Combined directed remote metalation-transition metal catalyzed cross coupling strategies: The total synthesis of the aglycones of the gilvocarcins V, M, and E and arnottin I

Article abstract of DOI:10.1021/jo9001454

(Chemical Equation Presented) A key directed remote metalation (DreM)-carbamoyl migration strategy was applied in an efficient synthesis of the naturally occurring 6H-naphtho[1,2-b]benzopyran-6-one defucogilvocarcin V (1a, Scheme 11). The required biarylcarbamate 33d was best prepared by a high yielding Suzuki coupling reaction of 31a with the differentially protected trioxygenated naphthalene coupling partner 32d which was synthesized using a selective acylation of a juglone derivative. In the late stages of the synthesis, the triflate 39 served as the common intermediate to install the required C-8 vinyl group of 1a (Stille coupling) as well as the required substituents for the preparation of defucogilvocarcins M (1b) and E (1c). A variety of protecting group strategies were investigated and provided insight into which groups are preferred for the DreM-carbamoyl migration process. The strategic lessons learned from this total synthesis were applied in the successful total synthesis of the structurally similar natural product arnottin I (2).

Full text of DOI:10.1021/jo9001454

Combined Directed Remote Metalation-Transition Metal Catalyzed
Cross Coupling Strategies: The Total Synthesis of the Aglycones of
the Gilvocarcins V, M, and E and Arnottin I
Clint A. James† and Victor Snieckus*,‡
Department of Chemistry, UniVersity of Waterloo, Waterloo, ON, Canada N2L 3G1
snieckus@chem.queensu.ca
ReceiVed February 4, 2009
A key directed remote metalation (DreM)-carbamoyl migration strategy was applied in an efficient
synthesis of the naturally occurring 6H-naphtho[1,2-b]benzopyran-6-one defucogilvocarcin V (1a, Scheme
11). The required biarylcarbamate 33d was best prepared by a high yielding Suzuki coupling reaction of
31a with the differentially protected trioxygenated naphthalene coupling partner 32d which was synthesized
using a selective acylation of a juglone derivative. In the late stages of the synthesis, the triflate 39
served as the common intermediate to install the required C-8 vinyl group of 1a (Stille coupling) as well
as the required substituents for the preparation of defucogilvocarcins M (1b) and E (1c). A variety of
protecting group strategies were investigated and provided insight into which groups are preferred for
the DreM-carbamoyl migration process. The strategic lessons learned from this total synthesis were
applied in the successful total synthesis of the structurally similar natural product arnottin I (2).
Introduction
step (Scheme 2, 3 f 4). The work is a rational extension of the
discovery2 and application3 of the DreM tactic for the construc-
tion of dibenzopyranone 4 derivatives and natural products,4
isolated mainly from plant and microbial sources5 and exhibiting
cytotoxic6 and antiestrogen activity,7 and related to the more
complex ellagic acids and chartreusin that, owing to their
additional important biological activities (antiviral,8 antitumor,9
antitopoisomerase,10 anitestrogen11), have also elicited synthetic
interest.12
We report on the total synthesis1 of the aglycones of the
gilvocarcins 1, 1a (R′ ) H, R ) vinyl), 1b (R′ ) H, R ) Me),
and 1c (R′ ) H, R ) Et) and arnottin I (2) (Scheme 1) by a
strategy that originates with sequential directed ortho metalation
(DoM) and Suzuki-Miyaura cross coupling reactions and is
terminated by a directed remote metalation (DreM)-lactonization
† Present address: Boehringer-Ingelheim Research and Development, Laval,
Quebec, Canada, H7S 2G5.
The naphtho[b,d]benzopyran-6-ones (Scheme 1, 1A-F),
benzannulated analogues to the dibenzopyranones (4), constitute
‡ Present address: Department of Chemistry, Queen’s University, Kingston,
ON, Canada K7L 3N6.
(1) For a preliminary report of our total syntheses of defucogilvocarcins V,
M and E see: James, C. A.; Snieckus, V. Tetrahedron Lett. 1997, 38, 8149.
Nomenclature of the aglycones used throughout: Defucogilvocarcin V: 1a,
R’ ) H, R ) vinyl, Defucogilvocarcin M: 1b, R′ ) H, R ) Me, and
Defucogilvocarcin E: 1c, R′ ) H, R ) Et. Defucogilvocarcin V is itself a natural
product, see ref 13e.
(2) Wang, W.; Snieckus, V. J. Org. Chem. 1992, 57, 424.
(3) (a) Cai, X.; Snieckus, V. Org. Lett. 2004, 6, 2293. (b) Kalinin, A.; Reed,
M. A.; Norman, B. H.; Snieckus, V. J. Org. Chem. 2003, 68, 5992. (c) Mohri,
S.-I.; Stefinovic, Snieckus, V. J. Org. Chem. 1997, 62, 7072. For a brief review,
see: (d) Macklin, T.; Snieckus, V. In Handbook of C-H Transformations; Dyker,
G., Ed.; Wiley-VCH: Weinheim, 2005; p 106.
4080 J. Org. Chem. 2009, 74, 4080–4093
10.1021/jo9001454 CCC: $40.75 2009 American Chemical Society
Published on Web 05/14/2009

Combined Directed Remote Metalation
SCHEME 1
dissimilarity at the C-8 position: gilvocarcin V (1a, R ) vinyl),
gilvocarcin M (1b, R ) Me), and gilvocarcin E (1c, R ) Et).14
This class of natural products exhibits diverse bioactivity which
includes bactericidal,15 antitumor,16 and photochemotherapeu-
tic properties.17,18
In comparison to the gilvocarcins, arnottin I (Scheme 1, 2),
a sugarless naptho[b,d]benzopyranone with a different oxygen-
ation pattern, was isolated in 1977 by Ishikawa and co-workers
as a minor constituent from the bark of Xanthoxylum arnot-
tianum19 together with arnottin II (a spirolactone oxidatively
related to 2). The structural elucidation of arnottin I was not
achieved20 until 1993 due, in part, to the fact that the producing
plant yielded only small quantities of the material. The coiso-
lation of the benzophenanthridine alkaloid chelerythrine21 was
a biogenetic hint for the relationship of these three natural
products and their dissimilarity to the gilvocarcins, which are
SCHEME 2
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Peter, M. G.; Redden, P. R. J. Med. Chem. 2003, 46, 1289.
(13) Gilvocarcin V, M and E: (a) Nakano, H.; Matsuda, Y.; Ito, K.; Ohkubo,
S.; Morimoto, M.; Tomita, F. J. Antibiot. 1981, 34, 266. (b) Balitz, D. M.;
O’Herron, F. A.; Bush, J.; Vyas, D. M.; Nettleton, D. E.; Grulich, R. E.; Bradner,
W. T.; Doyle, T. W. J. Antibiot. 1981, 34, 1544. (c) Hatano, K.; Hagashide, E.;
Kameda, Y.; Horii, S.; Mizuno, K. Agric. Biol. Chem. 1980, 44, 1157. (d) Wei,
T. T.; Byrne, K. M.; Warnick-Pickle, D.; Greenstein, M. J. Antibiot. 1982, 35,
545. Defucogilvocarcin V: (e) Misra, R.; Tritch III, H. R.; Pandey, R. C. J.
Antibiot. 1985, 38, 1280. Virenomycin M, V: (f) Streilitz, F.; Flon, H.; Asheshov,
I. N. J. Bacteriol. 1955, 69, 280Ravidomycins: (g) Sehgal, S. N.; Vezina, C.
Eur. Pat. Appl. 10 964; Chem. Abstr. 1985, 102, 130–570s. (h) Narita, T.;
Matsumoto, M.; Mogi, K.; Kukita, K.-I.; Kawahara, R.; Nakashima, T. J. Antibiot.
1989, 42, 347. Albacarcin M, V: (i) Matson, J. A.; Myllymaki, R. W.; Doyle,
T. W.; Bush, J. A. Chem. Abstr. 1985, 102, 4456a U. S. Patent 4,461,831.
(14) Structural Elucidation: (a) Findlay, J. A.; Liu, J.-S.; Radics, L. Can.
J. Chem. 1983, 61, 323. (b) Takahashi, K.; Yoshida, M.; Tomita, F.; Shirahata,
K. J. Antibiot. 1981, 34, 271. X-ray crystal structure of gilvocarcin M: (c)
Hirayama, N.; Takahashi, K.; Shirahata, K.; Ohashi, Y.; Sasada, Y. Bull. Chem.
Soc. Jpn. 1981, 54, 1338. For isolation of compounds related to gilvocarcin M
but bearing a C-12 glycoside: (d) Kojiri, K.; Arakawa, H.; Satoh, F.; Kawamura,
K.; Okura, A.; Suda, H.; Okanashi, M. J. Antibiot. 1991, 44, 1054. (e) Nakajima,
S.; Kojiri, K.; Suda, H.; Okanishi, H. J. Antibiot. 1991, 44, 1061.
(15) Tomita, F.; Takahashi, K.-I.; Tamaoki, T. J. Antibiot. 1982, 35, 1038.
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(b) Morimoto, M.; Okubo, S.; Tomita, F.; Marumo, H. J. Antibiot. 1981, 34,
701. (c) Bockstahler, L. E.; Elespuru, R. K.; Hitchins, V. M.; Carney, P. G.;
Olvey, K. M.; Lytle, C. D. Photochem. Photobiol. 1990, 51, 477.
(17) (a) Elespuru, R. K.; Gonda, S. K. Science 1984, 223, 69. (b) Greenstein,
M.; Monji, T.; Yeung, R.; Maiese, W. M.; White, R. J. Antimicrob. Agents
Chemother. 1986, 29, 861. For recent discussion of the differentiation of the
mechanism of action of the gilvocarcins relative to other DNA intercalators see:
(c) Matsumoto, A.; Hanawalt, P. C. Cancer Res. 2000, 60, 3921. RAJIV17For
the elucidation of the complete gene cluster of gilvocarcin V see: (d) Fischer,
C.; Lipata, F.; Rohr, J. J. Am. Chem. Soc. 2003, 125, 7818. For further studies
on the biosynthesis of gilvocarcin V: (e) Liu, T.; Fischer, C.; Beninga, C.; Rohr,
J. J. Am. Chem. Soc. 2004, 126, 12262. (f) Liu, T.; Kharel, M. K.; Fischer, C.;
McCormick, A.; Rohr, J. ChemBioChem 2006, 7, 1070.
(18) For studies on the mechanism of action see: (a) McGee, L. R.; Misra,
R. J. Am. Chem. Soc. 1990, 112, 2386, and references cited therein. (b)
Matsumoto, A.; Hanawalt, P. C. Cancer Res. 2000, 60, 3921.
(19) Ishii, H.; Ishikawa, T.; Haginiwa, J. Yakugaku Zasshi 1977, 97, 890
Chem. Abstr. 1977, 87, 197250g.
(20) Ishii, H.; Ishikawa, T.; Murota, M.; Aoki, Y.; Harayama, T. J. Chem.
Soc., Perkin Trans. 1 1993, 1019.
(21) Ishii, H.; Ishikawa, T.; Takeda, S.; Suzuki, M.; Harayama, T. Chem.
Pharm. Bull. 1992, 40, 2002.
J. Org. Chem. Vol. 74, No. 11, 2009 4081

James and Snieckus
SCHEME 3
polyketide derived. In fact, Ishikawa has suggested22 that
arnottin I was a potential biosynthetic intermediate of chel-
erythrine. Although the biological activity of the arnottins has
not been established, compounds related to chelerythrine have
shown significant antileukemic properties.23,24
M, McGee26c used the Pechmann condensation28 to generate
the key bond (path B). Jung26d and co-workers made use of the
versatile Suzuki coupling process (path C) whereas the strategy
of Hart26e involved the 1,4-addition of a lithiated oxazoline to
a naphthoquinone derivative (path D). The diazonium Meerwein
coupling29 in conjunction with the Stille coupling strategy
allowed McKenzie26f-h to prepare a series of derivatives varying
the substituents at C-8 (Path F). Parker26i used a Fischer
carbene-alkyne reaction as the key de noVo ring B generation
step (path G) in a convergent but inefficient synthesis of
defucogilvocarcin V methyl ether. A palladium catalyzed biaryl
bond construct was used by Martin26j as the key step in the
synthesis of defucogilvocarcins M and E and also by Suzuki in
an elegant syntheses of gilvocarcins M30 and V31 (path E).
In contrast to the rich synthetic activity in the gilvocarcin
area, only three syntheses of Arnottin I have been reported:
Ishii32 used a strategy involving the oxidative cleavage of a
benzofuran derivative for lactone generation and Harayama33
developed a route similar to those of Martin and Suzuki (Scheme
3, path C) Recently, Cheng34 developed a concise synthesis of
Arnottin I based on the nickel-catalyzed ring-opening of 1,4-
epoxynaphthalenes with aryliodides.
The considerable synthetic effort25,26 toward the construction
of the gilvocarcin ring system has generally focused on the
formation of the C10a-C10b biaryl bond followed by lacton-
ization to generate the tetracyclic ring system (Scheme 3). Thus,
Findlay26a and Danishefsky26b used the Meyers27 nucleophilic
aromatic substitution tactic of ortho-methoxyl aryloxazolines
with aryl Grignards in independent syntheses of defucogilvo-
carcin V (path A). In a convergent approach to defucogilvocarcin
(22) Ishii, H.; Ishikawa, T.; Murota, M.; Aoki, Y.; Harayama, T. J. Chem.
Soc., Perkin Trans. 1 1993, 1019.
(23) Ishii, H.; Chen, I.-S.; Ishikawa, T. J. Chem. Soc., Perkin Trans. 1 1987,
671.
(24) Stermitz, F. R.; Larson, K. A.; Kim, D. K. J. Med. Chem. 1973, 16,
939.
(25) For a review, see: (a) Hua, D. H.; Saha, S. Recl. TraV. Chim. Pays-Bas
1995, 114, 341. For an elegant three component synthesis of the gilvocarcin
framework: (b) Takemura, I.; Imura, K.; Matsumoto, T.; Suzuki, K. Org. Lett.
2004, 6, 2503. For methods involving early-stage incorporation of the C-
glycoside: (c) Cordero-Vargas, A.; Quiclet-Sire, B.; Zard, S. Z. Org. Biomol.
Chem. 2005, 3, 4432. (d) Cordero-Vargas, A.; Quiclet-Sire, B.; Zard, S. Z.
Tetrahedron Lett. 2004, 45, 7335.
(26) For literature concerning structural determination and an organized
collection of the synthetic work, see: (a) Findlay, J. A.; Daljeet, A.; Murray,
P. J.; Rej, R. N. Can. J. Chem. 1987, 65, 427. (b) Patten, A. D.; Nguyen, N. H.;
Danishefsky, S. J. J. Org. Chem. 1988, 53, 1003. (c) McGee, L. R.; Confalone,
P. N. J. Org. Chem. 1988, 53, 3695. (d) Jung, M. E.; Jung, Y. H. Tetrahedron
Lett. 1988, 29, 2517. Defucogilvocarcin M: (e) Hart, D. J.; Merriman, G. H.
Tetrahedron Lett. 1989, 30, 5093. (f) McKenzie, T. C.; Hassen, W.; McDonald,
S. J. F. Tetrahedron Lett. 1987, 28, 5435. (g) McKenzie, T. C.; Hassen, W.
Tetrahedron Lett. 1987, 28, 2563. (h) MacDonald, S. J. F.; McKenzie, T. C.;
Hassen, W. D. J. Chem. Soc., Chem. Commun. 1987, 1528. (i) Parker, K. A.;
Coburn, C. A. J. Org. Chem. 1991, 56, 1666. (j) Deshpande, P. P.; Martin, O. R.
Tetrahedron Lett. 1990, 31, 6313. Defucogilvocarcin E: (k) Hua, D. H.; Saha,
S.; Roche, D.; Maeng, J. C.; Iguchi, S.; Baldwin, C. J. Org. Chem. 1992, 57,
399.
We set these natural products as targets in order to test the
viability of our evolving methodologies in DoM, DreM, and
cross coupling. Furthermore, we concentrated on the construc-
(28) Sethna, S.; Phadka, R. Org. React. 1953, 7, 1.
(29) Rondestvedt, C. S., Jr. Org. React. 1976, 24, 225.
(30) Matsumoto, T.; Hosoya, T.; Suzuki, K. J. Am. Chem. Soc. 1992, 114,
3568.
(31) Hosoya, T.; Takashiro, E.; Matsumoto, T.; Suzuki, K. J. Am. Chem.
Soc. 1994, 116, 1004.
(32) Ishii, H.; Ishikawa, T.; Murota, M.; Aoki, Y.; Harayama, T. J. Chem.
Soc., Perkin Trans. 1 1993, 1019.
(33) (a) Harayama, T.; Yasuda, H.; Akiyama, T.; Takeuchi, Y.; Abe, H. Chem.
Pharm. Bull. 2000, 48, 861. (b) Harayama, T.; Yasuda, H. Heterocycles 1997,
46, 61.
(27) (a) Meyers, A. I.; Gabel, R.; Mihelich, E. D. J. Org. Chem. 1978, 43,
1372. (b) Meyers, A. I.; Avila, W. B. J. Org. Chem. 1981, 46, 3881.
(34) Madan, S.; Cheng, C.-H. J. Org. Chem. 2006, 71, 8312.
4082 J. Org. Chem. Vol. 74, No. 11, 2009

Combined Directed Remote Metalation
SCHEME 4
SCHEME 5
tion of the gilvocarcin aglycones in view of the extensive
available work on glycosylation of gilvocarcins35,25d and related
structures as well as the demonstration for lack of requirement
of the sugar moiety for antitumor activity.36 While successful,
these journeys taught additional lessons in protection-deprotection
strategies which are consistent with common wisdom.37
Results and Discussion
regioselective synthesis of a differentially protected trioxygen-
ated naphthalene26d,j requirement for 24 were evident. However,
the advantages in the choice of, and ability to interconvert M1,
M2-Y combinations in the cross coupling partners 23 and 25,
the power of the O-carbamate39 favoring regioselective DoM
in 24, and, most significantly, DreM protocol facilitating piggy-
backing the amide into the alternate ring, 22 f 21 (Scheme 4),
hence allowing the use of less hindered cross coupling partners
compared to those required by a direct method, encouraged
pursuit of the retrosynthetic plan.
Construction of the A/B Ring Precursor. The initial task
was the preparation of the highly oxygenated naphthalene
derivative 24 as the A/B ring fragment. In previous syntheses
of naptho[b,d]benzopyranones, the construction of trioxygenated
naphthalenes involved the differentiation of juglone (5-hydroxy-
1,4-naphthaquinone) derivatives by reductive lactonization,
protection - reprotection sequences or selective alkylation or
acylation methods40 which, although proceeding from readily
available starting materials and incorporating high yielding key
steps, were protracted.41 To devise a short and convenient
method, initial efforts focused on the application of the
cycloaddition of alkoxyarynes to 2-methoxyfuran developed by
Suzuki and co-workers42 and subsequently evolved into an
instructive foray into alternate aryne precursors (Scheme 5) as
well as useful lessons in DoM chemistry of some deceptively
simple substrates.43 Consideration of phenol protection as its
isopropyl ether was based on its known stability under the
DReM conditions2 and its mild and selective cleavage in the
presence of arylmethyl ethers,44 and similarly, the MOM
derivative 27b was available analogously.
Defucogilvocarcins V, M, and E. Retrosynthetic Ana-
lysis. The envisaged approach to defucogilvocarcins V (1a), M
(1b), and E (1c) (Scheme 4) incorporates a C8 alkyl group
scission to the penultimate intermediate triflate 20 which would
serve efficiently for transition metal catalyzed coupling processes
(e.g., Kumada-Corriu, Suzuki-Miyaura, Negishi, Stille)38 to the
three aglycones and, potentially, to analogues for bioscreening
purposes. Lactone opening reveals the phenol amide 21 which
is expected to be derived from 22 by a key Directed remote
Metalation (DreM)-carbamoyl migration2 step followed by
standard lactonization. Biaryl carbamate 22 is disconnected to
naphthyl carbamate 24 and arene 25 Via a transition metal
catalyzed cross coupling retron. Initial concerns of choice of
PG1, PG2 to withstand cross coupling and DreM conditions and
(35) Ravidomycin: (a) Suzuki, K. Pure Appl. Chem. 2000, 72, 1783. (b)
Futagami, S.; Ohashi, Y.; Imura, K.; Hosoya, T.; Ohmori, K.; Matsumoto, T.;
Suzuki, K. Tetrahedron Lett. 2000, 41, 1063. (c) Parker, K. A.; Su, D.-S.
J. Carbohyd. Chem. 2005, 24, 187. Gilvocarcins: see ref 41. For general methods
of C-arylglycosidation, see: (d) Yamamoto, Y.; Saigoku, T.; Nishiyama, H.;
Ohgai, T.; Itoh, K. Org. Biomol. Chem. 2005, 3, 1768. (e) Taillefumier, C.;
Chapleur, Y. Chem. ReV. 2004, 104, 263. (f) Somsa´k, L. Chem. ReV. 2001, 101,
81. (g) Smoliakova, I. P. Curr. Org. Chem. 2000, 4, 589. (h) Togo, H.; He, W.;
Waki, Y.; Yokoyama, M. Synlett 1998, 700. (i) Du, Y.; Linhardt, R. J.; Vlahov,
I. R. Tetrahedron 1998, 54, 9913. (k) Postema, M. H. Tetrahedron 1992, 48,
8545. (l) Daves, G. D., Jr. Acc. Chem. Res. 1990, 23, 201.
(36) (a) Tse-Dinh, T. C.; McGee, L. R. Biochem. Biophys. Res. Commun.
1987, 143, 808. (b) See ref 11e. (c) See however ref 16f.
(37) See Kocienski, ProtectiVe Groups, 3rd ed.; Thieme Verlag: Stuttgart
2003, p 2: “Protection is not a principle but an expedient” attributed to Disraeli,
B., March 17, 1845.
(38) For excellent coverage of all reactions, see: (a) Diederich, F., de Meijere,
A., Eds. Metal-Catalyzed Cross-Coupling Reactions, Vols 1 and 2; Wiley-VCH:
Weinheim, 2004. For a review on the DoM-cross coupling strategy, see: (b)
Anctil, E. J.-G.; Snieckus, V. In Metal-Catalyzed Cross-Coupling Reactions,
2nd ed; De Meijere, A., Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004; Vol
1, pp 761-813. (c) For applications of cross coupling reactions to total synthesis
Nicolau, K. C.; Bulger, P. G.; Sartah, Angew. Chem. Int. Ed 2005, 44, 4442.
(39) Sibi, M. P.; Snieckus, V. J. Org. Chem. 1983, 48, 1935.
(40) See refs 22a,b,d,e,j for examples of this strategy.
J. Org. Chem. Vol. 74, No. 11, 2009 4083

James and Snieckus
SCHEME 6
SCHEME 7
Although reasonably efficient routes to the desired oxygenated
naphthols 27a and 27b had been established via the aryne
methodology, the expense and difficult preparation of 2-meth-
oxyfuran encouraged return to juglone-related approaches. Thus
(Scheme 6), using a modification of the procedure for the
selective acetylation of juglone derivatives by Giles,45 treatment
of isopropoxy juglone46 29 with ClCONEt2 in the presence of
pyridine and Zn dust afforded the selectively carbamoylated
naphthol 30 which was then smoothly methylated to furnish
the required A/B ring precursor 28a (3 steps, 45% overall yield
from commercial juglone). Although both isopropoxy (28a) and
OMOM (28b) derivatives were available in modest yields via
the aryne chemistry ultimately, due to its relative brevity and
ability to work on scale-up, the selective carbamoylation
intermediate 30 was used as the advanced intermediate. Subjec-
tion of 28a and 28b to the standard carbamate metalation
conditions followed by iodine quench afforded the required cross
coupling partners 31a and 31b in respectrable yields.
conditions to establish the biaryl bond (Scheme 7). The choice
of the TBS protection was chosen based on ease of cleavage in
the presence of aryl methyl and isopropyl ethers. Lithiation of
28a (s-BuLi/THF/-78 °C/20 min) followed by addition of a
solution of ZnCl2 and direct treatment with bromide 32a in the
presence of Pd(PPh3)4 at reflux afforded the key biaryl 33a in
45% yield (Table 1, entry 1). Subsequently, a two step, inverted
partner, protocol was found to be more efficient. Negishi
coupling of the iodide 31a with the arylzinc reagent derived
from metal-halogen exchange and ZnCl2 transmetalation of 32a
provided the desired biaryl in excellent yield (Table 1, entry
2). A similar protocol applied to the 5-OMOM carbamate 31b
led to the corresponding biaryl 33b in comparable yield (Table
1, entry 3). As will become evident, the C4′-TBS series 33a-b
was inappropriate for the conclusion of the total synthesis of
the gilvocarcins and was superseded by the corresponding C4′-
i-Pr 33c and C4′-MOM 33d derivatives. The preparation of these
biaryls by the Negishi protocol using both possible combina-
tions, met initial difficulties. Thus, DoM s Zn transmetalation
of 28a followed by coupling with 32b failed (Table 1, entry 4)
and inversion of partners and coupling of 31a with the arylzinc
derived from 32b afforded 33c in only 21% yield (Table 1, entry
5). Turning to the Suzuki-Miyaura reaction, application of
standard conditions to the coupling of 31a with the arylboronic
acid 32e derived by metal-halogen exchange s boronation of
32b led to similarly poor results (Table 1, entry 6) However,
changing the base from Na2CO3 to Ba(OH)2,48 led to substantial
improvement affording the isopropoxy biaryl 33c (Table 1, entry
Formation of A/B-C Ring Biaryl Bond by Cross
Coupling. With the A/B ring moiety 31a in hand and the
necessary D ring coupling fragments 32a-c, available Via a
reported regioselective tosylation technology of 4-bromoresor-
cinol,47 initial studies focused on Negishi cross coupling
(41) For example, Findlay’s route (see ref 26a) furnishes an arylbromide
precursor to a Suzuki coupling in 3 steps but is not selectively protected and
requires a protection-deprotection sequence late in the synthesis. The synthesis
by Jung provides a differentially protected arylboronic acid Suzuki precursor in
5 steps and ca 67% yield; however, the boronic acid is used in crude form and
the overall yield is not known (see ref 26d).
(42) Matsumoto, T.; Hosoya, T.; Katsuki, M.; Suzuki, K. Tetrahedron Lett.
1991, 32, 6735.
(43) Full details of the routes pursued, their rationale and lessons learned
are given in the Supporting Information (Section 1).
(45) Chorn, T. A.; Giles, R. G. F.; Green, I. R.; Hugo, V. I.; Mitchell, P. R. K.;
Yorke, S. C. J. Chem. Soc., Perkin Trans. 1 1984, 1339.
(46) Laatsch, H. Liebigs Ann. Chem. 1985, 251.
(44) (a) Sala, T.; Sargent, M. V. J. Chem. Soc., Perkin Trans. 1 1979, 2593.
(b) Banwell, M. G.; Flynn, B. L.; Stewart, S. G. J. Org. Chem. 1998, 63, 9139.
(47) Bos, M. E.; Wulff, W. D.; Miller, R. A.; Chamberlin, S.; Brandvold,
T. A. J. Am. Chem. Soc. 1991, 113, 9293.
4084 J. Org. Chem. Vol. 74, No. 11, 2009

