Total Syntheses of Furaquinocin A, B, and E

Article abstract of DOI:10.1021/ja0364118

A modular approach to the total synthesis of furaquinocins culminated in the total syntheses of furaquinocin A, B, and E. A Pd-catalyzed dynamic kinetic asymmetric transformation (DYKAT) on carbonates derived from Baylis-Hillman adducts, followed by a reductive Heck cyclization allows the enantio- and diastereoselective construction of dihydrobenzofuran 32. Introduction of a double unsatured side chain via Horner-Wadsworth-Emmons reaction and assembly of the naphthoquinone with squaric acid based methodology leads to furaquinocin E. The use of differentially substituted squaric acid derivatives allows the synthesis of three analogues of furaquinocin E. The additional stereocenters in furaquinocin A and B can be introduced with a diastereoselective Sakurai allylation. The stereoselective elongation of the side chain is possible using cross metathesis or ring closing metathesis. The obtained late-stage intermediates were successfully transformed to furaquinocin A and B.

Full text of DOI:10.1021/ja0364118

Published on Web 10/04/2003
Total Syntheses of Furaquinocin A, B, and E
Barry M. Trost,* Oliver R. Thiel, and Hon-Chung Tsui
Contribution from the Department of Chemistry, Stanford UniVersity,
Stanford, California 94305-5080
Received May 29, 2003; E-mail: bmtrost@stanford.edu.
Abstract: A modular approach to the total synthesis of furaquinocins culminated in the total syntheses of
furaquinocin A, B, and E. A Pd-catalyzed dynamic kinetic asymmetric transformation (DYKAT) on carbonates
derived from Baylis-Hillman adducts, followed by a reductive Heck cyclization allows the enantio- and
diastereoselective construction of dihydrobenzofuran 32. Introduction of a double unsatured side chain via
Horner-Wadsworth-Emmons reaction and assembly of the naphthoquinone with squaric acid based
methodology leads to furaquinocin E. The use of differentially substituted squaric acid derivatives allows
the synthesis of three analogues of furaquinocin E. The additional stereocenters in furaquinocin A and B
can be introduced with a diastereoselective Sakurai allylation. The stereoselective elongation of the side
chain is possible using cross metathesis or ring closing metathesis. The obtained late-stage intermediates
were successfully transformed to furaquinocin A and B.
Introduction
The furaquinocins (1-8; Figure 1) are a class of antibiotics
isolated from the fermentation broth of Streptomyces sp. KO-
3998 by Ohmura.1 They show a wide range of biological effects
including in vitro cytotoxicity against HeLa S3 and B16
melanoma cells, antihypertensive activity, and inhibition of
platelet aggregation and coagulation. All members of the
furaquinocins share a densely functionalized naphthoquinone
core, differing only in the degree of oxidation of the isoprenoid
side chain. The relative and absolute stereochemistry was
assigned by extensive correlations between the members of the
family and by a single-crystal X-ray analysis of furaquinocin
A (1).2 The biological activity, as well as the challenging
structural features, make this class of compounds prime targets
for synthesis. Smith reported a short chiral-pool based synthesis
of furaquinocin C (3)3 and Suzuki prepared furaquinocin A (1),
B (2), D (4), and H (8).4 We recently described a concise total
synthesis of furaquinocin E (5), based on a dynamic asymmetric
kinetic transformation (DYKAT) process.5 In this full account,
we present the development of our synthetic approach in greater
detail. The flexibility of this strategy allows easy variations of
the side chain as demonstrated by the synthesis of additional
Figure 1. Furaquinocins.
furaquinocins A (1) and B (2) as well as variations of the
substituents on the naphthoquinone moiety.
Results and Discussion
Despite some recent progress in the development of an
asymmetric Baylis-Hillman reaction, the present methods for
this type of transformation still have serious drawbacks, which
preclude their use in asymmetric synthesis.6-8 We developed
an efficient alternative to the asymmetric Baylis-Hillman
(1) (a) Funayama, S.; Ishibashi, M.; Anraku, Y.; Komiyama, K.; Ohmura, S.
Tetrahedron Lett. 1989, 30, 7427. (b) Komiyama, K.; Funayama, S.;
Anraku, Y.; Ishibashi, M.; Takahashi, Y.; Ohmura, S. J. Antibiot. 1990, 43,
247. (c) Funayama, S.; Ishibashi, M.; Komiyama, K.; Ohmura, S. J. Org.
Chem. 1990, 55, 1132. (d) Ishibashi, M.; Funayama, S.; Anraku, Y.;
Komiyama, K.; Ohmura, S. J. Antibiot. 1991, 44, 390.
(2) (a) Dormer, P. G.; Smith, A. B., III; Funayama, S.; Ohmura, S. Tetrahedron
Lett. 1992, 33, 1717.
(3) (a) Smith, A. B., III.; Sestelo, J. P.; Dormer, P. G. J. Am. Chem. Soc. 1995,
117, 10 755. (b) Smith, A. B., III.; Sestelo, J. P.; Dormer, P. G. Heterocycles
2000, 52, 1315.
(6) For a recent review on the Baylis-Hillman reaction, see: Basavaiah, D.;
Rao, A. J.; Satyanarayana, T. Chem. ReV. 2003, 103, 811.
(7) (a) Yang, K.; Lee, W.; Pan, J.; Chen, K. J. Org. Chem. 2003, 68, 915. (b)
Shi, M.; Jiang, J. Tetrahedron: Asymmetry 2002, 13, 1941. (c) Iwabuchi,
Y.; Furukawa, M.; Esumi, T.; Hatekeyama, S. Chem. Commun. 2001, 2030.
(d) Iwabuchi, Y.; Nakatami, M.; Yokoyama, N.; Hatekayama, S. J. Am.
Chem. Soc. 1999, 121, 10 219. (e) Barrett, A. G. M.; Cook, A. S.;
Kamimura, A. Chem. Commun. 1998, 2533. (f) Hayase, T.; Shibata, T.;
Soai, K.; Wakalsuki, Y. Chem. Commun. 1998, 1271. (g) Marko, I. E.;
Giles, P. R.; Hindley, N. J. Tetrahedron 1997, 53, 1015. (h) Oishi, T.;
Oguri, H.; Hirama, M. Tetrahedron: Asymmetry 1995, 6, 1241.
(4) (a) Saito, T.; Morimoto, M.; Akiyama, C.; Matsumoto, T.; Suzuki, K. J.
Am. Chem. Soc. 1995, 117, 10 757. (b) Saito, T.; Suzuki, T.; Morimoto,
M.; Akiyama, C.; Ochiai, T.; Takeuchi, K.; Matsumoto, T.; Suzuki, K. J.
Am. Chem. Soc. 1998, 120, 11 633.
(5) Trost, B. M.; Thiel, O. R.; Tsui, H. C. J. Am. Chem. Soc. 2002, 114, 11 616.
9
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Trost et al.
compound was also not a reactive nucleophile in the allylic
alkylation of carbonate 12.
Revised Approach. Since the introduction of the naphtho-
quinone as a nucleophile in the allylic alkylation reaction failed,
we had to revise our retrosynthetic strategy (Figure 3). We chose
furaquinocin E (5) as the initial target molecule. Late stage
construction of the naphthoquinone should be possible from
intermediate 21 using the squaric acid based methodology
developed earlier by Moore and Liebeskind.12 Disconnection
of the doubly unsaturated side chain leads to aldehyde 22.
This aldehyde could be obtained from benzofuran 23. We
thought that we could establish the absolute and relative
stereochemistry of this key intermediate with a sequence of
Pd-catalyzed allylic alkylation and diastereoselective reductive
Heck cyclization.
Figure 2. Initial retrosynthetic analysis.
Construction of the Benzofuran. Initially we investigated
the monoalkylation of 2-iodoresorcinol 2413 with carbonates
25-27 (Scheme 2).14 In agreement with our previous results
concerning the DYKAT on similar substrates, we observed the
best results with nitrile derivative 25.8 Use of the corresponding
methyl and ethyl ester derivatives 26 and 27 resulted in
diminished enantioselectivity. Unfortunately, we were not able
to obtain high yields of the monoalkylated product. Even in
the presence of an excess of the nucleophile (1.5 equiv), the
isolated yield of compound 28 was only 63%. Nonetheless, we
investigated 28-30 as substrates in the reductive Heck cycliza-
tion.15 The reaction of the methyl ester 29 under conditions
reported previously in the literature (different palladium sources
such as PdCl2(CH3CN)2, Pd(OAc)2, Pd(CF3CO2)2, or PdCl2-
(PPh3)2, NaCO2H, K2CO3, DMF, 50 °C)15a,b led to the pre-
dominant formation of the 6-endo-cyclization product. Whereas
the use of the ethyl ester 30 led to similar results, switching to
the nitrile 28 as substrate led to a reversal in selectivity. The
5-exo-cyclization was now the major reaction pathway. Using
the conditions that we applied successfully in the synthesis of
aflatoxin B1 (PdCl2(CH3CN)2, HCOOH, TEA, DMF, 50 °C)15c,d
we could obtain a 40% yield of product 32, after acetylization
of the free phenol. The use of phenol 28 as substrate in the
reductive Heck cyclization revealed that the allylic ether moiety
was rather labile under the reaction conditions, simple cleavage
of the allyl ether was a major competing pathway. While we
contemplated the possibility of utilizing a protecting group for
the phenol to improve the yield in the allylic alkylation and to
minimize the side reactions, a more attractive alternative that
might improve both palladium-catalyzed reactions arose.
