A simple and efficient synthesis of 3prime;-azido-3′-deoxythymidine (AZT) employing a convergent route

Article abstract of DOI:10.1055/s-2001-15234

The syn-homoallyl alcohol 2a has been prepared with absolute stereoselectivity following PDC oxidation of the mixture of diastereomers 2a, 2b and subsequent K-selectride reduction of the resulting ketone 3. Compound 2a has been efficiently utilized for a simple synthesis of AZT I in a convergent manner.

Full text of DOI:10.1055/s-2001-15234

PAPER
1337
A Simple and Efficient Synthesis of 3 -Azido-3 -deoxythymidine (AZT)
Employing a Convergent Route
Facile Synthesis
h
3
a
-deoxythy
s
midine (A
k
Z
T) ar Dhotare, Angshuman Chattopadhyay*
Bio-Organic Division, Bhabha Atomic Research Centre Mumbai-400,085, India
Received 8 February 2001; revised 27 March 2001
drugs. Regarding the convergent synthesis of I, the sugar
unit has been produced either through the exploitation of
different chirons of natural origin, e.g., D-xylose,4a,b D-
mannitol,4c 2-deoxy-D-ribose,4d L-allose,4e etc, or via
asymmetric epoxidation of olefin.5 We present here a sim-
ple and efficient synthesis of I following a convergent
route utilizing D-mannitol, albeit in a different manner
from the reported one.4c
Abstract: The syn-homoallyl alcohol 2a has been prepared with ab-
solute stereoselectivity following PDC oxidation of the mixture of
diastereomers 2a, 2b and subsequent K-selectride® reduction of the
resulting ketone 3. Compound 2a has been efficiently utilized for a
simple synthesis of AZT I in a convergent manner.
Key words: AIDS, convergent synthesis, (R)-2,3-O-cyclohexy-
lideneglyceraldehyde, K-selectride, syn selective reduction, open
chain model, flexibility
In our approach, we started with easily available (R)-2,3-
O-cyclohexylideneglyceraldehyde (1).6a Earlier, 1 on Zn
mediated allylation in the presence of water and allyl
Grignard addition produced homoallylic alcohol (2) with
a very high6b and moderate6a anti selectivity (2b), respec-
tively. Our earlier experience on the synthesis of a 3-azido
2,3-dideoxy-D-xylofuranose 96c from 2b suggested that
syn-allylation product 2a should be the right choice as the
chiral template for the synthesis of I, which has opposite
stereochemistry at C-3 compared to that of 9 (Scheme). In
this pursuit, we have accomplished the stereoselective
preparation of 2a following an indirect route. Here, the
mixture of 2a and 2b, obtained by using either of the pub-
lished procedures,6a,b was first subjected to PDC
oxidation7 and the resulting ketone 3 was then reduced
with K-selectride®. To our great delight, the reduction
took place with absolute (> 99%) syn selectivity to pro-
duce 2a in 77% combined yield (oxidation/reduction
steps). The diastereomeric purity of 2a was clearly evi-
Acquired immunodeficiency syndrome (AIDS) was first
recognized as a disease in early 1980s. For the last two de-
cades, AIDS has become the most dangerous epidemic
creating an unprecedented panic all over the world. The
pandemic spread of this disease has drawn significant at-
tention from synthetic chemists, working in collaboration
with biologists, to make efforts to combat it. Subsequent-
ly, the discovery that several 2’,3’-dideoxynucleosides are
potentially effective therapeutic agents for the treatment
of AIDS patients has triggered considerable attention in
designing and synthesizing a variety of nucleoside ana-
logs.1 These nucleosides inhibit the growth of human im-
muno-deficiency virus (HIV) and act as prodrugs, which
need to be triphosphorylated at the 5’-hydroxy group in
vivo by cellular enzymes in order to be effective inhibitors
of HIV-encoded enzyme HIV-1 Reverse Tran-
scriptase.1a,b,2,3 Among the nucleosidic drugs for AIDS, zi-
dovudine (AZT, I) and subsequently zalcitabine (DDC),
didanosine (DDI), stavunine (D4T), lamividine (3TC) and
abacavir have been approved by United States Food and
Drug Administration (FDA).3 However, at present I is the
most frequently used drug for the polytherapeutic treat-
ment of AIDS patients. Hence, in view of its immense po-
tential, I is considered to be an important target molecule
for synthesis.