Combined Directed Remote Metalation
TABLE 1. Cross Coupling Reactions for the Preparation of 33a-d
Entry
ArX
R1
X
ArY
Y
R2
Conditions
Yld,a
%
1
2
3
4
5
6
7
8
28a
31a
31b
28a
31a
31a
31a
31a
i-Pr
i-Pr
MOM
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
ZnCl
I
I
32a
32a
32a
32b
32b
32d
32d
32e
Br
ZnCl
ZnCl
Br
TBS
TBS
TBS
iPr
iPr
iPr
Pd(PPh3)4/THF/reflux/12 h
Pd(PPh3)4/THF/reflux/12 h
Pd(PPh3)4/THF/reflux/12 h
Pd(PPh3)4/THF/reflux/12 h
Pd(PPh3)4/THF/reflux/48 h
aq Na2CO3/DME/reflux/12 h
aq Ba(OH)2/DME/reflux/12 h
aq Ba(OH)2/DME/reflux/1 h
45
90
90
0
21
28
92
99
ZnCl
I
I
I
I
ZnCl
B(OH)2
B(OH)2
B(OH)2
iPr
MOM
a Yields of isolated products.
SCHEME 8
the C-5 isopropoxy proved labile accounting for 39% of the
reaction mixture in the form of products 34h and 34j.51 The
site of isopropyl group cleavage in 34j was established by
cyclization to the lactone 36 and subsequent NOE experie-
ments.52 In a separate experiment, treatment of 33c with LDA
and direct conversion into the tetracyclic lactone bis-isopropyl
ether 35 (Scheme 9) and cleavage of the isopropoxy group with
1
BCl3 gave lactone 36 which was identical by H NMR to the
material obtained from 34j. Susequent NOE diference experi-
ments confirmed these results.52 Unfortunately, attempts under
a variety of conditions, including excess BCl3 treatment, to
obtain the 4′,5-bisphenol by double deprotection failed, thus
thwarting the test of selective 4′-triflation in order to proceed
for final alkyl or vinyl group introduction by cross coupling
tactics for the completion of the total syntheses.
TABLE 2. DreM Reactions of O-Carbamate 33a
34
R1
R2
R3
R4
R5
Yld,a
%
a
b
c
d
e
f
i-Pr
i-Pr
H
i-Pr
i-Pr
H
TBS
H
H
TBS
H
H
H
H
H
H
H
4
27
16
4
21
13
TBS
TBS
H
TBS
TBS
CONEt2
H
H
H
H
CONEt2
CONEt2
CONEt2
Contemplation of the failures with feeble (33a) and robust
(33c) protective groups led to examination of the 4-OMOM
derivative 33d (Scheme 10) as a potential expedient and practical
solution.37 Subjection of 33d to the standard conditions for the
DreM protocol afforded the desired hydroxyl amide 37 in a
disappointing but, at this stage encouraging, 28% yield.
Optimization was achieved after considerable experimentation
of the migration conditions. Thus, introduction of LDA in two
portions (1.3 equiv and then 1.3 equiv after 1 h, followed by
treatment of the reaction mixture with 1:1 HOAc:H2O afforded
38 in 70% yield. The introduction of the base in two portions
may serve to keep the concentration of LDA low during the
reaction, suppressing the base induced cleavage of the isopro-
poxy and carbamoyl groups.53
C-8 Substituent Introduction. Completion of the Total
Syntheses of defucogilvocarcins V (1a), M (1b), and E
(1c). In pursuit of the end game (Scheme 11), the phenol 38
was converted, after several failures owing to solubility
problems, into the corresponding triflate 39 employing NEt3 as
a cosolvent (5 equiv) at -78 °C followed by a low temperature
quench with NaHCO3. Modified Stille conditions54 using tri-
n-butyl vinylstannane furnished 1-isopropoxydefucogilvocarcin
a Yields of isolated products.
7) as well as the MOM derivative 33d in excellent yield (Table
1, entry 8). The boronic acid 32e was prepared analogously to
the preparation of 32d (see Supporting Information).
Directed Remote Metalation (DreM) Reaction.
Completion of the Tetracyclic Ring System: C-Ring Con-
struction. Subjection of biarylcarbamate 33a to the standard
LDA induced DreM-carbamoyl migration conditions2 led to
initially discouraging results (Scheme 8, Table 2). Of the
compounds isolated, several are derived from the desired
carbamoyl migration process (34d-f); however, the desired
product 34d was obtained in only 4% yield. The formation of
compound 34a in very low yield resulting from carbamate
cleavage was expected based on previous results.2 On the other
hand, the characterization of 34b, 34e, and 34f (total 61% yield),
indicative of competitive C-3′ metalation followed by 4′-O
f3′-C TBS migration,49 suggested the need for a more robust
protecting group. Cleavage of the C-1 protective group as
evidenced by product 34c was also competitive, presumably
resulting from LDA induced E2 reaction (Vide infra).
As a possible circumvention of the lability of the 4′-TBS
protective group to DreM conditions, the corresponding O-i-Pr
derivative 33c was tested under the standard LDA conditions
(Scheme 9).50 Again, a complex reaction mixture resulted;
although cleavage of the C-4′ isopropoxy group was not
observed and the desired product 34i was obtained in 41% yield,
(51) Selective 5-i-Pr cleavage suggests bridging 5-Oi-Pr-4-OMe coordination
with LDA and E2 -type elimination with excess of the reagent, a result which
may be rationalized by the Complex Induced Proximity Effect (CIPE): Whisler,
M. C.; MacNeil, S.; Snieckus, V.; Beak, P. Angew. Chem., Int. Ed. 2004, 43,
2206–2225. This rationalization may also be invoked for the reaction of 34i to
give 34j (90%) under the standard DReM conditions. For a related case, see ref
1.
(52) James, C. A. Ph.D thesis, University of Waterloo, 1998.
(53) That the improved yield of 33d f 38 (combined process) vs 33d f 37
f 38 (stepwise) results from the portion-wise introduction of LDA is supported
by the relative amounts of C-5 phenolic products observed for the former reaction
compared to the corresponding reactions of 33a and 33c. However, this
suggestion is speculative since an experiment with the same substrate using the
two different sets of DReM conditions, and to a common product was not carried
out. Furthermore, a detailed analysis of DReM reaction products of 33d was
not performed due to the relatively less straightforward (cf. Scheme 8 and 9)
purification of the reaction mixtures and the instability of some fractions on
silica gel.
(48) (a) Campi, E. M.; Jackson, W. R.; Marcuccio, S. M.; Naeslund, C. G. M.
J. Chem. Soc., Chem. Commun. 1994, 2395. (b) Suzuki, A. Pure Appl. Chem.
1994, 66, 213.
(49) For precedents see: (a) Billideau, R. J.; Sibi, M. P.; Snieckus, V.
Tetrahedron Lett. 1983, 24, 4515. (b) Sinhababu, A. K.; Kawase, M.; Borchhardt,
R. T. Tetrahedron Lett. 1987, 28, 4139.
(50) This work was encouraged by the previously demonstrated stability of
isopropyl ethers under LDA mediated carbamate DreM rearrangements (ref 1)
as well as model studies (ref 51, p 77.)
J. Org. Chem. Vol. 74, No. 11, 2009 4085

James and Snieckus
SCHEME 9
SCHEME 10
n-BuLi at -78 and -100 °C respectively in the presence of a
large excess of furan afforded the cycloadduct 44a in good to
excellent yields whose ring-opening-aromatization was effected
with BCl3 under low temperature conditions to furnish the
naphthol 45a which, in turn, was acylated to provide the key
O-carbamate 46a. Subsequently, the DoM-ZnCl2 transmeta-
lation-cross coupling sequence of 46a with arylbromide 48a
or its inverted partner reaction, 47a, available in modest yield
by metalation-iodination of 46a, with the zinc reagent derived
from arylbromide 48a afforded biaryl 49a in acceptable yield
(see Table 3).
Attempts to effect DreM-carbamoyl migration reactions
using LDA, LiTMP, and the Martin in situ LiTMP/TMSCl59
conditions on 49a were categorically unsuccessful,52 (Scheme
14) leading to mixtures of starting material, decomposition
products, and formation of the catechol 49c in 22-43% yields
as the somewhat predicted product from strong base derived
cleavage of the methylenedioxy group.57
To circumvent this impasse, the diisopropoxy biaryl 49b was
prepared for a DreM study based on the consideration that the
position of the protection would mitigate LDA mediated
elimination as had been observed in the gilvocarcin series (33a
Scheme 8, 33c Scheme 9). Initial Negishi coupling (Scheme
13) afforded the desired biaryl 49b in poor yield. Success was
achieved again drawing on the lessons learned in the synthesis
ofthedefucogilvocarcins(Table1,entry7).Thus,Suzuki-Miyaura
coupling of 48b and 47b using Ba(OH)2 as base afforded the
diisopropoxy biphenyl DReM precursor 49b in nearly quantita-
tive yield.
V 40a in satisfactory yield. Treatment of 39 under Negishi-
Quesnelle coupling conditions with MeZnCl55 afforded the
corresponding methyl derivative 40b in 59% yield while Suzuki
conditions56 with BEt3 afforded 1-isopropoxydefucogilvocarcin
E 40c in 75% yield and concluded a demonstration of the
richness of modern cross coupling chemistry. Finally, as
established above for related systems, BCl3 induced isopropyl
ether deprotection proceeded smoothly to afford defucogilvo-
carcin V 1a in 95% yield which was shown to be identical with
the natural product by comparison of physical and spectroscopic
data (see Supporting Information). Similar deprotection of 40b
and 40c afforded defucogilvocarcin M (1b) and defucogilvo-
carcin E (1c) in 83 and 86% yields, respectively.
Arnottin I. With the protection-deprotection gambit of the
defucogilvocarcins en arrie`re, arnottin I (2) was initially
recognized as a less daunting target molecule the retrosynthetic
plan for which would follow similar lines (Scheme 12).
However, the presence of the methylenedioxy functionality was
cause for concern in view of its known sensitivity to strong
base conditions.57
After considerable experimentation to effect the carbamoyl
migration, the lessons learned in the synthesis of gilvocarcin
33d f 38 (Scheme 10) bore fruit in that portion-wise addition
of LDA to a solution of 49b at rt provided a migration product
in 68% yield. Although the operation of a DMG effect of the
2-OMe was expected to produce 50a, 1H NMR failed to clearly
The construction of the A/B ring precursors 46a,b (Scheme
13) was initiated from readily available bromosesamol58 (43a)
which was smoothly converted into the triflate 43b and tosylate
43c derivatives in high yields. Treatment of 43b and 43c with
(57) (a) ProtectiVe Groups in Organic Synthesis, 3rd ed; Greene, T. W., Wuts,
P. G. M., Eds.; John Wiley and Sons, Inc.: New York, 1999. For sensitivity
during addition of RMgX reagents: (b) Pizzonero, M,; Keller, L.; Dumas, F.;
Ourevitch, M.; Morgant, G.; De-Bire Spasojevic, A.; Bogdanov, G.; Ghermani,
N. E.; D’Angelo, J. J. Org. Chem. 2004, 69 (13), 4336. Alkoxides and NaCN: (c)
Imakura, Y.; Okimoto, K.; Konishi, T.; Hisazumi, M.; Yamazaki, J.; Kobayashi,
S.; Yamashita, S. Chem. Pharm. Bull. 1992, 40 (7), 1691.
(58) Alexander, B. H.; Oda, T. A.; Brown, R. T.; Gertler, S. I. J. Org. Chem.
1958, 23, 1969.
(59) Krizan, T. D.; Martin, J. C. J. Am. Chem. Soc. 1983, 105, 6155.
(54) Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585.
(55) Quesnelle, C. A.; Familoni, O. B.; Snieckus, V. Synlett 1994, 349.
(56) (a) Harada, T.; Yoshida, T.; Inoue, A.; Takeuchi, M.; Oku, A. Synlett
1995, 283. (b) Oh-e, T.; Miyaura, N.; Suzuki, A. J. Org. Chem. 1993, 58, 2201.
4086 J. Org. Chem. Vol. 74, No. 11, 2009

Combined Directed Remote Metalation
SCHEME 11
SCHEME 12
SCHEME 13
TABLE 3. Cross Coupling Reactions for the Preparation of 49a,b
characterize due to their insolubility. NMR analysis suggested
loss of the isopropyl protective group in addition to competitive
3′-demethylation, resulting from initial coordination of reagent
to the amide or lactone carbonyl.60
The use of the successful MOM protection strategy devised
and used in the gilvocarcin series (Scheme 10) for Arnottin I
was initially discounted due to previous DreM results observed
for substrate 33b.61 In the hope of altering cyclization conditions
that may allow isolation of 51b (Scheme 14), this protection
mode was now placed to the test on the available 49b. BCl3
49
R
X
Y
Yld, %
a
a
b
b
-CH2-
-CH2-
i-Pr
ZnCl
I
ZnCl
I
Bra
ZnCl
Br
60
68
32
b
i-Pr
B(OH)2
>95
a Pd(PPh3)4/THF/reflux. b Ba(OH)2/DME/reflux.
establish the regiochemistry of the product and therefore the
crude material was cyclized to the lactone 51a (62% yield over
two steps) for structural verification. Isopropyl ether cleavage
with BCl3 of either 50a or 51a under a variety of conditions52
led to complex mixtures whose products were difficult to
(60) (a) Quillinan, A. J.; Scheinmann, F. J. Chem. Soc., Perkin Trans. 1
1973, 1329–1337. (b) Nagaoka, H.; Schmid, G.; Iio, H.; Kishi, Y. Tetrahedron
Lett. 1981, 22, 899.
J. Org. Chem. Vol. 74, No. 11, 2009 4087

