Synthesis of the acutumine spirocycle via a radical-polar crossover reaction

Article abstract of DOI:10.1021/ol701757f

A new radical-polar crossover reaction was developed that consists of intramolecular conjugate addition of an aryl radical followed by enolate formation and hydroxylation. A C-C bond, a C-O bond, and two congested stereocenters are created in the process.

Full text of DOI:10.1021/ol701757f

ORGANIC
LETTERS
2007
Vol. 9, No. 20
4033-4036
Synthesis of the Acutumine Spirocycle
via a Radical Polar Crossover Reaction
−
Fang Li and Steven L. Castle*
Department of Chemistry and Biochemistry, Brigham Young UniVersity,
ProVo, Utah 84602
scastle@chem.byu.edu
Received July 23, 2007
ABSTRACT
A new radical
enolate formation and hydroxylation. A C
obtained as a single isomer. The method was used to synthesize the spirocyclic subunit of the alkaloid acutumine.
−polar crossover reaction was developed that consists of intramolecular conjugate addition of an aryl radical followed by
−
C bond, a C O bond, and two congested stereocenters are created in the process. The product is
−
Acutumine (1, Figure 1) is a tetracyclic alkaloid isolated from
the Asian vine Menispermum dauricum1 that manifests
and a neopentylic secondary chloride. The chloride resides
in the cyclopentane ring along with three contiguous
quaternary stereocenters, two of which are all-carbon qua-
ternary centers. Previously, we constructed the propellane-
type substructure of 1;4,5 recently, Sorensen disclosed the
preparation of a similar fragment of the natural product.6
Herein, we report the synthesis of the spirocycle of acutumine
via a novel, stereoselective radical-crossover reaction7,8 that
combines an intramolecular radical conjugate addition9 with
a subsequent enolate hydroxylation.10
The proposed radical-polar crossover reaction is depicted
in Scheme 1. We reasoned that exposure of substrate 2 to a
Figure 1. Acutumine.
(2) Yu, B.-W.; Chen, J.-Y.; Wang, Y.-P.; Cheng, K.-F.; Li, X.-Y.; Qin,
G.-W. Phytochemistry 2002, 61, 439.
(3) Qin, G.-W.; Tang, X.-C.; Lestage, P.; Caignard, D.-H.; Renard, P.
PCT Int. Appl. WO 2004000815, 2003.
(4) (a) Reeder, M. D.; Srikanth, G. S. C.; Jones, S. B.; Castle, S. L.
Org. Lett. 2005, 7, 1089. (b) Jones, S. B.; He, L.; Castle, S. L. Org. Lett.
2006, 8, 3757.
selective T-cell cytotoxicity2 and antiamnesic properties.3 The
structure of 1 includes a propellane-type system, a spirocycle,
(5) For a review on the synthesis of propellane-containing natural
products, see: Pihko, A. J.; Koskinen, A. M. P. Tetrahedron 2005, 61,
8769.
(6) Moreau, R. J.; Sorensen, E. J. Tetrahedron 2007, 63, 6446.
(7) For a review, see: Murphy, J. A. In Radicals in Organic Synthesis;
Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim, 2001; Vol. 1, pp
298-315.
(8) For a recent review of tandem radical reactions, see: Albert, M.;
Fensterbank, L.; Lacoˆte, E.; Malacria, M. Top. Curr. Chem. 2006, 264, 1.
(1) (a) Tomita, M.; Okamoto, Y.; Kikuchi, T.; Osaki, K.; Nishikawa,
M.; Kamiya, K.; Sasaki, Y.; Matoba, K.; Goto, K. Chem. Pharm. Bull.
1971, 19, 770. (b) Tomita, M.; Okamoto, Y.; Kikuchi, T.; Osaki, K.;
Nishikawa, M.; Kamiya, K.; Sasaki, Y.; Matoba, K.; Goto, K. Tetrahedron
Lett. 1967, 2421. (c) Tomita, M.; Okamoto, Y.; Kikuchi, T.; Osaki, K.;
Nishikawa, M.; Kamiya, K.; Sasaki, Y.; Matoba, K.; Goto, K. Tetrahedron
Lett. 1967, 2425. (d) Goto, K.; Sudzuki, H. Bull. Chem. Soc. Jpn. 1929, 4,
220.
10.1021/ol701757f CCC: $37.00
© 2007 American Chemical Society
Published on Web 08/31/2007