1
dent from TLC, and the H NMR spectrum of the crude
product. The latter showed a spectral pattern [comprising
of only a triplet (J = 6.5 Hz, 1H) at = 2.24 ppm and three
distinct multiplets at = 3.5–3.6 (1H), 3.7–3.8 (1H) and
3.9–4.1 (2H)], which was identical with that of pure 2a.6a
Moreover, 2b could not be isolated at all following col-
umn chromatography of the crude residue of this reduc-
tion product.
So far, several syntheses of I have been reported in the lit-
erature employing both convergent1a–d,4,5a,b and divergent
(from thymidine)5c–e strategies. However, the convergent
synthesis of any nucleoside drug has an inherent advan-
tage since it is possible to carry out a desired modification
of the sugar unit prior to its combination with base. This
in turn is likely to give an opportunity for gaining an en-
hanced knowledge of the structure-activity relationship of
the resulting analogs that may be developed into new
Hence, a very simple protocol for the preparation of a ver-
satile functionalized alcohol 2a in homochiral form has
been developed by us, to add to our earlier success in the
highly stereoselective preparation of 2b. Our method
comprising allylation,6a,b oxidation, and reduction should
have some practical relevance as all these reactions are
reasonably good yielding and operationally simple. Inci-
dentally, our earlier efforts to prepare 2a via copper medi-
ated syn selective allylation of 1 following a reported
procedure8a were met with disappointing results. More-
over, our approach provides better syn selectivity for the
preparation of 2a than that reported by Roush et al8b
(90%), who employed addition of a chiral allyboronate to
Synthesis 2001, No. 9, 29 06 2001. Article Identifier:
1437-210X,E;2001,0,09,1337,1340,ftx,en;Z02101SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

1338
B. Dhotare, A. Chattopadhyay
PAPER
Scheme Reagents and conditions: i) PDC, CH2Cl2; ii) K-Selectride, THF, –78°C; iii) p-TsCl–Py; iv) CF3COOH–H2O; v) PhCOCN–Et3N,
0°C, CH2Cl2; vii) MeOH–p-TsOH; viii) NaN3–DMF, heat; ix) Thymine, TMS triflate, BSA, CH3CN; x) NH3, MeOH
the corresponding isopropylidene derivative of 1. Further- meric position of furanoside 6 was not attempted in view
more, K-selectride reduction in this case gives better syn of the fact that the introduction of the nucleobase at a later
selectivity compared to that reported by Dondoni et al8c,d stage would go via the formation of oxonium ion interme-
(95%). Interestingly, in a recent report, K-selectride re- diate.1a-d SN2 displacement of the tosyloxy group of 6 by
duction of a 2,3-epoxyketone yielded the anti-alcohol as azide afforded the erythro-furanoside 7 after inversion of
the major product.8e The high syn selectivity of the K-se- stereochemistry at C-3. The coupling of thymine base
lectride reduction of 2a corroborates nicely with the open- with 7 was effected to produce a reasonably good yield of
chain model9 that is favored due to the presence of bulky 8 as a mixture of anomers ( and ), which could not be
cyclohexylidene protecting group at the - and
-
separated by column chromatography. Finally, debenzoy-
hydroxyls of the carbonyl. Presumably, the contribu- lation (NH3, MeOH) of the anomeric mixture of 8 afford-
tion of -chelated transition state involving the carbonyl ed AZT I and its -anomer II, which could be separated
and the -oxygen, that should be responsible for anti se- easily by column chromatography (0–5% MeOH in
lective reduction,9c is not favored here due to the presence CHCl3). The spectral and optical data of both I and II are
of the bulky sec-butyl groups of K-selectride and cyclo- well in conformity with the reported ones.4a The isolated
hexylidene moiety.
yields of I and II suggested that the stereoselectivity of the
base coupling of 7 under the present conditions was al-
most 1:1 (Scheme).
