A concise synthesis of (-)-aplyviolene facilitated by a strategic tertiary radical conjugate addition

Article abstract of DOI:10.1002/anie.201204977

A second-generation synthesis of the rearranged spongian diterpene aplyviolene is reported. The key step is the addition of a trialkyl tertiary radical generated by photoredox-mediated fragmentation of a N-(acyloxy) phthalimide to an α-chloropentenone (se

Full text of DOI:10.1002/anie.201204977

Angewandte
Chemie
DOI: 10.1002/anie.201204977
Total Synthesis
A Concise Synthesis of (À)-Aplyviolene Facilitated by a Strategic
Tertiary Radical Conjugate Addition**
Martin J. Schnermann and Larry E. Overman*
Aplyviolene (1) and macfarlandin E (2, Scheme 1A) are
representative of the more complex members of the rear-
[
1,2]
ranged spongian diterpene class of natural products.
These
diterpenes are structurally defined by attached cis-perhy-
droazulene and 6-acetoxy-2,7-dioxabicyclo[3.2.1]octan-3-one
fragments. The substantial challenge in assembling these
structures centers on the construction of the sensitive bicyclic
lactone subunit and the formation of the C8–C14 s-bond
joining the two ring systems, a challenge augmented by the
[3]
quaternary nature of C8. We previously reported prepara-
tion of the lactone subunits of 1 and 2 by the synthesis of
[4]
truncated congeners 3 and 4 (Scheme 1A), as well as the
[5]
first total synthesis of aplyviolene (outlined in Scheme 1B).
In this latter effort, the key C8–C14 s-bond was formed by
[
6]
Michael addition of tertiary enolate 5 to enone 6. Subse-
quent elaboration of product 7 provided intermediate 8,
which was converted to (À)-aplyviolene along the lines of our
earlier synthesis of 3. Undesirable aspects of this first-
generation synthesis are the lengthy preparation of the cis-
perhydroazulene unit and the need to remove the extraneous
ketone carbonyl group from the product of the fragment-
coupling step.
[
7]
As described in the accompanying Communication, our
initial attempt to streamline the synthesis by using a tertiary
organocuprate derived from cis-perhydroazulene nitrile 9 in
the key fragment coupling was prevented by exclusive
formation of adduct 11, which is epimeric to aplyviolene at
the critical quaternary carbon stereocenter (Scheme 1C).
This unexpected stereochemical outcome of the organocup-
rate conjugate addition reaction provoked consideration of an
alternative strategy in which the C8–C14 s-bond would be
formed by the union of the tertiary radical 12 and enone 13
[*] Dr. M. J. Schnermann, Prof. L. E. Overman
Department of Chemistry, University of California Irvine
1102 Natural Sciences II, Irvine, CA 92697-2025 (USA)
E-mail: leoverma@uci.edu
Homepage: http://faculty.sites.uci.edu/overman/
[
**] We thank Dr. Joe Ziller, University of California, Irvine, for the single-
crystal X-ray analyses and Dr. John Greaves, University of California,
Irvine, for mass spectrometric analyses. This research was sup-
ported by the NIH Neurological Disorders & Stroke Institute (Grant
R01-NS12389), the NIH National Institutes of General Medical
Sciences (Grant R01-GM098601), and by an NIH postdoctoral
fellowship for M.J.S. (CA138084). NMR spectra, mass spectra, and
the X-ray analyses were obtained at UC Irvine using instrumentation
acquired with the assistance of NSF and NIH Shared Instrumen-
tation grants. Unrestricted funds from Amgen and Merck are also
gratefully acknowledged.
Scheme 1. A) Structurally complex rearranged spongian diterpenes,
B,C) previous synthetic efforts, and D) current synthetic approach.
TMS=trimethylsilyl; TBS=tert-butyldimethylsilyl.
(Scheme 1D, X = leaving group). Reductive silylation of the
coupled product 14 would then provide enoxy silane 8, an
advanced intermediate in the synthesis of (À)-aplyviolene.
Despite the many advances in stereoselective radical chemis-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201204977.
