Et3B-mediated radical-polar crossover reaction for single-step coupling of O,Te-acetal, α,β-unsaturated ketones, and aldehydes/ketones

Article abstract of DOI:10.1021/ol402563v

Et₃B-mediated three-component coupling reactions between O,Te-acetal, α,β-unsaturated ketones, and aldehydes/ketones were developed. Et₃B promoted the generation of the potently reactive bridgehead radical from the O,Te-acetal of the

Full text of DOI:10.1021/ol402563v

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Et3B‑Mediated Radical-Polar Crossover
Reaction for Single-Step Coupling of O,
Te-Acetal, r,β-Unsaturated Ketones, and
Aldehydes/Ketones
Daigo Kamimura, Daisuke Urabe, Masanori Nagatomo, and Masayuki Inoue*
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan
inoue@mol.f.u-tokyo.ac.jp
Received September 5, 2013
ABSTRACT
Et3B-mediated three-component coupling reactions between O,Te-acetal, R,β-unsaturated ketones, and aldehydes/ketones were developed. Et3B
promoted the generation of the potently reactive bridgehead radical from the O,Te-acetal of the trioxaadamantane structure and converted the
R-carbonyl radical of the resultant two-component adduct to the boron enolate, which then underwent a stereoselective aldol reaction with the
aldehyde/ketone. This powerful, yet mild, radical-polar crossover reaction efficiently connected the hindered linkages between the three units and
selectively introduced three new stereocenters.
One-pot, three-component coupling is a powerful and
rapid means for construction of functionalized molecules1
because it minimizes the number of synthetic operations
and maximizes the build up of structural and functional
complexity. While these reactions have historically employed
either ionic or radical processes, the in situ combination of
radical and ionic reactions, designated as radical-polar
crossover reactions, has recently emerged.2,3 Since the re-
activities of the radical and ionic intermediates are ortho-
gonal, sequential application of these two mechanisms
offers great advantages in the assembly of complex mole-
cular architectures. Despite these synthetically valuable
features, these reactions have been unexplored in the context
of target-oriented synthesis.
Multiply fused and highly oxygenated structures of
terpenoids generally present a daunting synthetic challenge
(Scheme 1).4 We have been interested in developing new
three-component coupling reactions for construction of the
substructures of bioactive terpenoids, such as cytotoxic
trigohownin A5 and potassium channel blocker correolide.6
These compounds share a common motif, in which the
(1) For recent reviews on the multicomponent reactions, see: (a)
ꢀ
Multicomponent Reactions; Zhu, J., Bienayme, H., Eds.; Wiley-VCH:
ꢀ
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H. Chem. Rev. 2013, 113, 442.
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Sasaki, M. J. Am. Chem. Soc. 1978, 100, 4314. (b) Nozaki, K.; Oshima,
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Takai, K.; Matsukawa, N.; Takahashi, A.; Fujii, T. Angew. Chem., Int.
Ed. 1998, 37, 152. (f) Bazin, S.; Feray, L.; Siri, D.; Naubron, J.-V.;
Bertrand, M. P. Chem. Commun. 2002, 2506. (g) Yamamoto, Y.;
Nakano, S.; Maekawa, H.; Nishiguchi, I. Org. Lett. 2004, 6, 799. (h)
Godineau, E.; Landais, Y. J. Am. Chem. Soc. 2007, 129, 12662.
(3) For reviews on the radical-polar cross over reactions, see: (a) Ryu,
I. Chem. Rec. 2002, 2, 249. (b) Murphy, J. A. The Radical-Polar
Crossover Reaction. In Radicals in Organic Synthesis, Renaud, P., Sibi,
M. P., Eds.; Wiley-VCH: Weinheim, 2001; Vol. 1, pp 298. (c) Godineau, E.;
Landais, Y. Chem.;Eur. J. 2009, 15, 3044.
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K. C.; Vourloumis, D.; Winssinger, N.; Baran, P. S. Angew. Chem., Int.
Ed. 2000, 39, 44. (b) Maimone, T. J.; Baran, P. S. Nature Chem. Biol.
2007, 3, 396.
