A facile three-component one-pot synthesis of structurally constrained tetrahydrofurans that are t-RNA synthetase inhibitor analogues

Article abstract of DOI:10.1021/jo0497508

A one-pot procedure for the efficient synthesis of tRNA inhibitor analogues was developed. Thus, three-component 1,3-dipolar cycloaddition reactions of carbonyl ylides derived from diazoindan-1,3-dione and aldehydes with other dipolarophiles in 1,1,2,2-tetrachloroethane in 80 °C gave ring-fused tetrahydrofurans having three stereocenters in good yield.

Full text of DOI:10.1021/jo0497508

SCHEME 1
A F a cile Th r ee-Com p on en t On e-P ot
Syn th esis of Str u ctu r a lly Con str a in ed
Tetr a h yd r ofu r a n s Th a t Ar e t-RNA
Syn th eta se In h ibitor An a logu es
Chong-Dao Lu, Zhi-Yong Chen, Hui Liu,
Wen-Hao Hu,* and Ai-Qiao Mi
Key Laboratory for Asymmetric Synthesis and
Chirotechnology of Sichuan Province, Chengdu Institute of
Organic Chemistry, Chinese Academy of Sciences,
Chengdu 610041, China
Michael P. Doyle*
conditions to make the intermolecular carbonyl-ylide
cycloaddition as a dominant pathway.
Department of Chemistry and Biochemistry, University of
Maryland, College Park, Maryland 20742
Ring-fused tetrahydrofurans 1 inhibit the enzymatic
activity of transfer ribonucleic acid (tRNA) synthetase
and are useful as antimicrobial agents.6 Their amide
hydrolysis products were also used for potential treat-
ment of papilloma virus (PV) infection, particularly
human papilloma virus (HPV).7a cis-cis-1 (R ) 4-ClPh,
R′ ) piperonyl) was the only lead out of 140 000 com-
pounds screened for HPV inhibitors.7b The reported
protocol for the synthesis of 1 involved multiple steps
(condensation of indan-1, 3-dione with aldehyde, epoxi-
dation, and then thermal 1,3-dipolar cycloaddition)
(Scheme 1),7b,8 and poor overall yields in some cases have
limited this synthetic approach. For example, when
cinnamaldehyde and N-4-acetophenylmaleimide were
used, only 4% overall yield of product (1: R ) trans-
PhCHdCH, R′ ) p-MeCOPh) was obtained (first step
with 11% yield and 38% overall yield of second and third
steps).8
Synthetically, metal-catalyzed three-component car-
bonyl ylide formation/cycloaddition reaction of 2-diazoin-
dan-1,3-dione with aldehydes and maleimides could
afford 1 in a one-pot process (Scheme 2). Unfortunately,
previous studies toward this objective were frustrating.
For example, dirhodium(II)-catalyzed diazo decomposi-
tion of 2 with piperonal (3d ) and N-piperonylmaleimide
(4e) in refluxing benzene gave the corresponding product
1 in only 8% yield,7 and other examples from our
laboratory gave a similar outcome. In this paper, we
report our efforts to modify reaction conditions to opti-
mize this convenient three-component 1,3-dipolar pro-
cess.
huwh@cioc.ac.cn; mdoyle3@umd.edu
Received February 11, 2004
Abstr a ct: A one-pot procedure for the efficient synthesis
of tRNA inhibitor analogues was developed. Thus, three-
component 1,3-dipolar cycloaddition reactions of carbonyl
ylides derived from diazoindan-1,3-dione and aldehydes with
other dipolarophiles in 1,1,2,2-tetrachloroethane in 80 °C
gave ring-fused tetrahydrofurans having three stereocenters
in good yield.
The synthesis of highly substituted tetrahydrofurans,
which are found in many biologically interesting natural
products, has attracted considerable attention in recent
years.1 Tandem carbonyl ylide/1,3-dipolar cycloaddition,
especially via intramolecular reactions, is a powerful
strategy for the construction of tetrahydrofurans,2 and
they have been applied broadly in the syntheses of
natural products. In contrast, the utility of comparable
intermolecular reactions has received limited attention.
Pioneering studies initiated by Huisgen established a
methodology for tetrahydrofuran synthesis through 1,3-
dipolar cycloaddition of carbonyl ylides derived from diazo
compounds and aromatic aldehydes with an electron-
deficient alkene.3 There are only a few diazo compounds
that have been successfully employed in this three-
component intermolecular process to give 1,3-dipolar
addition products in good yield.4 Since several reaction
pathways may be involved to compete with the desired
process (e.g., cycloaddition of carbonyl ylide give to a
dioxolane5), we set out to explore and refine the reaction
(4) (a) Alt, M.; Maas, G. Tetrahedron 1994, 50, 7435. (b) Doyle, M.
P.; Forbes, D. C.; Protopopova, M. N.; Stanley, S. A.; Vasbinder, M.
M.; Xavier, K. R. J . Org. Chem. 1997, 62, 7210. (c) Wenkert, E.,
Khatuya, H. Tetrahedron lett. 1999, 40, 5439. (d) Hamaguchi, M.;
Matsubara, H.; Nagai, T. J . Org. Chem. 2001, 66, 5395. (e) J ohnson,
T.; Cheshire, D. R.; Stocks, M. J .; Thurston, V. T. Synlett 2001, 646.
(f) Skaggs, A. J .; Lin, E. Y.; J amison, T. F. Org. Lett. 2002, 4, 2277. (g)
Nair, V.; Mathai, S.; Varma, R. L.; J . Org. Chem. 2004, 69, 1413.
(5) Huisgen, R.; de March, P. J . Am. Chem. Soc. 1982, 104, 4952.
(6) Finn, J .; Yu, X. Y.; Wang, Z. G.; Hill, J .; Keith, D.; Gallant, P.;
Wendler, P. PCT Int. Appl. WO 0018772, 2000; Chem. Abstr. 2000,
132, 251137.
(7) (a) Yoakim, C.; Hache, B.; Ogilvie, W.; O’Meara, J . A.; White, P.
W.; Goudreau, N. PCT Int. Appl. WO 0250082, 2002; Chem. Abstr.
2002, 137, 63181. (b) Yoakim, C.; Ogilvie, W. W.; Goudreau, N.; Naud,
J .; Hache´, B.; O′Meara, J . A.; Cordingley, M. G.; Archambault, J .;
White, P. W. Bioorg. Med. Chem. Lett. 2003, 13, 2539.
(1) Reviews: (a) Greve, S.; Reck, S.; Friedrichsen, W. Prog. Hetercycl.
Chem. 1998, 10, 129. (b) Elliott, M. C.; Williams, E. J . Chem. Soc.,
Perkin Trans. 1 2001, 2303.
(2) Reviews: (a) 1,3-Dipolar Cycloaddition Chemistry; Padwa, A.,
Ed.; Wiley-Interscience: New York, 1984. (b) Doyle, M. P. Chem. Rev.
1986, 86, 919. (c) Padwa, A.; Hornbuckle, S. F. Chem. Rev. 1991, 91,
263. (d) Doyle, M. P.; Forbes, D. C. Chem. Rev. 1998, 98, 911. (e) Doyle,
M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods for Organic
Synthesis with Diazo Compounds; Wiley & Sons: New York, 1998. (f)
Padwa, A.; Pearson, W. H. The Chemistry of Heterocyclic Compounds;
Wiley & Sons: New York, 2002; Chapter 4. (g) Mehta, G.; Muthusamy,
S. Tetrahedron 2002, 58, 9477. (h) Hodgson, D. M.; Pierad, F. Y. T.
M.; Stupple, P. A. Chem. Soc. Rev. 2001, 30, 50.
(8) Krysin, M. Yu.; Anokhina, I. K.; Zalukaev, L. P. Khim. Geterotsikl.
Soedin. 1987, 11, 1463.
(3) Huisgen, R.; de March, P. J . Am. Chem. Soc. 1982, 104, 4953.