The alternate envisions a dialkylation approach, which should
give higher yields in both the allylic alkylation and the reductive
Heck cyclization (Scheme 3). Reaction of 2-iodoresorcinol 24
with allylic carbonate 25 (2.85 equiv) in the presence of
Pd2(dba)3‚CHCl3 (1 mol %) and (R,R)-ligand 10 (3 mol %) gave
the desired product 31 in excellent yield (97%) and good
diastereoselectivity (dr 92/8).16 In contrast to our previously
reaction. The carbonates of Baylis-Hillman adducts can be used
as substrates in the Pd-catalyzed allylic alkylation with phenols
as nucleophiles (eq 1).9A dynamic kinetic asymmetric trans-
formation (DYKAT)10 leads to the corresponding products in
good yields and high enantioselectivity.
Initial Approach. Our initial retrosynthetic approach is
depicted in Figure 2. All furaquinocins should be available from
the common intermediate 10, by late-stage introduction of the
appropriate side chains. This intermediate 10 should be obtained
via diastereoselective epoxidation and subsequent electrophilic
cyclization of substrate 11. Allylic alkylation of carbonate 12
with the phenolic nucleophile 13 should establish the absolute
stereochemistry.
To test the feasibility of our strategy, we prepared naphtho-
quinone 16 through a Diels-Alder reaction of bromoquinone
14 with diene 15 (Scheme 1).11 The diol 16 was monoprotected
to afford naphthoquinone 17. The palladium-catalyzed reaction
of allylic carbonate 12 with this nucleophile failed. This failure
can be attributed to an incompatibility between the palladium(0)
catalyst and the oxidizing naphthoquinone moiety and to the
decreased nucleophilicity of the phenol due to a strong hydrogen
bond with the adjacent carbonyl moiety. To circumvent these
problems, the naphthoquinone 16 was protected as the diacetate,
reduced to the dihydronaphthoquinone, and protected as the
bismethoxymethyl ether. Saponification of the acetates and
monosilylation afforded the phenol 19. To our surprise, this
(8) For use of chiral auxiliaries in Baylis-Hillman reactions, see: (a) Radha
Krishna, P.; Kannan, V.; Sharma, G. V. M.; Ramana Rao, M. H. V. Synlett
2003, 888. (b) Radha Krishna, P.; Kannan, V.; Ilangovan, A.; Sharma, G.
V. M. Tetrahedron: Asymmetry 2001, 12, 829. (c) Brzezinski, L. J.; Rafel,
S.; Leahy, J. W. J. Am. Chem. Soc. 1997, 119, 4317. (d) Brzezinski, L. J.;
Rafel, S.; Leahy, J. W. Tetrahedron 1997, 53, 16 423.
(9) Trost, B. M.; Tsui, H.-C.; Toste, F. D. J. Am. Chem. Soc. 2000, 122,
3534.
(10) Trost, B. M.; Van Vranken, D. L.; Bingel, C. J. Am. Chem. Soc. 1992,
114, 9327. For a recent review: Trost, B. M. Chem. Pharm. Bull. 2002,
50, 1.
(11) Botha, M. E.; Giles, R. G. F.; Yorke, S. C. J. Chem. Soc., Perkin Trans.
1 1991, 85.
(12) (a) Moore, H. W.; Perri, S. T. J. Org. Chem. 1988, 53, 996. (b) Perri, S.
T.; Foland, S. D.; Decker, O. H. W.; Moore, H. W. J. Org. Chem. 1986,
51, 3067. (c) Liebeskind, L. S.; Iyer, S.; Jewell, C. F. J. Org. Chem. 1986,
51, 3065. (d) Liebeskind, L. S. Tetrahedron 1989, 45, 3053.
(13) Thomsen, I.; Torssell, K. B. G. Acta Chem. Scand. 1991, 45, 539.
(14) The carbonates were obtained from the corresponding Baylis-Hillman
adducts in good yields by reaction with methylchloroformate/potassium
carbonate.
(15) (a) Schmidt, B.; Hoffmann, H. M. R. Tetrahedron 1991, 47, 9357. (b)
Hoffmann, H. M. R.; Schmidt, B.; Wolff, S. Tetrahedron 1989, 45, 6113.
(c) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1999, 121, 3543. (d)
Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 2003, 125, 3090.
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Total Syntheses of Furaquinocin A, B, and E
A R T I C L E S
Scheme 1. Synthesis of Nucleophiles 17 and 19a
a Conditions: (a) toluene, TEA, 65%. (b) TBDMSCl, imidazole, CH2Cl2, 95%. (c) Ac2O, DMAP, pyridine, CH2Cl2, reflux, 75%. (d) (i) Pd/C, H2, CH2Cl2;
(ii) MOMCl, DIPEA, CH2Cl2, 72%. (e) (i) LiAlH4, THF; (ii) TBDMSCl, imidazole, CH2Cl2, 57%.
Figure 3. Revised retrosynthetic analysis.
Scheme 2. Monoalkylation of 24a
Scheme 3. Two-Step Construction of the Furaquinocin Corea
a Conditions: (a) 24, Pd2(dba)3‚CHCl3 (1 mol %), ligand (R,R)-9 (2.65
mol %), CH2Cl2, room temperature, 97%, (dr 92/8). (b) (i) PdCl2(CH3CN)2
(10 mol %), HCOOH, PMP, DMF, 50 °C; (ii) Ac2O, TEA, DMAP, CH2Cl2,
room temperature, 81%, 87% ee (99% ee after recrystallization).
a Conditions: (a) 24 (1.5 equiv), Pd2(dba)3‚CHCl3 (1 mol %), (R,R)-9
(3 mol %), CH2Cl2, room temperature; 28 (R) CN), 64%, 91% ee; 29
(R) CO2Me), 62%, 74% ee; 30 (R) CO2Et), 52%, 71% ee.
Since we were not able to separate the diastereomers of 31
using crystallization or column chromatography, the mixture
was subjected to the next reaction. Reductive Heck cyclization
under the same conditions we used for the cyclization of 28
(PdCl2(CH3CN)2, HCOOH, TEA, DMF, 50 °C) showed poor
reproducibility. Significant competing pathways were the 6-endo-
cyclization and reionization of the substrate. Switching to the
sterically hindered base pentamethylpiperidine (PMP) led to a
great improvement in yield and reproducibility.17 The reaction
proceeded with good regio- and diastereoselectivity and the
reported examples, no formation of the regioisomer resulting
from the attack of the phenol at the terminal position was
observed.9 No attempts were made at this stage to assign the
absolute stereochemistry of 31. Based upon our previous
experience we believed that the use of (R,R)-10 as ligand in
the allylic alkylation led to the formation of (R,R)-31 as major
stereoisomer. This assumption was confirmed by the conver-
sion of this intermediate to the natural enantiomers of the
furaquinocins. Ionization of the carbonate 25 leads to the two
diastereomeric syn-π-allylpalladium complexes I and II (Figure
4). These two complexes are in equilibrium via a π-σ-π-
isomerization. The nucleophile attacks the allyl complex in an
exo mode. The matched reaction pathway leads to the R-
configured product.
(16) This diastereomeric ratio reflects the ratio of (R,R)-31 and meso-31. No
(S,S)-31 was formed.
(17) For the beneficial use of PMP as base in Heck reactions, see, for example:
(a) Ashimori, A.; Bachand, B.; Overman, L. E.; Poon, D. J. J. Am. Chem.
Soc. 1998, 120, 6477. (b) Ashimori, A.; Bachand, B.; Calter, M. A.; Govek,
S. P.; Overman, L. E.; Poon, D. J. J. Am. Chem. Soc. 1998, 120, 6488.
9
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Scheme 4. Model Study for Naphthoquinone Assemblya
Figure 4. Rationale for asymmetric induction in the allylic alkylation.
a Conditions: (a) 2-lithioanisole, THF, -78 °C, 33%. (b) (i) toluene,
110 °C; (ii) Ag2O, K2CO3, room temperature, 66%. (c) (i) MeLi, THF,
-100 °C; (ii) trifluoroacetic anhydride, -78 °C; (iii) aniline, -78 to -15
°C (53%). (d) (i) 2-lithioanisole, THF, -78 °C; (ii) oxalic acid, THF/H2O,
53%. (e) (i) toluene, 110 °C; (ii) Ag2O, K2CO3, room temperature, 79%.
blocks 24 and 25. This compound serves as the pivotal
intermediate which provides access to several furaquinocins and
their analogues.
