaou, K. C.; Pfefferkorn, J. A.; Barluenga, S.; Mitchell, H. J.;
Roecker, A. J.; Cao, G.-Q. J. Am. Chem. Soc. 2000, 122, 9968-9976.
(30) Skehan, P.; Storeng, R.; Scudiero, D.; Monks, A.; McMahon, J.; Vistica,
D.; Warren, J. T.; Bokesch, H.; Kenney, S.; Boyd, M. R. J. Natl. Cancer
Inst. 1990, 82, 1107-1112.
a (a) Et3N (10 equiv), CH2Cl2, 25 °C, 1 h, 63ab (30%) and 63c (66%).
AD10 (transformed 1A9, producing drug transporter pgp). The
first noteworthy observation was that these compounds are not
substrates for pgp because the IC50 values are not so different
in the two assays as shown in Table 2. Second, it was noted
that compound 58 is the most potent of the series, being 4-5
times more potent than 1-O-methyllateriflorone (2). Interest-
ingly, the benzoquinone monoketal 56, which lacks the spiro-
9
5500 J. AM. CHEM. SOC. VOL. 126, NO. 17, 2004

Total Synthesis of 1-O-Methyllateriflorone
A R T I C L E S
Table 1. Synthesis of Benzopyran System via 6π
Table 2. Cytotoxicity of Selected Compounds against 1A9,
Electrocyclizationsa
A2780, and AD10 Human Carcinoma Cellsa
1A9
A2780/AD10
entry
compounds
(IC50 in µM)
(pgp expresser)
1
2
3
4
5
6
7
8
9
52
54
17
57
18
14
16b
16a
56
58
59
2
150
87
63
28
56
96
17
37
9
150
136
99
63
81
104
25
49
10
5
10
11
12
5
17
25
23
37
a The antiproliferative effects of the tested compounds against the parental
1A9 and resistant clones (A2780 and AD10) were determined in a 72 h
growth inhibition exposure using the SRB (sulforhodamine-B) assay.30
precursor domains of lateriflorone, building blocks chromene
quinone 14 and hydroxy acid 54, showed poor activity against
these cell lines.
Conclusion
Described herein is a convergent strategy for the synthesis
of the unprecedented and highly unusual structure of 1-O-
methyllateriflorone (2). The synthetic journey to this target
required several redesigns and attempts to cast the final C-O
bond of the novel spirolactone moiety. The successful final
fusion turned out to be that involving the carboxylate residue,
and not the tertiary alcohol, a finding that may bear on the
biosynthetic pathway through which nature is generating this
structure. On the way to the final destination, we also uncovered
a number of interesting cascade sequences to complex ben-
zopyran systems involving facile 6π electrocyclizations which
may find applications in complex molecule constructions. We
were also able to produce and biologically evaluate a small
library of lateriflorone analogues and related systems. These
chemical biology investigations established the first structure
activity relationships within this class of compounds.
Acknowledgment. We thank Drs. D. H. Huang, G. Siuzdak,
and R. Chadha for NMR spectroscopic, mass spectrometric, and
X-ray crystallographic assistance, respectively. This work was
financially supported by the National Institutes of Health (USA),
The Skaggs Institute for Chemical Biology, Merck, and Pfizer.
We thank Drs. Andreas Ritze´n and Kenji Namoto for some early
experimental work on this project.
a Reactions were carried out on 1.0 mmol scale in dichloromethane with
10 equiv of Et3N at room temperature for 1 h. b 2:1 equilibrium mixture.
c 1:1 equilibrium mixture. d 10:1 equilibrium mixture.
Supporting Information Available: Experimental procedures,
compound characterization, and selected 1H and 13C NMR
spectral data (PDF and CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
lactone moiety, exhibited approximately 2.5 times the activity
of 2. It is also of interest to note that the seco-analogues (open
forms) 16a and 16b were found to be more or less equipotent
to their cyclized counterpart, compound 2. Finally, the two
JA040037+
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J. AM. CHEM. SOC. VOL. 126, NO. 17, 2004 5501