PPTS gave the Boc-protected amino alcohol 22 in 75% yield
over two steps. The free primary alcohol 22 was capped with
a TBDPS group followed by a Dibal-H reduction of the ester
intermediate to afford allyl alcohol 23 in 81% yield over
two steps.
18 with 6-n-butyl-4-bromo-2-pyrone 2419 was pursued to give
amino pyrone 25 in 61% yield. Deacylation and Ley-
Griffith’s oxidation20 provided enal 26 in 85% yield over
two steps.
With the annulation precursor enal 26 in hand, the key
intramolecular aza-[3 + 3] annulation was found to proceed
smoothly in toluene with 0.5 equiv of piperidinium acetate
as the catalyst for vinyliminium ion formation. After the
mixtre was heated at 150 °C for 12 h, tetracyclic annulation
product 27 was obtained in 68% yield as two separable
diastereomers in a ratio of 9:1 over several runs favoring of
the desired isomer as shown. The relative stereochemistry
of the major isomer was assigned rigorously using X-ray at
a later stage (see Scheme 5).
Protection of 23 using Ac2O followed by removal of the
Boc group using TFA led to chiral amine 18 (Scheme 4).
Scheme 4. Key Intramolecular Aza-[3 + 3] Annulation
Scheme 5. Installation of the C4-Carbonyl Group
The access to chiral amine 18 provides a significant
flexibility in choosing an appropriate vinylogous amide (see
17 in Scheme 2). We elected to use bromopyrone 24 because
we had already developed a protocol for reductive ring-
opening of R-pyrones.15c Accordingly, condensation of amine
(13) For a review on vinylogous amide chemistry, see: Kucklander, U.
Enaminones as Synthons. In The Chemistry of Functional Groups: The
Chemistry of Enamines; Rappoport, Z., Ed.; John Wiley & Sons: New York,
1994; Part I, p 523.
(14) For recent studies in this area, see: (a) Goodenough, K. M.; Moran,
W. J.; Raubo, P.; Harrity, J. P. A. J. Org. Chem. 2005, 70, 207. (b) Bose,
G.; Nguyen, V. T. H.; Ullah, E.; Lahiri, S.; Go¨rls, H.; Langer, P. J. Org.
Chem. 2004, 69, 9128. (c) Abelman, M. M.; Curtis, J. K.; James, D. R.
Tetrahedron Lett. 2003, 44, 6527. (d) Hedley, S. J.; Moran, W. J.; Price,
D. A.; Harrity, J. P. A. J. Org. Chem. 2003, 68, 4286.
(15) For leading references on intermolecular aza-[3 + 3], see: (a)
Sydorenko, N.; Hsung R. P.; Darwish, O. S.; Hahn, J. M.; Liu, J. J. Org.
Chem. 2004, 69, 6732. (b) Sklenicka, H. M.; Hsung, R. P.; McLaughlin,
M. J.; Wei, L.-L.; Gerasyuto, A. I.; Brennessel, W. W. J. Am. Chem. Soc.
2002, 124, 10435. (c) McLaughlin, M. J.; Hsung, R. P.; Cole, K. C.;
Hahn, J. M.; Wang, J. Org. Lett. 2002, 4, 2017. (d) Wei, L.-L.; Hsung,
R. P.; Xiong, H.; Mulder, J. A.; Nkansah, N. T. Org. Lett. 1999, 1,
2145.
(16) For intramolecular aza-[3 + 3], see: (a) Wei, L.-L.; Sklenicka, H.
M.; Gerasyuto, A. I.; Hsung, R. P. Angew. Chem., Int. Ed. 2001, 40, 1516.
(b) Gerasyuto, A. I.; Hsung, R. P.; Sydorenko, N.; Slafer, B. W. J. Org.
Chem. 2005, 70, 4248. For some simple applications, see: (c) Sydorenko,
N.; Zificsak, C. A.; Gerasyuto, A. I.; Hsung, R. P. Organic Biomol. Chem.
2005, 3, 2140. (d) Luo, S.; Zificsak, C. Z.; Hsung, R. P. Org. Lett. 2003,
5, 4709.
Success in this key intramolecular aza-[3 + 3] annulation
reaction provided us with an opportunity to complete our
total synthesis of (-)-cylindricine C. The remaining goal is
to install the desired ketone functionality at C4. However,
this proved to be the most challenging facet of this endeavor.
We ultimately were able to employ an interesting sequence
that entails a halohydrin formation specifically using NCS
in t-BuOH/H2O (Scheme 5). This led to the chlorohydrin
28 in 76% yields as a single diastereomer.21 TPAP-oxida-
tion20 followed by a reductive removal of the tertiary Cl
(20) Griffith, W. P.; Ley, S. V. Aldrichim. Acta 1990, 23, 13.
(21) Although we did not rigorously assign the relative stereochemistry
at C4 and C5, we believed that NCS should have approached from the less
hindered bottom face as observed in the hydrogenation of 27 that gave i in
90% yield as a single diastereomer. The relative stereochemistry C4 and
C5 is unambiguous on the basis of coupling constants obtained for H4a
and H4b.
(17) (a) Campbell, A. D.; Raynham, T. M.; Taylor, R. J. K. Synthesis
1998, 1707. (b) McKillop, A.; Taylor, R. J. K.; Watson, R. J.; Lewis, N. J.
Synthesis 1994, 31.
(18) Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981, 11, 513.
(19) See the Supporting Information.
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