Communications
the availability of an achiral pathway leading to a racemic
ment/intramolecular trapping delivers the tricyclic oxazolidi-
none 18.
product. When performed in the absence of both nucleophile
and LiCl, the yield of b-lactone was reduced to 7%, which
suggested an achiral pathway promoted to some extent by
LiCl (Table 4, entry 2). This prompted us to study the use of
tosic anhydride as activating agent, both with and without
LiClO4, in an effort to remove all chloride counterion.[11,12]
Even under these conditions, without added Lewis base, a
considerable amount of b-lactone was formed ( ꢂ 16–20%,
Table 4, entries 3 and 4). In the presence of (S)-HBTM (6)
under these latter conditions, enantioselectivities were similar
(91% ee) but yields were greatly reduced (21%, Table 4,
entry 5). This suggests that the chloride ion is not detrimental
to enantioselectivity and may in fact promote the rate of the
NCAL process, possibly through formation of acid chloride
and/or ketene intermediates leading to an increased rate for
generation of the required acyl ammonium intermediate
(Scheme 4). Further mechanistic studies are underway to gain
a better understanding of this process.
In conclusion, a practical, catalytic, asymmetric NCAL
process of keto acids was developed that highlights a novel
utility of Birmanꢀs homobenzotetramisole derivative
(HBTM, 6). The optimized process, which makes use of
inexpensive TsCl as an activating agent and LiCl as mild
Lewis acid co-catalyst, provides bi- and tricyclic b-lactones in
excellent enantioselectivities and good to excellent yields, and
demonstrates the first catalytic desymmetrization through the
NCAL process. The use of LiCl as a Lewis acid co-catalyst
substantially increased yields of a variety of b-lactone systems
with only slight reduction in enantioselectivity in some cases.
The process has added value for structural diversity given the
inherent reactivity of the b-lactone nucleus, as demonstrated
by subsequent dyotropic rearrangement, ring expansions to
oxazolidinones, and simple reductions and ring openings.
Moreover, Baeyer–Villiger oxidations can be performed with
the resident ketone without detriment to the b-lactone. The
enantioselective NCAL process with keto acids represents a
mild, versatile, and highly practical strategy for rapid
construction of complexity leading to optically active carbo-
cyclic frameworks, which should find great utility in natural
product and diversity-oriented synthesis. Studies along these
lines continue in our laboratory.
Received: July 28, 2010
Published online: November 4, 2010
Keywords: asymmetric catalysis · enantioselectivity · keto acids ·
.
lactones · polycycles
[1] For some lead references, see: a) L. F. Tietze, Chem. Rev. 1996,
96, 115; b) L. F. Tietze; A. Modi, Med. Res. Rev. 2000, 20, 304;
c) L. F. Tietze; N. Rackelmann, Pure Appl. Chem. 2004, 76, 1967.
[2] For reviews, see: a) A. Pommier, J.-M. Pons, Synthesis 1993, 441;
b) H. W. Yang, D. Romo, Tetrahedron 1999, 55, 6403; c) Y.
Wang, R. L. Tennyson, D. Romo, Heterocycles 2004, 64, 605;
d) C. Lowe, J. C. Vederas, Org. Prep. Proced. Int. 1995, 27, 305;
e) V. C. Purohit, A. S. Matla, D. Romo, Heterocycles 2008, 76,
949.
[3] a) G. S. Cortez, R. Tennyson, D. Romo, J. Am. Chem. Soc. 2001,
123, 7945; b) G. S. Cortez, S. H. Oh, D. Romo, Synthesis 2001,
1731; c) S. Oh, G. Cortez, D. Romo, J. Org. Chem. 2005, 70, 2835.
[4] H. Henry-Riyad, C. Lee, V. C. Purohit, D. Romo, Org. Lett. 2006,
8, 4363.
Scheme 4. Reagents and conditions: a) ZnCl2 (2.2 equiv), CH2Cl2,
238C, 48 h, 78%; b) DIBAl-H (6.0 equiv), CH2Cl2, 08C, 3 h, 60%
(d.r.ꢂ2:1); c) MeOH, K2CO3 (1.3 equiv), 238C, 3 h, 83%; d) HNMeO-
Me·HCl (1.4 equiv), iPr2NEt, 2-hydroxypyridine, CH2Cl2, 238C, 20 h,
78%; e) m-CPBA (3.0 equiv), Na2HPO4 (8.0 equiv), CH2Cl2, 238C,
5 days, 23% (68% rec SM); f) i) NaOH (5.4 equiv), THF/H2O, 238C,
3.5 h; ii) DPPA (1.1 equiv), Et3N, PhCH3, reflux, 36 h, 36% (2 steps).
Bn=benzyl, DIBAl-H=diisobutylaluminum hydride, m-CPBA=meta-
chloroperbenzoic acid, DPPA=diphenylphosphoryl azide.
[5] a) G. Ma, H. Nguyen, D. Romo, Org. Lett. 2007, 9, 2143; b) H.
Nguyen, G. Ma, D. Romo, Chem. Commun. 2010, 46, 4803.
[6] V. C. Purohit, A. S. Matla, D. Romo, J. Am. Chem. Soc. 2008,
130, 10478.
[7] V. B. Birman, X. Li, Org. Lett. 2006, 8, 1351.
[8] V. B. Birman, X. Li, Org. Lett. 2008, 10, 1115.
[9] X. Yang, G. Lu, V. B. Birman, Org. Lett. 2010, 12, 892, and
references therein.
[10] P. K. Padakanti, PhD thesis, Washington University in St. Louis
(USA), 2010.
[11] C. Zhu, X. Shen, S. G. Nelson, J. Am. Chem. Soc. 2004, 126, 5352,
and references therein.
To demonstrate the utility of these tricyclic b-lactones for
accessing structural diversity through the inherent reactivity
of the b-lactone moiety, we explored several transformations
that significantly alter the topology of these compounds
(Scheme 4). A dyotropic process delivers the tricyclic bridged
g-lactone 13 under modified conditions with ZnCl2 compared
to that reported previously.[19] Simple reduction and nucleo-
philic addition under mild conditions delivers the triol 14 and
hydroxy ester 15 and amide 16, respectively. Mild Baeyer–
Villiger oxidation under buffered conditions delivers the
ring-expanded bis-lactone 17 without consequence to the
b-lactone. Finally, hydrolysis followed by Curtius rearrange-
[12] M. A. Calter, O. A. Tretyak, C. Flaschenreim, Org. Lett. 2005, 7,
1809.
[13] J. L. Vicario, D. Badia, L. J. Carrillo, J. Org. Chem. 2001, 66,
5801.
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 9479 –9483