[8]
try, bimolecular reactions that transform trialkyl-substituted
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Angewandte
Communications
tertiary radicals to stereogenic quaternary carbons are
[9]
extremely rare. Moreover, the use of tertiary radicals to
couple two complex fragments in the context of target-
[10]
oriented synthesis is also uncommon.
Encouraged by
reports that achiral tertiary radicals undergo particularly
diastereoselective additions to chiral alkenes, we chose to
[11]
pursue this strategy. Reported herein is a much-improved
second-generation total synthesis of (À)-aplyviolene (1) that
features the stereoselective coupling of a tertiary carbon
radical and a carbon electrophile to combine chiral fragments
with formation of a new quaternary carbon stereocenter.
A critical consideration was the identity of the radical
precursor. The common option of employing a bromide or
iodide precursor was not viable, as preliminary studies
showed that these tertiary halide intermediates were not
Scheme 2. Synthesis of 18: a) 15, 16 (1.5 equiv), 17 (1.5 equiv), Ru-
bpy) Cl (0.01 equiv), THF/H O (2:1), blue LEDs, RT, 90 min, 70%.
NPhth=N-phthalimido; bpy=2,2’-bipyridine.
(
3
2
2
tion of nitrile 20 with diisobutylaluminum hydride and Z-
selective Wittig reaction of the resulting crude aldehyde
products with 3-hydroxypropyltriphenylphosphonium bro-
mide yielded a 2:1 mixture of (Z)-allylic alcohol 21 and its
[8]
accessible in satisfactory yield. Barton esters were also
[
12]
1,5
[21]
unsuited for this application.
The use of such radical
D
isomer. Separation of the alkene isomers was possible
precursors would entail the coupling of 12 and enone 13 (X =
H) to provide product 14 (X = 2-thiopyridine), whose reduc-
tive silylation to form enoxy silane 8 was expected to be
unsuccessful. By contrast, an (N-acyloxy)phthalimide pre-
cursor appeared distinctly advantageous. Over 20 years ago
Okada demonstrated that, when exposed to visible light,
at this stage by column chromatography on silver nitrate-
embedded silica gel, which could be carried out on large scale
to give pure 21 in 55% overall yield (up to 25 g of 21 isolated
per batch) from the Beckman fragmentation product 20.
Homoallylic alcohol 21 was converted to the corresponding
nitro compound 22 by way of the primary iodide in 67%
[
13]
[
22]
[
Ru(bpy) ]Cl2 (bpy = 2,2’-bipyridine), and the hydrogen
yield.
Intramolecular nitrile oxide cycloaddition of 22
3
donor 1-benzyl-1,4-dihydronicotinamide, such compounds
proceeded efficiently at 908C under Mukaiyama conditions
are transformed in the presence of a,b-unsaturated ketones
to provide the desired isoxazoline product, which did not
[
14]
[23,24]
to products of conjugate addition in excellent yield. We
noted that in a single instance a tertiary radical (1-adman-
tanyl) had been coupled effectively. Surprisingly, the use of
require purification prior to further use.
After some
experimentation, we found the most effective way to process
the crude oxazoline intermediate to enone 24 was by initial
hydrogenation using a mixture of 10% palladium on carbon
and Raney-nickel in the presence of boric acid to provide the
(N-acyloxy)phthalimides as radical precursors in conjugate
addition reactions has not been described since this initial
disclosure, and their photosensitized cleavage has only rarely
[25,26]
b-hydroxy ketone product 23.
Acid-catalyzed dehydra-
[
15]
been reported in any form. We hoped that realizing the
proposed demanding application of the Okada chemistry
would be assisted by insight gained from recent advances in
tion of 23 in toluene at elevated temperature provided enone
[
27]
24 in 61% overall yield from nitro diene 22.
The conversion of enone 24 to the N-(acyloxy)phthal-
imide coupling partner 27 was ultimately achieved by way of
only two isolated intermediates. Addition of the cuprate
derived from copper cyanide and 2 equiv of vinylmagnesium
bromide in THF containing hexamethylphosphoramide at
08C afforded vinyl addition product 25 as a 4.8:1 mixture of
[
16,17]
photoredox catalysis.
Prior to exploring the union of the complex fragments
depicted in Scheme 1D, we examined the addition of the
tertiary radical generated from a simpler (N-acyloxy)phthal-
imide to methyl vinyl ketone. Using a slight modification of
[
28,29]
Okadaꢀs conditions, a THF/H O solution of (N-acyloxy)-
cis-perhydroazulene epimers in 77% yield.
Attempted
2
[
18]
phthalimide 15 and methyl vinyl ketone (1.5 equiv) was
elaboration of alkenyl ketone 25 to carboxylic acid 26 by
initial methylenation of the ketone, followed by selective
oxidative cleavage of the terminal vinyl group was prevented
by competitive oxidation of the exomethylene functionality.
As an alternative, slow addition of 25 to a mixture of
(trimethylsilyl)methyllithium in pentane at À788C provided
the b-silyl alcohol adduct. Without purification, this inter-
mediate was exposed sequentially to ozone in CH Cl at
coupled using 1 mol% of [Ru(bpy) ]Cl , excess 1,4-dihydro-
3
2
nicotinamide 17, and 1.5 h irradiation with blue light to give
[
19]
adduct 18 in 70% yield (Scheme 2).
The coupling took
place with high selectivity from the convex face (d.r. > 20:1).
This finding was particularly promising because the corre-
sponding addition of an organocuprate intermediate provided
[
7]
1
8 as the minor component of a mixture of epimeric adducts.
Encouraged by these initial studies, we developed a syn-
thesis of the cis-perhydroazulene N-(acyloxy)phthalimide 27
Scheme 3). The synthesis began with inexpensive (+)-fen-
chone (19), which was readily transformed by Beckmann
2
2
À788C, triphenylphosphine and HF-pyridine to cleanly gen-
erate the exomethylene aldehyde product. Sodium chlorite
oxidation of this unpurified intermediate delivered carboxylic
acid 26 in 74% overall yield from 25. The desired radical-
coupling partner 27 was then secured in 84% yield by
carbodiimide coupling of carboxylic acid 26 with N-hydroxy-
phthalimide.
(
[
20]
fragmentation to tertiary nitrile 20.
Heating the oxime
intermediate in 4m H SO for 8 h provided 20 in 83% yield as
2
4
1
,2
a 2:1 mixture of alkene regioisomers favoring the desired D
isomer, whereas halting the reaction after 30 min gave 20 as
With convenient access to cis-perhydroazulene N-(acyl-
oxy)phthalimide 27 in hand, we investigated the pivotal
fragment-coupling reaction. To our delight, initial efforts to
the 1:1 mixture of double bond isomers described by Kreiser
[
20]
in the original description of this transformation. Reduc-
2
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Scheme 3. Formal total synthesis of (À)-aplyviolene: Synthesis of enoxysilane 8: a) 1. 19, sodium acetate (2 equiv), NH OH·HCl (1.75 equiv),
2
1
,2
1,5
EtOH, reflux, 36 h; 2. 4m H SO , reflux, 8 h, 83% as a 2:1 mixture of D :D isomers. b) 1. 20, DIBAL-H (1.2 equiv), CH Cl , À788C, 1 h; 2. 3-
2
4
2
2
hydroxypropyltriphenylphosphonium bromide (2 equiv), nBuLi (4 equiv), TMSCl (2 equiv), THF, 08C, 20 min; + aldehyde from step 1, À788C, 1 h;
2
n H SO , RT, 18 h; 55%. c) 21, I (1.05 equiv), PPh (1.05 equiv), imidazole (1.1 equiv), benzene, 18 h, RT, 94%. d) alkyl iodide from (c), AgNO
2
4
2
3
2
(
(
(
(
1.5 equiv), 18 h, RT, 67%. e) 1. 22, PhNCO (3 equiv), Et N (0.5 equiv), toluene, 18 h, 908C; 2. H , 10% Pd/C (5 wt%), Raney-Ni (5 wt%), B(OH)
3
2
3
3 equiv), MeOH/H O (5:1), 36 h, RT, 67% f) 23, TsOH (0.1 equiv), 5 h, 1008C, 91%. g) 1m vinylmagnesium bromide (5 equiv), CuCN
2
2.5 equiv), THF/HMPA (5:1), 10 min, 08C, + 24, 7 h, 08C, 77%. h) 1. TMSCH Li (5 equiv), pentane, À788C; + 25; 2. O , CH Cl , À788C; Ph P
2
3
2
2
3
1.5 equiv), HF-pyridine, 1 h, 08C; 3. NaClO (3 equiv), 2-methyl-2-butene (3 equiv), NaH PO (1 equiv), acetone/H O (30:1), RT, 1 h, 74%. i) 26,
2
2
4
2
DCC (1.5 equiv), N-(hydroxy)phthalimide (1.7 equiv), DMAP (0.05 equiv), THF, 18 h, RT, 84%. j) 27, 28 (1.5 equiv), 29 (1.5 equiv), iPr EtN
2
(
(
2.25 equiv), [Ru(bpy) ](BF ) (0.01 equiv), CH Cl , blue LEDs, 2.5 h, RT, 61%. k) 31, Me CuCNLi (2.0 equiv), TBSCl (5 equiv), Et O/THF/HMPA
3 4 2 2 2 2 2 2
4:2:1), 1 h, À208C, 76%. DIBAL-H=Diisobutylaluminum hydride; TsOH=p-toluenesulfonic acid; DCC=N,N’-dicyclohexylcarbodiimide;
DMAP=4-dimethylaminopyridine; HMPA=hexamethylphosphoramide.
implement the radical coupling of N-(acyloxy)phthalimide 27
addition of the tertiary radical generated by photoredox-
mediated fragmentation of N-(acyloxy)phthalimide 27 to a-
chlorocyclopentenone 28, a reaction that combines two
fragments of significant complexity and fashions adjacent
quaternary and tertiary carbon stereocenters with high
stereoselectivity. This transformation highlights the largely
untapped utility of addition reactions of tertiary carbon
radicals in the construction of quaternary carbon stereocen-
ters and in stereoselectively fashioning demanding s-bonds
[30,31]
and a-chlorocyclopentenone 28
using only a minor
modification (Scheme 3) of the conditions of Okada provided
the crystalline addition product 30 as a single diastereomer,
[
32]
albeit in low and variable yields (20–40%). The low yield is
attributed to the sensitivity of 30, as chloride reduction and
[
33]
hydrolysis byproducts were observed. Seeking to minimize
the latter, we were attracted to a recent report by Gangꢁ
disclosing the photoredox-mediated reaction of glycosyl
halides and electron-deficient alkenes under anhydrous con-
[
34]
ditions. In this way, irradiation of a 1.5:1 mixture of enone
and N-(acyloxy)phthalimide 27, [Ru(bpy) ](BF ) ,
2
8
3
4 2
Hantzsch ester 29, N,N-diisopropylethylamine and dichloro-
methane with blue light provided coupled product 30,
containing < 5% of the reductively dechlorinated analogue
[
35]
as an inseparable byproduct, in a 61% yield. Reductive
enol silylation of 30 using dilithium dimethyl(cyano)cuprate
in the presence of tert-butyldimethylsilyl chloride at À208C
delivered tricyclic enoxysilane 8, which we had previously
[5]
carried on to (À)-aplyviolene.
In summary, we report an improved second-generation
total synthesis of aplyviolene (1) that is more efficient and
proceeds by way of five fewer isolated intermediates than our
original synthesis. The defining feature of this synthesis is the
Scheme 4. Complimentary stereoselection in forming quaternary
carbon stereocenters by the reaction of tertiary carbon radicals and
tertiary organometallic intermediates with carbon electrophiles.
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.
Angewandte
Communications
that join two rings. Furthermore, the results of this study, and
example: a) B. Giese, T. Witzel, Tetrahedron Lett. 1987, 28,
571; b) T. Toru, Y. Watanabe, M. Tsusaka, Y. Ueno, J. Am.
[
7]
2
those reported in the accompanying Communication, show
that the creation of quaternary carbon stereocenters by the
union of trialkyl-tertiary carbon radicals and related organ-
ometallic intermediates with carbon electrophiles can take
place with complimentary stereoselection (Scheme 4). The
generality of this observation and its exploitation in fragment
coupling steps in stereoselective synthesis are under active
investigation in our laboratories.
Chem. Soc. 1993, 115, 10464; c) A. Hayen, R. Koch, W. Saak, D.
Haase, J. O. Metzger, J. Am. Chem. Soc. 2000, 122, 12458.
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generated from Barton esters to form achiral quaternary
carbons, see: a) D. H. R. Barton, D. Crich, G. Kretzschmar,
Tetrahedron Lett. 1984, 25, 1055; b) D. H. R. Barton, D. Crich, G.
Kretzschmar, J. Chem. Soc. Perkin Trans. 1 1986, 39.
[
[13] A. Lebsack, Ph.D. Dissertation, University of California, Irvine
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(
[
14] K. Okada, K. Okamoto, N. Morita, K. Okubo, M. Oda, J. Am.
Chem. Soc. 1991, 113, 9401.
Received: June 25, 2012
Published online: && &&, &&&&
[
15] a) Okada also reported light-promoted decarboxylative reduc-
tion, chlorination, and selenylation of N-(acyloxy)phthalimides,
see: b) K. Okada, K. Okamoto, M. Oda, J. Am. Chem. Soc. 1988,
Keywords: fragment-coupling · fused-ring systems ·
.
photoredox chemistry · terpenoids · total synthesis
1
10, 8736; c) K. Okada, K. Okamoto, M. Oda, J. Chem. Soc.
Chem. Commun. 1989, 1636; d) K. Okada, K. Okubo, N. Morita,
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Org. Chem. 1991, 56, 5826; h) M. Cano, G. Fabrias, F. Camps, J.
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[
1
[16] For important recent contributions, see: a) D. A. Nicewicz,
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stereocenters and examples, see: L. E. Overman, E. J. Velt-
huisen, J. Org. Chem. 2006, 71, 1581.
[
[
4] a) M. J. Schnermann, C. M. Beaudry, A. V. Egorova, R. S.
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Genung, S. M. Canham, N. L. Untiedt, B. D. W. Karanikolas, C.
Sutterlin, L. E. Overman, J. Am. Chem. Soc. 2011, 133, 17494.
5] M. J. Schnermann, L. E. Overman, J. Am. Chem. Soc. 2011, 133,
[
[
16425.
[
18] Available in five steps from cyclooctene oxide, see Supporting
Information for details.
6] For the initial development of this strategy in the context of
a total synthesis of a structurally less complex spongian
diterpene, see: A. D. Lebsack, L. E. Overman, R. J. Valenteko-
vich, J. Am. Chem. Soc. 2001, 123, 4851.
[
19] An excess (1.5 equiv) of the hydrogen donor was required to
suppress over-addition of methyl vinyl ketone. The use of blue
LEDs strips was experimentally convenient; the reaction took
place in similar yield using a compact fluorescent bulb.
20] W. Kreiser, P. Below, Liebigs Ann. Chem. 1985, 203.
21] The hydroxy group of the ylide was protected in situ as
a trimethylsilyl ether and then cleaved during workup using 2n
hydrochloric acid, see: M. Couturier, Y. L. Dory, F. Rouillard, P.
Deslongchamps, Tetrahedron 1998, 54, 1529.
22] a) The displacement of the primary iodide with silver nitrite was
most effective in the absence of solvent, in which case only
a slight excess of AgNO2 was required; b) This reaction is
typically carried out in ethereal solvents using 3 – 5 equiv of
[
7] M. J. Schnermann, N. L. Untiedt, G. Jimꢁnez-Osꢁs, K. N. Houk,
L. E. Overman, Angew. Chem. 2012, DOI: 10.1002/
ange.201205001; Angew. Chem. Int. Ed. 2012, DOI: 10.1002/
anie.201205001.
[
[
[
8] For select recent reviews, see: a) G. Bar, A. F. Parsons, Chem.
Soc. Rev. 2003, 32, 251; b) G. S. C. Srikanth, S. L. Castle,
Tetrahedron 2005, 61, 10377.
[
[
9] No examples of the stereoselective formation of quaternary
carbon stereocenters from intermolecular additions of alkyl-
substituted tertiary radicals to alkenes are mentioned in a recent
comprehensive treatise, see a) Quaternary Stereocenters-Chal-
lenges and Solutions for Organic Synthesis (Eds.: J. Christoffers,
A. Baro), Wiley-VCH, Weinheim, 2005, pp. 287 – 314. We are
aware of only one report of such reactions occurring with high
stereoselectivity, see: b) A. Gansꢂuer, H. Bluhm, B. Rinker, S.
Narayan, M. Schick, T. Lauterbach, M. Pierobon, Chem. Eur. J.
AgNO ; see, for example: A. T. Hewson, D. T. Macpherson, J.
Chem. Soc. Perkin Trans. 1 1985, 2625.
23] For the use of this approach in forming a perhydroazulene ring
system, see: A. P. Kozikowski, B. B. Mugrage, B. C. Wang, Z. B.
Xu, Tetrahedron Lett. 1983, 24, 3705.
2
[
[
[
[
24] T. Mukaiyama, T. Hoshino, J. Am. Chem. Soc. 1960, 82, 5339.
25] D. P. Curran, J. Am. Chem. Soc. 1983, 105, 5826.
26] We found that Raney-nickel was most effective for cleaving the
NÀO bond and Pd/C for hydrogenation of the alkene. Elevated
2003, 9, 531. For examples of such reactions that take place with
poor to moderate diastereoselectivity, see: c) W. Damm, B.
Giese, J. Hartung, T. Hasskerl, K. N. Houk, H. Zipse, J. Am.
Chem. Soc. 1992, 114, 4067; and d) A. Srikrishna, P. Hemamalini,
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temperature with either catalyst delivered the b-hydroxy ketone,
[
10] For one example, see; J. Cossy, S. Bouzbouza, A. Hakiki,
Tetrahedron 1999, 55, 11289.
albeit in reduced yield.
[27] This sequence was readily scaled; more than 25 g of 23 has been
prepared by this method.
[28] This mixture of isomers is inconsequential; it can be carried
forward to the coupling reaction or separated at this stage.
[
11] The addition of achiral tertiary radicals to chiral alkenes often
take place with higher diastereoselectivity than the correspond-
ing reactions of secondary and primary radicals; see, for
4
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Angewandte
Chemie
[
29] The use of HMPA is required in this reaction; in its absence 25
was not observed and only complex mixtures of products were
obtained.
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[33] The use of the corresponding a-bromoenone (13, X = Br) in the
radical coupling reaction resulted in extensive reductive debro-
mination of coupled product.
[
30] Available in 83% yield by chlorination of the corresponding
[
4]
[31]
enone with the Mioskowski reagent (Et NCl ), at 08C.
4
3
[
31] T. Schlama, K. Gabriel, V. Gouverneur, C. Mioskowski, Angew.
Chem. 1997, 109, 2440; Angew. Chem. Int. Ed. Engl. 1997, 36,
[34] a) R. S. Andrews, J. J. Becker, M. R. Gagnꢁ, Angew. Chem. 2010,
122, 7432; Angew. Chem. Int. Ed. 2010, 49, 7274; b) R. S.
Andrews, J. J. Becker, M. R. Gagnꢁ, Org. Lett. 2011, 13, 2406.
2342.
[
16d,34]
[
32] The relative configuration of 30 was secured by crystallographic
analysis: CCDC 885482 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
[35] In line with previous observations,
we found that the use of
29 in conjunction with N,N-disopropylethylamine was essential
for realizing high yields and short reaction times.
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Total Synthesis
M. J. Schnermann,
L. E. Overman*
&&&& — &&&&
A Concise Synthesis of (À)-Aplyviolene
Facilitated by a Strategic Tertiary Radical
Conjugate Addition
A second-generation synthesis of the
rearranged spongian diterpene aplyvio-
lene is reported. The key step is the
addition of a trialkyl tertiary radical gen-
erated by photoredox-mediated fragmen-
tation of a N-(acyloxy)phthalimide to an
a-chloropentenone (see scheme). This
process fashioned a quaternary stereo-
center while combining two units of
significant complexity.
6
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
These are not the final page numbers!