New methodology for 2-alkylation of 3-furoic acids: Application to the synthesis of tethered UC-781/d4T bifunctional HIV reverse-transcriptase inhibitors

Article abstract of DOI:10.1016/j.tetlet.2005.04.034

New methodology for 2-alkylation of 3-furoic acids is presented involving Wittig reactions of the 3-methoxycarbonyl-2-furanylmethylphosphonium salt. The methodology has been used to prepare a tethered 2-alkylated-UC-781/d4T conjugate as a potentially new type of HIV reverse-transcriptase inhibitor.

Full text of DOI:10.1016/j.tetlet.2005.04.034

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4023–4026
New methodology for 2-alkylation of 3-furoic acids:
application to the synthesis of tethered UC-781/d4T bifunctional
HIV reverse-transcriptase inhibitors
Gareth Arnott, Roger Hunter,* Linda Mbeki and Ebrahim Mohamed
Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa
Received 24 February 2005;accepted 7 April 2005
Abstract—New methodology for 2-alkylation of 3-furoic acids is presented involving Wittig reactions of the 3-methoxycarbonyl-2-
furanylmethylphosphonium salt. The methodology has been used to prepare a tethered 2-alkylated-UC-781/d4T conjugate as a
potentially new type of HIV reverse-transcriptase inhibitor.
ꢀ 2005 Elsevier Ltd. All rights reserved.
2,3-Disubstituted furans constitute a widely encountered
sub-unit in a range of natural and synthetic products.
2-Alkylation of 3-furoic acids has been a commonly
employed strategy for entry1 into this sub-unit with two
carbanionic methodologies standing out as versatile
options. Knight was the first person to demonstrate2 that
treatment of 3-furoic acid with 2 equiv of LDA (THF/
ꢀ78 ꢁC) regioselectively furnishes the dianion 1 (Fig.
1), which can be alkylated with a range of reactive elec-
trophiles. However, with less reactive electrophiles, for
example, ethyl iodide, yields were low. Keay and
co-workers subsequently3 demonstrated that 2-methyl-
3-furoic acid reacts with 2 equiv of n-BuLi at ꢀ20 ꢁC
to furnish the 2-lithiomethyl dianion 2 which is more sta-
ble than 1, giving higher yields with less reactive electro-
philes. Development of 2 followed pioneering work by
Tada et al.4 on use of the 2-dianion of 2,4-dimethyl-3-
furoic acid 3 in natural product synthesis (Fig. 1).
As part of a programme to synthesise novel, bifunc-
tional HIV reverse-transcriptase inhibitors, we needed
access to quantities of 2-alkylated-3-furoates in conjunc-
tion with incorporation of the non-nucleoside inhibitor
UC-7815 into a bifunctional inhibitor. In view of the
unattractive prospect of using large quantities of n-
BuLi, we embarked on a study to identify an alternative,
which we successfully report in this communication. It
occurred to us that Wittig methodology based on the
3-methoxycarbonyl-2-furanylmethylphosphonium salt
might provide the answer in view of the option of using
a mild base to generate the stabilised ylide. Although 2-
furanylmethylphosphonium salts6 have been known and
used in synthesis for some time, the corresponding
3-furoates are hitherto unknown. To this end, radical
bromination of commercially available methyl 2-methyl-
furoate using conditions recently reported by Khatuya7
furnished methyl 2-bromomethyl furoate in high yield,
which, following evaporation of the solvent and addi-
tion of triphenylphosphine in toluene furnished (rt,
overnight) the desired and novel triphenylphosphonium
salt 4 by filtration. Isolation of product involved no
chromatography, with a single crystallisation from
methanol returning analytically pure material in 80%
overall yield.
O
O
O
OLi
Li
OLi
Li
OLi
Li
O
O
O
1
3
2
Knight
Ketay
Tada
Figure 1.
Keywords: Furan alkylation;Wittig reaction of 2-furanylphosphonium
salt;Alkylated-UC-781;Bifunctional HIV reverse-transcriptase
inhibitors.
Pleasingly, reaction of 4 in methanol with sodium meth-
oxide as base (5 M in MeOH;1.1 equiv) at rt followed
by addition of hexanal (1.2 equiv) as a model aldehyde
*
Corresponding author. Tel.: +27 021 650 2544;fax: +27 021 689
7499;e-mail: roger@science.uct.ac.za
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.04.034