James and Snieckus
SCHEME 14
mediated isopropyl ether cleavage proceeded smoothly to give
the corresponding catechol which, upon treatment with MOMCl
furnished the requisite 49d in high yield. Exploration of a variety
of conditions using LDA as base afforded the hydroxyl- amide
50c in optimal 34% yield. Attempts at simultaneous cyclization-
MOM cleavage resulted, as feared, in the formation of mixtures
of intractable products which, when subjected to conditions of
methylenedioxy formation (CH2Br2/CuO/K2CO3/DMF/reflux),62
led, in irreproducible manner, to a hint of the formation of
arnottin I (2). However, treatment of 49d with excess LDA
followed by cyclization with TsOH in MeOH led to the desired
catechol 51c which fortunately precipitated from the reaction
mixture, allowing its isolation in 44% yield. Of the available
methods for catechol methylenation,62,63 the reliable conditions
of Clark64 were adapted to the insoluble 51c to furnish arnottin
I (2) in 39% yield. Synthetic arnottin I was shown to be identical
with the natural product by physical and spectral data compari-
son (see Experimental Section).
laboratories. Secondary but rational thought at the outset and
as the work progressed taught us the protection-deprotection
requirements for aryl oxygen functionality. In the events,
nuances in reactivity and drastic contrasts in physical properties
of intermediates led to unpredictable impasses and the need for
several renewed ascents as may be predicted with certainty in
total synthesis endeavors.
Nevertheless, defucogilvocarcin V (1, Scheme 11) was
conquered in 9 steps and 16% overall yield starting from
commercially available juglone. Aryl - furan cycloaddition (see
Supporting Information) and the more reliable reductive acy-
lation of isopropoxy juglone routes were established for the
construction of the differentially protected trioxygenated naph-
thalenes 28a and 31a (Scheme 6). Thence, convergence to the
key C4′-triflate 39 was achieved by application of modern cross
coupling strategies (Suzuki-Miyaura, Negishi, Stille) which
allowed the efficient additional syntheses of defucogilvocarcin
M (1b, Scheme 11) and defucogilvocarcin E (1c, Scheme 11)
in 9 steps and 15% overall yields. These routes may be adaptable
to the preparation of non-natural analogues with an eye toward
biological screening. As one possibility, appendage of OMe,
CO2R, Ph, or alkene substituents to the vinyl group of
defucogilvocarcin V (1a, Scheme 1) may sufficiently alter the
chromophore for potentially enhanced interaction with DNA
under UV irradiation.17
The total synthesis of arnottin I (2, Scheme 14) was achieved
in a less satisfactory 11 steps and 2% overall yield. The
DreM-carbamoyl migration protocol (Scheme 14) was shown
to be an effective, convergent strategy for the construction of
the naphtho[1,2-b]benzo[d]pyran-6-one framework of these
natural products which led to its generalization for the prepara-
tion of heterocyclic counterparts.66 Considerable useful knowl-
edge was gained in use of isopropyl and silyl aryl ethers as
protective groups under LDA conditions and the instability of
the methylenedioxy group to such conditions was confirmed.
Conclusions
Although thought and experiment is being expended in
protective group-free strategies,65 practice of organic synthesis
continues to require circuitous protection regimens that cause
annoyance, two additional steps (or more) and, at times,
completely incapacitate a total synthesis project at a very
inappropriate stage. Synthesis thence continues with strong
dependency and expediency on protective measures chosen from
the armory of approximately one thousand protective groups.63
In the present synthetic programs to the defucogilvocarcins and
arnottin I, the key objective was to assess the application of
key metalation and cross coupling methods evolving in our
(61) DreM reactions of 33b were as complex as those of 33a, yielding several
C5-phenolic products. The subsequent successful use of a C4′- MOM PG in
33c provided the impetus for its deployment for the protection of 49c (Scheme
14). See also ref 53.
(62) Bick, I. R. C.; Russell, R. A. Aust. J. Chem. 1969, 22, 1563.
(63) ProtectiVe Groups in Organic Synthesis, 4th ed.; Greene, T. W., Wuts,
P. G. M., Eds.; John Wiley and Sons, Inc.: New York, 2007; p 424.
(64) Clark, J. H.; Holland, H. L.; Miller, J. L. Tetrahedron Lett. 1976, 17,
3361.
Experimental Section
For General Methods and Standard Procedures see the Supporting
Information.
(65) (a) Jackson, R. F. W.; Rilatt, I.; Murray, P. J. Org. Biomol. Chem. 2004,
2, 110. (b) Baran, P. S.; Richter, J. M. J. Am. Chem. Soc. 2005, 127, 15394. (c)
Jeanmart, S.; Taylor, R. K. Tetrahedron Lett. 2005, 46, 9043. (d) McFadden,
R. M.; Stoltz, B. M. J. Am. Chem. Soc. 2006, 128, 7738. (e) Uchiyama, M.;
Furuyama, T.; Kobayashi, M.; Matsumoto, Y.; Tanaka, K. J. Am. Chem. Soc.
2006, 128, 8404.
N,N-Diethyl O-(4-Hydroxy-5-isopropoxy)naphthyl-1-carbam-
ate (30). A mixture of 5-isopropoxyjuglone (29)46 (0.289 g, 1.34
(66) James, C. A.; Snieckus, V. J. Org. Chem. 2009, 74, DOI: 10.1021/
jo900146d.
4088 J. Org. Chem. Vol. 74, No. 11, 2009

Combined Directed Remote Metalation
mmol), ClCONEt2 (0.5 mL, 3.95 mmol), pyridine (0.32 mL, 3.96
mmol), and Zn dust (0.917 g, 14.03 mmol) in CHCl3 (7.0 mL)
was heated at reflux until disappearance of starting material (TLC,
2 h). The reaction mixture was cooled, diluted with H2O followed
by 10% aq HCl, and the layers were separated. The aqueous layer
was extracted with CHCl3 (×2), and the combined organic layers
were washed (H2O, brine), dried (Na2SO4), and concentrated in
Vacuo. The residue was purified by column chromatography (4:1
hexane/EtOAc) and then by recrystallization (EtOH/H2O), affording
the title compound as light-brown plates (0.294 g, 70%). Mp 66-67
°C (EtOH/H2O). IR (KBr) ν (max) 3374, 3064, 2977, 2934, 1715,
1635, 1393, 1514, 1462, 1404, 1350, 1316, 1267, 1235, 1211, 1154,
1109, 1033 cm-1; 1H NMR (250 MHz, CDCl3) δ 9.69 (s, 1H), (dd
J ) 8.4, 1.3 Hz, 1H), 7.32 (t J ) 7.4, Hz, 1H), 7.12 (d J ) 8.4 Hz,
1H), 6.82 (d J ) 7.6, 1.0 Hz, 1H), 6.79 (d J ) 8.4 Hz, 1H), 4.85
(sept J ) 6.1 Hz, 1H), 3.57 (q, br, J ) 7.0 Hz, 2H), 3.42 (q, br, J
) 7.0 Hz, 2H), 1.49 (d J ) 6.1 Hz, 6H), 1.35 (t, br, J ) 7.0 Hz,
3H), (t, br, J ) 7.0 Hz, 3H); 13C NMR (62.9 MHz, CDCl3) δ 154.6
(e), 154.3 (e), 152.3 (e), 139.3 (e), 130.2 (e), 126.2 (o), 120.1 (o),
116.3 (e), 115.0 (o), 109.1 (o), 107.0 (o), 72.89 (o), 42.25 (e), 41.89
(e), 21.96 (o), 14.42 (o), 12.61 (o), MS (EI (70 eV)) m/e: (rel
intensity) 317 (M+, 25), 260 (0.5), 204 (1.3), 175 (12), 147 (1.6),
100 (100), 72 (27); Anal. Calcd for C18H23NO4: C, 68.12; H, 7.30;
N, 4.41 found: C, 68.26; H, 7.36; N, 4.33.
N,N-Diethyl-5-isopropoxy-4-methoxy-1-naphthyl-O-carbam-
ate (28a). Procedure 1: From Naphthol 27a. According to General
Procedure A, a mixture of naphthol 27a (see Supporting Informa-
tion) (2.86 g, 12.32 mmol), K2CO3 (2.92 g, 18.5 mmol), ClCONEt2
(2.34 mL, 18.47 mmol) in CH3CN (100 mL) was heated at reflux
for 12 h. Standard workup followed by column chromatography
(7:3 hexane/Et2O), and recrystallization (hexane/Et2O) afforded the
title compound as colorless plates (3.68 g, 90%). Mp 84-85 °C
(hexane/Et2O); IR (KBr) ν (max) 3070, 2950, 1722, 1586, 1513,
1323, 1249, 1105 cm-1; 1H NMR (250 MHz, CDCl3) δ 7.45 (dd J
) 8.4, 1.1 Hz, 1H), 7.36 (dd J ) 8.4, 7.6 Hz, 1H), 7.10 (d J ) 8.4
Hz, 1H), 6.90 (dd J ) 7.6, 1.1 Hz, 1H), 6.80 (d J ) 8.4 Hz, 1H),
4.55 (sept J ) 6.0 Hz, 1H), 3.90 (s, 3H), 3.61 (q J ) 7.0 Hz, 2H),
3.40 (q J ) 7.0 Hz, 2H), 1.42 (d J ) 6.0 Hz, 6H), 1.36 (t J ) 7.0
Hz, 3H), 1.23 (t J ) 7.0 Hz, 3H); 13C NMR (62.9 MHz, CDCl3) δ
155.2 (e), 154.7 (e), 141.1 (e), 131.2 (e), 126.8 (o), 120.4 (e), 118.4
(o), 114.8 (o), 113.8 (o), 106.2 (o), 73.30 (o), 56.93 (o), 42.39 (e),
42.02 (e), 22.13 (o), 14.56 (o), 13.52 (o); MS (EI (70 eV)) m/e:
(rel intensity) 331 (M+, 46), 289 (2), 231 (4), 189 (20), 100 (100),
72 (58); Anal. Calcd for C19H25NO4: C, 68.86; H, 7.60; N, 4.23;
found: C, 69.00; H, 7.71; N, 4.22.
J ) 7.1 Hz, 3H); 13C NMR (62.9 MHz, CDCl3) δ 155.2 (e), 154.9
(e), 152.9 (e), 142.2 (e), 131.2 (e), 127.6 (o), 119.8 (e), 114.9 (o),
114.8 (o), 113.6 (o), 88.16 (e), 73.1 (e), 56.7 (o), 42.4 (e), 42.1
(e), 21.9 (o), 14.5 (o), 13.3 (o); MS (EI (70 eV)) m/e: (rel intensity)
457 (M+; 14), 315 (13), 357 (0.1) 100 (100), 72 (63); HRMS (EI
(70 eV)) m/e calcd for C19H24NO4I: 457.0750, found 457.0731.
2-Methoxy-4-methoxymethoxybromobenzene (32c). To a sus-
pension of NaH (0.833 g, 60% dispersion in mineral oil, 20.83
mmol), in DMF (20 mL) at 0 °C was added a solution of 4-bromo-
3-methoxyphenol47 (2.38 g, 11.78 mmol) in DMF (15 mL). The
resulting mixture was allowed to stir at 0 °C until the evolution of
H2 ceased (30 min); MOMCl (1.50 mL, 19.75 mmol) was then
added, and the reaction mixture was allowed to warm to rt over
2 h. The resulting suspension was poured slowly into 150 mL of
ice water and the whole was extracted with Et2O (3 × 75 mL).
The combined organic layers were washed (H2O (5 × 100 mL),
brine), dried (Na2SO4), and concentrated in Vacuo. The residue was
purified by distillation giving a colorless liquid (2.64 g, 91%). Bp
100-105 °C/0.2 mmHg; IR (neat) ν (max) 2935, 2831, 1587, 1471,
1
1409, 1288, 1215, 1192, 1155, 1079 cm-1; H NMR (250 MHz,
CDCl3) δ 7.23 (d J ) 8.6 Hz, 1H), 6.46 (d J ) 2.6 Hz, 1H), 6.39
(dd J ) 8.6, 2.4 Hz, 1H), 4.99 (s, 2H), 3.70 (s, 3 h), 3.31 (s, 3H);
13C NMR (62.9 MHz, CDCl3) δ 157.8 (e) 156.5 (e), 133.2 (o),
108.9 (o), 103.7 (e), 101.6 (o), 94.6 (e), 56.1 (o), 56.0 (o); MS (EI
(70 eV)) m/e: (rel intensity) 248 (100), 246 (100), 218 (41), 216
(41), 175 (18), 173 (18); HRMS (EI (70 eV)) m/e calcd for
C9H11BrO3: 245.9891, found 245.9882.
2-Methoxy-4-methoxymethoxyphenylboronic acid (32e). To
a solution of 4-methoxymethoxy-2-methoxybromobenzene (32c)
(2.13 g, 8.60 mmol) in THF (50 mL) at -78 °C was added a
solution of n-BuLi (1.64 mL, 1.75 mol/L) and the resulting solution
was allowed to stir for 10 min. A solution of B(OMe)3 (3.00 mL,
26.42 mmol) was added in one portion and the mixture was allowed
to warm slowly to rt. The reaction mixture was quenched with satd
NH4Cl solution and the THF ws removed in vacuo. The residue
was diluted with H2O and acidified to ca. pH 5-6 with 10% HCl.
The acidic aqueous solution was then extracted with CH2Cl2 (3 ×
75 mL) and the combined organic layers were washed (H2O, brine),
dried (Na2SO4) and concentrated in Vacuo. The residue was purified
by recrystallization (hexane/Et2O) giving the title compound as
colorless plates (1.31 g, 72%). mp 79-81 °C (hexane/Et2O); IR
(KBr) ν (max) 3320 (br), 1604, 1572, 1540, 1504, 1455, 1419,
1
1341, 1306, 1260, 1190, 1149, 1118, 1076 cm-1; H NMR (250
MHz, CDCl3) δ 7.76 (d J ) 8.2 Hz, 1H), 6.70 (dd J ) 8.2, 2.0 Hz,
1H), 6.60 (d J ) 2.0 Hz, 1H), 5.86 (s (br), 2H), 5.21 (s, 2H), 3.90
(s, 3H), 3.49 (s, 3H); 13C NMR (62.9 MHz, CDCl3) δ 165.8 (e),
161.1 (e), 138.6 (o), 137.9 (o), 108.0 (o), 99.1 (o), 94.1(e), 56.0
(o), 55.4 (o); MS (EI (70 eV)) m/e: (rel intensity) 212 (M+, 11),
182 (5.3), 168 (3.2), 138 (2.7), 69 (5.3), 45 (100); Anal. Calcd for
C9H13BO5: C, 50.99; H, 6.18; found: C, 50.90; H, 6.27.
Procedure 2: From Hydroxycarbamate 30. A mixture of 30
(1.37 g, 4.35 mmol), K2CO3 (3.39 g, 24.53 mmol), and MeI (1.60
mL, 25.7 mmol) in acetone (50 mL) was heated at reflux for 12 h.
The reaction mixture was cooled to rt and standard workup followed
by column chromatography (silica plug, 2:1 hexane/EtOAc), and
recrystallization (hexane/Et2O) afforded the title compound as
colorless plates (1.21 g, 84%). Mp 86-87 °C (hexane/Et2O).
Mixture mp with a sample prepared by Procedure 1: 85-86 °C.
Spectral properties were found to be identical with those for material
prepared by procedure 1.
N,N-Diethyl O-[4-Methoxy-5-isopropoxy-2-(2-methoxy-5-
methoxymethoxyphenyl)]-1-naphthylcarbamate (33d). Accord-
ing to General Procedure G, a mixture of naphthyl iodide 31a (1.00
g, 2.1970 mmol), arylboronic acid 32e (0.677 g, 3.1920 mmol),
Ba(OH)2•8H2O (1.73 g, 5.48 mmol), and Pd(PPh3)4 (0.140 g, 0.121
mmol) in DME (100 mL) and H2O (10 mL) was refluxed for 3 h.
Standard workup followed by column chromatography (2:1 hexane/
EtOAc) afforded the title compound as a gum (1.05 g, 99%). IR
(neat) ν (max) 2961, 1715, 1581, 1509, 1460, 1380 cm-1; 1H NMR
(250 MHz, CDCl3) δ 7.47 (dd J ) 8.4,1.3 Hz, 1H), 7.35 (dd J )
8.4, 7.5 Hz, 1H), 7.24 (dd J ) 7.5, 1.3 Hz, 1H), 6.93 (dd J ) 7.5,
1.3 Hz, 1H), 6.76 (s, 1H), 6.68 (m, 2H), 5.21 (s, 2H), 4.53 (sept J
) 6.0 Hz, 1H), 3.91 (s, 3H), 3.74 (s, 3H), 3.51 (s, 3H), 2.05 (m,
4H), 1.39 (d J ) 6.0 Hz, 6H), 1.03 (m, 6H); 13C NMR (62.9 MHz,
CDCl3) δ 157.8 (e), 157.5 (e), 154.6 (e), 153.6 (e), 153.5 (e), 138.1
(e), 127.7 (e), 126.3 (o), 120.4 (e), 119.4 (e), 115.1 (o), 113.2 (o),
109.3 (o), 106.8 (o), 99.9 (o), 94.1 (e), 72.7 (o), 56.3 (o), 55.4 (o),
55.1 (o), 41.5 (e), 41.2 (e), 21.6 (o), 13.6 (o), 12.7 (o); MS (EI (70
eV)) m/e: (rel intensity) 497 (M+, 36) 455 (6.2), 397 (32), 331
N,N-Diethyl O-(2-Iodo-5-isopropoxy-4-methoxy)-1-naphth-
ylcarbamate (31a). According to General Procedure B, a solution
of N,N-diethyl O-(4-methoxy-5-isopropoxy)-1-naphthylcarbamate
(28a) (0.278 g, 0.839 mmol) and TMEDA (0.15 mL, 0.99 mmol)
in THF (10 mL) at -78 °C was treated with a solution of s-BuLi
(0.79 mL, 1.28 mol/L). The reaction mixture was stirred for 20
min, a solution of I2 in THF (5 mL) was added and the resulting
solution was allowed to warm to rt (6 h). Standard workup followed
by column chromatography (4:1 hexane/EtOAc) afforded the title
compound (0.383 g, 94%) as a viscous oil. IR (neat) ν (max) 2976,
1
2983, 1724, 1609, 1575, 1502, 1457, 1424 cm-1; H NMR (250
MHz, CDCl3) δ 7.37 (m, 2H), 7.07 (s, 1H), 6.94 (t J ) 4.4 Hz,
1H), 4.51 (sept J ) 6.0 Hz, 1H), 3.90 (s, 3H), 3.63 (m, 2H), 3.42
(m, 2H), 1.42 (t J ) 7.1 Hz, 3H), 1.36 (d J ) 6.0 Hz, 6H), 1.25 (t
J. Org. Chem. Vol. 74, No. 11, 2009 4089