Studies Directed Toward the Synthesis of Regioisomeric
Naphthoquinones. Squaric acid based methodology is available
for the construction of naphthoquinones.12 To examine selectiv-
ity issues as well as to establish reaction conditions, we
employed the addition of 2-lithioanisole to the squaric acid
derivatives 33 and 34 as a model system for the furaquinocin
synthesis. Use of the derivative 33 leads to nucleophilic attack
of an organometallic compound on the more reactive carbonyl
group adjacent to the methoxy group (Scheme 4). After
rearrangement and oxidation this furnishes naphthoquinone 36,
which is regioisomeric to the furaquinocins with regard to the
substituents on the quinone.12d To reverse the chemoselectivity,
a temporary protecting group was introduced.18 Taking advan-
tage of the higher reactivity of the C-2 carbonyl group, the imine
34 could be obtained from dimethyl squarate 54 in good yield
through a one-pot procedure. Addition of 2-lithioanisole to imine
34 followed by hydrolysis of the imine under mild acidic
conditions afforded regioisomer 37. This compound could be
rearranged and oxidized to provide naphthoquinone 38. Thus,
both positional isomers are readily accessible.
Completion of the Furaquinocin E Synthesis. Having
established the two stereogenic centers of 32 in an efficient
manner and with a selective naphthoquinone synthesis available,
we were confident that we could sucessfully complete the total
synthesis of furaquinocin E (5). The formation of the required
aryllithium required access to an aryl bromide precursor. Direct
bromination of the free phenol 39 with tetra-n-butylammonium
perbromide gave an 84% yield of monobromide, but as a 1:1
mixture of the ortho and para (with respect to the phenolic OH)
products. To direct the reaction to form the desired para bromide,
a bulky triisopropylsilyl group was placed on the free phenol.
Indeed, bromination with NBS proceeded regioselectively to
form monobromide 41 (Scheme 5).19 For installation of the side
chain, the nitrile was reduced with DIBAL and the resultant
Figure 5. Crystal structure of 32.
Figure 6. Possible diastereomeric intermediates in the reductive Heck
cyclization.
second allyl moiety was cleaved under the reaction conditions.
After acetylization of the free phenol, the desired diastereomer
32 was obtained in very good yield. A strong NOE between
the methyl C-3 and the hydrogen at C-2 established their cis
relationship. The relative stereochemistry was finally confirmed
by single-crystal X-ray analysis (Figure 5). This stereochemical
outcome is expected based on minimization of steric strain in
the transition state for the intramolecular carbapalladation step
(Figure 6). The reaction pathway leading to the major dia-
stereomer leads to intermediate III, in which the methyl group
and the bulky palladium-bearing methylene group are oriented
trans to each other. The diastereoselectivity of the reductive
Heck cyclization was diminished in the case of the substrates
29 and 30. The ester substituents are bulkier than the nitrile
and therefore intermediate IV becomes a more accessible
pathway. The enantiomeric excess obtained in the allylic
alkylation was determined to be 87%. Recrystallization of
acetate 32 led to enantiopure material (85% recovery). With
this strategy, the absolute and relative stereochemistry of the
benzofuran was established using two Pd-catalyzed steps. Thus
a simple two-step protocol provided the dihydrobenzofuran core
enantiomerically pure in 67% yield from two simple building
(18) Winters, M. P.; Stranberg, M.; Moore, H. W. J. Org. Chem. 1994, 59,
7572.
(19) Bromination of acetate 32, the free phenol 33, or the corresponding
TBDMS-ether were unselective.
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Total Syntheses of Furaquinocin A, B, and E
A R T I C L E S
Scheme 5. Conversion of 32 to Furaquinocin E (5)a
regioisomer 49 of furaquinocin E could be obtained. The use
of compound 50 gave rise to the dimethylnaphthoquinone 53,
and employment of compound 54 resulted in the dimethoxy-
naphthoquinone 57. The thermal rearrangement of compound
55 under the relatively mild conditions that were successfully
applied to all other furaquinocins (toluene, 110 °C) led to
incomplete conversions. Hence the reaction was performed
under microwave irradiation (toluene, 180 °C, 30 min), affording
an acceptable yield of 58% after oxidation to the naphtho-
quinone. The analogues 49, 53, and 57 were submitted to
biological testing, but unfortunately no cytotoxicity against
HEK293T, LnCAP, and A2780 cell lines was observed in the
micromolar range.21
Syntheses of Furaquinocin A and B. Our modular approach
allowed easy access to several analogues of furaquinocin E. We
were also interested in the synthesis of other members of the
furaquinocin family that would bear more complicated side
chains. We chose furaquinocins A (1) and B (2) as additional
targets. Compared to furaquinocin E, they have an additional
stereogenic center bearing a hydroxyl group in the side chain.
Furaquinocins A and B only differ in the stereochemistry of
the double bond in the side chain. We envisioned that we could
introduce the side chain by addition of organometallic reagents
to aldehyde 58, which we already obtained from the reduction
of nitrile 41 (Scheme 7). Since the introduction of the side chain
as a whole failed in earlier approaches,4b we only briefly
investigated this possibility.22 As our efforts in this direction
were only met with limited success, we concentrated on the
allylation of the aldehyde. Such a strategy would postpone the
elaboration of the complete side chain toward subsequent stages.
Addition of allylmagnesium bromide to aldehyde 58 proceeded
in good yield (65% from 41), but no diastereoselectivity (dr
1:1) was observed. The Lewis acid (BF3 or TiCl4) mediated
addition of allyltributylstannane afforded the corresponding
alcohols with better selectivity (dr 4:1). The best results were
obtained with the addition of allyltrimethylsilane mediated by
TiCl4 (9:1).23 The desired homoallylic alcohol 59 could be
obtained in pure form after purification by column chromatog-
raphy (67% from 41).24 Attempts to perform the allylation with
allyltrimethylsilane in the presence of a Lewis acidic catalyst
(FeCl325 or Sc(OTf)326) led to no conversion. The activation of
the allylating reagent with TBAF27 only led to cleavage of the
TIPS group of aldehyde 58. The observed diastereoselectivity
a Conditions: (a) NaOMe, MeOH, room temperature, 94%. (b) TIPSOTf,
TEA, CH2Cl2, 96%. (c) NBS, THF, room temperature, 92%. (d) (i) DIBAL,
CH2Cl2, -78 °C; (ii) 42, LHMDS, THF, 0 °C, 89%. (e) (i) DIBAL, CH2Cl2,
-78 °C; (ii) TBDMSCl, imidazole, CH2Cl2, reflux, 89% (2 steps). (f) (i)
n-BuLi, THF, -78 °C; (ii) 34, THF, -78 °C; (iii) oxalic acid, THF/H2O,
50%. (g) (i) toluene, 110 °C; (ii) air, room temperature, 64%. (h) TBAF,
THF, 0 °C, 65%.
aldehyde was subjected to a Horner-Wadsworth-Emmons
reaction with phosphonate 4220 to yield the desired (E,E)-diene
43 exclusively. Reduction of the methyl ester to the alcohol
followed by TBDMS protection completed the elaboration of
the side chain. The stage was now set to inspect the scope of
the naphthoquinone synthesis on a more elaborate substrate.
Halogen-metal exchange on bromide 44 and addition of the
generated organolithium to imine 34 followed by hydrolysis of
the resulting imine under mild acidic conditions led to the
addition product 45 in acceptable yield. All efforts to improve
the yield by using cerium- or magnesium-derived organo-
metallics failed. Thermal rearrangement followed by oxidation
in air delivered the desired naphthoquinone 46. Furaquinocin
E (5) was obtained upon deprotection of the silyl ethers with
TBAF in THF. The spectroscopic data are in full agreement
with those published for the natural product,1d thereby confirm-
ing the chemoselectivity in the attack of the protected squaric
acid derivative.
Synthesis of Furaquinocin E Analogues. Although we were
initially disappointed that our original retrosynthetic approach
had failed, we realized that our revised approach was more
modular in nature. It should enable us to access analogues of
furaquinocin E with different substitution patterns on the
naphthoquinone very easily. We therefore used the intermediate
44 to prepare several analogues. The reactions leading to the
analogues proceeded in analogy to the synthesis of furaquinocin
E (Scheme 6). Using the squaric acid derivative 33, the
(21) Cytotoxicity of the compounds was evaluated in HEK293T, LnCAP and
A2780 cell lines using viable stainin with Alamar Blue (O’Brien, J.; Wilson,
I.; Orton, T.; Pognan, F. Eur. J. Biochem. 2000, 267, 5421.
(22) We believed that we could access the secondary alcohol 53 by palladium-
catalyzed reductive opening of the vinyl epoxide 54. Attempts to selectively
epoxidize the disubstituted double bond of dienes 43 and 44 failed. An
alternative approach toward the epoxide 53 would be the addition of sulfur
ylides to the aldehyde 58. Initial attempts in this directions were not
successful, and this route was therefore abandoned.
(23) (a) Hosomi, A.; Sakurai, H. Tetrahedron Lett. 1976, 16, 1295. (b)
Heathcock, C. H.; Kiyooka, S.; Blumenkopf, T. A. J. Org. Chem. 1984,
49, 4214.
(20) Evans, D. A.; Miller, S. J.; Ennis, S. D. J. Org. Chem. 1993, 58, 471.
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Scheme 6. Synthesis of Furaquinocin E Analoguesa
a Conditions: (a) (i) n-BuLi, THF, -78 °C; (ii) 33, THF, -78 °C, 74%. (b) (i) toluene, 110 °C; (ii) air, room temperature, 92%. (c) TBAF, THF, 0 °C,
93%. (d) (i) n-BuLi, THF, -78 °C; (ii) 50, THF, -78 °C, 61%. (e) (i) toluene, 110 °C; (ii) Ag2O, K2CO3, room temperature, 55%. (f) TBAF, THF, 0 °C,
77%. (g) (i) n-BuLi, THF, -78 °C; (ii) 54, THF, -78 °C, 81%. (h) (i) toluene, microwave, 180 °C; (ii) air, room temperature, 58%. (i) TBAF, THF, 0 °C,
94%.
in the Lewis acid mediated allylation can be explained by the
Scheme 7. Diastereoselctive Allylationa
polar model proposed by Evans (Figure 7).28 The extended
Newman projection depicts the conformation that minimizes
the dipole moment. The bottom face of the aldehyde is blocked
toward the attack of nucleophiles by the â-methyl substituent.
Homoallylic alcohol 59 served as a common intermediate
toward both furaquinocin A and B by using olefin metathesis
a Conditions: (a) DIBAL, CH2Cl2, -78 °C. (b) allyltrimethylsilane,
TiCl4, CH2Cl2, room temperature, 67% (isolated yield of 59 based on 41).
(24) The configuration of the newly formed stereogenic center of 59 was deduced
from the 1H NMR spectra of the O-methylmandelate derivatives of the
major and minor diastereomer. See: Trost, B. M.; Belletire, J. L.; Godleski,
S.; McDougal, P. G.; Balkovec, J. M.; Baldwin, J. J.; Christy, M. E.;
Ponticello, G. S.; Varga, S. L.; Springer, J. P. J. Org. Chem. 1986, 51,
2370. Final proof of this assignment was possible by transformation of 59
to the natural products.
Figure 7. Rationalization of the diastereoselectivity in the allylation.
chemistry.28 Grubbs reported on the use of methacrolein in the
cross metathesis using new NHC-substituted ruthenium com-
plexes.30 This reaction proceeds stereoselectively to give the
thermodynamically favored (E) double bond isomer. We
therefore subjected acetate 60, derived from alcohol 59, to the
cross metathesis (Scheme 8).31 Alkene 60 was reacted with
methacrolein in the presence of complex 61 as precatalyst32 to
(29) For leading reviews, see: (a) Fu¨rstner, A. Angew. Chem., Int. Ed. Engl.
2000, 39, 3012. (b) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res.. 2001,
34, 18. (c) Connon, S. J.; Blechert, S. Angew. Chem., Int. Ed. Engl. 2003,
42, 1900.
(30) Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H. J. Am. Chem.
Soc. 2000, 122, 3783.
(25) Watahiki, T.; Oriyama, T. Tetrahedron Lett. 2002, 43, 8959.
(26) Aggarwal, V. K.; Vennall, G. P. Tetrahedron Lett. 1996, 37, 3745.
(27) Hosomi, A.; Shirahata, A.; Sakurai, H. Tetrahedron Lett. 1978, 18, 3043.
(28) (a) Evans, D. A.; Duffy, J. L.; Dart, M. J. Tetrahedron Lett. 1994, 35,
8537. (b) Evans, D. A.; Dart, M. J.; Duffy, J. L.; Yang, M. G. J. Am.
Chem. Soc. 1996, 116, 4322.
(31) The free alcohol 53 or the TBDMS-protected derivative led to inferior results
in the cross metathesis.
(32) (a) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953. (b) Trnka, T. M.; Morgan, J. P.; Sanford, M. S.; Wilhelm, T. E.; Scholl,
M.; Choi, T.; Ding, S.; Day, M. W.; Grubbs, R. H. J. Am. Chem. Soc.
2003, 125, 2546.
9
13160 J. AM. CHEM. SOC. VOL. 125, NO. 43, 2003

Total Syntheses of Furaquinocin A, B, and E
A R T I C L E S
Scheme 8. Synthesis of Furaquinocin B (2)a
Scheme 9. Synthesis of Furaquinocin Aa
a Conditions: (a) methacroyl chloride, TEA, DMAP, CH2Cl2, room
temperature, 14 h, 78%. (b) 61 (5 mol %), CH2Cl2, reflux, 16 h, 66%. (c)
(i) DIBAL, CH2Cl2, room temperature, 2 h; (ii) NaBH4, MeOH, 62%. (d)
TBDMSOTf, 2,6-lutidine, CH2Cl2, room temperature, 5 h, 86%. (e) (i)
n-BuLi, THF, -78 °C; (ii) 34, THF, -78 °C; (iii) oxalic acid, THF/H2O,
59%. (f) (i) toluene, 110 °C, 2 h; (ii) air, room temperature, 81%. (g) HF,
acetonitrile, 18 h, room temperature, 70%.
a Conditions: (a) Ac2O (5 equiv), DMAP (0.5 equiv), pyridine, 91%.
(b) methacrolein (10 equiv.), 61 (10 mol %), CH2Cl2, reflux, 89%. (c)
DIBAL, CH2Cl2, room temperature, 94%. (d) TBDMSOTf, 2,6-lutidine,
CH2Cl2, room temperature, 4 h, 81%. (e) (i) n-BuLi, THF, -78 °C; (ii) 34,
THF, -78 °C, (iii) oxalic acid, THF/H2O, 56%. (f) (i) toluene, 110 °C, 2
h; (ii) air, room temperature, 70%. (g) HF, acetonitrile, 20 h, room
temperature, 61%.
(0.035 mmol). On a larger scale (0.5 mmol), the reduction with
DIBAL stopped partially at the stage of the lactol and the crude
mixture could then be reduced with NaBH4 in MeOH. Protection
of the diol 69 with TBDMSOTf/2,6-lutidine afforded intermedi-
ate 70. The synthesis of furaquinocin A (1) was completed by
the same route as for furaquinocin B and E. Addition of the
lithium anion generated by bromine-lithium exchange of
intermediate 70 to the imine 34 led to 71 in good yield. Thermal
rearrangement and oxidation in air afforded the fully protected
naphthoquinone 72. The final deprotection with HF in aceto-
nitrile gave furaquinocin A (1). The analytical data for synthetic
1 were determined to be identical with the data reported for the
natural product.1d
construct the trisubstituted double bond. The large excess of
methacrolein was needed, due to the propensity of this reagent
to polymerize under the reaction conditions. Reduction of the
R,â-unsaturated aldehyde 62 and cleavage of the acetate group
with DIBAL proceeded uneventfully to afford diol 63. Use of
TBDMSOTf/2,6-lutidine was necessary for the bis-TBDMS
protection because of the sterically hindered nature of the
secondary alcohol. Intermediate 64 was transformed to furaquino-
cin B via the already established synthetic strategy (vide supra).
Bromine-lithium exchange and addition of the resulting lithium
anion to imine 34 led to compound 65 in good yield. Thermal
rearrangement and oxidation with air afforded naphthoquinone
66. Deprotection of the silyl ethers was first attempted under
the conditions that were successfully applied in the synthesis
of furaquinocin E (TBAF/THF). Unfortunately the silyl group
on the secondary alcohol was resistant to these conditions.
However, the use of aqueous HF in acetonitrile afforded
furaquinocin B (2) in good yield. The analytical data for
synthetic 2 was identical with the data reported for the natural
product.1d
A stereoselective crossmetathesis was used to control the
geometry of the double bond in the synthesis of furaquinocin
B. It was envisioned that the opposite double bond isomer should
be obtained via a ring-closing metathesis approach (Scheme 9).
Esterification with methacroyl chloride afforded methacrylate
67. Ring-closing metathesis of the methyacrylate 67 proceeded
well with NHC-substituted ruthenium complexes.30,33 Reduction
of lactone 68 afforded the advanced diol 69 with the (Z)-alkene.
This reduction proceeded well with DIBAL on small scale
Conclusion
Asymmetric syntheses of furaquinocin A, B, and E are
described. This work highlights the ability to use racemic
Baylis-Hillman adducts for asymmetric synthesis. A Pd-
catalyzed DYKAT, followed by a reductive Heck cyclization
was used to establish the absolute and relative stereochemistry
of the common benzohydrofuran core. A diastereoselective
Sakurai reaction set the third stereogenic center in furaquinocin
A and B. All stereogenic centers are therefore derived from the
use of a catalytic amount of ligand 10 in the allylic alkylation
step. The control over the olefin geometry in the construction
of the side chain is possible using olefin metathesis reactions.
Ring-closing metathesis gave the (Z)-olefin 69 needed for the
synthesis of furaquinocin A. Cross metathesis with methacrolein
led to the (E)-olefin 63 which was further transformed to
furaquinocin B. The naphthoquinone part of the furaquinocins
could be constructed regioselectively using the protected squaric
acid derivative 34. The preparation of furaquinocin analogues
(33) Fu¨rstner, A.; Thiel, O. R.; Ackermann, L.; Schanz, H.-J.; Nolan, S. P. J.
Org. Chem. 2000, 65, 2204.
9
J. AM. CHEM. SOC. VOL. 125, NO. 43, 2003 13161

A R T I C L E S
Trost et al.
trifluoroacetic anhydride (1.41 mL, 10.0 mmol) was added. After stirring
for 15 min, aniline (1.00 mL, 11.0 mmol) was added. The reaction
mixture was warmed to -15 °C, before being quenched with saturated
aqueous NaHCO3 (50 mL) and extracted with ether (3 × 50 mL). The
combined organic phases were dried over MgSO4. Evaporation of the
solvents in vacuo and purification of the residue by flash chromatog-
raphy (SiO2, petroleum ether/ether 3:2) gave 34 (1.07 g, 53%) as a
yellow solid. mp ) 60-62 °C. IR (film): 3062, 2996, 1772, 1682,
was easily achieved by using other squaric acid derivatives.
Thus, a modular strategy emerges wherein both the naphtho-
quinone and the side chain moieties can be readily varied from
a simply available common intermediate.
Experimental Section
(R)-3-[3-((R)-2-Cyano-1-methylallyloxy)-2-iodophenoxy]-2-meth-
ylenebutyronitrile (31). Pd2(dba)3‚CHCl3 (72.5 mg, 0.0700 mmol),
ligand (R,R)-9 (146.8 mg, 0.1860 mmol), and 2-iodoresorcinol (24)
(1.65 g, 7.00 mmol) were weighed into a flask directly. The flask was
put under vacuum, refilled with argon (repeated 3 times), and cooled
to 0 °C. Allylic carbonate 25 (3.10 g, 20.0 mmol) was weighed into
another flask and CH2Cl2 (200 mL) was added. The solution was purged
with argon for 30 min, cooled to 0 °C, and then cannulated into the
other flask. The mixture was allowed to stir at room temperature for 4
h. Solvents were removed in vacuo and purification of the residue by
flash chromatography (SiO2, petroleum ether/ether 2:1 f 1:1) gave
bisallylic ether 31 (2.66 g, 97%) as a colorless solid. mp ) 65-66 °C.
IR (film): 2985, 2935, 2227, 1912, 1586, 1456, 1409, 1378, 1285,
1247, 1095, 1022, 954, 853, 764 cm-1. 1H NMR (300 MHz, CDCl3) δ
7.20 (t, J ) 8.3 Hz, 1 H), 6.46 (d, J ) 8.3 Hz, 2 H), 6.13 (d, J ) 1.3
Hz, 2 H), 6.05 (d, J ) 1.3 Hz, 2 H), 4.92 (q, J ) 6.3 Hz, 2 H), 1.66
(d, J ) 6.3 Hz, 6 H). 13C NMR (75 MHz, CDCl3) δ 157.2, 131.2,
129.7, 124.0, 116.5, 108.2, 81.8, 74.9, 20.4. HRMS m/z C16H15N2O2I
(M+). Calcd: 394.0178. Found: 394.0182. Stereoisomers were sepa-
rated by HPLC on chiral cel OD eluting with heptane/2-propanol 97:3
(1 mL/min): R,R 29.51, R,S 32.45, S,S 34.47. The prepared sample
showed the diasteremeric ratio 92:8 ((R,R):(S,S)).
1583, 1487, 1463, 1387, 1354, 1090, 1027, 962, 905, 771, 694 cm-1
.
1H NMR (300 MHz, CDCl3) δ: 7.39-7.31 (m, 4 H), 7.20-7.14 (m,
1 H), 4.45 (s, 3 H), 2.07 (s, 3 H). 13C NMR (75 MHz, CDCl3) δ: 190.1,
188.6, 168.0, 156.5, 145.5, 128.6, 128.4, 126.1, 123.5, 60.3, 8.6. HRMS
m/z C12H11NO2 (M+). Calcd: 201.0790. Found: 201.0799.
(2R,3R)-3-[(1E,3E)-(tert-Butyldimethylsilanyloxy)methylpenta-
1,3-dienyl]-7-methoxy-2,3,8-trimethyl-4-triisopropylsilanyloxy-2,3-
dihydronaphtho[1,2-b]furan-6,9-dione (46). n-BuLi (197 µL, 0.315
mmol, 1.6 M in hexanes) was added at -78 °C to a solution of aryl
bromide 44 (183 mg, 0.300 mmol) in THF (3 mL). After stirring for
30 min, a solution of imine 34 (91 mg, 0.450 mmol) in THF (3 mL)
was added dropwise at -78 °C. After stirring for 60 min at -78 °C,
the reaction was quenched by addition of saturated aqueous NH4Cl (5
mL), extracted with ether (3 × 25 mL), dried over MgSO4, filtered,
and evaporated under reduced pressure to afford the crude imine. The
crude product is dissolved in THF (20 mL); a solution of oxalic acid
(100 mg) in H2O (5 mL) is added. The reaction mixture was stirred
for 10 min before being quenched with saturated aqueous NaHCO3
(10 mL) and extracted with ether (3 × 25 mL). The combined organic
phases were dried over MgSO4. Evaporation of the solvents in vacuo
and purification of the residue by flash chromatography (SiO2,
petroleum ether/ether 4:1 f 2:1) afforded 45 (98 mg, 50%) as a
colorless oil.
Acetic Acid (2R,3S)-3-Cyano-2,3-dimethyl-2,3-dihydrobenzo-
furan-4-yl Ester (32). Bisallylic ether 31 (2.64 g, 6.70 mmol) and
PdCl2(CH3CN)2 (173 mg, 0.670 mmol) were dissolved in dry DMF
(150 mL) at room temperature. 1,2,2,6,6-Pentamethylpiperidine (7.26
mL, 40.1 mmol) and formic acid (1.01 mL, 26.8 mmol) were added.
The mixture was heated at 50 °C for 6 h. After being cooled to room
temperature, the mixture was diluted with ether (50 mL). The organic
phase was washed with brine (2 × 20 mL), dried over MgSO4, and
filtered. Evaporation of the solvents and purification of the residue by
flash chromatography (SiO2, petroleum ether/ether 4:1 f 2:1) gives
crude benzofuran 39, which is used directly in the next step. The crude
product is dissolved in CH2Cl2 (20 mL) and triethylamine (3.42 mL,
25.7 mmol); acetic anhydride (1.54 mL, 16.3 mmol) and a catalytic
amount of DMAP were added. After being stirred at room temperature
for 1 h, the mixture is quenched with water (5 mL) and diluted with
ether (10 mL). Layers were separated and the aqueous layer was
extracted with ether (2 × 10 mL). The combined organic layers were
dried over MgSO4 and filtered. Solvents were removed in a vacuum
and flash chromatography (SiO2, petroleum ether/ether 10:1) gave
benzofuran 32 (1.26 g, 81%) as a colorless oil. ee ) 87% (determined
by chiral HPLC). Enantiomerically pure material (ee ) 99%) can
obtained by recrystallization from petroleum ether/ether as colorless
needles. mp ) 63-64 °C. [R]25D +139.7° [c 1.06, CH2Cl2]. IR (film):
2985, 2937, 1771, 1617, 1601, 1456, 1386, 1261, 1196, 1175, 1091
A solution of 45 (98 mg, 0.149 mmol) in toluene (5 mL) was heated
to 110 °C for 3.5 h. After cooling to room temperature the reaction
mixture was stirred in air for an additional 2 h. Evaporation of the
solvents in vacuo and purification of the residue by flash chromatog-
raphy (SiO2, petroleum ether/ether 10:1 f 4:1) afforded 46 (62 mg,
64%) as a yellow foam. [R]24 -24.6° (c 0.66, CH2Cl2). IR (film):
D
2949, 2868, 1666, 1651, 1619, 1589, 1463, 1413, 1392, 1295, 1257,
1204, 1167, 1112, 1089, 1064, 1018, 882, 838, 776, 748 cm-1. 1H NMR
(500 MHz, CDCl3) δ: 7.08 (s, 1 H), 6.08-5.99 (2 H, m), 5.58-5.51
(m, 1 H), 4.62 (q, J ) 6.6 Hz, 1 H), 4.04 (s, 3 H), 4.02 (s, 2 H), 2.06
(s, 3 H), 1.59 (s, 3 H), 1.57 (s, 3 H), 1.39 (d, J ) 6.6 Hz, 3 H), 1.35
(sept, J ) 7.3 Hz, 3 H), 1.09 (d, J ) 7.3 Hz, 9 H), 1.08 (d, J ) 7.3 Hz,
9 H), 0.89 (s, 9 H), 0.04 (s, 3 H), 0.03 (s, 3 H). 13C NMR (125 MHz,
CDCl3) δ: 183.9, 180.9, 161.2, 157.2, 156.7, 136.9, 133.5, 133.4, 132.3,
130.3, 126.4, 122.8, 110.9, 109.7, 91.9, 67.8, 60.7, 49.0, 25.9, 22.3,
18.4, 17.95, 17.9, 15.6, 13.8, 13.1, 9.3, -5.4. HRMS m/z C37H58O6Si2
(M+). Calcd: 654.3772. Found: 654.3774.