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Prod. 2011, 74, 1255.
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F.; Tamayo-Castillo, G.; Slaughter, R. S.; Felix, J.; Ball, R. G. Tetra-
hedron Lett. 1998, 39, 2895.
r
10.1021/ol402563v
XXXX American Chemical Society

tetrasubstituted carbon of the highly oxygenated cyclohex-
anol derivatives is linked to the tertiary carbon of the 2,3-
trans-disubstituted cycloalkane structures (highlighted in
blue and red). Here, we report development of a novel
three-component coupling reaction using O,Te-acetal 1,
R,β-unsaturated ketone 2, and aldehyde/ketone 3. The single-
step reaction proceeded through the radical-polar crossover
mechanism under mild conditions and generated the complex
ring connection motifs (4) of trigohownin A or correolide
with stereoselective formation of the one CÀO and two CÀC
bonds.
Scheme 2. Preparation and Et3B-Mediated Radical Reaction of
O,Se-Acetal A and O,Te-Acetal 1a
Scheme 1. Plan of Radical-Polar Crossover Reaction
a EDCI = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.
of the highly activated CÀTe bond of 1 to produce R-
alkoxy bridgehead radical B.8À12 Since the sterically un-
shielded radical B possesses potent reactivity as a nucleo-
philic radical, a congested CÀC bond would be formed
through the intermolecular addition of B to cycloalkenone
2, leading to C. Radical intermediate C would then be
converted to anionic intermediate E via the reaction with
Et3B and subsequent ejection of ethyl radical.2b,13 Finally,
aldol reaction of the resultant boron enolate E with the
carbonyl group of 3 would yield 4. This attractive sequen-
tialreaction can onlybe realizedwhen the reactivityofeach
component is completely differentiated and Et3B enables
theradicalinitiating(1fB) andtrapping processes(CfE).
We previously reported the radical-based three-component
coupling of O,Se-acetal A, R,β-unsaturated ketone 2, and
allyl tributyltin (Scheme 1).10 The CÀSe bond of A was
homolytically cleaved by the action of tributyltin radical
at 110 °C, and two subsequent radical reactions led to
product D. Thus, A was first treated with Et3B, the key
ingredient of the radical-polar crossover process (Scheme 2).
However, the CÀSe bond was found to be inert upon
treatment with Et3B/O2 at 0 °C, and A was almost quanti-
tatively recovered. Therefore, the CÀSe bond in A was
replaced with the weaker CÀTe bond in the alternative
A possible scenario of the radical-polar reaction is
illustrated in Scheme 1. We selected O,Te-acetal 1 with
the 2,4,10-trioxadamantane orthoester structure as the
radical precursor and Et3B as the radical initiator and
terminator. Ethyl radical, which is generated by the reac-
tion of Et3B and O2,7 would induce the homolytic cleavage
(9) For a review on bridgehead radicals, see: Walton, J. C. Chem. Soc.
Rev. 1992, 21, 105.
(10) Urabe, D.; Yamaguchi, H.; Inoue, M. Org. Lett. 2011, 13, 4778.
(11) Murai, K.; Katoh, S.; Urabe, D.; Inoue, M. Chem. Sci 2013, 4, 2364.
(12) Bridgehead radicals have been rarely used for synthetic studies
on natural products; for example, see: (a) Kraus, G. A.; Andersh, B.; Su,
Q.; Shi, J. Tetrahedron Lett. 1993, 34, 1741. (b) Kraus, G. A.; Su, Q.
Synlett 1994, 237. (c) Kraus, G. A.; Siclovan, T. M.; Watson, B. Synlett
1995, 201. (d) Kim, S.; Cheong, J. H. Synlett 1997, 947.
(13) Nozaki, K.; Oshima, K.; Utimoto, K. Bull. Chem. Soc. Jpn.
1991, 64, 403.
(14) (a) Curran, D. P.; Martin-Esker, A. A.; Ko, S.-B.; Newcomb, M.
J. Org. Chem. 1993, 58, 4691. (b) Smart, B. A.; Schiesser, C. H. J. Chem.
Soc., Perkin. Trans. 2 1994, 2269. (c) Schiesser, C. H.; Smart, B. A.
Tetrahedron 1995, 51, 6051.
(7) (a) Nozaki, K.; Oshima, K.; Utimoto, K. J. Am. Chem. Soc. 1987,
109, 2547. For a review, see: (b) Ollivier, C.; Renaud, P. Chem. Rev. 2001,
101, 3415.
(8) (a) Barton, D. H. R.; Ozbalik, N.; Sarma, J. C. Tetrahedron Lett.
1988, 29, 6581. (b) He, W.; Togo, H.; Waki, Y.; Yokoyama, M. J. Chem.
Soc., Perkin. Trans. 1 1998, 2425.
B
Org. Lett., Vol. XX, No. XX, XXXX

radical donor 1.14,15 Condensation of carboxylic acid 5
with 2-mercaptopyridine N-oxide using EDCI yielded
Barton ester 6,16 which was immediately photoirradiated
in the presence of (PhTe)2 to afford the requisite O,Te-
acetal 1.17,18 The reaction of 1 and cyclopentenone 2a
(3 equiv) in the presence of Et3B (3 equiv) under air in CH2Cl2
proceeded at 0 °C within 15 min to produce 7 in 85% yield.
This facile adduct formation at low temperature without
the toxic tin reagent19,20 clearly demonstrated the super-
iority of 1 over A as the radical donor. When CH3OD
(10 equiv) was present in the same reaction mixture,
deuterated 7-d1 (85% D) was exclusively obtained, indicat-
ing that the boron enolate was indeed formed and quenched
by the acidic deuteron of CH3OD.
substructure of correolide. These results demonstrated the
potential utility of the present one-pot reaction in building up
the multiply oxygenated natural products.
The stereostructures of the coupling products 4a and 4c
were established by X-ray crystallography, and the stereo-
chemistries of 4b, 4d, and 4e were confirmed by NMR
experiments on derivatized compounds.22 Importantly,
Table 1. Three-Component Coupling of 1, 2aÀd, and 3aa
Once the radical initiating and trapping ability of Et3B
was verified by the deuteration experiment, benzaldehyde
3a was applied as the third component together with O,Te-
acetal 1 and various cycloalkenones 2aÀd (Table 1). When
a mixture of 1, cyclopentenone 2a and 3a was treated
with Et3B/O2 in CH2Cl2 at 0 °C for 15 min, the coupling
adduct 4a was produced through stereoselective installation
of the three new stereocenters (89%, 9:1 dr at the benzylic
position, entry 1). The radical addition to 4-TBSoxycyclo-
pentenone 2b proceeded selectively from the opposite face of
the C4-substituent, giving rise to 4b as a single diastereomer
(entry 2). Moreover, 2-acetoxycyclopentenone 2c21 under-
went the three-component coupling with 1 and 3a to provide
4c (entry 3). Not only the cyclopentenone structures but also
cyclohexenone 2d (entry 4) was applicable as the radical
acceptors. However, the aldol adduct 4d was prone to under-
go retroaldol reactions to produce large amounts of the two-
component adduct 8 under the original conditions (entry 4).
To increase the yield of the three-component adduct over the
two-component counterpart, 4d was silylated in the same pot
(entry 5). As a result, TMS-ether 4e was isolated in 73% yield
(3:2 dr). It is worth noting that the four contiguous stereo-
centers in 4c directly matched those of trigohownin A (circled
in gray in Scheme 1), and compound 4e possessed the bicyclic
a Conditions: 1 (1 equiv), 2 (3 equiv), 3a (3 equiv), Et3B (3 equiv),
CH2Cl2 (0.1 M), 0 °C, 15 min. b 4a was obtained as the major isomer.
c Product was obtained as a single isomer. d Conditions: 1 (1 equiv), 2c
(2 equiv), 3a (5 equiv), Et3B (3 equiv), CH2Cl2 (0.1 M), rt, 60 min.
e Conditions: 1 (1 equiv), 2d (2 equiv), 3a (5 equiv), Et3B (3 equiv),
CH2Cl2 (0.1 M), 0 °C, 15 min. f Compound 8 was obtained in 65% yield.
g Conditions: 1 (1 equiv), 2d (2 equiv), 3a (5 equiv), Et3B (3 equiv),
CH2Cl2 (0.1 M), 0 °C, 15 min; TMS-imidazole (10 equiv), DMAP
(0.3 equiv), 0 °C, 3 h. Compound 4e was obtained as the major isomer.
(15) For reviews on radical reactions using organotellurium com-
pounds, see: (a) Togo, H.; He, W.; Waki, Y.; Yokoyama, M. Synlett
1998, 700. (b) Yamago, S. Synlett 2004, 1875. (c) Petragnani, N.; Stefani,
H. A. Tellurium in Organic Synthesis, 2nd, updated and enlarged ed.;
Elsevier: New York, 2007.
(16) (a) Barton, D. H. R.; Crich, D.; Motherwell, W. B. J. Chem. Soc.,
Chem. Commun. 1983, 939. For reviews on Barton esters, see: (b) Crich,
D.; Quintero, L. Chem. Rev. 1989, 89, 1413. (c) Saraiva, M. F.; Couri,
M. R. C.; Hyaric, M. L.; de Almeida, M. V. Tetrahedron 2009, 65, 3563.
(17) Barton, D. H. R.; Bridon, D.; Zard, S. Z. Tetrahedron Lett. 1984,
25, 5777.
(18) For CÀC bond formations using O,Te-acetals as radical pre-
cursors, see: (a) Barton, D. H. R.; Ramesh, M. J. Am. Chem. Soc. 1990,
112, 891. (b) He, W.; Togo, H.; Yokoyama, M. Tetrahedron Lett. 1997,
38, 5541. (c) Yamago, S.; Miyazoe, H.; Yoshida, J. Tetrahedron Lett.
1999, 40, 2343. (d) Miyazoe, H.; Yamago, S.; Yoshida, J. Angew. Chem.,
Int. Ed. 2000, 39, 3669. (e) Yamago, S.; Miyazoe, H.; Goto, R.;
Hashidume, M.; Sawazaki, T.; Yoshida, J. J. Am. Chem. Soc. 2001,
123, 3697. (f) Yamago, S.; Miyoshi, M.; Miyazoe, H.; Yoshida, J.
Angew. Chem., Int. Ed. 2002, 41, 1407. (g) Yamago, S.; Iida, K.; Yoshida,
J. J. Am. Chem. Soc. 2002, 124, 2874. See also ref 8b.
the stereochemical relationship of the newly introduced
three centers of 4aÀc was consistent. This remarkable
selectivity isexplained by the six-memberedtransitionstate
model depicted in Figure 1.23 After the addition of bridge-
head radical B to the radical acceptor and subsequent
formation of boron enolate E, 3a can only approach from
the face opposite to the bulky trioxadamantane structure,
thereby establishing the trans-relationship between the
radical donor and the electrophile. The chairlike six-membered
(22) See the Supporting Information for details.
€
(19) Boyer, I. J. Toxicology 1989, 55, 253.
(20) For a review on tin-free radical reactions, see: Baguley, P. A.;
Walton, J. C. Angew. Chem., Int. Ed. 1998, 37, 3072.
(21) (a) Maignan, C.; Rouessac, F. Bull. Soc. Chim. Fr. 1971, 3041.
(b) Lange, G. L.; Campbell, H. M.; Neidert, E. J. Org. Chem. 1973, 38,
2117.
