Stereoselective cascade reactions that incorporate a 7-exo acyl radical cyclization

Article abstract of DOI:10.1021/ol0604264

Radical cascades that feature a 7-exo acyl radical cyclization followed by a 6-exo or 5-exo alkyl radical cyclization proceed with very good yields and diastereoselectivities. Two Stereocenters are created by the reaction, and a single isomeric product wa

Full text of DOI:10.1021/ol0604264

ORGANIC
LETTERS
2006
Vol. 8, No. 9
1867-1870
Stereoselective Cascade Reactions that
Incorporate a 7-exo Acyl Radical
Cyclization
Seth W. Grant, Koudi Zhu, Yu Zhang, and Steven L. Castle*
Department of Chemistry and Biochemistry, Brigham Young UniVersity,
ProVo, Utah 84602
scastle@chem.byu.edu
Received February 17, 2006
ABSTRACT
Radical cascades that feature a 7-exo acyl radical cyclization followed by a 6-exo or 5-exo alkyl radical cyclization proceed with very good
yields and diastereoselectivities. Two stereocenters are created by the reaction, and a single isomeric product was obtained from each of the
five substrates examined. The relative configurations of the products are consistent with cyclizations occurring via chairlike or pseudochairlike
transition states.
The synthesis of seven-membered rings via radical cycliza-
tion is rare and usually limited to specialized substrates.1
Acyl radical cyclizations represent a large subset of the
known 7-exo radical processes. The slower reduction rates
of acyl radicals relative to alkyl radicals render them more
useful in 7-exo cyclizations.2 In a seminal report, Boger
demonstrated that 7-exo-trig acyl radical cyclizations with
unactivated alkene acceptors are facile, provided that an
aromatic ring is present in the tether between the radical and
the acceptor.3 Evans,4 Bonjoch,5 and Ryu6 have subsequently
disclosed various 7-exo ring closures involving acyl radicals.
Significantly, Evans found that these reactions can proceed
with excellent diastereoselectivity.4 Despite these advances,
to the best of our knowledge, there are no published reports
of cascade reactions that incorporate a 7-exo acyl radical
cyclization.7
Lyconadin A (1, Figure 1) is an anticancer alkaloid isolated
(1) (a) Justicia, J.; Oller-Lo´pez, J. L.; Campan˜a, A. G.; Oltra, J. E.;
Cuerva, J. M.; Bun˜uel, E.; Ca´rdenas, D. J. J. Am. Chem. Soc. 2005, 127,
14911. (b) Lang, S.; Corr, M.; Muir, N.; Khan, T. A.; Scho¨nebeck, F.;
Murphy, J. A.; Payne, A. H.; Williams, A. C. Tetrahedron Lett. 2005, 46,
4027. (c) Srikrishna, A. In Radicals in Organic Synthesis; Renaud, P., Sibi,
M. P., Eds.; Wiley-VCH: Weinheim, 2001; Vol. 2, pp 163-187.
(2) (a) Chatgilialoglu, C.; Crich, D.; Komatsu, M.; Ryu, I. Chem. ReV.
1999, 99, 1991. (b) Boger, D. L. Israel J. Chem. 1997, 37, 119.
(3) (a) Boger, D. L.; Mathvink, R. J. J. Org. Chem. 1988, 53, 3377. (b)
Boger, D. L.; Mathvink, R. J. J. Org. Chem. 1992, 57, 1429.
(4) (a) Evans, P. A.; Roseman, J. D. J. Org. Chem. 1996, 61, 2252. (b)
Evans, P. A.; Raina, S.; Ahsan, K. Chem. Commun. 2001, 2504. (c) Evans,
P. A.; Manangan, T.; Rheingold, A. L. J. Am. Chem. Soc. 2000, 122, 11009.
(d) Evans, P. A.; Manangan, T. Tetrahedron Lett. 1997, 38, 8165. (e) Evans,
P. A.; Manangan, T. J. Org. Chem. 2000, 65, 4523.
Figure 1. Lyconadin A (bicyclo[5.4.0]undecane shown in bold).
by Kobayashi from the club moss Lycopodium complana-
tum.8 Its unique molecular skeleton makes 1 an attractive
(5) (a) Quirante, J.; Escolano, C.; Bonjoch, J. Synlett 1997, 179. (b)
Quirante, J.; Vila, X.; Escolano, C.; Bonjoch, J. J. Org. Chem. 2002, 67,
2323.
10.1021/ol0604264 CCC: $33.50
© 2006 American Chemical Society
Published on Web 04/01/2006