Furaquinocin E (5). To a suspension of dried 4-Å molecular sieves
(20 mg) and quinone 46 (12.6 mg, 0.019 mmol) in THF (2 mL) is
added TBAF (115 µL, 0.115 mmol, 1M in THF) and the reaction
mixture was stirred at 0 °C for 30 min. Then a ph 7.4 buffer solution
(2 mL) was added, the mixture extracted with ether (3 × 10 mL), and
the combined organic layers dried over MgSO4 and evaporated in vacuo.
Purification of the residue by flash chromatography (SiO2, CHCl3/
MeOH 98:2) afforded 5 (4.8 mg, 65%) as a bright yellow solid. mp )
1
1032, 867, 862, 737 cm-1. H NMR (300 MHz, CDCl3) δ: 7.26 (dd,
J ) 8.3 Hz, J ) 8.1 Hz, 1 H), 6.75 (d, J ) 8.3 Hz, 1 H), 6.71 (d, J )
8.1 Hz, 1 H), 4.55 (q, J ) 6.3 Hz, 1 H), 2.34 (s, 3 H), 1.73 (s, 3 H),
1.63 (d, J ) 6.3 Hz, 3 H). 13C NMR (75 MHz, CDCl3) δ: 168.6, 159.7,
147.5, 131.3, 118.7, 118.6, 115.7, 108.3, 87.3, 44.5, 24.2, 20.8, 17.6.
HRMS m/z C13H13NO3 (M+). Calcd: 231.0895. Found: 231.0891.
Enantiomers were separated by HPLC on chiralcel OD eluting with
heptane/2-propanol 99:1 (1 mL/min); 2R,3S 15.73, 2S,3R 17.95.
183-185 °C (lit. mp 184-186 °C). [R]24 -76.5° [c 0.22, MeOH]
D
(lit. [R]18D -79° [c 0.26, MeOH]). IR (film): 3312, 2924, 2853, 1667,
1637, 1628, 1574, 1433, 1410, 1383, 1293, 1261, 1203, 1162, 1112,
1
1080, 1052, 1012, 742 cm-1. H NMR (500 MHz, CD3OD) δ: 7.08
(s, 1 H), 6.09-6.03 (m, 2 H), 5.63-5.57 (m, 1 H), 4.57 (q, J ) 6.5
Hz, 1 H), 4.00 (s, 3 H), 3.94 (s, 2 H), 2.00 (s, 3 H), 1.64 (s, 3 H), 1.58
(s, 3 H), 1.36 (d, J ) 6.6 Hz, 3 H). 13C NMR (126 MHz, CD3OD) δ:
185.4, 182.0, 162.5, 160.6, 158.4, 138.2, 135.0, 134.0, 133.8, 127.5,
127.4, 125.3, 109.8, 109.6, 93.1, 68.4, 61.1, 50.2, 22.5, 15.5, 14.1, 9.3.
The analytic data match the data reported for the natural product.1d
3-Methoxy-2-methyl-4-phenyliminocyclobut-2-enone (34). Methyl-
lithium (6.25 mL, 10.0 mmol, 1.6 M in ether) is added slowly to a
solution of 3,4-dimethoxy-3-cyclobutene-1,2-dione (1.42 g, 10.0 mmol)
in THF (50 mL) at - 100 °C (N2/ether). After stirring for 30 min at
this temperature the reaction mixture is warmed to -78 °C and
9
13162 J. AM. CHEM. SOC. VOL. 125, NO. 43, 2003

Total Syntheses of Furaquinocin A, B, and E
A R T I C L E S
(R)-1-((2R,3S)-2,3-Dimethyl-4-triisopropylsilanyloxy-2,3-dihydro-
benzofuran-3-yl)but-3-en-1-ol (59). DIBAL-H (8.40 mL, 8.40 mmol,
1 M in CH2Cl2) was added dropwise to a solution of nitrile 41 (2.03 g,
4.80 mmol) in CH2Cl2 (150 mL) at -78 °C. Stirring was continued
for 60 min at this temperature and then the reaction quenched by
addition of ethyl acetate. After being warmed to room temperature,
saturated aqueous NH4Cl (20 mL) was added. The reaction mixture
was diluted with a saturated solution of potassium sodium tartrate (100
mL) and ether (100 mL) and stirred for 1 h. Extraction with ether (3
× 50 mL), drying over MgSO4, filtration, evaporation of the solvents
under reduced pressure, and filtration through a plug of silica gel
(petroleum ether/ether 20:1) gave the crude aldehyde 58, which was
directly used in the next reaction. TiCl4 (2.40 mL, 4.80 mmol, 2 M in
CH2Cl2) was added at room temperature to a solution of the crude
aldehyde 58 in CH2Cl2 (50 mL). After stirring for 5 min, allyltrimethyl-
silane (1.15 mL, 7.20 mmol) was added. Stirring is continued at room
temperature for an additional 5 min. The reaction was quenched with
saturated aqueous NaHCO3, extracted with ether, dried over MgSO4,
filtered, and evaporated in vacuo. Purification of the residue by flash
chromatography (SiO2, petroleum ether/ether 10:1) afforded 59 (1.50
g, 67%) as a colorless oil. Diastereomeric ratio: 9:1 (determined by
integration of 1H NMR of the crude product, q at 4.42 and 4.48 ppm).
Major diastereomer in the allylation: [R]25D +35.0° [c 3.57, CH2Cl2].
IR (film): 3568, 2946, 2869, 1590, 1477, 1419, 1386, 1283, 1224,
(2R,3R)-3-[(R)-(E)-Bis(tert-butyldimethylsilanyloxy)methylpent-
3-enyl]-7-methoxy-2,3,8-trimethyl-4-triisopropylsilanyloxy-2,3-dihy-
dronaphtho[1,2-b]furan-6,9-dione (66). n-Butyllithium (142 µL, 0.200
mmol, 1.4 M in hexanes) was added at -78 °C to a solution of aryl
bromide 64 (148.4 mg, 0.200 mmol) in THF (2 mL). After stirring for
5 min, a solution of 34 (60.0 mg, 0.300 mmol) in THF (2 mL) was
added dropwise at -78 °C. After stirring for 30 min at -78 °C, the
reaction was quenched by addition of saturated aqueous NH4Cl (10
mL) and the mixture was extracted with ether (3 × 10 mL). After drying
of the combined organic layers over MgSO4 and filtration, evaporation
of the solvents in vacuo afforded the crude imine. The crude product
was dissolved in THF (10 mL) and a solution of oxalic acid (80 mg)
in water (4 mL) was added. The reaction mixture was stirred for 10
min before being quenched with saturated aqueous NaHCO3 (5 mL)
and extracted with ether (3 × 10 mL). The combined organic phases
were dried over MgSO4. Evaporation of the solvents in vacuo and
purification of the residue by flash chromatography (SiO2, petroleum
ether/ether 4:1 f 2:1) afforded 65 (89.0 mg, 56%) as a colorless oil.
A solution of 65 (38.7 mg, 0.049 mmol) in toluene (2 mL) was
heated to 120 °C for 2 h. After cooling to room temperature, the reaction
mixture was stirred in air overnight. Evaporation of the solvents in
vacuo and purification of the residue by flash chromatography (SiO2,
petroleum ether/ether 4:1) afforded 66 (26.9 mg, 70%) as a yellow
foam. [R]24 -39.1° [c 1.65, CH2Cl2]. IR (film): 2929, 2857, 1667,
D
1
1079, 1045, 1016, 993, 917, 883, 830, 787, 689 cm-1. H NMR (300
1652, 1622, 1589, 1463, 1415, 1392, 1292, 1255, 1204, 1174, 1099,
1
1056, 882, 836, 775, 744 cm-1. H NMR (400 MHz, CDCl3) δ: 7.04
MHz, CDCl3) δ: 7.10 (d, J ) 8.8 Hz, 1H), 6.24 (d, J ) 8.8 Hz, 1 H),
5.80-5.64 (m, 1 H), 5.08-4.98 (m, 2 H), 4.42 (q, J ) 6.8 Hz, 1 H),
3.84-3.76 (m, 1 H), 2.34-2.20 (m, 2 H), 1.63 (d, J ) 6.8 Hz, 3 H),
1.48 (s, 3 H), 1.32 (sept, J ) 6.8 Hz, 3 H), 1.11 (d, J ) 7.3 Hz, 9 H),
1.10 (d, J ) 7.3 Hz, 9 H). 13C NMR (75 MHz, CDCl3) δ: 158.3, 153.1,
135.8, 131.8, 121.2, 117.9, 112.6, 94.6, 89.9, 74.5, 52.8, 37.8, 20.7,
18.0, 14.1, 13.4. Anal. Calcd for C23H37BrO3Si: C, 58.83; H, 7.94.
(s, 1 H), 5.03 (t, J ) 6.5 Hz, 1 H), 4.56 (q, J ) 7.0 Hz, 1 H), 4.13 (dd,
J ) 6.5, 5.0 Hz, 1 H), 4.03 (s, 3 H), 3.76-3.67 (m, 2 H), 2.40-2.31
(m, 1 H), 2.26-2.17 (m, 1 H), 2.05 (s, 3 H), 1.81 (d, J ) 7.0 Hz, 3 H),
1.54 (s, 3 H), 1.43 (sept, J ) 7.3 Hz, 3 H), 1.32 (s, 3 H), 1.17 (d, J )
7.3 Hz, 9 H), 1.16 (d, J ) 7.3 Hz, 9 H), 0.90 (s, 9 H), 0.84 (s, 9 H),
0.09 (s, 3 H), 0.02 (s, 3 H), -0.03 (s, 3 H), -0.04 (s, 3 H). 13C NMR
Found: C, 59.04; H, 7.55. Minor diastereomer in the allylation: [R]25
(100 MHz, CDCl3) δ: 183.7, 180.8, 161.9, 157.0, 156.6, 134.7, 133.5,
D
+0.3° [c 4.56, CH2Cl2]. IR (film): 3528, 2947, 2870, 1641, 1586, 1476,
1418, 1386, 1279, 1266, 1224, 1178, 1079, 1053, 1018, 918, 883, 846,
829, 800, 752, 689 cm-1. 1H NMR (300 MHz, CDCl3) δ: 7.10 (d, J )
8.8 Hz, 1 H), 6.27 (d, J ) 8.8 Hz, 1 H), 5.89-5.74 (m, 1 H), 5.04-
4.94 (m, 2 H), 4.48 (q, J ) 6.8 Hz, 1 H), 3.64-3.55 (m, 1 H), 2.42 (d,
J ) 9.1 Hz, 1 H), 2.24 (d, J ) 9.1, 6.1 Hz, 1 H), 1.54 (s, 3 H), 1.48
(d, J ) 6.8 Hz, 3 H), 1.33 (sept, J ) 6.8 Hz, 3 H), 1.12 (d, J ) 7.3 Hz,
9 H), 1.10 (d, J ) 7.3 Hz, 9 H). 13C NMR (75 MHz, CDCl3) δ: 157.9,
152.7, 136.6, 131.8, 122.0, 116.8, 112.5, 95.1, 89.3, 74.9, 53.5, 39.2,
20.8, 18.0, 17.9, 13.8, 13.3.
133.4, 130.0, 122.8, 110.6, 109.7, 91.4, 76.8, 68.3, 60.7, 51.3, 33.0,
29.7, 26.0, 25.9, 23.9, 18.3, 18.2, 18.1, 18.0, 15.9, 13.3, 9.3, -3.9,
-4.0, -5.5. Anal. Calcd for C43H74O7Si3: C, 65.60; H, 9.47. Found:
C, 65.47; H, 9.29.
Furaquinocin B (2). HF (48 wt % in water, 0.5 mL) was added to
a solution of 66 (33.0 mg, 0.0420 mmol) in acetonitrile (3 mL). After
stirring for 14 h at room temperature, additional HF (48 wt % in water,
0.3 mL) was added and stirring was continued for 6 h. The reaction
mixture was poured into saturated aqueous NaHCO3 and extracted with
CH2Cl2. The combined organic phases were dried over MgSO4 and
evaporated in vacuo. Purification of the residue by preparative thin-
layer chromatography (SiO2, CHCl3/MeOH 20:1) afforded 2 (10.2 mg,
61%) as a bright yellow solid. mp ) 102-104 °C (lit. mp 101-104
°C). [R]25D -133.6° [c 0.33, CHCl3] (lit. [R]19D -132° [c 0.57, CHCl3]).
IR (film): 3374, 2925, 2859, 1666, 1641, 1582, 1433, 1408, 1302,
1277, 1202, 1168, 1111, 1071, 1021, 985, 897, 772, 732 cm-1. 1H NMR
(400 MHz, CDCl3) δ: 7.16 (s, 1 H), 5.56-5.49 (m, 1 H), 4.70 (q, J )
6.4 Hz, 1 H), 4.10 (s, 2 H), 4.07 (d, J ) 1.2 Hz, 1 H), 4.01 (s, 3H),
2.63-2.53 (m, 1 H), 2.23-2.17 (m, 1 H), 2.05 (s, 3 H), 1.74 (s, 3 H),
1.37 (s, 3 H), 1.32 (d, J ) 6.4 Hz, 3 H). 13C NMR (100 MHz, CDCl3)
δ: 183.6, 180.7, 160.4, 158.4, 156.9, 140.1, 134.1, 133.7, 124.4, 119.9,
110.7, 109.2, 88.8, 73.0, 67.9, 60.7, 52.3, 31.8, 18.9, 16.1, 14.3, 9.3.
The analytic data match the data reported for the natural product.1d
Acetic Acid (R)-(E)-1-((2R,3R)-7-Bromo-2,3-dimethyl-4-triiso-
propylsilanyloxy-2,3-dihydrobenzofuran-3-yl)-4-methyl-5-oxopent-
3-enyl Ester (62). Ruthenium complex 61 (9.2 mg, 0.011 mmol, 10
mol %) was added to a solution of olefin 60 (60.6 mg, 0.110 mmol)
and methacrolein (91 µL, 1.1 mmol) in CH2Cl2 (1 mL). The reaction
mixture was heated at reflux for 5 h and then quenched by addition of
ethyl vinyl ether. Evaporation of the solvents under reduced pressure
and purification of the residue by flash chromatography (SiO2,
petroleum ether/ether 10:1 to 4:1) afforded 62 (54.0 mg, 89%) as a
colorless solid. mp ) 117-119 °C. [R]23 -84.4° [c 0.54, CH2Cl2].
D
IR (film): 2947, 2869, 2713, 1746, 1693, 1646, 1585, 1479, 1419,
1386, 1372, 1284, 1226, 1150, 1082, 1047, 1024, 922, 882, 827, 793,
751, 715 cm-1. 1H NMR (500 MHz, CDCl3) δ: 9.14 (s, 1 H), 7.11 (d,
J ) 8.8 Hz, 1 H), 6.25 (d, J ) 8.8 Hz, 1 H), 6.08-6.03 (m, 1 H), 5.49
(dd, J ) 8.0, 6.5 Hz, 1 H), 4.48 (q, J ) 7.1 Hz, 1 H), 2.74-2.66 (m,
1 H), 2.62-2.54 (m, 1 H), 2.06 (s, 3 H), 1.73 (d, J ) 7.1 Hz, 3 H),
1.58 (s, 3 H), 1.49 (s, 3 H), 1.35 (sept, J ) 7.4 Hz, 3 H), 1.14 (d,
J ) 7.4 Hz, 9 H), 1.13 (d, J ) 7.4 Hz, 9 H). 13C NMR (126 MHz,
CDCl3) δ: 194.7, 170.2, 158.0, 153.2, 149.2, 139.8, 132.6, 121.2, 112.6,
94.6, 88.9, 74.9, 51.7, 31.3, 21.8, 20.9, 18.0, 17.9, 14.9, 13.3, 9.2.
HRMS m/z C27H41BrO5Si (M+). Calcd: 552.1907. Found: 552.1900.
Anal. Calcd for C27H41BrO5Si: C, 58.58; H, 7.46. Found: C, 58.70;
H, 7.53.
(R)-6-((2R,3R)-7-Bromo-2,3-dimethyl-4-triisopropylsilanyloxy-
2,3-dihydrobenzofuran-3-yl)-3-methyl-5,6-dihydropyran-2-one (68).
Ruthenium complex 61 (47 mg, 0.056 mmol, 5 mol %) was added to
a solution of methacrylate 67 (600 mg, 1.12 mmol) in CH2Cl2 (40 mL).
The reaction mixture was heated at reflux for 16 h and then quenched
by addition of ethyl vinyl ether. Evaporation of the solvents under
reduced pressure and purification of the residue by flash chromatog-
raphy (SiO2, petroleum ether/ether 20:1) afforded 68 (413 mg, 66%)
as a colorless oil. [R]25 +29.3° [c 0.49, CH2Cl2]. IR (film): 2946,
D
2869, 1728, 1586, 1478, 1418, 1387, 1281, 1243, 1224, 1126, 1082,
9
J. AM. CHEM. SOC. VOL. 125, NO. 43, 2003 13163

A R T I C L E S
Trost et al.
1046, 1021, 883, 831, 744, 682 cm-1. 1H NMR (400 MHz, CDCl3) δ:
7.14 (d, J ) 8.8 Hz, 1 H), 6.48-6.43 (m, 1 H), 6.25 (d, J ) 8.8 Hz,
1 H), 4.69 (dd, J ) 13.9, 4.0 Hz, 1 H), 4.53 (q, J ) 7.0 Hz, 1 H),
2.78-2.68 (m, 1 H), 1.90 (s, 3 H), 1.87-1.78 (m, 1 H), 1.67 (d, J )
7.0 Hz, 3 H), 1.66 (s, 3 H), 1.32 (sept, J ) 7.4 Hz, 3 H), 1.10 (d, J )
7.4 Hz, 9 H), 1.09 (d, J ) 7.4 Hz, 9 H). 13C NMR (100 MHz, CDCl3)
δ: 165.8, 157.9, 152.9, 139.3, 132.4, 128.0, 121.0, 112.5, 94.5, 89.1,
79.9, 51.0, 25.8, 21.8, 18.0, 17.1, 15.4, 13.3. HRMS m/z C25H37BrO4-
Si (M+). Calcd: 508.1644. Found: 508.1641. Anal. Calcd for C25H37-
BrO4Si: C, 58.93; H, 7.32. Found: C, 58.85; H, 7.44.
(2R,3R)-3-[(R)-(E)-Bis(tert-butyldimethylsilanyloxy)methylpent-
3-enyl]-7-methoxy-2,3,8-trimethyl-4-triisopropylsilanyloxy-2,3-dihy-
dronaphtho[1,2-b]furan-6,9-dione (72). n-Butyllithium (71 µL, 0.10
mmol, 1.4 M in hexanes) was added at -78 °C to a solution of aryl
bromide 70 (74.2 mg, 0.100 mmol) in THF (1 mL). After stirring for
5 min a solution of 6 (30.0 mg, 0.15 mmol) in THF (1 mL) was added
dropwise at -78 °C. After stirring for 30 min at -78 °C, the reaction
was quenched by addition of saturated aqueous NH4Cl (5 mL) and
extracted with ether (3 × 10 mL). The combined organic layers were
dried over MgSO4 and filtered. Evaporation of the solvents under
reduced pressure afforded the crude imine. The crude product was
dissolved in THF (5 mL) and a solution of oxalic acid (40 mg) in water
(2 mL) was added. The reaction mixture was stirred for 10 min before
being quenched with saturated aqueous NaHCO3 (5 mL) and extracted
with ether (3 × 10 mL). The combined organic phases were dried over
MgSO4. Evaporation of the solvents in vacuo and purification of the
residue by flash chromatography (SiO2, petroleum ether/ether 4:1)
afforded 71 (46.5 mg, 59%) as a colorless oil.
18.3, 18.1, 18.0, 15.9, 13.3, 9.2, -4.0, -4.1, -5.4, -5.5. Anal. Calcd
for C43H74O7Si3: C, 65.60; H, 9.47. Found: C, 65.31; H, 9.35.
Furaquinocin A (1). HF (48 wt % in water, 0.5 mL) was added to
a solution of 72 (32.1 mg, 0.0410 mmol) in acetonitrile (3 mL). After
stirring for 14 h at room temperature, additional HF (48 wt % in water,
0.3 mL) was added and stirring was continued for 6 h. The reaction
mixture was poured into saturated aqueous NaHCO3 and extracted with
CH2Cl2. The combined organic phases layers were dried over MgSO4
and then evaporated in vacuo. Purification of the residue by flash
chromatography (SiO2, CHCl3/MeOH 50:1) afforded 1 (11.5 mg, 70%)
as a bright yellow solid. Mp ) 181-183 °C (lit. mp 182-183 °C).
[R]25D -46.9° [c 0.36, CHCl3] (lit. [R]19D -46.7° [c 0.58, CHCl3]). IR
(film): 3402, 2924, 2850, 1668, 1636, 1582, 1433, 1408, 1433, 1408,
1297, 1278, 1198, 1168, 1111, 1026, 999, 899, 772, 732 cm-1. 1H NMR
(500 MHz, CDCl3) δ: 7.15 (s, 1 H), 5.54-5.50 (m, 1 H), 4.69 (q, J )
6.4 Hz, 1 H), 4.44 (d, J ) 11.3 Hz, 1 H), 4.01 (d, J ) 11.3 Hz, 1 H),
4.00 (s, 3 H), 3.95 (dd, J ) 9.5, 1.1 Hz, 1 H), 2.65-2.57 (m, 1 H),
2.14 (dd, J ) 15.8, 6.0 Hz, 1 H), 2.05 (s, 3 H), 1.88 (s, 3 H), 1.32 (s,
3 H), 1.31 (d, J ) 6.4 Hz, 3 H). 13C NMR (126 MHz, CDCl3) δ: 183.7,
180.8, 160.5, 158.8, 156.9, 138.1, 134.0, 133.6, 125.1, 124.8, 111.0,
108.9, 88.8, 71.2, 61.5, 60.6, 52.7, 32.5, 23.4, 18.9, 16.1, 9.3. The
analytic data match the data reported for the natural product.1d
Acknowledgment. We thank the National Science Foundation
and the National Institutes of Health (GM 33049) for their
generous support of our programs. O.R.T. thanks the Alexander-
von-Humboldt foundation for a postdoctoral fellowship. We are
grateful to A. Cole for solving the X-ray structure of 32. We
thank Susan Korenchuk, Elisabeth McAvoy, Janet Lineberger,
and Dr. Samuel Graham of Merck Research Laboratories, West
Point, for providing the biological data of analogues 49, 53,
and 57. Mass spectra were provided by the Mass Spectrometry
Facility, University of San Francisco, supported by the NIH
Division of Research Resources. The microwave experiment
was performed with a Smith Synthesizer for which we thank
Personal Chemistry.
A solution of 71 (46.5 mg, 0.0590 mmol) in toluene (2 mL) was
heated to 120 °C for 2 h. After cooling to room temperature the reaction
mixture was stirred in air for 2 h. Evaporation of the solvents in vacuo
and purification of the residue by flash chromatography (SiO2,
petroleum ether/ether 10:1) afforded 72 (37.8 mg, 81%) as a yellow
foam. [R]24 -26.2° [c 1.01, CH2Cl2]. IR (film): 2929, 2857, 1667,
D
1652, 1622, 1589, 1463, 1414, 1392, 1292, 1252, 1204, 1181, 1098,
.
1076, 1056, 1024, 882, 836, 776, 744 cm-1 1H NMR (500 MHz,
CDCl3) δ: 7.05 (s, 1 H), 4.78 (t, J ) 6.6 Hz, 1 H), 4.56 (q, J ) 7.1
Hz, 1 H), 4.08 (7, J ) 5.8 Hz, 1 H), 4.02 (s, 3 H), 3.93 (d, J ) 11.8
Hz, 1 H), 3.62 (d, J ) 11.8 Hz, 1 H), 2.40-2.33 (m, 1 H), 2.31-2.23
(m, 1 H), 2.05 (s, 3 H), 1.79 (d, J ) 7.1 Hz, 3 H), 1.53 (s, 3 H), 1.45
(s, 3 H), 1.43 (sept, J ) 7.3 Hz, 3 H), 1.18 (d, J ) 7.3 Hz, 9 H), 1.17
(d, J ) 7.3 Hz, 9 H), 0.91 (s, 9 H), 0.82 (s, 9 H), 0.09 (s, 3 H), 0.03
(s, 3 H), -0.05 (s, 3 H), -0.06 (s, 3 H). 13C NMR (126 MHz, CDCl3)
δ: 183.5, 180.7, 161.9, 157.1, 156.6, 134.8, 133.6, 133.4, 129.7, 124.5,
110.6, 109.7, 91.3, 76.8, 61.6, 60.7, 51.1, 33.3, 25.9, 25.8, 24.0, 21.1,
Supporting Information Available: Full experimental details
and characterization data for compounds 28-30, 35-41, 43,
44, 48, 49, 52, 53, 56, 57, 60, 63, 64, 67, 69, and 70. This
material is available free of charge via the Internet at http://
pubs.acs.org. Crystallographic (CIF) data for 32 can be found
in the supporting information of ref 5.
JA0364118
9
13164 J. AM. CHEM. SOC. VOL. 125, NO. 43, 2003