Carbohydrate-based routes to salicylate natural products: Formal total synthesis of (+)-apicularen A from D-glucal

Article abstract of DOI:10.1016/S0040-4039(01)01038-3

A synthesis of apicularen analogue (-)-4 in 18 steps from D-glucal is reported. As (+)-4 has been converted into apicularen A in 8 steps, this constitutes a formal total synthesis of this potent naturally occurring anti-cancer agent.

Full text of DOI:10.1016/S0040-4039(01)01038-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5549–5552
Carbohydrate-based routes to salicylate natural products:
formal total synthesis of (+)-apicularen A from -glucal
D
Arwel Lewis,a Ian Stefanuti,a Simon A. Swain,a Stephen A. Smithb and Richard J. K. Taylora,*
aDepartment of Chemistry, University of York, Heslington, York YO10 5DD, UK
bGlaxoSmithKline, New Frontiers Science Park, Harlow, Essex CM19 5AW, UK
Received 28 May 2001; accepted 13 June 2001
Abstract—A synthesis of apicularen analogue (−)-4 in 18 steps from
D-glucal is reported. As (+)-4 has been converted into
apicularen A in 8 steps, this constitutes a formal total synthesis of this potent naturally occurring anti-cancer agent. © 2001
Elsevier Science Ltd. All rights reserved.
(−)-Apicularen A 1 and (−)-apicularen B 2 are recently
discovered1 members of the rapidly growing family of
salicylate anti-tumour natural products. Other members
of this family of macrolides include the salicylihala-
mides discovered in 1997,2 the lobatamides,3 CJ-
12,950,4 and the oximidines (e.g. Oximidine I 3),5 all of
which exhibit high levels of biological activity, notably
towards tumour cells.
correlation with the profile of any other anti-tumour
compound, thus indicating a novel mode of action. As
a result, interest in the total synthesis of this novel class
of compounds,6 their analogues7 and unique enamide
side chains8 has flourished.
The first total synthesis of (−)-apicularen A, in which
the tetrahydropyran unit was constructed via hetero-
Diels–Alder chemistry, was recently published by De
Brabander et al.6a,7a Allyl-substituted macrolide (+)-4
was a key intermediate in this route, side chain elabora-
tion (eight steps, 4% overall yield) completing the natu-
ral product synthesis. This Letter reports the synthesis
of (−)-4 via an alternative carbohydrate-based route,
and thus constitutes a formal total synthesis of (+)-apic-
ularen A.
Jansen et al. reported very high cytostatic activity for
apicularen A against nine different human cancer cell
lines, including the multi-drug resistant line KB-V1
(IC50 values ranging between 0.3 and 3 ng/ml), and the
induction of several abnormal effects in tumour cells.1
In addition, in the 60 cell line tumour screen at the
NCI, apicularen A (in common with the salicylihala-
mides and the lobatamides) exhibited no significant
* Corresponding author. E-mail: rjkt1@york.ac.uk
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01038-3

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A. Lewis et al. / Tetrahedron Letters 42 (2001) 5549–5552
Our approach to the apicularen nucleus is shown in
retrosynthetic form in Fig. 1. We envisaged the use of
-glucal 5 as a chiral building block for the construc-
tion of the key apicularen precursor 6. Pyran 6 is
doubly electrophilic and initial cross-coupling with a
protected salicylic acid synthon 7 to provide the 9-(aryl-
methyl)tetrahydropyran 8 followed by elaboration of
the anomeric position would furnish hydroxy-acid 9.
Macrolactonisation of 9 should lead to the required
12-membered macrocycle (−)-4.