Compound 2a was tosylated and then deacetalized (aque-
ous CF3COOH) to yield the diol 4 in almost quantitative
yield (Scheme). Regioselective monobenzoylation at Thus, a facile and straightforward synthesis of I has been
1-OH of 4 afforded 5, which was successively subjected developed in a convergent manner. The efficacy of our
to ozonolysis and PPh3 reduction in the same pot. The re- strategy lies on the absolute stereoselective preparation of
action mixture was concentrated by solvent removal un- 2a, the high stability and easy availability of 1 that has
der reduced pressure and the resulting furanose residue, many operational advantages compared to the corre-
without being further purified, was directly ketalized by sponding isopropylidene derivative, which is used com-
treatment with acidified MeOH to afford threo-furanoside monly. Additionally, it has an inherent advantage of
6, which was isolated from the residue in pure form by attaining stereochemical flexibility at C-3' of AZT
column chromatography. Compound 6 consisted of al- through individual exploitation of both 2a and 2b that can
1
most one anomer ( or ) as evident from its H NMR now be prepared in good yield and with very high selec-
spectrum which showed two prominent singlets at tivity under separate conditions. Admittedly, like all pre-
= 2.35 ppm (due to tosylate Me) and at = 3.34 (due to viously reported convergent syntheses4,5a,b of AZT, the
-OMe). The assignment of the stereochemistry of the ano- selectivity of base coupling could not be achieved due to
Synthesis 2001, No. 9, 1337–1340 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Facile Synthesis of 3 -Azido-3 -deoxythymidine (AZT)
1339
(2R,3R)-1-Benzoyloxy-3-tosyloxy-5-hexen-2-ol ( 5)
the absence of any substituent at C-2 of 7, however this
has been overcome by the easy separation of I and II by
column chromatography. In addition, it is quite logical
that application of our strategy with the easily available
(S)-110 will produce another series of stereochemical ana-
logs of I.
To a cooled (0°C) solution of 4 (1.43 g, 5 mmol) and Et3N (0.3 mL,
2 mmol) in CH2Cl2 (40 mL) was added dropwise a solution of ben-
zoyl cyanide (0.6 mL, 5.1 mmol) in CH2Cl2 (10 mL) over 30 min.
The mixture was stirred for an additional hour at 0°C and treated
with H2O. The organic layer was separated and washed with H2O,
and brine. Solvent removal followed by column chromatography of
the residue (silica gel, 0–20% EtOAc in petroleum ether) afforded
the monobenzoate 5 (1.64 g, 83.9%).
IR spectra were recorded on a Perkin Elmer spectrophotometer
model 837. The NMR spectra were scanned with a Brucker Ac-200
(200 MHz) instrument in CDCl3. The optical rotations were mea-
sured with a Jasco DIP-360 polarimeter. Chemicals used as starting
materials are commercially available and were used without further
purification, unless otherwise mentioned. The organic extracts were
desiccated over Na2SO4.
[ ]D22 +18.09 (c 5.9, CHCl3).
IR (film): = 3500, 3069, 3032, 1721, 1642, 1363, 1175, 995, 927
cm–1.
1H NMR (CDCl3): = 1.64 (br s, D2O exchangeable, 1H), 2.39 (s,
3H), 2.4–2.7 (m, 2H), 3.7–4.1 (m, 1H), 4.2–4.6 (m, 2H), 4.75 (m,
1H), 5.0–5.2 (m, 2H), 5.5–5.7 (m, 1H), 7.3–8.2 (m, 9H).
(2R)-2,3-Cyclohexylidene-hex-5-en-3-one (3)
Anal. Calcd for C20H22O6S: C, 61.52; H, 5.68. Found: C, 61.78; H,
5.42.
To a suspension of PDC (17 g, 0.045 mol) in CH2Cl2 (100 mL) con-
taining pyridinium trifluoroacetate (2.3 g, 0.012 mol) was added a
solution of a mixture of 2a and 2b (6.36 g, 0.03 mol) in CH2Cl2 (50
mL). The mixture was stirred for 36 h, filtered, and washed thor-
oughly with CH2Cl2. The filtrate was concentrated under reduced
pressure and the residue was chromatographed (silica gel, 0–10%
EtOAc in hexane) to yield pure 3 (5.1g, 80.9%).
[ ]D22 + 37.95 (c 2.7, CHCl3).
IR (film): = 3005, 1710, 1650, 995, 920 cm–1.
1H NMR (CDCl3): = 1.4–1.6 (m, 10H), 3.3–3.5 (m, 2H), 3.9–4.05
(m, 1H), 4.1–4.3 (m, 1H), 4.5 (dd, J = 7.7, 5.5 Hz, 1H), 5.0–5.2 (m,
2H), 5.7–6.0 (m, 1H).
Methyl 5-O-Benzoyl-3-O-tosyl-2-deoxy-D-xylofuranoside (6)
To a stirred and cooled (–78°C) solution of 5 (1.56 g, 4 mmol) in
CH2Cl2 (100 mL), O3 was bubbled through until a blue colour per-
sisted. The excess O3 was removed by flushing with Ar, and PPh3
(1.1 g, 4.15 mmol) was added to the mixture. The blue color disap-
peared immediately. The solution was brought to r.t., stirred over-
night, and concentrated under reduced pressure. The residue
containing furanose was dissolved in MeOH (50 mL) containing
p-toluenesulphonic acid (100 mg). The solution was stirred at r.t.
for 5 h, neutralized by the addition of NaHCO3, and concentrated
under reduced pressure. The residue was chromatographed (silica
gel, 0–25% EtOAc in petroleum ether) to afford 6 (1.37 g, 84.4%)
as a colorless oil. The tosylate is prone to become colored on long
standing probably due to decomposition and hence was immediate-
ly used for the next reaction.