4024
G. Arnott et al. / Tetrahedron Letters 46 (2005) 4023–4026
O
O
O
OMe
OMe
OMe
(i), (ii)
(iii), (iv)
C5H11
O
O
O
+PPh3
Br-
6
4
Scheme 1. Reagents and conditions: (i) NBS, (BzO)2 (cat), CCl4, D;(ii) PPh 3, toluene, rt (80% over two steps);(iii) NaOMe (1.1 equiv), MeOH,
C5H11CHO (92%);(iv) H 2, Pd–C, EtOH (80%).
Table 1. Wittig olefination and hydrogenation of 4 with various
aldehydes
O
O
S
R of RCHO
% Yield of 5
% Yield of 6
(a) H
(b) CH3
92
90
92
91
80
61
80
84
N
H
Cl
H2NCl
(c) C5H11
(d) C4H9OBn
O
UC-781
9
Figure 2.
resulted in rapid transformation to the Wittig product 5
in high yield as a mixture (ꢁ1:1) of E/Z stereoisomers.
Carrying the reaction out in THF using sodium hydride
as base gave a significantly lower yield (ꢁ50%) of the
Wittig product in a higher E/Z ratio. Subsequent hydro-
genation (H2/Pd–C) gave the anticipated 2-alkylated
product 6 in high yield (80%). A small percentage
(ꢁ10%) of the 4,5-dihydro-2-alkylated product8 was
also obtained, which could be minimised by varying
the reaction conditions, but not completely eliminated
(Scheme 1).
To this end, hydrogenolysis of 6d to alcohol 7 followed
by tosylation and substitution with propargyloxy anion
furnished the propynyl ether 8. Interestingly, the substi-
tution proceeded more cleanly this way round, that is,
was superior than propargylation of the alkoxide of 7
with propargyl bromide. Subsequent base-mediated
ester hydrolysis, conversion to the acid chloride with
thionyl chloride followed by substitution with substi-
tuted aniline 910 (Fig. 2) furnished amide 10 in high
overall yield from the acid. Finally, thiation of amide
10 with LawessonÕs reagent11 produced the C-2 elon-
gated UC-781 derivative 1112 for biological probing13
of substituent effects in the HIV reverse-transcriptase
pocket (Scheme 3).
A range of aldehydes appropriate to producing alkyl-
ated side chains were subjected to the olefination/hydro-
genation sequence and the results are presented in Table
1. Yields cited are relevant to reactions carried out in
1–10 mmol range. Reactions involving formaldehyde,
ethanal and 5-benzyloxypentanal9 all underwent smooth
Wittig reactions in high yield as with the model reaction
and, where appropriate, similarly to products with
about an equal E/Z isomer ratio. Subsequent hydro-
genation of each one gave a small percentage of the
4,5-dihydro derivative as in the hexanal case, which
could be separated from the desired alkylated product
by careful silica-gel column chromatography. Hydro-
genation of alkene 5d resulted in concomitant hydrogen-
olysis of the benzyl ether (Scheme 2).
Alkyne 10 was also subjected to a Sonogashira14 reac-
tion with the nucleoside reverse-transcriptase inhibitor
derivative, 50-O-benzoyl-5-iodo-d4T,15 to afford conju-
gate 1216 following benzoyl group deprotection. Conju-
gate 12 involves a combination of the two antiretroviral
drugs d4T and UC-781, albeit with the amide of UC-781
unthiated. Significant interest has been shown recently
in conjugates17 of this type, in view of the fact that the
nucleotide substrate binding-site is proximal to the
non-nucleoside binding pocket. Compound 12 is the first
example of a UC-781-derived conjugate (unthiated) as a
result of developing this methodology. Further work on
thiation is in progress to produce UC-781 analogues
(Scheme 4).
As part of a programme on the synthesis of new HIV
reverse-transcriptase inhibitors, we were able to demon-
strate applicability of the methodology to two new C-2
variants of the potent thiocarboxanilide non-nucleoside
HIV reverse-transcriptase inhibitor, UC-7815 (Fig. 2).
In summary, new methodology applicable to medium to
large-scale work has been developed for C-2 alkylation
O
O
O
OMe
OMe
OMe
(i)
(ii)
R
O
R
O
O
Br- +PPh3
4
5
6
Scheme 2. Reagents: (i) NaOMe, MeOH, RCHO;(ii) H 2, Pd–C, EtOH.

G. Arnott et al. / Tetrahedron Letters 46 (2005) 4023–4026
4025
O
S
O
8'
O
3'
7'
1'
2'
3
N
H
Cl
OMe
OMe
(iii) - (vi)
(i), (ii)
5
(CH2)5
(CH2)5
O
O
O
1"
(CH2)5
OH
O
1
6"
O
11
7
8
9"
Scheme 3. Reagents and conditions: (i) p-TsCl, NEt3, CH2Cl2, DMAP (cat) (97%);(ii) propargyl alcohol (10 equiv), NaH (10 equiv), THF, D;(iii)
KOH, EtOH, (85%, two steps);(iv) SOCl 2, D;(v) RNH 2, Py, (99%, two steps to give amide 10);(vi) Lawesson Õs reagent, NaHCO3, toluene, D (70%).
Cl
30
29
O
O
O
24
O
O
26
H
13
10
N 23
N
7
20
N
Cl
(i), (ii)
O
H
8
6
O
H
HO
9
N
1
22
O
18
(CH2)5
O
O
5
O
10
12
Scheme 4. Reagents and conditions: (i) 50-benzoyl-5-iodo-d4T, Pd(PPh3)4 (10%), CuI (50%), NEt3 (2 equiv), DMF–THF (1:2), rt (65%);(ii) NaOMe,
MeOH, rt (52%).
Donohoe, T. J.;Raoof, A.;Freestone, G. C.;Linney, I.
D.;Cowley, A.;Helliwell, M. Org. Lett. 2002, 4, 3059–
3062.
of 3-furoates of interest to both natural product synthe-
sis and medicinal chemistry.
9. Prepared from 1,5-pentanediol via the sequence: (a) NaH,
BnBr, THF, D (63%);(ii) Swern oxidation (99%).
10. Prepared from 2-amino-5-nitrophenol via the following
sequence: (i) (a) aq NaNO2, HCl, NH2SO3H (cat);(b)
CuCl (69%);(ii) K 2CO3, 4-bromo-2-methyl-2-butene, 2-
butanone, rt (94%);(iii) Fe, HCl, EtOH, D (82%).
11. Jesberger, M.;Davis, T. P.;Barner, L. Synthesis 2003, 13,
1929–1958.
References and notes
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12. Data for compound 11 (see numbering in Scheme 3): mmax
/
cmꢀ1 (CHCl3): 3234m (N–H, thioamide), 2858s (C–H,
aliphatic), 2270s (C@C, alkyne), 1618s (C@C, aromatic),
1389s+1162s (C@S stretches); 1H NMR (400 MHz, C6D6):
dH 1.24–1.46 (8H, m, H-200, 300, 400, 500), 1.45+1.51 (6H,
2 · s, H-100, 110), 2.02 (1H, t, J 2.4 Hz, H-900), 3.00 (2H, t,
J 7.6 Hz, H-100), 3.28 (2H, t, J 6.4 Hz, H-600), 3.83 (2H, d, J
2.4 Hz, H-700), 4.41 (2H, d, J 6.1 Hz, H-80), 5.47 (1H, tt, J
6.1, 1.4 Hz, H-90), 6.13 (1H, d, J 1.2 Hz, H-4), 6.38 (1H, d,
J 7.3 Hz, H-70), 6.82 (1H, d, J 7.6 Hz, H-60), 7.15 (1H, d, J
1.2 Hz, H-5), 7.98 (1H, s, NH), 8.17 (1H, s, H-30); 13C
NMR (75 MHz, C6D6): dC 17.9 (CH3), 25.5 (CH2), 25.9
0
(CH3), 27.9 (C-100+CH2), 29.1+29.5 (CH2 s), 57.8 (C-700),
66.1 (C-80), 69.8 (C-600), 73.9 (C-900), 80.5 (C-800), 106.1 (C-
30), 108.1 (C-4), 109.4 (C-70), 115.7 (C-3), 119.7 (C-50),
120.6 (C-90), 130.1 (C-5+C-60), 138.2 (C-20), 138.7 (C-120),
141.1 (C-2), 154.8 (C-40), 160.0 (C-10);HRMS: m/z (rel
int.) 459.16343 [M+] (9). Calculated for C25H30O3NSCl:
459.16349 [M+].
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4026
G. Arnott et al. / Tetrahedron Letters 46 (2005) 4023–4026
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16. Data for compound 12 (see numbering in Scheme 4):
[a]D ꢀ15.7 (c 1.03, CHCl3); mmax/cmꢀ1 (CHCl3): 3592br
(O–H, free), 2932s (C–H, aliphatic), 2254s (C@C, alkyne),
1720s (C@O, ester), 1693s (C@O, amide), 1599s (N–H and
C–N stretching), 1514s+1492s (C@C, aromatic); 1H NMR
(400 MHz, CDCl3): dH 1.24–1.33 (8H, m, H-14, 15, 16,
17), 1.73–1.79 (6H, 2 · s, H-33, 34), 2.70 (1H, s,
–OH), 3.03 (2H, t, J 7.6 Hz, H-18), 3.46 (2H, t, J 6.8 Hz,
H-13), 3.78 (1H, d, J 12.4 Hz, H-1), 3.88 (1H, d, J 12.4 Hz,
H-1), 4.21 (2H, s, H-12), 4.59 (2H, d, J 6.7 Hz, H-30), 4.91
(1H, s, H-2), 5.51 (1H, tt, J 6.7, 1.4 Hz, H-31), 5.83 (1H,
dt, J 5.9, 1.9 Hz, H-3), 6.32 (1H, dt, J 5.9, 1.6 Hz, H-4),
6.56 (1H, d, JAB 2.2 Hz, H-21), 6.96 (2H, m, H-5,29), 7.26
(1H, m, H-28), 7.30 (1H, d, JAB 2.2 Hz, H-22), 7.53 (1H, s,
H-9), 7.74 (1H, s, NH), 8.05 (1H, s, H-25), 8.23 (1H, s,
H-6); 13C NMR (75 MHz, CDCl3): dC 18.3, 25.6, 25.8,
27.2, 27.7, 28.7, 29.2, 58.7, 63.0, 66.2, 70.2, 76.8 · 2, 87.6,
89.9, 90.3, 99.5, 106.4, 108.2, 112.7, 115.6, 119.1, 125.9,
129.9, 134.9, 137.7, 138.6, 140.6, 144.4, 149.7, 149.7, 154.5,
161.8, 162.2.
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