Scheme 1. Proposed Radical-Polar Crossover Reaction
Scheme 2. Synthesis of Weinreb Amide 6 and Vinyl Iodide
10
species capable of generating an aryl radical (“In•”) would
cause a 5-exo-trig radical cyclization to occur. The regio-
chemistry of this process would be governed by the polarity
of the enone acceptor, and the bulky silyloxy group would
presumably direct the aryl radical to the opposite face of
the alkene. Then, reaction of the resultant R-keto radical with
an organometallic reagent capable of undergoing homolytic
cleavage (“M-R”) should create an enolate. If a suitable
oxidant (“O-X”) were present in the mixture, this enolate
would be hydroxylated, providing spirocyclic R-hydroxy
ketone 3. We hypothesized that the aryl hydrogen would
shield the re face of the enolate, delivering the desired isomer
of 3. Thus, we envisioned installing a ring, an alcohol, and
two stereocenters including a quaternary carbon in a single
step. An isolated report from Kunz of a tandem radical
conjugate addition-enolate hydroxylation11 served as en-
couraging precedent. However, successful reactions in this
prior study were limited to additions of methyl radicals
generated from Me2AlCl. We required a process that would
permit use of an aryl radical in the addition step. Moreover,
we were concerned about the potential lability of the allylic
chloride of 2 in the presence of radicals.
Cyclization substrate 2 was constructed via a convergent
route featuring the union of aryl and cyclopentene subunits.
The requisite coupling partners were synthesized as outlined
in Scheme 2. Wittig homologation of known aldehyde 44b
afforded aldehyde 5. Oxidation and subsequent amidation
provided Weinreb amide 6. Silylation of enantiopure alcohol
712 followed by pivaloate cleavage delivered alcohol 8, which
was transformed into enone 9 by oxidation and iodination.13
Then, Luche reduction14 and silylation afforded vinyl iodide
10, in which the two alcohol moieties are differentially
protected.
The vinyl Grignard reagent derived from 10 (prepared
according to Knochel’s procedure)15 was added to Weinreb
amide 6, affording enone 11 (Scheme 3). Notably, the aryl
iodide was unaffected by this reaction. We were pleased to
find that 11 could be reduced in diastereoselective fashion
by the Corey-Bakshi-Shibata catalyst (CBS cat.).16 Iden-
tification of the optimal reaction temperature (10 °C), time
(e4 h), and ratio of reactants (11/CBS cat./BH3‚THF ) 1:0.2:
1.2) proved critical to obtaining reproducibly high yields and
diastereomeric ratios. The stereochemistry at the hydroxyl-
bearing carbon was established by Mosher ester analysis.17
Then, SN2 chlorination of the allylic alcohol of 12 was
accomplished with methanesulfonyl chloride and triethy-
lamine.18 The TES group of 13 could be selectively cleaved
in the presence of the TBS moiety, and oxidation of the
resultant alcohol provided enone 2.
The results of our investigation of the radical-polar
crossover reaction of 2 are summarized in Table 1. Hexa-
butylditin was employed to generate an aryl radical from 2
under nonreducing conditions. We discovered that Et3Al19
was more effective at mediating the radical-polar crossover
step than Et2Zn20 or Et3B21 (cf. entry 6 vs entries 1 and 3 or
entry 7 vs entries 2 and 4). Both O222 and dimethyldioxirane
(15) (a) Krasovskiy, A.; Knochel, P. Angew. Chem., Int. Ed. 2004, 43,
3333. (b) Ren, H.; Krasovskiy, A.; Knochel, P. Chem. Commun. 2005, 543.
(c) Krasovskiy, A.; Straub, B. F.; Knochel, P. Angew. Chem., Int. Ed. 2006,
45, 159.
(16) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986.
(17) (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512. (b)
Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991,
113, 4092.
(18) Artman, G. D., III; Grubbs, A. W.; Williams, R. M. J. Am. Chem.
Soc. 2007, 129, 6336.
(19) Liu, J.-Y.; Jang, Y.-J.; Lin, W.-W.; Liu, J.-T.; Yao, C.-F. J. Org.
Chem. 2003, 68, 4030.
(9) For reviews, see: (a) Srikanth, G. S. C.; Castle, S. L. Tetrahedron
2005, 61, 10377. (b) Zhang, W. Tetrahedron 2001, 57, 7237.
(10) For a review, see: Chen, B.-C.; Zhou, P.; Davis, F. A.; Ciganek,
E. Org. React. (N.Y.) 2003, 62, 1.
(11) Ru¨ck, K.; Kunz, H. Angew. Chem., Int. Ed. Engl. 1991, 30, 694.
(12) Myers, A. G.; Hammond, M.; Wu, Y. Tetrahedron Lett. 1996, 37,
3083.
(13) Johnson, C. R.; Harikrishnan, L. S.; Golebiowski, A. Tetrahedron
Lett. 1994, 35, 7735.
(14) Gemal, A. L.; Luche, J.-L. J. Am. Chem. Soc. 1981, 103, 5454.
4034
Org. Lett., Vol. 9, No. 20, 2007

varying amounts of iodide 14 and reduced compound 15
were isolated. While 15 is presumably derived from reduction
of either the R-keto radical or enolate intermediates, the
origin of 14 is unclear. It may be produced via reaction of
the R-keto radical or enolate with Bu3SnI or an electrophilic
iodine species generated via in situ oxidation of Bu3SnI.25
Spirocycles 3, 14, and 15 were each obtained as single
diastereomers. The stereochemistry of 3 was established via
NOE experiments performed on a p-methoxybenzyl ether
derivative; the relevant correlations are depicted in Figure
2. The structures of 14 and 15 are assigned via analogy to
Scheme 3. Synthesis of Enone 2
(DMDO)23 were able to hydroxylate the intermediate enolate
and provide the desired R-hydroxy ketone 3. However,
significantly better yields were obtained with 3-phenyl-2-
(phenylsulfonyl)oxaziridine24 as the hydroxylating agent
(entry 8). Screening other oxidants and solvents as well as
varying the equivalents of each reagent established the
conditions of entry 8 as optimal. Conducting the experiments
at temperatures above or below 0 °C led to greatly reduced
yields. Importantly, the allylic chloride moiety of 2 remained
intact for the duration of the reaction. However, in most cases
Figure 2. NOE enhancements used to assign the structure of 3.
3. The configurations of the two stereocenters formed in the
radical-polar crossover reaction are consistent with the
proposed reaction pathway shown in Scheme 1.
The product distribution (see Table 1, entry 8) indicates
that the cyclization is proceeding with 72% yield and the
hydroxylation is occurring with 86% yield. Additionally, we
have converted 14 into 3 with 62% yield by exposing the
iodide to Et2Zn and air in the presence of the oxaziridine
(Scheme 4). Thus, the overall yield of 3 from 2 is 66%.
Table 1. Radical-Polar Crossover Reaction of 2
Scheme 4. Conversion of 14 into 3
reagent
(equiv)
oxidant
(equiv)
3/14/15
(%)
entry
solvent
THF
THF
THF
THF
THF
THF
THF
1
2
3
4
5
6
7
8
Et3B (1)
Et3B (1)
Et2Zn (4) O2
Et2Zn (4) DMDO (10)
Et2Zn (4) oxaziridineb (4)
Et3Al (1) O2
O2
DMDO (10)
21/20/19
16/18/24
28/23/5
20/18/3
29/27/17
33/22/19
25/11/9
62/7/3
Interestingly, Et2Zn was superior to Et3Al (40% yield) in
this reaction.
In conclusion, we have constructed the enantiomerically
pure acutumine spirocycle by means of a novel radical-
polar crossover reaction consisting of an intramolecular aryl
Et3Al (1) DMDO (10)
Et3Al (3) oxaziridineb (5) THF
(20) (a) Bazin, S.; Feray, L.; Siri, D.; Naubron, J.-V.; Bertrand, M. P.
Chem. Commun. 2002, 2506. (b) Bazin, S.; Feray, L.; Vanthuyne, N.;
Bertrand, M. P. Tetrahedron 2005, 61, 4261. (c) Miyabe, H.; Asada, R.;
Yoshida, K.; Takemoto, Y. Synlett 2004, 540. (d) Miyabe, H.; Asada, R.;
Takemoto, Y. Tetrahedron 2005, 61, 385.
(21) (a) Nozaki, K.; Oshima, K.; Utimoto, K. Tetrahedron Lett. 1988,
29, 1041. (b) Nozaki, K.; Oshima, K.; Utimoto, K. Bull. Chem. Soc. Jpn.
1991, 64, 403. (c) Chandrasekhar, S.; Narsihmulu, C.; Reddy, N. R.; Reddy,
M. S. Tetrahedron Lett. 2003, 44, 2583.
9
Et3Al (3) t-BuOOH (5)
Et3Al (3) (Me3SiO)2
THF
THF
34/3/27
12/-/-
42/11/3
40/9/13
10
11
12
13
14
15
Et3Al (3) oxaziridineb (5)
Et3Al (3) oxaziridineb (5)
Et3Al (3) oxaziridineb (5)
Et3Al (1) oxaziridineb (1)
Et3Al (5) oxaziridineb (10)
CH2Cl2
PhCF3
THF/PhH 1:1 47/10/5
THF
THF
9/4/-
45/6/4
(22) (a) Gardner, J. N.; Carlon, F. E.; Gnoj, O. J. Org. Chem. 1968, 33,
3294. (b) Wender, P. A.; Mucciaro, T. P. J. Am. Chem. Soc. 1992, 114,
5878.
a A sunlamp was used. b 3-Phenyl-2-(phenylsulfonyl)oxaziridine.
Org. Lett., Vol. 9, No. 20, 2007
4035

radical conjugate addition followed by enolate formation and
hydroxylation. A spirocyclic quaternary carbon and an
adjacent secondary alcohol are each created with complete
stereochemical fidelity. Furthermore, an allylic chloride
survives the transformation unscathed. The ability to form a
congested and functionalized structure with excellent selec-
tivity and good yield suggests that this process may have
broad utility. Accordingly, explorations of its scope as well
as continuation of the total synthesis of acutumine are
currently in progress.
Acknowledgment. We thank Brigham Young University
and the National Institutes of Health (GM70483) for support
of this work.
Supporting Information Available: Experimental pro-
cedures, characterization data, and NMR spectra for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(23) (a) Guertin, K. R.; Chan, T. H. Tetrahedron Lett. 1991, 32, 715.
(b) Adam, W.; Prechtl, F. Chem. Ber. 1991, 124, 2369. (c) Adam, W.;
Mueller, M.; Prechtl, F. J. Org. Chem. 1994, 59, 2358.
(24) Davis, F. A.; Vishawakarma, L. C.; Billmers, J. G.; Finn, J. J. Org.
Chem. 1984, 49, 3241.
(25) For similar observations with Bu3SnBr, see: Blaszykowski, C.;
Dhimane, A.-L.; Fensterbank, L.; Malacria, M. Org. Lett. 2003, 5, 1341.
OL701757F
4036
Org. Lett., Vol. 9, No. 20, 2007