[ ]D22 +19.54 (c 1.77, CHCl3).
IR (film): = 3064, 3050, 3045, 1723, 1599, 1366, 1177 cm–1.
1H NMR (CDCl3): = 2.1–2.5 (m, 2H, H-2), 2.35 (s, 3H), 3.34 (s,
3H, -OMe), 4.3–4.6 (m, 4H, H-3, H-4, H-5), 5.1–5.3 (m, 1H, H-1),
7.3–8.0 (m, 9H).
(2R,3R)-2,3-Cyclohexylidene-hex-5-en-3-ol (2a)
To a stirred solution of (4) (2.5 g, 0.012 mol) in THF (70 mL) at
–78°C was added a 1 M solution of K-selectride (24 mL, 0.024 mol)
over 30 min. The mixture was stirred at –78°C for 2 h more, brought
gradually to r.t., and treated successively with H2O and EtOAc. The
organic layer was separated and the aqueous layer was thoroughly
extracted with EtOAc. The combined organic layer was washed
with brine, dried, and concentrated under reduced pressure. The
crude residue, showing only 2a (TLC and 1H NMR), was chromato-
graphed through a short silica gel column (5–20% EtOAc in hex-
ane) to give 2a (2.4 g, 95%). The spectral and optical data were
identical with those reported.6a
Anal. Calcd for C20H22 O7S: C, 59.10; H, 5.45. Found: C, 59.35; H,
5.27.
Methyl 5-O-Benzoyl-3-azido-2,3-dideoxy-D-ribofuranoside (7)
Compound 6 (1 g, 2.5 mmol) was heated in DMF (30 mL) with an
excess of NaN3 (325 mg, 5 mmol) at 80°C for 6 h. The solvent was
removed in vacuo. The crude product was dissolved in anhyd Et2O
from which the insoluble salt was filtered off. Solvent removal and
column chromatography of the residue (silica gel, 0–20% Et2O in
petroleum ether) furnished 7 (475 mg, 68.3%) as clear oil.
(2R,3R)-3-Tosyloxy-5-hexene-1,2-diol (4)
To an ice cooled solution of 2a (4.24 g, 0.02 mol) in pyridine (30
mL) was added p-toluenesulphonyl chloride (4.2 g, 0.022 mol). The
mixture was stirred overnight at r.t., treated with H2O and extracted
with Et2O. The organic extract was washed with dilute HCl, H2O,
brine, and dried. Solvent removal under reduced pressure afforded
the corresponding tosylate in almost quantitative yield. This was
mixed with 90% aq trifluoroacetic acid (20 mL), stirred for 5 h at
0°C, and diluted with H2O. The mixture was extracted with CHCl3.
The combined organic extracts was washed with H2O to remove ac-
id, then with brine, and dried. Solvent removal and chromatography
of the residue (silica gel, 0–5% MeOH in CHCl3) afforded pure 4
(5.6 g, 95%).
[ ]D22 +124.3 (c 5.6, CHCl3).
1
IR (film): = 3065, 2104, 1723, 1605 cm .
1H NMR (CDCl3): = 2.0–2.5 (m, 2H, H-2), 3.4 (s, 3H,-OMe), 3.9–
4.05 (m, 1H, H-4), 4.2–4.35 (m, 1H, H-3), 4.4–4.5 (m, 2H, H-5),
5.1–5.2 (m, 1H, H-1), 7.4–8.1 (m, 5H). Anal. Calcd for C13H15N3O4:
C, 56.31; H, 5.45; N, 15.15. Found: C, 56.55; H, 5.23; N, 15.41.
[ ]D22 +5.91 (c 3.6, CHCl3).
IR (film): = 3500, 3075, 3005, 1365, 1178, 1096, 990, 910 cm–1.
1-[5-O-Benzoyl-3-azido-2,3-dideoxy- , -D-erythro-pento-
furanosyl]-thymine (8)
1H NMR (CDCl3): = 2.02 (br s, D2O exchangeable, 2H), 2.2–2.7
(m, 2H), 2.45 (s, 3H), 3.6–3.9 (m, 3H), 4.6–4.8 (m, 1H), 5.0–5.2 (m,
2H), 5.5–5.7 (m, 1H), 7.34 (d, J = 8.0 Hz, 2H), 7.78 (d, J = 8.0 Hz,
2H).
To a stirred suspension of 7 (388 mg, 1.4 mmol) and thymine (530
mg, 4.2 mmol) in anhyd CH3CN (40 mL) was drop-wise added
bis(trimethylsilylacetamide) (2.2 mL, 8.7 mmol) at r.t. under Ar.
The mixture was stirred for 3 h and cooled to 30°C. Trimethylsilyl
trifluoromethanesulphonate (1 mL, 5.6 mmol) was added to the
mixture, which was stirred for 7 d at r.t. and then diluted with
Anal. Calcd for C13H18O5S: C, 54.53; H, 6.33. Found: C, 54.77; H,
6.57.
Synthesis 2001, No. 9, 1337–1340 ISSN 0039-7881 © Thieme Stuttgart · New York

1340
B. Dhotare, A. Chattopadhyay
PAPER
CH2Cl2. The organic layer was washed with sat. NaHCO3, H2O,
brine, and dried. After removal of the solvent under reduced pres-
sure, the residue was loaded onto a short silica gel column and elut-
ed with 0–5% MeOH in CHCl3 to obtain 8 (326 mg, 62.8%) as an
inseparable mixture of - and -anomers. This was used as such for
the next step.
[ ]D22 +39.9 (c 1.4, CHCl3).
IR (film): = 3335, 2107, 1732–1690 cm–1.
References
(1) (a) Huryn, D. M.; Okabe, M. Chem. Rev. 1992, 92, 1745; and
references cited therein. (b) Dueholm, K. L.; Pedersen, E. B.
Synthesis 1992, 1; and references cited therein.
(c) Lipshutz, B. H.; Hayawaka, H.; Kato, K.; Lowe, R. F.
Synthesis 1994, 1476; and references cited therein.
(d) Wilson, L. J.; Hager, M. W.; El-Kattan, Y. A.; Liotta, D.
C. Synthesis 1995, 1465; and references cited therein.
(e) Jung, M. E.; Nichols, C. J. J. Org. Chem. 1998, 63, 347.
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Matsuda, A. J. Org. Chem. 1998, 63, 746. (g) Sorensen, M.
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1H NMR (CDCl3): = 1.95 (s, 3H), 2.2–2.9 (m, 2H, H-2'), 4.2 4.7
(m, 4H, H-3', H-4', H-5'), 6.17 (t, J = 6.2 Hz) and 6.26 (dd, J = 6.1
Hz, 3.2 Hz) (total 1H, H-1), 7.2–8.0 (m, 6H), 8.2 (br s, 1H).
3’-Azido-3’-deoxythymidine(I) and 1-(3-Azido-2,3-dideoxy-a-D-
erythro-pentofuranosyl)-thymine (II)
A solution of 8 (326 mg, 0.88mmol) in sat. methanolic ammonia (30
mL) was stirred for 18 h at r.t. The solvent was removed under re-
duced pressure and the residue was chromatographed (silica gel, 0–
5% MeOH in CHCl3) to afford I and II.
Compound I:
Yield: 97 mg, 38.8%; Rf = 0.53 (EtOAc); mp 120–122°C.
[ ]D22 +59.5 (c 0.91, MeOH).
IR (CHCl3): = 2107, 1750–1600 cm–1.
UV (MeOH): max = 264 nm.
1H NMR (CDCl3): 1.92 (s, 3H), 2.42 (m, 1H), 2.52 (m, 1H), 3.81
(dd, J = 11.8, 2.3 Hz, 1H), 3.95–3.98 (m, 1H), 4.00–4.04 (m, 1H),
4.38–4.41 (m, 1H), 6.05 (t, J = 6.4 Hz, 1H), 7.37 (s, 1H), 8.53 (br s,
1H).
Compound II:
Yield: 95 mg, 37.7%; Rf = 0.42 (EtOAc); mp 70–72°C.
[ ]D22 +37.5 (c 0.99, MeOH).
IR (CHCl3): = 2107, 1750–1600 cm–1.
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UV (MeOH): max = 267 nm.
1H NMR (CDCl3): 1.95 (s, 3H), 2.12–2.21 (m, 1H), 2.82–2.90 (m,
1H), 3.68–3.72 (m, 1H), 3.81–3.86 (m, 1H), 4.29 (m, 2H), 6.26 (dd,
J = 7.7, 4.3 Hz, 1H), 7.31 (s, 1H), 8.77 (br s, 1H).
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Synthesis 2001, No. 9, 1337–1340 ISSN 0039-7881 © Thieme Stuttgart · New York