(23) (a) Fenzl, W.; Koster, R. Liebigs Ann. Chem. 1975, 1322. (b)
Inoue, T.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 1980, 53, 174. (c) Evans,
D. A.; Nelson, J. V.; Vogel, E.; Taber, T. R. J. Am. Chem. Soc. 1981, 103,
3099. For reviews on aldol reactions using boron enolate, see: (d)
Mukaiyama, T. Org. React. 1982, 28, 203. (e) Cowden, C. J.; Paterson,
I. Org. React. 1997, 51, 1.
Org. Lett., Vol. XX, No. XX, XXXX
C

Thereactionsofenolizableacetaldehyde3band n-heptanal
3c with O,Te-acetal 1, cyclopentenone 2a and Et3B/O2
resulted in efficient formation of 4f and 4g, respectively, as
the sole stereoisomers (entries 1 and 2). The sterically more
cumbersome aliphatic aldehydes 3d and 3e also served as
electrophiles without decreasing the yields to afford 4h and
4i, respectively (entries 3 and 4). Even the R,β-unsaturated
aldehydes 3f and 3g were found to be applicable to the three-
component coupling reactions (entries 5 and 6), although
these compounds can function as both radical and carba-
nion acceptors. The bridgehead radical B was preferentially
added to R,β-unsaturated ketone 2a in the presence of 3f and
3g, and the resultant boron enolate selectively reacted with
the aldehyde, leading to 4j and 4k, respectively. Signifi-
cantly, the adducts 4fÀk were obtained as single isomers,
further supporting the stereochemical rationale in Figure 1.
When acetone 3h was mixed with 1 and 2a in the
presence of Et3B/O2, the in situ aldol reaction constructed
a new tetrasubstituted carbon center to afford 4l (entry 7).
Furthermore, the three cyclic structures were connected in
a single step upon using the cyclic ketones (entries 8À11).
Cyclopentanone 3i and cyclohexanone 3j were coupled
with 1 and 2a to deliver the tricarbocyclic structures 4m
and 4n, respectively (entries 8 and 9). The tetrahydropyran
and piperidine structureswereeffectivelyincorporatedinto
the coupling adducts 4o and 4p by using 3k and 3l,
respectively, as the third components (entries 10 and 11).
The smooth formation of 4lÀp under mild conditions
reflected the generality of the present method for connecting
the sterically hindered bonds between the three components.
In conclusion, we have developed a new three-component
coupling reaction to construct 4 from O,Te-acetal 1,
R,β-unsaturated ketone 2 and aldehyde/ketone 3 by the
action of Et3B and O2. The single-step reaction simulta-
neously constructed the bridgehead carbon center in a stereo-
specific fashion, and the contiguous three stereocenters in a
stereoselective fashion. The tin-free procedure, the mild
conditions, the broad substrate scope, the high stereoselectiv-
ity, and the efficient construction of the two hindered linkages
are particularly useful features for the target-oriented syn-
thesis. Because of these advantages, this three-component
coupling introduces a novel and valuable strategy for stream-
lined synthesis of multiply functionalized terpenoids with
complex architectures.
Figure 1. Rationale of the stereochemical outcome.
Table 2. Three-Component Couplings of 1, 2a, and 3bÀla
Acknowledgment. This research was financially sup-
ported by the Funding Program for Next Generation
World-Leading Researchers (JSPS) to M.I. and a Grant-
in-Aid for Young Scientists (B) (JSPS) to D.U. We thank
S. Yoshioka, Dr. Y. Inokuma, and Prof. M. Fujita (all at
The University of Tokyo) and Dr. K. Yoza (Bruker AXS)
for X-ray crystallographic analyses.
a Conditions: 1 (1 equiv), 2a (3 equiv), 3 (3 equiv), Et3B (3 equiv),
CH2Cl2 (0.1 M), 0 °C, 15 min. b Product was obtained as a single isomer.
c 10 equiv of 3b was used. d Conditions: 1 (1 equiv), 2a (2 equiv), 3
(5 equiv), Et3B (3 equiv), CH2Cl2 (0.1 M), rt, 60 min. e 2 equiv of 2a was
used. f Conditions: 1 (1 equiv), 2a (2 equiv), 3 (5 equiv), Et3B (3 equiv),
CH2Cl2 (0.1 M), 0 °C, 15 min. g Compound 7 was obtained in 63% yield.
Supporting Information Available. Experimental pro-
cedures and spectroscopic and analytical data for relevant
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
transition state F would then control the stereocenters of the
R- and β-positions of the ketone, resulting in formation of
the adduct 4 in a stereoselective fashion.
The broad scope of the present coupling was further
demonstrated using3bÀl asthe third component (Table2).
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX