Figure 3. Synthesis of key pyrrologlycal intermediate 10 from
D-thymidine and pyrrole dicarboxaldehyde 9.
Figure 2. Retrosynthetic analysis of acortatarins A and B
(original structures) via key pyrrologlycal intermediates 1.
intermediates 1 would originate from coupling of appro-
priate pyrroles 2 with ribal derivative 3, accessed via
nucleobase elimination of thymidine.11 At the outset of
our studies, the revised structures of the acortatarins had
not been reported but, recognizing that both enantiomers
of thymidine are commercially available, initial work was
carried out with the less expensive, natural D-congener.
Thus, TIPS-protected12 ribal 611 underwent C1-formy-
lation13 and reduction to provide hydroxymethyl ribal 7,
which was then converted to iodide 8 (Figure 3).14 The
pyrrole dicarboxaldehyde 915,16 was then coupled under
biphasic conditions17 to afford the key pyrrologlycal 10.
analysis of its pyranose congener pollenopyrroside A (not
shown).2
Subsequently, Sudhakar reported the first total synthe-
ses of acortatarins A and B from 2-deoxy-D-ribose and
D-arabinose, respectively, leading to structural revisions of
both absolute configurations as well as the relative config-
uration of acortatarin B (Figure 1).5 Thus, acortatarin A
and pollenopyrroside B are now recognized to be identical.
A second synthesis of acortatarin A from D-mannitol was
also reported recently by Brimble.6 These reports provide
the first synthetic access to the acortatarins, but their
practical utility is limited by low overall yields and reliance
upon classical acid-catalyzed spiroketalization reactions
that afford low or even undesired diastereoselectivity.7
Our laboratory has a long-standing interest in the
stereocontrolled synthesis of spiroketals from glycals,8ꢀ10
and we envisioned that both acortatarins A and B could be
synthesized by spirocyclizations of glycals 1 (Figure 2).
Direct spirocyclization would provide acortatarin A while
epoxidationꢀspirocyclization would lead to acortatarin B.
In the latter case, we recognized that the oxidation state of
the pyrrole substituents would be important for enabling
chemoselective epoxidation of the glycal. These key
(9) For selected early studies on the synthesis of spiroketals from
cyclic enol ethers, see: (a) Knabe, J.; Schaller, K. Arch. Pharm. 1968, 301,
457–464. (b) Clark-Lewis, J. W.; McGarry, E. J. Aust. J. Chem. 1975, 28,
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J. Org. Chem. 1983, 48, 3865–3866. (e) Amouroux, R. Heterocycles 1984,
22, 1489–1492. (f) Iwata, C.; Hattori, K.; Uchida, S.; Imanishi, T.
Tetrahedron Lett. 1984, 25, 2995–2998. (g) Cremins, P. J.; Wallace,
T. W. J. Chem. Soc., Chem. Commun. 1986, 1602–1603. (h) Bernet, B.;
Bishop, P. M.; Caron, M.; Kawamata, T.; Roy, B. L.; Ruest, L.; Soucy,
P.; Deslongchamps, P. Can. J. Chem. 1985, 63, 2814–2818. (i) Yeates, C.;
Street, S. D. A.; Kocienski, P.; Campbell, S. F. J. Chem. Soc., Chem.
Commun. 1985, 1388–1389. (j) Diez-Martin, D.; Grice, P.; Kolb, H. C.;
Ley, S. V.; Madin, A. Tetrahedron Lett. 1990, 31, 3445–3448. (k) Kurth,
M. J.; Olmstead, M. M.; Rodriguez, M. J. J. Org. Chem. 1990, 55, 283–
288. (l) Friesen, R. W.; Sturino, C. F. J. Org. Chem. 1990, 55, 5808–5810.
(m) Dubois, E.; Beau, J. M. Tetrahedron Lett. 1990, 31, 5165–5168.
(n) Jeong, J. U.; Fuchs, P. L. J. Am. Chem. Soc. 1994, 116, 773–774.
(o) Boyce, R. S.; Kennedy, R. M. Tetrahedron Lett. 1994, 35, 5133–5136.
(p) Holson, E. B.; Roush, W. R. Org. Lett. 2002, 4, 3719–3722.
(10) For asymmetric variants, see: (a) Uchiyama, M.; Oka, M.;
Harai, S.; Ohta, A. Tetrahedron Lett. 2001, 42, 1931–1934. (b) Coric,
I.; List, B. Nature 2012, 483, 315–319. (c) Sun, Z.; Winschel, G. A.;
Borovika, A.; Nagorny, P. J. Am. Chem. Soc. 2012, 134, 8074–8077.
(11) Cameron, M. A.; Cush, S. B.; Hammer, R. P. J. Org. Chem.
1997, 62, 9065–9069.
(5) Sudhakar, G.; Kadam, V. D.; Bayya, S.; Pranitha, G.; Jagadeesh, B.
Org. Lett. 2011, 13, 5452–5455.
(6) Geng, H. M.; Chen, J. L.-Y.; Furkert, D. P.; Jiang, S.; Brimble,
M. A. Synlett 2012, 23, 855–858.
(7) Reference 5 provides acortatarin A in 3.7% over 10 steps, with the
key spirocyclization proceeding in 1.4:1 diastereoselectivity; accounting
for epimerization of both anomers in a subsequent step to a 9:1 mixture
favoring the desired diastereomer, the overall yield increases to 6.4%.
Acortatarin B is accessed in 0.9% yield over 10 steps, with the key
spirocyclization proceeding in 1:4.6 unfavorable diastereoselectivity.
Reference 6 provides acortatarin A in 1.7% yield over 13 steps, with
the key spirocyclization proceeding in 1.5:1 diastereoselectivity.
(8) (a) Potuzak, J. S.; Moilanen, S. B.; Tan, D. S. J. Am. Chem. Soc.
2005, 127, 13796–13797. (b) Moilanen, S. B.; Potuzak, J. S.; Tan, D. S.
J. Am. Chem. Soc. 2006, 128, 1792–1793. (c) Liu, G.; Wurst, J. M.; Tan,
D. S. Org. Lett. 2009, 11, 3670–3673. (d) Wurst, J. M.; Liu, G.; Tan, D. S.
J. Am. Chem. Soc. 2011, 133, 7916–7925.
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(13) Paquette, L. A.; Schulze, M. M.; Bolin, D. G. J. Org. Chem.
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(14) Gallier, F.; Hussain, H.; Martel, A.; Kirschning, A.; Dujardin, G.
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(15) Muchowski, J. M.; Hess, P. Tetrahedron Lett. 1988, 29, 777–780.
(16) See Supporting Information for full details.
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