target for total synthesis. In the course of planning such an
endeavor, we recognized that a bicyclo[5.4.0]undecane ring
system is embedded within the framework of 1 (depicted in
bold in Figure 1). A tandem 7-exo-6-exo radical cyclization
would be a particularly efficient means of preparing this
structural motif. Accordingly, we decided to study the facility
and stereoselectivity of this process with model substrates
prior to commencing the total synthesis. Herein, we report
that 7-exo-6-exo and 7-exo-5-exo cascade cyclizations which
employ an acyl radical in the initial ring closure proceed in
good yields with excellent levels of diastereoselectivity.
To mimic the 2-pyridone moiety of 1 and take advantage
of the precedent of Boger,3 we targeted phenyl-tethered
phenyl selenoester 12 as our initial cyclization substrate and
prepared it as outlined in Scheme 1. Thus, saponification of
forded ester 3, which was reduced with LiAlH4. Treatment
of the resultant crude alcohol with TBS-Cl provided differ-
entially protected diol 4. Cleavage of the PMB ether
delivered phenethyl alcohol 5, which was converted into the
corresponding bromide in excellent yield. Alkylation of
diethyl acetone 1,3-dicarboxylate (DEADC) by this bromide
provided 6 in good yield. Careful optimization of Johnson’s
conditions10 was required to preclude styrene formation via
elimination of the bromide.
Reduction of 6 with NaBH4 was modestly syn selective11
and provided 7 as a mixture of diastereomers after TBS
protection. The minor anti diastereomer was gradually
removed over the course of the next few steps. Conversion
of both ester moieties to the corresponding Weinreb amides
was followed by attempts to form bisolefin 10 via a
reduction-Wittig olefination sequence. Unfortunately, sig-
nificant differences in the reduction rates of the two amides
necessitated the stepwise approach to 10 portrayed in Scheme
1. Then, selective cleavage of the primary benzylic silyl ether
mediated by camphorsulfonic acid (CSA) was followed by
oxidation and phenyl selenoesterification,12 delivering cy-
clization substrate 12 in good yield.
Scheme 1. Preparation of Phenyl Selenoester 12
Pleasingly, treatment of 12 with Et3B, air, and tris-
(trimethylsilyl)silane according to a slight modification of
the conditions disclosed by Evans4c provided tricycle 13 in
excellent yield as a single diastereomer (Scheme 2). The trans
Scheme 2. Tandem 7-exo-6-exo Cyclization of 12
ring fusion and relative configuration of the methyl-bearing
stereocenter of 13 are consistent with data obtained from
both 1D and 2D NMR experiments.13 Notably, (TMS)3SiH
proved critical to the success of the cyclization, as use of
the more rapid hydrogen-atom donor Bu3SnH resulted in a
complex mixture from which prematurely reduced byprod-
ucts could be tentatively identified. Interestingly, we found
that vigorous stirring of the reaction mixture was crucial to
the reproducibility of the reaction. We propose that fast
stirring leads to an increase in the surface area of the solution
that is exposed to air, thereby increasing the concentration
of oxygen in solution and resulting in more efficient initiation
of the radical cascade process.
Intrigued by this result, we next examined cascade
cyclizations of substrates related to 12 in order to ascertain
1-isochromanone (2)9 and exhaustive PMB protection af-
(6) (a) Ryu, I.; Miyazato, H.; Kuriyama, H.; Matsu, K.; Tojino, M.;
Fukuyama, T.; Minakata, S.; Komatsu, M. J. Am. Chem. Soc. 2003, 125,
5632. (b) Tojino, M.; Otsuka, M.; Fukuyama, T.; Matsubara, H.; Schiesser,
C. H.; Kuriyama, H.; Miyazato, H.; Minakata, S.; Komatsu, M.; Ryu, I.
Org. Biomol. Chem. 2003, 1, 4262.
(7) For a review on radical cascade reactions, see: McCarroll, A. J.;
Walton, J. C. Angew. Chem., Int. Ed. 2001, 40, 2224. For examples of
cascades employing acyl radicals, see ref 2a.
(9) Kim, S. S.; Sar, S. K.; Tamrakar, P. Bull. Korean Chem. Soc. 2002,
23, 937.
(10) Johnson, W. S.; Plummer, M. S.; Reddy, S. P.; Bartlett, W. R. J.
Am. Chem. Soc. 1993, 115, 515.
(11) Williams, R. M.; Lee, B. H.; Miller, M. M.; Anderson, O. P. J.
Am. Chem. Soc. 1989, 111, 1073.
(12) Singh, U.; Ghosh, S. K.; Chadha, M. S.; Mamdapur, V. R.
Tetrahedron Lett. 1991, 32, 255.
(8) Kobayashi, J.; Hirasawa, Y.; Yoshida, N.; Morita, H. J. Org. Chem.
2001, 66, 5901.
(13) See Supporting Information for details on structural assignments.
1868
Org. Lett., Vol. 8, No. 9, 2006

the origins of the excellent diastereoselectivity. To probe the
role of the OTBS group, we generated free alcohol 14 from
12 via treatment with CSA as illustrated in Scheme 3.
compound was formulated as 22 on the basis of NMR
experiments.13 Therefore, it appears that this 7-exo-6-exo
cascade radical cyclization occurs with outstanding diaste-
reoselectivity regardless of the relative configuration of the
OTBS substituent.
Although not directly relevant to our targeted natural
product 1, we also examined the corresponding 7-exo-5-
exo tandem radical cyclizations to learn more about the scope
of the cascade reaction. The synthesis of requisite phenyl
selenoester 31 is detailed in Scheme 5. Alkylation of diethyl
Scheme 3. Tandem Cyclization of Alcohol 14
Scheme 5. Preparation of Phenyl Selenoester 31
Interestingly, cyclization of 14 provided alcohol 15 as a
single diastereomer which was identical in structure to
material obtained from deprotection of 13. Accordingly, the
bulky silyl ether moiety is not required to achieve stereo-
selectivity in this process.
By simply changing the conditions for reduction of ketone
6, we were able to access phenyl selenoester 21, the
diastereomer of our original cyclization substrate 12. Thus,
exposure of 6 to freshly prepared Zn(BH4)214 and silylation
of the resultant alcohol delivered anti isomer 16 in 4:1 dr
(Scheme 4). Conversion of 16 into 21 proceeded without
Scheme 4. Synthesis and Cyclization of 21
malonate with the bromide derived from 5 and reduction of
the resultant diester afforded 1,3-diol 24 in excellent yield.
Monoprotection of this diol as a PMB ether followed by
oxidation and vinyl Grignard addition provided allylic
alcohol 26 as ca. a 1:1 mixture of diastereomers. This mixture
was carried on as such through the remainder of the synthesis.
Then, TBS protection of the secondary alcohol and PMB
ether cleavage delivered primary alcohol 28. This compound
was transformed into diene 29 via an oxidation-Wittig
methylenation sequence. Conversion of 29 into phenyl
selenoester 31 mirrors the routes shown in Schemes 1 and 4
used to prepare the 7-exo-6-exo cyclization substrates.
Exposure of 31 to the previously developed tandem
cyclization conditions resulted in a separable 1:1 mixture of
tricyclic compounds 32 and 33, whose structures were
elucidated via 1D and 2D NMR spectroscopy (Scheme 6).13
Because 32 and 33 are epimeric only at the OTBS-bearing
carbon, we believe that the 7-exo-5-exo radical cyclization
incident via the route employed for the synthesis of 12.
Gratifyingly, 21 produced a single tricyclic product upon
treatment with Et3B-(TMS)3SiH. The structure of this
Org. Lett., Vol. 8, No. 9, 2006
1869

Scheme 6. Tandem 7-exo-5-exo Cyclization of 31
cascade was highly stereoselective, with each diastereomer
of the starting material delivering a single product.
The stereochemical course of the reactions is consistent
with cyclization via chairlike or pseudochairlike transition
states in which the number of equatorial or pseudoequatorial
substituents is maximized (Figure 2). Evans has postulated
similar transition states for other stereoselective 7-exo-trig
acyl radical cyclizations.4a It is noteworthy that the cycliza-
tion of 21 provided a single diastereomer. Apparently, the
presence of an axial hydrogen in the transition state of the
second cyclization (see Figure 2, R1 ) H) is sufficient to
force the alkene to reside in an equatorial orientation due to
the strain inherent in the alternative axial conformer.
Comparison of the structures of tricycles 13, 15, and 22
with that of lyconadin A reveals that our tandem cyclizations
create the proper stereochemistry at the methyl-bearing
carbon but the improper stereochemistry at the R-carbonyl
ring junction. Fortunately, it should be possible to invert the
configuration at the latter carbon. We are currently investi-
gating this transformation.
Figure 2. Proposed pathways of tandem cyclizations.
define the scope and limitations of this process and apply it
to the total synthesis of natural products are in progress.
In conclusion, we have found that 7-exo acyl radical
cyclizations followed by 6-exo or 5-exo alkyl radical cy-
clizations can occur with excellent yields and diastereose-
lectivities. In fact, of the five cyclization substrates exam-
ined,15 all were transformed into a single detectable
diastereomer. The stereochemistry of the adducts is consistent
with the cyclizations proceeding via chairlike or pseudoch-
airlike transition states. To the best of our knowledge, these
reactions represent the first examples of radical cascades that
incorporate a 7-exo acyl radical cyclization. Studies to fully
Acknowledgment. We thank Brigham Young University
and the National Institutes of Health (GM70483) for support
of this work. S.W.G. thanks the BYU Cancer Research
Center for a Summer Research Fellowship.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds,
as well as 1H and 13C NMR spectra for selected compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(14) Overman, L. E.; Angle, S. R. J. Org. Chem. 1985, 50, 4021.
(15) This analysis counts each diastereomer of 31 as a separate substrate.
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