10.1021/jo0497508 CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/11/2004
4856
J . Org. Chem. 2004, 69, 4856-4859

SCHEME 2
SCHEME 4
SCHEME 3
in toluene revealed that aromatic substitution9 occurred
to give 7 and 8 together with a three-component side
product 9 (Scheme 3). However, solvent was found to
have a pronounced effect on the reaction. With 1,2-
dichloroethane product yield was increased from less
than 5% to 35% to give diastereomers 5a and 6a favoring
endo selectivity (5a /6a ) 79:21). We were pleased to find
that an even higher yield (60%, 5a /6a ) 79:21) could be
obtained by using 1,1,2,2-tetrachloroethane, also at 80
°C. Addition of molecular sieves 4 Å powder10 in 1,1,2,2-
tetrachloroethane gave the best result 78% yield (5a /6a
) 79:21). Detailed results are summarized in Table 1.
Compounds 5a and 6a were reported as potent tRNA
synthetase inhibitors with IC50 in 0.6 and 0.004 µM,
respectively.6
TABLE 1. Rea ction of Dia zoin d a n -1,3-d ion e (2) w ith
Ben za ld eh yd e (3a ) a n d N-3,4-Dich lor op h en ylm a leim id e
(4a ) in Differ en t Rea ction Con d ition sa
In addition to dirhodium acetate, copper catalysts were
also employed in this reaction, but they were less efficient
than the rhodium catalyst. For example, the reaction
proceeded slowly with CuOTf or Cu(OTf)2 even at el-
evated reaction temperature (120 °C), and a complex
mixture of products was observed. This system was not
examined further.
With optimum reaction conditions in hand, various
aldehydes and maleimides were explored to demonstrate
the generality of the reaction (Scheme 4). Product yields
were good in this three-component reaction, and the
results are summarized in Table 2. The electronic effects
of substituents of Scheme 4, both N-arylmaleimides and
aromatic aldehydes, on the diastereoseletivity and the
product yields were insignificant in this reaction (entries
3, 4 and 7, 8). Satisfactory yields were obtained in most
entries. Extension of applicability from aromatic alde-
hydes to cinnamaldehyde also resulted in ylide-derived
tetrahydrofuran products in moderate yields (entries 11
and 12). For example, treatment of diazoindan-1,3-dione
with cinnamaldehyde and N-4-acetophenylmaleimide
resulted in the desired product, formed in 53% yield. This
is encouraging in contrast to the reported three-step
approach (condensation, epoxidation, and thermal 1,3-
Rh2(OAc)4 time 4 Å yieldb endo/exoc
entry
solvent
(mol %)
(h)
MS
(%)
(5a /6a )
1
2
3
4
5
(CH2Cl)2
(CHCl2)2
(CHCl2)2
(CH2Cl)2
(CHCl2)2
2
2
1
1
1
1.0
1.0
2.0
2.0
2.0
no
no
no
yes
yes
35
60
61
43
78
79:21
71:29
72:28
79:21
72:28
a
b
2/3a /4a )1:4:4 mmol at 80 °C. Isolated yield of 5a and 6a
diastereomers. c The ratios of two diastereomers were determined
by crude 1H NMR.
Initially, we thought a higher temperature might
improve product yields. Reexamination of this reaction
in refluxing toluene instead of benzene, however, did not
enhance earlier results. The reaction of 2, benzaldehyde
(3a ), and N-3,4-dichlorophenylmaleimide (4a ) catalyzed
by 2 mol % Rh2(OAc)4 in refluxing toluene afforded
desired product (5a + 6a ) in less than 5% yield. Exami-
nation of the side reaction from the reaction performed
(9) Rosenfeld, M. J .; Ravi Shankar, B. K.; Shecheter, H. J . Org.
Chem. 1988, 53, 2699.
(10) Suga, H.; Kakehi, A.; Ito, S.; Inoue, K.; Ishida, H.; Ibata, T.
Org. Lett. 2000, 2, 3145.
J . Org. Chem, Vol. 69, No. 14, 2004 4857

SCHEME 5
dipolar cycloaddition). The ratios of endo/exo were con-
sistent in favoring endo selectivity. Finally, the structures
and configurations of the two diastereomers were ascer-
tained by single-crystal X-ray analyses of 5a and 6b.
To further explore the generality of this reaction, other
dipolarophiles such as DMAD (10) and dimethyl fuma-
rate (11) were employed. These reactions underwent
cycloaddition smoothly to give 12 and 13/14 in moderate
yields; the relative stereochemistry of 13/14 was deter-
mined by ref 3 (Scheme 5).
TABLE 2. Ca ta lytic 1,3-Dip ola r Cycloa d d ition of
Dia zoin d a n -1,3-d ion e(2) w ith Va r iou s Ar om a tic
Ald eh yd es a n d Ma leim id esa
The overall process can be considered to proceed via
an initial formation of 1,3-dipolar intermediates from the
diazo compound and aldehydes. These intermediates are
further trapped by dipolarophiles such as N-arylmale-
imide to give the corresponding tetrahydrofuran deriva-
tives favoring the endo diastereoisomer. The reason for
the formation of the predominant endo isomer is unclear
at present, but may result from secondary orbital overlap
in the transition state for cycloaddition between aromatic
substituent of aldehyde and dipolarophile11 (Scheme 6).
The solvent has a profound effect on this intermolecu-
lar three-component 1,3-dipolar reaction. To obtain a
better understanding of the predominant formation of the
three-component side product 9 in toluene, aromatic
substitution products 7 and 8 were isolated as a mixture,
and the mixture was treated with maleimide 4a in
refluxing toluene (Scheme 7). Compound 9 was formed
from the reaction of 4a and 8, and a similar product
derived from the reaction of 4a and 7 was not observed.
The structure of 9 was further confirmed by its single-
crystal X-ray structure. Compound 9 was formed by
initial aromatic substitution yielding 8 followed by
Michael addition to maleimide 4a .
A similar outcome was found in the reaction between
2 and 4e using benzene as solvent. Repeating the reaction
in refluxing benzene, it was found that electrophilic
substitution to benzene occurred similarly to give major
side products 15 and three-component side product 16
(Scheme 8). Due to the competitive reaction with solvent
(benzene and toluene), the desired tetrahydrofuran prod-
uct derived from the three-component 1,3-dipolar reaction
was obtained only in very low yield.7 Padwa has also
reported a number of examples of competitive electro-
philic substitution with other diazo compounds.12
a
Reactions were carried out in 15 mL of (CHCl2)2 at 80 °C in
the presence of 1 mol % Rh2(OAc)4 and1.0 g of 4 Å MS for 2 h
(11) For diastereoselectivity controlled by secondary π-orbital in-
teractions, see: Tomohiko Ohwada, T. Chem. Rev. 1999, 99, 1337.
b
with 2/3/4 ) 1:4:4. Same as Table 1. c Same as Table 1.
4858 J . Org. Chem., Vol. 69, No. 14, 2004

SCHEME 6
method. By varying the substituents on aromatic alde-
hydes and dipolarphiles, structurally constrained tet-
rahydrofuran analogues were synthesized.
Exp er im en ta l Section
Rep r esen ta tive P r oced u r e: Com p ou n d s 5a a n d 6a . A
mixture of 2-diazo-1,3-indandione 2 (0.172 g, 1.0 mmol), benz-
aldehyde (4.0 mmol), N-3,4-dichlorophenylmaleimide (4.0 mmol),
Rh2(OAc)4 (4.4 mg, 0.01 mmol), and 1.0 g molecular sieves 4 Å
in 15 mL of (CHCl2)2 was stirred at 80 °C for ∼2-3 h under
argon atmosphere. The reaction mixture was filtered through
Celite, the filtrate was evaporated under reduced pressure, and
the residue was subjected to column chromatography on silica
gel (petroleum ether/ethyl acetate ) 4:1-2:1) to give product
5a and 6a . The product ratio was determined by NMR spectral
analysis of the crude reaction mixture.
(3R,3aR,6aS)-Spir o[1H-fu r o[3,4-c]pyr r ole-1,2′-[2H]in den e]-
1′,3′4,6(3H,5H)-tetr on e, 5-(3,4-d ich lor op h en yl)-3a ,6a -d ih y-
d r o-3-p h en yl (5a ): mp 194-196 °C; 1H NMR (300 MHz, CDCl3)
δ 8.16-8.09 (m, 2 H), 8.03-7.99 (m, 2 H), 7.52 (d, J ) 8.4 Hz, 1
H), 7.47 (d, J ) 2.4 Hz, 1 H), 7.45-7.35 (m, 5 H), 7.24 (dd, J )
8.4, 2.4 Hz, 1 H), 6.15 (d, J ) 7.5 Hz, 1 H), 4.08 (dd, J ) 8.1, 7.5
Hz, 1 H), 3.84 (d, J ) 8.1 Hz, 1 H); 13C NMR (75 MHz, CDCl3)
δ 197.9, 193.9, 172.5, 171.4, 141.5 (overlap, 2C), 139.4, 137.3,
137.2, 134.6, 132.9, 130.7, 130.4, 128.8, 128.4, 128.2, 126.1, 125.6,
124.4, 124.3, 84.4, 83.4, 51.5, 51.2; HRMS calcd for C26H15Cl2-
NO5 491.0327, found 491.0314 [M + H]+; the X-ray structure of
5a confirms the product structure.
SCHEME 7
(3R,3aS,6aR)-Spir o[1H-fu r o[3,4-c]pyr r ole-1,2′-[2H]in den e]-
1′,3′4,6(3H,5H)-tetr on e,5-(3,4-d ich lor op h en yl)-3a ,6a -d ih y-
d r o-3-p h en yl (6a ): mp 185-187 °C; 1H NMR (300 MHz, CDCl3)
δ 8.15-8.04 (m, 2 H), 8.01-7.97 (m, 2 H), 7.59 (d, J ) 8.4 Hz, 1
H), 7.58-7.56 (m, 2 H), 7.46-7.37 (m, 3 H), 7.24 (dd, J ) 8.4,
2.4 Hz, 1 H), 5.85 (d, J ) 6.9 Hz, 1 H), 4.21 (d, J ) 10.2 Hz, 1
H), 3.89 (dd, J ) 10.2, 6.9 Hz, 1 H); 13C NMR (75 MHz, CDCl3)
δ 190.8, 194.0, 173.5, 172.6, 141.4, 141.0, 138.2, 137.24, 137.22,
133.4, 133.3, 130.9, 130.6, 128.9, 128.8, 128.7, 125.98, 125.95,
124.6, 124.3, 85.0, 83.1, 55.2, 51.0; HRMS calcd for C26H15Cl2-
NO5 491.0327, found 491.0333 [M + NH4]+.
SCHEME 8
Ack n ow led gm en t. We are grateful for financial
support from the Chinese Academy of Sciences and the
National Science Foundation of China (Grant No.
20202011). M.P.D. thanks the National Science Foun-
dation and National Institutes of Health for their
support. We thank Prof. Kai-Bei Yu of Chengdu Insti-
tute of Organic Chemistry for X-ray measurements.
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal procedure; 1H NMR and 13C NMR spectra for 4a ,c-f,h ,
5a -l, 6a -l, 9, 12, 13, 14, and 16; crude 1H NMR spectra of
5a + 6a ; and X-ray crystal data for compound 5a , 6b, and 9
(CIF). This material is available free of charge via the Internet
at http://pubs.acs.org.
J O0497508
In summary, we have optimized a one-pot reaction for
the synthesis of ring-fused tetrahydrofurans through
intermolecular 1,3-dipolar cycloaddition derived from
diazoindan-1,3-dione. Reported tRNA synthetase inhibi-
tors such as 5a and 6a were prepared according to this
(12) (a) Padwa, A.; Wisnieff, T. J .; Walsh, E. J . J . Org. Chem. 1989,
54, 299. (b) Padwa, A.; Austin, D. J .; Hornbuckle, S. F.; Semones, M.
A.; Doyle, M. P.; Protopopova, M. N. J . Am. Chem. Soc. 1992, 114,
1874. (c) Padwa, A.; Austin, D. J .; Price, A. T.; Semones, M. A.; Doyle,
M. P.; Protopopova, M. N.; Winchester, W. R. J . Am. Chem. Soc. 1993,
115, 8669.
J . Org. Chem, Vol. 69, No. 14, 2004 4859