The completion of the synthesis of (−)-4 is shown in
Scheme 2. Initial studies were carried out to introduce
the 9-aryl-substituent using functionalised Grignard
reagents 7.12 Unfortunately, success in model studies
could not be repeated for the conversion of 13 into
adducts related to 16. After extensive study, Kotsuki’s
benzofuryl Grignard reagent 1413 was found to be the
most effective salicylate equivalent for triflate displace-
ment, providing reasonable yields of coupled product
15. Adduct 15 was oxidatively cleaved with ozone to
give aldehyde 16, and further oxidation, deprotection
and methylation provided methyl ester 17. Lewis acid-
mediated allylation of the anomeric methyl acetal was
carried out using allyltrimethylsilane to give an excel-
lent yield of a single stereoisomer, presumed to be the
a-C-glycoside.14 A significant amount of TPS group
cleavage was evident during this process, and the resul-
tant secondary alcohol could not be reprotected using
TPSCl. Therefore, complete removal of the TPS group
was carried out using fluoride and then treatment with
the more reactive silylating agent TBSOTf provided the
TBS ether 18 in good yield. Ozonolysis of 18 gave
aldehyde 19 which underwent reagent-controlled allyla-
D
The crucial triflate 6 required for the organometallic
coupling step was prepared from
D
-glucal 5 in a four-
step process (Scheme 1). Sequential derivatisation of
each hydroxyl in a one-pot procedure gave (thiocar-
bonyl)imidazolide 10, which underwent Bu3SnH-medi-
ated deoxygenation9 to give dihydropyran 11 in good
yield.10 Acid-catalysed addition of methanol across the
enol ether,11 together with concomitant deprotection of
the primary silyloxy group, was effected using
triphenylphosphine hydrobromide giving alcohol 12.
Reaction of 12 with triflic anhydride in the presence of
pyridine gave the unstable triflate 13, which was used
immediately after chromatographic purification.
Figure 1.
Scheme 1. Reagents and conditions: (a) imidazole, TBSCl, then imidazole, TPSCl, then (Im)2CS (65%); (b) Bu3SnH, AIBN,
toluene, D (85%); (c) Ph3P·HBr, MeOH, CH2Cl2, 0°C, 16 h (65%); (d) Tf2O, pyridine, CH2Cl2, −12°C, 10 min (96%).

A. Lewis et al. / Tetrahedron Letters 42 (2001) 5549–5552
5551
Scheme 2. Reagents and conditions: (a) 0.1 equiv. CuBr, THF, 0°C, 14 h (59%); (b) i. O3, CH2Cl2, −78°C, ii. PPh3, −78°C to rt,
2 h (68%); (c) H2O2, NaClO2, NaHSO3, NaH2PO4, H2O, MeCN, 3 h; (d) K2CO3, MeOH, 0.5 h; (e) MeI, K2CO3, acetone, D, 24
h (75%, three steps); (f) TMSOTf, allyltrimethylsilane, MeCN, −78°C; (g) TBAF, THF, 16 h; (h) TBSOTf, 2,6-lutidine, CH2Cl2,
0°C (81%, three steps); (i) i. O3, CH2Cl2, −78°C, ii. Ph3P, −78°C to rt, 3 h (98%); (j) (−)-B-allyl-b-(diisopinocampheyl)borane,
Et2O, −78°C (60%); (k) LiI, pyridine, D, 24 h (55%; 88% based on r.s.m.); (l) DCC, DMAP, DMAP·HCl, CHCl3, D (30%); (m)
9-iodo-9-BBN, CH2Cl2, 0°C, 2 h (70%); (n) TBSOTf, 2,6-lutidine, CH2Cl2, 0°C (80%).
tion using Brown’s diisopinocampheyl(allyl)borane15 to
supply an inseparable 90:10 mixture of diastereomeric
alcohols. The structure of the major isomer 20 was
assigned by literature precedent15 and by Mosher ester
studies16 on the mixture of 20 and its C-15 stereoiso-
mer. Lithium iodide-induced ester cleavage allowed
access to hydroxy-acid 21 in good yield.
(+)-apicularen A. We are currently optimising the route
described herein and extending it to other members of
the salicylate natural product family.
Acknowledgements
We thank the BBSRC and GlaxoSmithKline for a
CASE studentship (I.S.) and Elsevier Science for finan-
cial support (A.L. and S.A.S.).
Macrolactonisation of 21 was successful utilising
Keck’s protocol17 and gave a separable mixture of
12-membered lactone 22 in 30% yield {[h]D=−6.3 (c
0.5, CHCl3); mp 149–150°C} together with a trace of its
C-15 epimer. Deprotection of 22 using 9-iodo-9-BBN18
gave phenol 23, which was fully characterised and
shown to have comparable analytical/spectroscopic
data to that reported by De Brabander et al. {[h]D=
−4.5 (c 0.15, MeOH); lit. [h]D for enantiomer =+6.8 (c
0.16, MeOH)}.7a,19 Finally, silylation of both hydroxyl
groups provided the bis-TBS ether (−)-4 {[h]D=−19.7
(c 0.10, CHCl3)}.
References
1. (a) Jansen, R.; Kunze, B.; Sasse, F.; Reichenbach, H.;
Ho¨fle, G. Drugs from Natural Products Conference,
Dublin, 1998; (b) Jansen, R.; Kunze, B.; Reichenbach,
H.; Ho¨fle, G. Eur. J. Org. Chem. 2000, 913–919. The
structure of (−)-apicularen in the original publication1a
was subsequently revised to the enantiomeric form.1b
2. (a) Erickson, K. L.; Beutler, J. A.; Cardellina, II, J. H.;
Boyd, M. R. J. Org. Chem. 1997, 62, 8188–8192; (b)
Erickson, K. L.; Beutler, J. A.; Cardellina, II, J. H.;
Boyd, M. R. J. Org. Chem. 2001, 66, 1532.
The enantiomeric compound (+)-4 has been converted
into (−)-apicularen in eight steps (4% overall yield) by a
published procedure.6a The synthetic studies in this
Letter therefore constitute a formal total synthesis of

5552
A. Lewis et al. / Tetrahedron Letters 42 (2001) 5549–5552
12. Rottla¨nder, M.; Boymond, L.; Cahiez, G.; Knochel, P. J.
3. McKee, T. C.; Galinis, D. L.; Pannell, L. K.; Cardellina,
Org. Chem. 1999, 64, 1080–1081.
13. Kotsuki, H.; Araki, T.; Miyazaki, A.; Iwasaki, M.; Datta,
P. K. Org. Lett. 1999, 1, 499–502.
14. Gaertzen, O.; Misske, A. M.; Wolbers, P.; Hoffmann, H.
M. R. Tetrahedron Lett. 1999, 40, 6359–6363.
II, J. H.; Lakkso, J.; Ireland, C. M.; Murray, L.; Capon,
R. J.; Boyd, M. R. J. Org. Chem. 1998, 63, 7805–7810.
4. Dekker, K. A.; Aiello, R. J.; Hirai, H.; Inagaki, T.;
Sakakibara, T.; Suzuki, Y.; Thompson, J. F.; Yamauchi,
Y.; Kojima, N. J. Antibiot. 1998, 51, 14–20.
15. Jadhav, P. K.; Bhat, K. S.; Perumal, P. T.; Brown, H. C.
5. Kim, J. W.; Shin-ya, K.; Furihata, K.; Hayakawa, Y.;
Seto, H. J. Org. Chem. 1999, 64, 153–155.
J. Org. Chem. 1986, 51, 432–439.
16. Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J.
Am. Chem. Soc. 1991, 113, 4092–4096.
17. Boden, E. P.; Keck, G. E. J. Org. Chem. 1985, 50,
2394–2395.
18. Fu¨rstner, A.; Seidel, G. J. Org. Chem. 1997, 62, 2332–
2336.
6. (a) Bhattacharjee, A.; Seguil, O. R.; De Brabander, J. K.
Tetrahedron Lett. 2001, 42, 1217–1220; (b) Labrecque,
D.; Charron, S.; Rej, R.; Blais, C.; Lamothe, S. Tetra-
hedron Lett. 2001, 42, 2645–2648; (c) Wu, Y.; Esser, L.;
De Brabander, J. K. Angew. Chem., Int. Ed. 2000, 39,
4308–4310.
19. Compound (−)-23: Found (CI): 319.15453. C18H22O5
requires [MH+], 319.15455 (0.1 ppm error); wmax/cm−1
(thin film) 3262, 2924, 1716, 1583, 1464, 1294; m/z (CI)
319 [MH+, 100%], 301 (70), 283 (20), 162 (20), 134 (25);
1H NMR (500 MHz, acetone-D6) l 8.39 (1H, s, 3-OH),
7.11 (1H, dd, J 8.0, 7.7 Hz, H5), 6.77 (1H, d, J 8.0 Hz,
H4), 6.69 (1H, d, J 7.7 Hz, H6), 5.92 (1H, dddd, J 6.4,
7.6, 10.2, 17.2 Hz, H17), 5.48 (1H, dddd, J 2.4, 5.6, 5.6,
10.0 Hz, H15), 5.13 (1H, dddd, J 1.6, 1.6, 2.4, 17.2 Hz,
H18), 5.03 (1 H, dddd, J 1.6, 1.6, 2.4, 10.2 Hz, H18%),
4.24–4.30 (1H, m, H13), 3.96–4.03 (1H, m, H11), 3.85–
3.91 (1H, m, H9), 3.77–3.81 (1H, m, 11-OH), 3.34 (1H,
dd, J 9.8, 15.0 Hz, H8), 2.44 (1H, dd, J 1.0, 15.0 Hz,
H8%), 2.30–2.41 (2H, m, H16/16%), 1.93 (1H, ddd, J 4.5,
4.5, 12.7 Hz, H10), 1.77–1.86 (1 H, m, H14), 1.40–1.71
(4H, m, H10%, H14%, H12/12%); 13C NMR (125 MHz,
acetone-D6); l 169.2, 154.3, 140.2, 135.3, 130.3, 125.5,
122.3, 117.5, 114.4, 73.7, 73.6, 68.1, 64.9, 40.4, 40.1, 40.0,
39.7, 39.1. The 13C NMR data for this compound differ
slightly from those published for (+)-23.7a However, Pro-
fessor De Brabander has subsequently amended the pub-
lished data and there is now an extremely good
correlation (personal communication, May 2001).
7. (a) Bhattacharjee, A.; De Brabander, J. K. Tetrahedron
Lett. 2000, 41, 8069–8073; (b) Georg, G. I.; Ahn, Y. M.;
Blackman, B.; Farokhi, F.; Flaherty, P. T.; Mossman, C.
J.; Roy, S.; Yang, K. Chem. Commun. 2001, 255–256; (c)
Fu¨rstner, A.; Thiel, O. R.; Blanda, G. Org. Lett. 2000, 2,
3731–3734; (d) Wu, Y.; Seguil, O. R.; De Brabander, J.
K. Org. Lett. 2000, 2, 4241–4244; (e) Feutrill, J. T.;
Holloway, G. A.; Hilli, F.; Hu¨gel, H. M.; Rizzacasa, M.
A. Tetrahedron Lett. 2000, 41, 8569–8572.
8. (a) Snider, B. B.; Song, F. Org. Lett. 2000, 2, 407–408; (b)
Stefanuti, I.; Smith, S. A.; Taylor, R. J. K. Tetrahedron
Lett. 2000, 41, 3735–3738; (c) Raw, S. A.; Taylor, R. J.
K. Tetrahedron Lett. 2000, 41, 10357–10361; (d)
Kuramochi, K.; Watanabe, H.; Kitahara, T. Synlett
2000, 397–399; (e) Shen, R.; Porco, Jr., J. A. Org. Lett.
2000, 2, 1333–1336.
9. Rasmussen, J. R.; Slinger, C. J.; Kordish, R. J.; New-
man-Evans, D. D. J. Org. Chem. 1981, 46, 4843–4846.
10. All new compounds were fully characterised by high field
NMR spectroscopy and HRMS.
11. Bolitt, V.; Mioskowski, C. J. Org. Chem. 1990, 55, 5812–
5813.
.