James and Snieckus
(10), 271 (8.4), 227 (8.0), 168 (62), 100 (100), 72 (44); HRMS (EI
(70 eV)) m/e calcd for C28H35NO7: 497.2415, found: 497.2412.
252 (7.2), 236 (4.0); HRMS (EI (70 eV)) m/e calcd for C22H20O6:
380.1260, found 380.1257.
1-Isopropoxy-10,12-dimethoxy-8-trifluoro-methanesulfonyl-
6H-naphtho[1,2-b]benzo[d]pyran-6-one (39). To a suspension of
phenol 38 (0.699 g, 1.84 mmol) in CH2Cl2 (35 mL) at rt was added
Et3N (1.50 mL, 10.76 mmol) The resulting homogeneous yellow
solution was cooled to -78 °C, treated with Tf2O (0.40 mL, 2.37
mmol) by dropwise addition, and the whole was allowed to stir for
1 h, quenched with sat NaHCO3 and the cooling bath was removed.
Standard workup followed by column chromatography (7:2:1
hexane/CH2Cl2/EtOAc) afforded 39 (0.759 g, 81%) as bright-yellow
needles, mp 219-221 °C (hexane/CH2Cl2); IR (CH2Cl2) ν (max)
N,N-Diethyl 3-Methoxy-5-methoxymethoxy-2-(4-methoxy-5-
isopropoxy-1-hydroxynaphthyl)benzamide (37). According to
General Procedure C1, a solution of carbamate 33d (0.520 g, 0.956
mmol) in THF (8 mL) was added at 0 °C to a solution of LDA
(3.24 mmol) in THF (5 mL). The cooling bath was removed, and
the mixture was heated to reflux until disappearance of starting
material (TLC) (1 h). Standard workup followed by column
chromatography (3:2 hexane/EtOAc) afforded the title compound
(0.145 mg 28%) as a glass. IR (neat) ν (max) 3238, 2974, 2935,
1600, 1482, 1455, 1411, 1377, 1325, 1274, 1217, 1187, 1153, 1127,
1078 cm-1; NMR indicated a 3:1 mixture of rotamers. Absorptions
for the major rotamer is given followed by the corresponding peaks
for the minor rotamer: 1H NMR (250 MHz, CDCl3) δ 8.06 (d J )
8.3 Hz, 1H) 7.99 (d J ) 8.3 Hz, 1H), 7.32 (t J ) 8.0 Hz, 1H)
corresponding rotamer peak partially obscured, 6.94 (d J ) 7.6
Hz, 1H) 6.98 (d J ) 7.6 Hz, 1H), 6.71 (d J ) 2.2 Hz, 1H) 6.83
unresolved d 1H, 6.60 (d J ) 2.3 Hz, 1H) 6.69 unresolved d 1H,
6.56 (s 1H) 6.87 (s, 1H), 6.00 (s, br, 1H, exch) 7.57 (s, br, 1H,
exch), 5.24 (d J ) 6.8 Hz, 1H) corresponding rotamer peak partially
obscured, 5.17 (d J ) 6.8 Hz, 1H) 5.19 (d, J ) 6.6 Hz), 4.56, (sept
J ) 6.0 Hz, 1H) 4.45 (sept J ) 6.0 Hz), 3.83 (s, 3H) 3.89 (s), 3.66
(s, 3H) 3.85 (s), 3.50 (s, 3H) rotamer peak obscured, 3.42 (m, 1H)
3.56 (m), 3.20 (m, 1H) 2.83 (m), 3.01 (m, 2H) 2.55 (m), 1.40 (d J
) 6.0 Hz, 1H) 1.34 (d J ) 6.0 Hz), 0.98 (t J ) 7.0 Hz, 3H) 1.24
1
3058, 2982, 1728, 1592, 1462, 1424 1386, 1134 cm-1; H NMR
(250 MHz, CDCl3) δ 8.26 (s, 1H), 8.20 (dd J ) 8.5, 0.8 Hz, 1H),
7.99 (d J ) 2.5 Hz, 1H), 7.51 (dd J ) 8.2, 8.0 Hz, 1H), 7.17 (d J
) 2.5 Hz, 1H), 7.08 (d, br, J ) 7.5 Hz, 1H), 4.62 (sept, J ) 6.0
Hz, 1H), 4.13 (s, 3H), 3.99 (s, 3H), 1.45 (d J ) 6.0 Hz, 6H); 13C
NMR (62.9 MHz, CDCl3) δ 159.6 (e), 158.7 (e), 154.7 (e), 153.2
(e), 148.6 (e), 141.2 (e), 127.4 (e), 126.6 (e), 124.9 (e), 124.3 (e),
119.8 (e), 118.7 (e, q J ) 321 Hz), 103.6 (o), 72.9 (o), 56.7 (o),
56.5 (o), 22.0 (o); MS (EI (70 eV)) m/e: (rel intensity) 512 (41),
476 (49), 337 (100), 309 (9), 294 (26), 279 (14) Anal. Calcd for
C23H19SO8F3: C, 53.91; H, 3.74; found: C,54.14; H, 3.88.
1-Isopropoxy-10,12-dimethoxy-8-vinyl-6H-naphtho[1,2-b]ben-
zo[d]pyran-6-one (40a). A solution of triflate 39 (0.102 g, 0.199
mmol), vinyltributyltin (79.8 mg, 0.239 mmol), LiCl (45.0 mg, 1.06
mmol), tri-(2-furyl)phosphine (4.90 mg, 0.201 mmol), and Pd2dba3
(9.8 mg, 0.0107 mmol) in anhydrous NMP was stirred at rt under
Ar for 1 h. The reaction mixture was diluted with CH2Cl2 (10 mL)
and H2O (10 mL) and the layers were separated. The aqueous phase
was extracted with CH2Cl2 (2 × 10 mL), and the combined organic
layers were washed (H2O, brine) and dried (Na2SO4). The solvents
were removed under reduced pressure (high vacuum for remaining
NMP), and the residue was purified by column chromatography
(5:2 hexane/EtOAc) and recrystallization (CH2Cl2/hexane), afford-
ing the title compound (53.4 mg, 69%) as a fine yellow powder.
Mp 211-213 °C (CH2Cl2/hexane). IR (CH2Cl2) ν (max) 3154, 2984,
1722, 1587, 1422, 1384 cm-1; 1H NMR (250 MHz, CDCl3) δ 8.29
(s, 1H), 8.19 (dd J ) 8.4, 1.0 Hz, 1H), 8.07 (d J ) 1.5 Hz, 1H),
7.47 (dd J ) 7.8, 8.4 Hz, 1H), 7.26 (d overlaps solvent, 1H), 7.05
(dd J ) 7.8, 0.8 Hz, 1H), 6.74 (dd J ) 10.9, 17.5 Hz, 1H), 5.90 (d
J ) 17.5 Hz, 1H), 5.04 (d J ) 10.9 Hz, 1H), 4.58 (sept J ) 6.1
Hz, 1H), 4.05 (s, 3H), 3.97 (s, 3H), 1.43 (d J ) 6.1 Hz, 1H); 13C
NMR (50.3 MHz, CDCl3) δ 161.2 (e), 157.2 (e), 154.6 (e), 152.7
(e), 140.8 (e), 138.3 (e), 135.3 (o), 127.0 (o), 126.7 (e), 123.6 (e),
123.2 (e), 120.3 (o), 119.5 (e), 116.1 (e), 115.5 (o), 114.6 (o), 113.7
(o), 113.2 (e), 104.3 (o), 73.1 (o), 56.4 (o), 56.0 (o), 22.1 (o); MS
(EI (70 eV)) m/e: (rel intensity) 390 (M+, 34), 348 (100), 333 (44),
305 (37), 267 (14); Anal. Calcd for C24H22O5: C, 73.83; H, 5.70;
found: C, 73.90; H, 5.70.
(t J ) 7.0 Hz), 0.62 (t J ) 7.0 Hz, 3H) 0.69 (t J ) 7.0 Hz, H); 13
C
NMR (62.9 MHz, CDCl3) δ 171.5 (e) 169.3 (e), 158.7 (e) 158.4
(e), 158.1 (e) 156.1 (e), 153.9 (e) 154.4 (e), 149.8 (e) 149.9 (e),
144.1 (e) 142.5 (e), 138.6 (e) 140.6 (e), 131.0 (e) 128.9 (e), 125.2
(o) 125.5 (o), 120.1 (e) 120.0 (e), 118.4 (e) 117.1 (e), 117.4 (e)
116.5 (e), 117.2 (o) 116.6 (o), 113.1 (o) 115.5 (o), 111.9 (o) 109.7
(o), 104.5 (o) 107.9 (o), 101.0 (o) 100.6 (o), 94.4 (e) corresponding
rotamer peak obscured, 72.4 (o) 73.9 (o), 57.8 (o) 56.0 (o), 55.9
(o) 56.4 (o), 55.6 (o) 56.2 (o), 42.9 (e) 41.8 (e), 38.7 (e) 38.0 (e),
21.9 (o) 21.9 (o), 13.6 (o) 14.0 (o), 11.5 (o) 11.8 (o); MS (EI (70
eV)) m/e: (rel intensity) 497 (5) M+, 481 (10), 424 (100), 408 (45),
394 (8), 382 (97), 368 (30), 352 (10), 338 (31), 323 (13), 294 (14),
279 (12); HRMS (EI (70 eV)) m/e calcd for C28H35NO7: 497.2415,
found 497.2409.
8-Hydroxy-1-isopropoxy-10,12-dimethoxy-6H-naphtho[1,2-
b]benzo[d]pyran-6-one (38). According to General Procedure C2,
a solution of carbamate 33d (1.18 g, 2.38 mmol) in THF (15 mL)
was added to a solution of LDA (3.05 mmol) in THF (30 mL) and
the mixture heated at reflux for 2 h. At this point, a solution of
LDA (3.05 mmol) in THF (5 mL) was added. Heating was
continued until the disappearance of starting material (TLC) (1 h).
Standard workup afforded the crude hydroxyamide which was
dissolved in HOAc (10 mL) and the resulting solution was heated
at reflux for 10 min. After cooling, an equal volume of H2O was
added and heating was continued for 1 h. The reaction mixture
was cooled to rt, the solvents were removed in Vacuo, and the
residue was dissolved in acetone. Silica gel (10 g) was added and
the acetone was removed in vacuo. The residue was dry loaded
directly onto a flash column. Purification by column chromatog-
raphy (2:1 hexane/EtOAc f EtOAc) afforded the title compound
as a yellow powder (0.641 g, 70% which could not be recrystallized
due to its insolubility, mp > 260 °C (dec). IR (KBr) ν (max) 3393,
2956, 1693, 1601, 1487, 1452 cm-1; 1H NMR (250 MHz, pyridine-
d5) δ 8.56 (s, 1H) 8.29 (d J ) 8.5 Hz, 1H), 8.01 (d J ) 2.2 Hz,
1H), 7.50 (m, 1H overlapping with solvent), 7.20 (d J ) 2.2 Hz,
1H), 7.09 (d J ) 7.7 Hz, 1H), 5.50 (s, br, 1H), 4.61 (sept J ) 6.0
Hz, 1H), 4.02 (s, 3H), 3.90 (s, 3H), 1.40 (d J ) 6.0 Hz, 6H); 13C
NMR (62.9 MHz, CDCl3) δ 161.3 (e), 160.5 (e), 159.7 (e), 155.5
(e), 153.5 (e), 139.8 (e), 127.6 (e), 127.6 (o), 125.0 (e), 119.1 (e),
116.73 (e), 114.9 (o), 114.7 (e), 113.0 (o), 107.9 (o), 107.3 (o),
105.4 (o), 72.4 (o), 57.0 (o), 56.2 (o), 22.2 (o); MS (EI (70 eV))
m/e: (rel intensity) 380 (M+, 74), 338 (100), 323 (29), 295 (25),
1-Isopropoxy-10,12-dimethoxy-8-methyl-6H-naphtho[1,2-b]ben-
zo[d]-pyran-6-one (40b). To a solution of MeLi (0.96 mL, 2.20
mol/L in Et2O) in THF (10 mL) at -78 °C was added dropwise
Via canula a solution of flame-dried ZnCl2 (0.345 g, 2.53 mmol) in
THF (10 mL) over 15 min. The solution was maintained at -78
°C for 30 min and then allowed to warm to rt over a period of 1 h.
This solution was then added Via canula to a separate flame-dried
flask which was charged with triflate 39 (0.370 g, 0.722 mmol)
and NiCl2(dppp) (43.0 mg, 0.0793 mmol). The resulting solution
was stirred at rt for 2 h. Standard workup followed by column
chromatography (3:1 hexane/EtOAc) afforded the title compound
(0.161 g, 59%) as fine yellow needles. Mp 232-233 °C (hexane/
CH2Cl2). IR (CH2Cl2) ν (max) 3018, 2990, 1722, 1588, 1422, 1385
1
cm-1; H NMR (200 MHz, CDCl3) δ 8.23, (s, 1H), 8.18 (dd J )
7.7, 0.8 Hz, 1H), 7.85 (s, 1H), 7.47 (app t J ) 8.1 Hz, 1H), 7.03
(m, 2H), 4.58 (sept J ) 6.0 Hz, H), 3.98 (s, 3H), 3.96 (s, 3H), 2.42
(s, 3H), 1.43 (d J ) 6.0 Hz, 6H); 13C NMR (62.9 MHz, CDCl3) δ
161.4 (e), 157.0 (e), 154.5 (e), 152.6 (e), 140.5 (e), 139.6 (o), 126.9
(e), 126.8 (o), 122.5 (e), 121.8 (o), 119.3 (o), 117.9 (e), 115.5 (e),
4090 J. Org. Chem. Vol. 74, No. 11, 2009

Combined Directed Remote Metalation
114.4 (e), 113.4 (o), 73.1 (o), 56.6 (o), 56.0 (o), 21.5 (o); MS (EI
(70 eV)) m/e: (rel intensity) 378 (M+, 40), 336 (100), 321 (41),
293, (26),250 (9); Anal. Calcd for C23H22O5: C, 73.00; H, 5.86;
found: C, 72.58; H, 5.64.
336.0991. Spectral data were found to be identical to those reported
for the authentic material.67
1-Hydroxy-10,12-dimethoxy-8-ethyl-6H-naphtho[1,2-b]ben-
zo[d]pyran-6-one (Defucogilvocarcin E) (1c). To a solution of
isopropyl ether 40c (56.0 mg, 0.143 mmol) in CH2Cl2 (10 mL) at
0 °C was added dropwise BCl3 (0.72 mL, 1.0 mol/L in CH2Cl2)
over 5 min. The solution was stirred for 10 min and then treated
with H2O. The layers were separated, and the aqueous phase was
extracted with CH2Cl2 (2 × 10 mL). The combined organic layers
were washed (H2O, brine), dried (Na2SO4), and concentrated in
Vacuo. The residue was purified by column chromatography (2:1
CH2Cl2/EtOAc) and then recrystallization (CH2Cl2/hexane) to afford
1c as a fine yellow powder (43.2 mg, 86%). Mp 255-256 °C
(CH2Cl2/hexane) lit26c mp 242-244 °C 1H NMR (250 MHz,
CDCl3) δ 9.36 (s, 1H), 8.29 (s, 1H), 8.06 (dd J ) 8.4, 1.0 Hz, 1H),
7.95 (d J ) 1.6 Hz, 1H), 7.49 (app t J ) 8.1 Hz, 1H), 7.14 (d J )
1.6 Hz, 1H), 6.99 (dd J ) 7.7, 1.0 Hz, 1H), 4.09 (s, 3H), 4.07 (s,
3H), 2.79 (q J ) 7.6 Hz, 2H), 1.34 (t J ) 7.6 Hz, 3H); MS (EI (70
eV)) m/e: (rel intensity) 350 (M+, 100), 335 (25), 307 (30), 292
(5), 249 (9); HRMS (EI (70 eV)) m/e calcd for C21H18O5: 350.1154,
found 350.1159. Spectral data were found to be identical to those
reported for authentic material.26c
1-Isopropoxy-10,12-dimethoxy-8-ethyl-6H-naphtho[1,2-b]ben-
zo[d]pyran-6-one (40c). A suspension of K3PO4 (0.224 g, 1.05
mmol), PdCl2(dppf) (20.0 mg, 0.0301 mmol) and BEt3 (0.95 mL,
1.0 mol/L in hexane) in THF (5 mL) under Ar was stirred at rt for
10 min and a suspension of triflate 39 (0.231 g, 0.450 mmol) in
THF (4 × 5 mL) was added. The reaction mixture was heated at
reflux until disappearance of starting material (TLC) (1 h). The
reaction mixture was cooled to rt, treated with 5% NaOH (1.4 mL)
and 30% H2O2 (0.5 mL), and the whole was stirred at rt for 1.5 h.
The mixture was then poured into 10% HCl (20 mL) containing
ice and the whole was extracted with CH2Cl2 (3 × 15 mL). The
combined organic layers were washed (H2O, brine), dried (Na2SO4),
and concentrated in Vacuo. The residue was purified by column
chromatography (7:1:0.5 f 7:2:1 hexane/CH2Cl2/EtOAc) and
recrystallization to afford the title compound (0.132 g, 75%) as
fine yellow needles. Mp 215-216 °C (hexane/CH2Cl2). IR (KBr)
ν (max) 3055, 2975, 1719, 1610, 1586, 1484, 1448, 1382 cm-1
;
1H NMR (250 MHz, CDCl3) δ 8.23 (s, 1H), 8.18 (dd J ) 8.4, 0.9
Hz, 1H), 7.85 (d J ) 0.6 Hz, 1H), 7.46 (dd J ) 8.4, 7.8 Hz, 1H),
7.02 (m, 2H), 4.57 (sept J ) 6.0 Hz, 1H), 3.97 (s, 3H), 3.94 (s,
3H), 2.69 (q J ) 7.6 Hz, 4H), 1.43 (d J ) 6.0 Hz, 6H), 1.28 (t J
) 7.6 Hz, 6H); 13C NMR (62.9 MHz, CDCl3) δ 161.4 (e), 157.1
(e), 154.5 (e), 152.6 (e), 145.7 (e), 140.5 (e), 126.8 (e), 126.8 (o),
126.7 (e), 123.0 (e), 122.0 (e), 121.2 (o), 119.3 (e), 116.8 (o), 115.4
(o), 114.3 (o), 113.4 (e), 104.7 (e), 73.0 (o), 56.5 (o), 56.0(o), 28.8
(e), 22.1 (o), 14.9 (o); MS (EI (70 eV)) m/e: (rel intensity) 392
(M+, 54), 350 (100), 335 (41), 307 (34), 249 (9); Anal. Calcd for
C24H24O5: C, 73.45; H, 6.16; found: C, 73.37; H, 6.06.
4,5-Dibromo-1,2-diisopropoxybenzene (43d). To a solution of
1,2-diisopropoxybenzene68 (5.02 g, 26.4 mmol) and NaOAc (4.60
g, 55.5 mmol) in CHCl3 (75 mL) at rt was added a solution of Br2
(2.80 mL, 54.16 mmol) in CHCl3 (18 mL) dropwise over 1 h. After
complete addition the reaction mixture was allowed to stir for 1 h
and was diluted with enough H2O to dissolve the inorganic salts
and the layers separated. The aq phase was further extracted with
CHCl3 (2 × 50 mL) and the combined organic layers were washed
(H2O, brine), dried (Na2SO4) and concentrated in Vacuo. The residue
was purified by distillation affording the title compound as a light
yellow oil (7.41 g, 80%). bp 104-120 °C/0.2 mmHg. IR (neat) ν
1-Hydroxy-10,12-dimethoxy-8-vinyl-6H-naphtho[1,2-b]ben-
zo[d]pyran-6-one (defucogilvocarcin V) (1a). To a solution of
isopropyl ether 40a (33.1 mg, 0.0849 mmol) in CH2Cl2 (5 mL) at
0 °C was added dropwise BCl3 (0.40 mL, 1.0 mol/L in CH2Cl2).
The solution was stirred for 15 min and quenched with H2O.
Standard workup followed by column chromatography (4:1 CH2Cl2/
hexane) afforded 1a as a yellow solid (28.4 mg, 95%). Mp 259-264
°C (dec), lit mp26a 263-265 °C (dec). 1H NMR (250 MHz, CDCl3)
δ 9.34 (s, 1H, exch), 8.29 (s, 1H), 8.13 (d J ) 1.7 Hz, 1H), 8.06
(d J ) 8.5, 1.0 Hz, 1H), 7.49 (app t J) 8.0 Hz, 1H), 7.32 (d J )
1.7 Hz, 1H), 7.01 (dd J ) 7.7, 1.0 Hz, 1H), 6.92 (dd J ) 17.6,
10.9 Hz, 1H), 5.94 (d J ) 17.6 Hz, 1H), 5.45 (d J ) 10.9 Hz, 1H),
4.10 (s, 3H); MS (EI (70 eV)) m/e: (rel intensity) 348 (M+, 100),
333 (19), 319 (4.4), 262 (7.0), 305 (19), 234 (2.9), 205 (3.1), 174
(10), 149 (14); HRMS (EI (70 eV)) m/e calcd for C21H16O5:
348.0998, found 348.0992. Spectral data were found to be identical
to those reported for the authentic material.26a
(max) 3070, 2976, 1578, 1552, 1478, 1384, 1355, 1290, 1138 cm-1
;
1H NMR (250 MHz, CDCl3) δ 7.13 (s, 2H), 4.42 (sept J ) 6.1 Hz,
1H), 1.30 (d J ) 6.1 Hz, 6H); 13C NMR (62.9 MHz, CDCl3) δ
150.0 (e), 122.1 (o), 115.3 (e), 72.7 (o), 21.9 (o); MS (EI (70 eV))
m/e: (rel intensity) 354 (37), 352 (65), 350 (39), 312 (9.8), 310
(17), 308 (9.8), 270 (72), 268 (100), 266 (71), 241 (8.7), 239 (17),
237 (17); HRMS (EI (70 eV)) m/e calcd for C12H16Br2O2: 351.9497,
found 351.9485.
1,4-Dihydro-6,7-diisopropoxy-1,4-epoxynaphthalene (44b). To
a solution of furan (72.0 mL, 0.963 mol) and n-BuLi (47.0 mL,
1.65 mol/L) in Et2O (350 mL) at -74 °C (internal) was added a
solution of dibromide 43d (20.06 g, 57.02 mmol) in Et2O (100
mL) dropwise Via a dropping funnel over a period of 1.5 h. During
the addition the temperature was not allowed to rise above -70
°C (internal). After complete addition, the reaction mixture was
quenched with sat NH4Cl at -70 °C and was allowed to warm to
rt. Standard workup followed by purification by column chroma-
tography (8:1 hexane/EtOAc) and then recrystallization (hexane)
afforded the title compound (11.00 g, 74%) as colorless plates. Mp
52-52.5 °C (hexane); IR (KBr) ν (max) 2930, 1737, 1605, 1466,
1-Hydroxy-10,12-dimethoxy-8-methyl-6H-naphtho[1,2-b]ben-
zo[d]pyran-6-one, (Defucogilvocarcin M) (1b). To a solution of
isopropyl ether 40b (0.113 g, 0.298 mmol) in CH2Cl2 (20 mL) at
0 °C was added dropwise over 10 min BCl3 (1.50 mL, 1.0 mol/L
in CH2Cl2). The solution was stirred for 10 min and then treated
with H2O. The layers were separated and the aqueous phase was
extracted with CH2Cl2 (2 × 10 mL). The combined organic layers
were washed (H2O, brine), dried (Na2SO4) and concentrated in
Vacuo. The residue was purified by column chromatography (2:1
CH2Cl2/EtOAc) and recrystallization to give 1b (83.4 mg, 83%) as
a fine yellow powder, mp 271-274 °C (dec), (CH2Cl2/hexane),
1
1418, 1049 cm-1; H NMR (200 MHz, CDCl3) δ 6.99 (d J ) 0.6
Hz, 2H), 6.95 (s, 2H), 5.62 (d J ) 0.5 Hz, 2H), 4.37 (sept J ) 6.0
Hz, 1H), 1.28 (d J ) 6.0 Hz, 6H); 13C NMR (50 MHz, CDCl3) δ
145.8 (e), 142.9 (o), 142.3 (e), 113.1 (o), 82.3 (o), 72.7 (o), 72.6
(o), 22.2 (o); MS (EI (70 eV)) m/e: (rel intensity) 260 (M+, 91),
218 (18), 176 (55) 148 (100); Anal. Calcd for C16H20O3: C, 73.82;
H, 7.74; found: C, 73.68; H, 7.60.
lit67 mp 273-274 °C (dec). H NMR (250 MHz, CDCl3) δ 9.34
1
6,7-Diisopropoxy-1-naphthol (45b). A solution of epoxynaph-
thalene 44b (0.253 g, 0.973 mmol) and HCl (1 drop, 12 mol/L) in
MeOH (10 mL) was heated at reflux until the disappearance of
starting material as monitored by TLC (45 min). The reaction was
cooled and concentrated on the rotovap and the residue dissolved
in CH2Cl2 (20 mL). The organic layer was washed (H2O, brine),
dried (Na2SO4), and concentrated in Vacuo. The residue was purified
(s, 1H), 8.23 (s, 1H), 8.04 (dd J ) 8.4, 0.9 Hz, 1H), 7.89 (s, 1H),
7.48 (app t J ) 8.0 Hz, 1H), 7.07 (s, 1H), 6.99 (dd J ) 7.7, 0.9
Hz, 1H), 4.07 (s, 3H), 4.04 (s, 3H), 2.48 (s, 3H); MS (EI (70 eV))
m/e: (rel intensity) 336 (M+, 100), 321 (37), 293 (36), 250 (12);
HRMS (EI (70 eV)) m/e calcd for C20H16O5: 336.0998, found
(67) Merriman, G. H. Ph.D. Thesis, Ohio State University, Columbus, OH,
1990; Diss. Abstr. Int. B., 1991, 51, 5875, Order # 9111767.
(68) Buckley, T. F.; Rapoport, H. J. Am. Chem. Soc. 1980, 102 (9), 3056.
J. Org. Chem. Vol. 74, No. 11, 2009 4091

James and Snieckus
by recrystallization (hexane/Et2O) affording the title compound as
colorless plates (0.208 g, 82%). Mp 121-122 °C (hexane/Et2O).
IR (KBr) ν (max) 3402, 3085, 2978, 1629, 1593, 1515, 1470, 1387,
1329, 1282, 1177, 1068 cm-1; 1H NMR (250 MHz, CDCl3) δ 7.61
(s, 1H), 7.21 (d J ) 8.2 Hz, 1H), 7.09 (dd J ) 8.2, 7.4 Hz, 1H),
6.65 (dd J ) 7.4, 0.9 Hz, 1H), 6.37 (s, 1H), 4.65 (sept J ) 6.1 Hz,
1H), 1.38 (app t J ) 6.1 Hz, 12H); 13C NMR (62.9 MHz, CDCl3)
δ 150.7 (e), 149.2 (e), 148.3 (e), 131.0 (e), 124.2 (o), 120.2 (e),
118.7 (o), 111.8 (o), 107.4 (o), 106.2 (o), 71.9 (o), 21.9 (o); MS
(EI (70 eV)) m/e: (rel intensity) 260 (23), 218 (6.9), 176 (100),
147 (37); HRMS (EI (70 eV)) m/e calcd for C16H20O3: 260.1412,
found 260.1405.
(o), 56.0 (o), 55.8 (o), 42.1 (e), 41.9 (e), 22.0 (o), 22.0 (o), 14.2
(o), 13.3 (o); MS (EI (70 eV)) m/e: (rel intensity) 495 (M+, 26),
453 (1.0), 280 (11), 100 (100), 72 (38); HRMS (EI (70 eV)) m/e
calcd for C29H37NO6: 495.2622, found 495.2611.
N,N-Diethyl O-[6,7-Dihydroxy-2-(3,4-methoxyphenyl)]-1-
naphthylcarbamate (49c). To a solution of diisopropyl ether 49b
(0.197 g, 0.397 mmol) in CH2Cl2 (10 mL) at 0 °C was added BCl3
(2.40 mL, 1.0 mol/L in CH2Cl2). The reaction was allowed to stir
for 1 h and was then quenched with H2O (20 mL). The layers were
separated, and the aq phase was extracted with CH2Cl2 (2 × 20
mL). The combined organic layers were washed (H2O, brine), dried
(Na2SO4) and concentrated in Vacuo. The residue was purified by
recrystallization (hexane/CH2Cl2) affording N,N-Diethyl O-[6,7-
dihydroxy-2-(3,4-dimethoxy-phenyl)]-1-naphthyl-carbamate as col-
orless plates (0.145 g, 89%). mp 183-184 °C (hexane/CH2Cl2);
IR (KBr) ν (max) 3550-2550 (br), 3052, 2951, 1690, 1638, 1603,
N,N-Diethyl O-(6,7-Diisopropoxy)-1-naphthylcarbamate (46b).
According to general procedure A, a mixture of naphthol 45b (5.04
g, 19.38 mmol) K2CO3 (5.40 g, 39.07 mmol) and ClCONEt2 (3.70
mL, 29.07 mmol) in CH3CN (100 mL) was heated at reflux for
12 h. Standard workup followed by recrystallization (hexane/Et2O)
afforded the title compound as colorless needles (6.96 g, 84%).
Mp 113.5-114.5 °C (hexane/Et2O). IR (KBr) ν (max) 3056, 2980,
1
1579, 1514, 1420 cm-1; H NMR (250 MHz, CDCl3) δ 8.61 (s,
1H, exch), 8.53 (s, 1H, exch), 7.52 (d J ) 8.4 Hz, 1H), 7.24 (m,
3H), 7.09 (d J ) 1.3 Hz, 1H), 6.95-7.03 (m, 2H), 3.82 (s, 6H),
3.46 (q J ) 7.0 Hz, 2H), 3.29 (q J ) 7.0 Hz, 2H), 1.15 (t J ) 7.0
Hz, 3H), 1.05 (t J ) 7.0 Hz, 3H); 13C NMR (62.9 MHz, CDCl3) δ
154.6 (e), 149.9 (e), 149.6 (e), 147.8 (e), 147.3 (e), 143.7 (e), 132.5
(e), 130.8 (e), 129.8 (e), 126.3 (o), 125.1 (e), 124.3 (o), 122.4 (o),
114.1 (o), 112.7 (o), 110.5 (o), 105.1 (o), 56.2 (o), 42.5 (e), 14.6
(o), 13.6 (o); MS (EI (70 eV)) m/e: (rel intensity); 411 (M+, 85),
397 (2.0), 340 (1.6), 296 (1.9), 281 (3.6), 237 (1.5), 215 (2.1), 100
(100), 72 (34); Anal. Calcd for C23H25NO6: C, 67.14; H, 6.12; N,
3.41 found: C, 66.96; H, 6.21, N, 3.38.
1
2974, 1715, 1603, 1501, 1470, 1420 cm-1; H NMR (250 MHz,
CDCl3) δ 7.49 (d J ) 8.1 Hz, 1H), 7.29 (dd J ) 8.1, 7.6 Hz, 1H),
7.23 (s, 1H), 7.20 (s, 1H), 7.13 (dd J ) 7.6, 1.2 Hz, 1H), 4.59, (m,
2H), 3.41-3.59 (m, 4H), 1.40 (d J ) 6.1, Hz, 6H), 1.39 (d J )
6.1, Hz, 6H), 1.20-1.32 (m, 6H); 13C NMR (62.9 MHz, CDCl3) δ
154.1 (e), 149.4 (e), 149.3 (e), 146.3 (e), 130.9 (o), 123.6 (o), 123.5
(o), 123.3 (e), 116.2 (o), 112.3 (o), 105.5 (o), 71.8 (o), 71.7 (o),
42.3 (e), 42.0 (e), 21.9 (o), 14.4 (o), 13.4 (o); MS (EI (70 eV))
m/e: (rel intensity) 359 (M+, 29), 280 (0.26), 260 (0.40), 217 (1.0),
175 (7.0), 147 (11), 100 (100), 72 (45), 44 (11); Anal. Calcd for
C21H29NO4: C, 70.17; H, 8.13; N, 3.90; found: C, 70.26; H, 8.27;
N, 3.87.
N,N-Diethyl O-[6,7-Dimethoxymethoxy-2-(3,4-methoxyphe-
nyl)]-1-naphthylcarbamate (49d). To a suspension of NaH (1.20
g, 30.00 mmol) containing MOMCl (1.60 mL, 21.07 mmol) in dry
DMF (50 mL) at 0 °C was added a solution of N,N-Diethyl O-[6,7-
dihydroxy-2-(3,4-dimethoxy-phenyl)]-1-naphthyl-carbamate (49c)
in DMF (5 mL) dropwise. After the evolution of hydrogen had
ceased, the mixture was allowed to warm to rt over 2 h. The reaction
was then quenched by pouring slowly into 100 mL of H2O
containing ice. The resulting mixture was extracted with Et2O (3
× 50 mL), and the combined organic layers were washed with H2O
(5 × 100 mL), brine, dried (Na2SO4), and concentrated in Vacuo.
The residue was purified by column chromatography (1:1 hexane/
EtOAc) giving the title compound as a colorless glass (1.51 g, 95%).
N,N-Diethyl O-(2-Iodo-6,7-diisopropoxy)-1-naphthylcarbam-
ate (47b). According to general procedure B, carbamate 46b (0.692
g, 1.93 mmol) was treated sequentially with TMEDA (0.28 mL,
1.864 mmol), a solution of s-BuLi (1.40 mL, 1.41 mol/L) and I2
(0.552 g, 2.18 mmol). Standard workup followed by column
chromatography (6:1 hexane/EtOAc) afforded a the title compound
as a light-blue solid (0.654 g, 70%). Mp 102-103 °C (hexane/
Et2O). IR (KBr) ν (max) 2977, 2933, 1723, 1622, 1587, 1496, 1462,
1
1411 cm-1; H NMR (250 MHz, CDCl3) δ 7.58 (d J ) 8.6 Hz,
1H), 7.25 (d J ) 8.6 Hz, 1H), 7.13 (s, 1H), 7.11 (s, 1H), 4.49-4.61
(m, 2H), 3.57-3.66 (m, br, 2H), 3.43 (q J ) 7.1 Hz, 2H), 1.38 (t
J ) 6.3 Hz, 15H), 1.24 (t J ) 7.1 Hz, 3H); 13C NMR (62.9 MHz,
CDCl3) δ 152.4 (e), 149.8 (e), 149.6 (e), 146.8 (e), 132.5 (o), 130.4
(o), 125.3 (o), 124.4 (e), 111.8 (o), 105.5 (o), 86.6 (e), 71.7 (o),
71.6 (o), 42.3 (e), 42.1 (e), 21.8 (o), 21.7 (o), 14.5 (o), 13.3 (o);
MS (EI (70 eV)) m/e: (rel intensity) 485 (M+, 15), 358 (5.9), 301
(3.6), 273 (2.6), 174 (4.0), 100 (100), 72 (20); Anal. Calcd for
C21H28NO4I: C, 51.97; H, 5.81; N, 2.89; found: C, 52.00; H, 5.87;
N, 2.84.
IR (neat) ν (max) 2948, 2833, 1716, 1607, 1584, 1470, 1415 cm-1
;
1H NMR (250 MHz, CDCl3) δ 7.60 (d J ) 8.5 Hz, 1H), 7.56 (s,
1H), 7.51 (s, 1H), 7.36 (d J ) 8.5 Hz, 1H), 7.05-7.09 (m, 2H),
6.92 (d J ) 8.1 Hz, 1H), 5.38 (s, 2H), 5.35 (s, 2H), 3.91 (s, 3H),
3.89 (s, 3H), 3.55 (s, 3H), 3.53 (s, 3H), 3.49 (q J ) 6.6 Hz, 2H),
3.30 (q J ) 6.6 Hz, 2H), 1.21 (t J ) 6.6 Hz, 3H), 1.09 (t J ) 6.6
Hz, 3H); 13C NMR (62.9 MHz, CDCl3) δ 153.7 (e), 148.4 (e), 148.1
(e), 147.3 (e), 142.9 (e), 131.3 (e), 130.2 (e), 130.0 (e), 126.8 (o),
124.3 (e), 124.2 (o), 121.5 (o), 112.4 (o), 111.5 (o), 111.0 (o), 106.0
(o), 95.5 (e), 95.2 (e), 56.1 (o), 56.0 (o), 55.8 (o), 55.7 (o), 42.1
(e), 41.9 (e), 14.1 (o), 13.1 (o); MS (EI (70 eV)) m/e: (rel intensity)
499 (M+, 95), 467 (5.6), 455 (4.6), 437 (3.1), 399 (3.7), 350 (8.0),
336 (9.3), 323 (8.6), 292 (12), 265 (3.7), 165 (2.5), 100 (100), 72
(47); HRMS (EI (70 eV)) m/e calcd for C27H33NO8: 499.2206, found
499.2191.
N,N-Diethyl O-[6,7-Diisopropoxy-2-(3,4-dimethoxyphenyl)]-
1-naphthyl-carbamate (49b). According to general procedure F,
a solution of naphthylcarbamate 46b (1.81 g, 5.04 mmol) in THF
(20 mL) was sequentially treated with TMEDA (0.845 mL, 5.61
mmol), a solution of s-BuLi (4.70 mL, 1.18 mol/L), ZnCl2 (5.60
mL, 1.0 mol/L), a solution of 4-bromoveratrole (48a) (2.29 g, 10.55
mmol) in THF (10 mL) and Pd(PPh3)4 (130 mg, 0.112 mmol). The
reaction was heated at reflux for 12 h and standard workup followed
by column chromatography afforded the title compound as a
colorless oil (0.790 g, 32%). IR (neat) ν (max) 2978, 2935, 1712,
N,N-Diethyl 5,6-Dimethoxy-2-(1-hydroxy-6,7-bis(methoxyme-
thoxy)-2-naphthyl)benzamide (50c). Procedure 1. According to
general procedure C1, a solution of carbamate 49dc (0.463 g, 0.928
mmol) in THF (5 mL) was added to a solution of LDA (5.60 mmol)
in THF (10 mL) at 0 °C and the solution allowed to stir at rt for
6 h. Standard workup followed by column chromatography (3:2
hexane/EtOAc) afforded the title compound as a foam (0.114 g,
1606, 1500, 1469 cm-1 1H NMR (250 MHz, CDCl3) δ 7.55
;
(d J ) 8.4 Hz, 1H), 7.31 (d J ) 8.4 Hz, 1H), 7.22 (s, 1H), 7.18 (s,
1H), 7.04 (m, 2H), 6.92 (d J ) 8.0 Hz, 1H), 4.59 (2 overlapping
sept J ) 6.0 Hz, 2H), 3.91 (s, 3H), 3.88 (s, 3H), 3.40 (q J ) 7.0
Hz, 2H), 3.30 (q J ) 7.0 Hz, 2H), 1.40 (d J ) 6.0 Hz, 12H), 1.17
(t J ) 7.0 Hz, 3H), 1.08 (t J ) 7.0 Hz, 3H); 13C NMR (62.9 MHz,
CDCl3) δ 153.9 (e), 149.9 (e), 149.3 (e), 148.5 (e), 148.1 (e), 142.8
(e), 131.2 (e), 130.2 (e), 129.7 (e), 126.3 (o), 124.2 (e), 123.9 (o),
121.6 (o), 112.7 (o), 112.6 (o), 111.1 (o), 106.3 (o), 72.0 (o), 71.9
1
25%). H NMR (300 MHz, CDCl3) δ 8.71 (s, 1H, exch), 8.02 (s,
1H), 7.44 (s, 1H), 7.27 (d J ) 8.3 Hz, 1H), 7.05 (d J ) 8.3 Hz,
1H), 7.00 (d J ) 8.6 Hz, 1H), 6.95 (d J ) 8.6 Hz, 1H), 5.39 (s,
2H), 5.37 (s, 2H), 3.91 (s 6H), 3.56 (s, 3H), 3.55 (s, 3H), 3.40 (m,
1H), 3.21 (m, 1H), 3.04 (q J ) 7.2 Hz, 2H), 0.91-0.84 (m, 6H);
13C NMR (62.9 MHz, CDCl3) δ 169.6 (e), 151.6 (e), 148.9 (e),
4092 J. Org. Chem. Vol. 74, No. 11, 2009

Combined Directed Remote Metalation
147.6 (e), 146.6 (e), 143.7 (e), 131.3 (e), 130.7 (e), 129.1 (e), 127.5
(o), 127.3 (o), 123.0 (o), 118.8 (o), 112.8 (o), 110.8 (o), 107.9 (o),
95.3 (e), 95.0 (e), 61.4 (o), 56.2 (o), 56.1 (o), 55.7 (o), 43.0 (e),
38.9 (e), 13.4 (o), 11.8 (o); MS (EI (70 eV)) m/e (rel intensity)
499 (M+, 44), 456 (6.7), 426 (99), 396 (12), 382 (6.8), 365 (7.1),
350 (100), 335 (66), 321 (39), 293 (16), 100 (27), 72 (49); HRMS
(EI (70 eV)) m/e calcd for C27H33NO8: 499.2206, found 499.2198.
Procedure 2. According to general procedure C2, a solution of
carbamate 49d (0.560 g, 2.630 mmol) in THF (10 mL) was added
to a solution of LDA (4.53 mmol) in THF (20 mL) at 0 °C. The
cooling bath was removed, and the reaction was allowed to stir for
2 h at which point LDA (2.99 mmol, 10 mL THF) was added and
stirring was continued for 2 h. This process was repeated once more
followed by standard workup and column chromatography (3:2
hexane/EtOAc) to afford the title compound as a foam (0.169 g,
34%), which was shown to be identical by physical and spectro-
scopic property comparison with material prepared by Procedure
1.
heated to 110 °C for 24 h. The reaction was quenched with H2O,
the solvents removed in Vacuo, and the residue diluted with CHCl3
(50 mL) and H2O (50 mL) and layers separated. The organic phase
was washed (brine), dried (Na2SO4), concentrated and the residue
purified by column chromatography (3:2 hexane/EtOAc f 1:1
hexane/CHCl3) affording the title compound as a fluffy colorless
solid (24.0 mg, 39%). Mp 301-306 °C, lit19 mp 293-297 °C H
1
NMR (300 MHz, CDCl3) δ 7.89 (d J ) 9.1 Hz, 1H), 7.86 (s, 1H),
7.83 (d J ) J ) 8.8 Hz, 1H), 7.53 (d J ) 8.8 Hz, 1H), 7.44 (d J
) 8.8 Hz, 1H), 7.14 (s, 1H), 6.10 (s, 2H), 4.04 (s, 3H), 3.99 (s,
3H). Spectral data were found to be identical to those reported for
the authentic material.32
Procedure 2. According to general procedure D, a solution of
hydroxy amide 51c (0.169 g, 0.338 mmol) in HOAc (7 mL) was
heated at reflux for 20 min and H2O (7 mL) was added. The reaction
was heated at reflux for 1 h and cooled to rt. The resulting
precipitate was filtered and washed successively with H2O, (5 mL)
EtOH (5 mL), and Et2O (10 mL). The solid (81.7 mg) was dissolved
in degassed DMF (10 mL) and K2CO3 (65.2 mg, 0.4717 mmol),
CuO (56.5 mg, 0.710 mmol) and CH2Br2 (0.03 mL, 0.427 mmol)
were added. The mixture was heated at reflux under Ar for 12 h,
the DMF removed in vacuo and the residue diluted with H2O (50
mL) and CHCl3 (50 mL). The layers were separated and the aq
phase extracted twice more with CHCl3 and the combined organic
layers were washed, (brine), dried (Na2SO4), concentrated and the
residue purified by column chromatography (2:1 hexane/EtOAc f
2:2:1 hexane/CHCl3/EtOAc f CHCl3) affording the title compound
as a colorless solid (6.2 mg, 5.2%) whose spectral properties were
identical those observed for arnottin I prepared by Procedure 1.
3,4-Dihydroxy-7,8-dimethoxy-6H-naphtho[1,2-b]benzo[d]py-
ran-6-one (51c). According to general procedure C1, a mixture of
carbamate 49d (0.444 g, 0.890 mmol) in THF (5 mL) was added
to a solution of LDA (4.39 mmol) in THF (10 mL) at 0 °C. The
reaction mixture was allowed to stir at rt for 6 h, and standard
workup afforded the crude hydroxyamide 50c, which was dissolved
in MeOH (10 mL) and TsOH (0.850 g, 4.94 mmol) was added.
The reaction mixture was heated at reflux for 14 h at which point
it was cooled to 0 °C and the solid was removed by filtration. The
filtrate was diluted with 10 mL of H2O and cooled to 0 °C and
filtered. The precipitate (two crops) was washed with MeOH
affording the title compound (0.132 g, 44%) as a light-brown
powder. Mp 291-294 °C (dec); IR (KBr) ν (max) 3527, 3432 (br),
Acknowledgment. We thank NSERC Canada for support via
the NSERC/Monsanto Industrial Chair and Discovery Grant
programs. We are indebted to Jan Venne for careful NMR
spectroscopic assistance and the late Dr. Nick Taylor and Dr.
Brian Chapell for X-ray crystal structure determination of
compound 50. We thank Alexander Keith, Earl Street, for
motivating the completion of this paper.
1
2947, 1698, 1634, 1504, 1461 cm-1; H NMR (250 MHz, DMF-
d7) δ 10.02 (s, 2H), 8.18 (d J ) 9.0 Hz, 1H), 8.01 (d J ) 8.9 Hz,
1H), 7.74 (d J ) 8.9 Hz, 1H), 7.75 (s, 1H), 7.59 (d J ) 8.9 Hz,
1H), 7.32 (s, 1H), 4.01 (s, 3H), 3.94 (s, 3H); 13C NMR (50 MHz,
DMF-d7) δ 157.6 (e), 153.7 (e), 151.8 (e), 149.4 (e), 148.8 (e),
145.8 (e), 130.7 (e), 130.4 (e), 123.0 (o), 121.0 (o), 119.0 (e), 119.0
(o), 117.6 (o), 115.5 (e), 111.4 (e), 111.0 (o), 104.5 (o), 61.2 (o),
56.7 (o); MS (EI (70 eV)) m/e (rel intensity) 338 (M+, 100), 323
(33), 309 (23), 295 (14), 280 (7.4), 265 (5.7), 252 (9.5), 237 (6.1),
196 (15), 139 (8.1); HRMS (EI (70 eV)) m/e calcd for C19H14O6:
338.0790, found 338.0804.
6,7-Dimethoxy-3,4-methylenedioxy-6H-naphtho[1,2-b]ben-
zo[d]pyran-6-one (Arnottin I) (2). Procedure 1. A mixture of
catechol 51c (59.2 mg, 0.1751 mmol) and anhydrous CsF (0.310
g, 2.04 mmol) in dry DMF (5 mL) was allowed to stir at rt for 10
min and CH2Cl2 (0.1 mL, 1.56 mmol) was added and the mixture
Supporting Information Available: Experimental details for
compounds not included in main text. A detailed description
of the aryne cyloaddition methods used to prepare 27a,b and
associated experimental data. 1H NMR and 13C data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO9001454
J. Org. Chem. Vol. 74, No. 11, 2009 4093