Journal of the American Chemical Society
Communication
a
This total synthesis of ( )-bisabosqual A (1) is the first
synthesis of a bisabosqual. The key step, a 5-exo, 6-exo radical
cyclization, provides two rings and sets three of the five
stereogenic centers (two of them with complete specificity) in
the product. This approach showcases the power of radical
cyclizations to access complex polycyclic ring systems. It also
highlights the functional group selectivity of the trimethylalu-
minum reagent and the high regioselectivity of the Trost−
Hutchins reducing system. The synthesis requires 14 steps
(longest linear sequence) from commercially available materi-
als. The approach can be easily adapted to an asymmetric
synthesis, and it offers access to a variety of structural
analogues. The pursuit of these goals is currently underway.
Scheme 3. Elaboration of Bisabosqual A
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and spectroscopic, characterization,
and crystallographic (CIF) data. This material is available free
AUTHOR INFORMATION
Corresponding Author
■
Notes
The authors declare no competing financial interest.
a
Reagents and conditions: (a) CeCl3·7H2O, NaBH4, MeOH, −78 °C
→ 0 °C, 1 h; (b) AcCl, pyridine, CH2Cl2, 0 °C, 30 min; (c) 15,
[PdCl(allyl)]2, L-selectride (1 M in THF), 0 °C, 15 min, 86% (3
steps); (d) TBAF (1 M in THF), THF, rt, 1 h; (e) Dess−Martin
periodinane, CH2Cl2, rt, 1 h; (f) AlMe3 (2 M in heptane), toluene, 0
°C → rt, 30 min, 90%; (g) LAH (1 M in THF), THF, 0 °C, 45 min;
(h) Dess−Martin periodinane, CH2Cl2, 0 °C → rt, 1 h, 81% (2 steps).
ACKNOWLEDGMENTS
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This work was supported by the National Institutes of Health
(GM 74776) and by Pfizer Inc. The authors are grateful for
institutional support from Martin Pettersson, Christopher J.
O’Donnell, and Anabella Villalobos. We thank Kathleen A.
Farley for NMR support, Brian M. Samas for X-ray crystal
structures, James Bradow for separations, and Martin
Pettersson, John M. Humphrey, Christopher J. Helal, Patrick
B. Mullins, Thayalan Navaratnam, Michael E. Green, Todd W.
Butler, and Matthew E. Calder for insightful discussions.
reduction16 of ketone 6b followed by acetylation provided 14,
which was treated directly with [PdCl(allyl)]2, phosphite 15,
and L-selectride. This procedure, optimized for our system by
the rapid addition of L-selectride, provided the desired 16 in
excellent yield (86% for three steps) with only a trace of the
product of olefin migration.
Completion of the synthesis required modification of the
functionality at carbons 3, 7′, and 8′. Liberation of the
secondary alcohol at C-3 with tetrabutylammonium fluoride
(TBAF) followed by Dess−Martin periodinane oxidation17
cleanly delivered ketone 17 in 88% yield for two steps (Scheme
3). Exploratory attempts to add methylmagnesium bromide to
the keto group suggested that this reagent was not selective for
a single product. However, trimethylaluminum smoothly
provided the anticipated tertiary alcohol 5 as a single
diastereomer.18 Unambiguous assignment of the five stereo-
genic centers was confirmed by X-ray crystallography of this
diester (5, Figure 2).
REFERENCES
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All that remained was elaboration of the phthalaldehyde
functionality (Scheme 3). Reduction of diester 5 with lithium
aluminum hydride provided a diol which was unstable to
purification; consequently, it was used directly in the next step.
For the preparation of the dialdehyde, Dess−Martin
oxidation19 was found to be superior to Swern or barium
manganate conditions,20 cleanly providing bisabosqual A (1) in
81% yield for the two steps. The H NMR and 13C NMR
1
spectroscopic data of this product were indistinguishable from
those reported for naturally occurring (+)-bisabosqual A.
Moreover, the structure of bisabosqual A (1) was further
confirmed by X-ray crystallographic analysis (Figure 2).
(5) (a) Zhou, J.; Lobera, M.; Neubert-Langille, B. J.; Snider, B. B.
Tetrahedron 2007, 63, 10018. (b) Snider, B. B.; Lobera, M.
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dx.doi.org/10.1021/ja3108577 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX