Construction of carbo- And heterocycles using radical relay cyclizations initiated by alkoxy radicals

Article abstract of DOI:10.1021/ol900481e

An efficient method for the rapid construction of carbo- and heterocycles has been developed using radical relay cyclizations initiated by alkoxy radicals. Linear substrates were cyclized to form a wide range of cyclopentane, pyrrolidine, tetrahydropyran, and tetrahydrofuran derivatives in excellent yields. This methodology was utilized as a key step in the synthesis of the tetrahydrofuran fragment in (-)-amphidino-lide K.

Full text of DOI:10.1021/ol900481e

ORGANIC
LETTERS
2009
Vol. 11, No. 9
2019-2022
Construction of Carbo- and
Heterocycles Using Radical Relay
Cyclizations Initiated by Alkoxy Radicals
Hai Zhu, Jason G. Wickenden, Natalie E. Campbell, Joe C. T. Leung, Kayli
M. Johnson, and Glenn M. Sammis*
Department of Chemistry, 2036 Main Mall, UniVersity of British Columbia,
VancouVer, British Columbia V6T 1Z1, Canada
gsammis@chem.ubc.ca
Received March 7, 2009
ABSTRACT
An efficient method for the rapid construction of carbo- and heterocycles has been developed using radical relay cyclizations initiated by
alkoxy radicals. Linear substrates were cyclized to form a wide range of cyclopentane, pyrrolidine, tetrahydropyran, and tetrahydrofuran
derivatives in excellent yields. This methodology was utilized as a key step in the synthesis of the tetrahydrofuran fragment in (-)-amphidino-
lide K.
In the search for new methods that rapidly increase molecular
complexity from simple starting materials, there is increasing
emphasis on developing new techniques to convert unacti-
vated C-H bonds into reactive intermediates for the forma-
tion of carbon-carbon bonds. Significant advances have been
made in this field, particularly with metal-mediated meth-
odologies.1,2 Radical abstractions of C-H bonds serve as a
useful complement to these metal-mediated processes as
radicals display excellent functional group tolerance.3 For
example, vinyl and aryl radicals readily undergo a 1,5-
hydrogen abstraction4 followed by cyclization to afford
complex carbocycles.5-7 While these radical relay cycliza-
tions have been utilized in the synthesis of several natural
products,7 the overall versatility of the methodology is limited
(3) For reviews on carbon-radical cyclizations, see: (a) Ramaiah, M.
Tetrahedron 1987, 43, 3541–3676. (b) Curran, D. P. In ComprehensiVe
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford,
1991; Vol. 4, Chapter 4.1, pp 715-777. (c) Giese, B.; Kopping, B.; Go¨bel,
T.; Dickhaut, J.; Thoma, G.; Kulicke, K. J.; Trach, F. In Organic Reactions;
Paquette, L., Eds.; John Wiley & Sons, Inc.: New York, 1996; Vol. 48,
Chapter 2, pp 303-856. (d) Gansa¨uer, A.; Bluhm, H. Chem. ReV. 2000,
100, 2771–2788. (e) Curran, D. P. Synthesis 1988, 417–439. (f) Curran,
D. P. Synthesis 1988, 489–513
.
(4) 1,5-Hydrogen abstractions with subsequent functionalizations have
been studied extensively by Breslow. For a review, see: Breslow, R. Acc.
Chem. Res. 1980, 13, 170–177
.
(1) For recent advances, see: (a) Kalyani, D.; Deprez, N. R.; Desai, L. V.;
Sanford, M. S. J. Am. Chem. Soc. 2005, 127, 7330–7331. (b) Thalji, R. K.;
Ellman, J. A.; Bergman, R. G. J. Am. Chem. Soc. 2004, 126, 7192–7193.
(c) Huang, Q.; Fazio, A.; Dai, G.; Campo, M. A.; Larock, R. C. J. Am.
Chem. Soc. 2004, 126, 7460–7461. (d) Wakui, H.; Kawasaki, S.; Satoh,
T.; Miura, M.; Nomura, M. J. Am. Chem. Soc. 2004, 126, 8658–8659. (e)
Campeau, L.-C.; Parisien, M.; Leblanc, M.; Fagnou, K. J. Am. Chem. Soc.
2004, 126, 9186–9187. (f) Orito, K.; Horibata, A.; Nakamura, T.; Ushito,
H.; Nagasaki, H.; Yuguchi, M.; Yamashita, S.; Tokuda, M. J. Am. Chem.
(5) For early reports on the use of vinyl radicals for radical relay
cyclizations, see: (a) Heiba, E. I.; Dessau, R. M. J. Am. Chem. Soc. 1967,
89, 3772–3777. (b) Chenera, B.; Chuang, C.-P.; Hart, D. J.; Hsu, L.-Y. J.
Org. Chem. 1985, 50, 5409–5410. (c) Bennett, S. M.; Clive, D. L. J.
J. Chem. Soc., Chem. Commun. 1986, 878–880. (d) Lathbury, D. C.; Parsons,
P. J.; Pinto, I. J. Chem. Soc., Chem. Commun. 1988, 81–82. Curran, D. P.;
Kim, D.; Liu, H. T.; Shen, W. J. Am. Chem. Soc. 1988, 110, 5900–5902.
(e) Borthwick, A. D.; Caddick, S.; Parsons, P. J. Tetrahedron Lett. 1990,
31, 6911–6914
.
Soc. 2004, 126, 14342–14343
.
(6) For early reports on the use of aryl radicals for radical relay
cyclizations, see: (a) Snieckus, V.; Cuevas, J.-C.; Sloan, C. P.; Liu, H.;
Curran, D. P. J. Am. Chem. Soc. 1990, 112, 896–898. (b) Curran, D. P.;
Abraham, A. C.; Liu, H. J. Org. Chem. 1991, 56, 4335–4337. (c) Beckwith,
A. L. J.; O’Shea, D. M.; Gerba, S.; Westwood, S. W. J. Chem. Soc., Chem.
(2) For reviews, see: (a) Davies, H. M.; Manning, J. R. Nature (London)
2008, 451, 417–424. (b) Kakiuchi, F.; Chatani, N. AdV. Synth. Catal. 2003,
345, 1077–1101. (c) Davies, H. M.; Beckwith, R. E. J. Chem. ReV. 2003,
103, 2861–2904. (d) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. ReV. 2002,
102, 1731–1770
.
Commun. 1987, 666–667.
10.1021/ol900481e CCC: $40.75
Published on Web 03/27/2009
 2009 American Chemical Society

either by cyclization back onto the vinyl group or by the
resulting aryl-incorporated products.
produce 7 should be slower than the rate of cyclization to
form cyclized product 5. Trapping of the primary radical 5
with tributyltin hydride should then provide desired cyclized
product 6.
We began our study by optimizing the rate of addition of
tributyltin hydride in a radical relay cyclization using
N-alkoxyphthalimide 1a (Table 1, entries 1-3). Addition of
Radical relay cyclizations initiated by oxygen-centered
radicals are an attractive alternative to carbon-based initiators
as the oxygenated product facilitates further synthetic
transformations. While oxygen-centered radical promoted
1,5-hydrogen abstractions have been utilized extensively for
remote functionalizations,8,9 there are few examples of the
abstraction followed by a subsequent carbon-carbon bond-
forming reaction10-12 and no general solution for the
cyclization of linear substrates.
Table 1. Optimization Studies on the Rate of Addition of the
Metal Hydride
There are only two attempts at cyclizing acyclic
substrates.11a,b One example employs a radical relay cycliza-
tion initiated by a radical epoxide fragmentation.13 This
indirect method for generating oxygen-centered radicals
results in the formation of the cyclization acceptor.11b,c
Directly forming the oxygen-centered radical from homolysis
of an oxygen-heteroatom bond would enhance the generality
of cyclization from linear substrates as it allows for the
incorporation of different cyclization acceptors. The only
example of a direct oxygen-centered radical formation in a
linear system provided the resulting carbocycles in only
25-32% yield.11a We sought to develop a general solution
for the cyclization of simple linear precursors to carbo- and
heterocycles that allows flexibility in the choice of acceptor.
The problem with oxygen-centered radical-initiated relay
cyclizations is undesired quenching of the radical prior to
cyclization.11a We hypothesized that it is crucial to control
the concentration of the trapping agent during the course of
the radical relay cyclization to maximize the yield of cyclized
product. We were, therefore, interested in using N-alkox-
yphthalimides as oxygen-centered radical precursors (Scheme
1). The reaction of tributyltin hydride with N-alkoxyphthal-
metal
hydride
reaction
cyclization/
entrya
addition
time (h) linear (6a/7a)b
1
2
3
4
5
6
Bu3SnH
Bu3SnH
Bu3SnH
Ph3SnH
Ph3SnH
one portion
1 mL/h
0.5 mL/h
one portion
0.5 mL/h
1
2
3
1
3
1
77:23
92:8
95:5
67:33
80:20
90:10
(TMS)3SiH one portion
a Reactions were carried out on a 0.17 mmol scale. b Conversions
determined by NMR spectroscopic analyses of crude reaction mixtures.
tributyltin hydride in one portion (entry 1) provided a similar
distribution of cyclized (6a) to linear product (7a) as was
obtained with a comparable substrate.11a However, decreas-
ing the rate of addition of tributyltin hydride afforded the
desired cyclized product to linear alcohol in a ratio of up to
95:5 (entries 2 and 3). Slow addition of triphenyltin hydride
also provided the cyclized product (entries 4 and 5), although
the effect was not as pronounced as was observed with
tributyltin hydride (entry 3 vs entry 5). The same reaction
can be affected under tin-free cyclization conditions using
tris(trimethylsilyl)silane (entry 6).15,16 Since the rate of
Scheme 1
(7) For a recent review, see: Robertson, J.; Pillai, J.; Lush, R. K. Chem.
Soc. ReV. 2001, 30, 94–103
.
(8) For early reports, see: (a) Cainelli, G.; Mihaiovic, M. L.; Arigoni,
D.; Jeger, O. HelV. Chim. Acta 1959, 42, 1124–1127. (b) Barton, D. H. R.;
Beaton, J. M.; Geller, L. E.; Pechet, M. M. J. Am. Chem. Soc. 1960, 82,
2640–2641. (c) Barton, D. H. R.; Beaton, J. M.; Geller, L. E.; Pechet, M. M.
J. Am. Chem. Soc. 1960, 82, 2641–2641
.
ˇ
(9) For recent reviews and representative examples, see: (a) Cekovic´,
ˇ
ˇ
ˇ
Z. Serb. J. Chem. Soc. 2005, 70, 287–318. (b) Cekovic´, Z. Tetrahedron
ˇ
2003, 59, 8073–8090. (c) Hartung, J.; Gottwald, T.; Spehar, K. Synthesis
ˇ
ˇ
2002, 1469–1498. (d) Petrovic´, G.; Cekovic´, Z. Tetrahedron 1999, 55, 1377–
1390. (e) Majetich, G.; Wheless, K. Tetrahedron 1995, 51, 7095–7129. (f)
ˇ
ˇ
Petrovic´, G.; Saiˇıc´, R. N.; Cekovic´, Z. Tetrahedron 2003, 59, 187–196
.
ˇ
ˇ
(10) For intermolecular examples, see: (a) Petrovic´, G.; Cekovic´, Z.
Tetrahedron Lett. 1997, 38, 627–630. (b) Tsunoi, S; Ryu, I.; Okuda, T.;
Tanaka, M.; Komatsu, M.; Sonoda, N. J. Am. Chem. Soc. 1998, 120, 8692–
8701. (c) Mart´ın, A.; Pe´rez-Mart´ın, I.; Quintanal, L. M.; Sua´rez, E.
Tetrahedron Lett. 2008, 49, 5179–5181
.
ˇ
ˇ
imide 1 results in the formation of alkoxy radical 3 and
byproduct 2,14 which is completely unreactive under these
reaction conditions. The oxygen-centered radical can then
undergo a 1,5-hydrogen abstraction to provide radical 4. If
the concentration of tributyltin hydride is kept low, through
slow addition, then the rate of the hydrogen-quench to
(11) For intramolecular examples, see: (a) Cekovic´, Z.; Ilijev, D.
Tetrahderon Lett. 1988, 29, 1441–1444. (b) Rawal, V. H.; Newton, R. C.;
Krishnamurthy, V. J. Org. Chem. 1990, 55, 5181–5183. (c) Rawal, V. H.;
Krishnamurthy, V. Tetrahedron Lett. 1992, 33, 3439–3442. (d) Moman,
E.; Nicoletti, D.; Mourin˜o, A. Org. Lett. 2006, 8, 1249–1251
(12) For a single example of a radical relay cyclization initiated by a
nitrogen-centered radical, see: Kim, S.; Yeon, K. M.; Yoon, K. S.
.
Tetrahedron Lett. 1997, 38, 3919–3922
.
2020
Org. Lett., Vol. 11, No. 9, 2009

hydrogen abstraction for the silane is slower than for the
stannane, a slow addition rate was not required to obtain
good selectivity for cyclized product 6a.
Table 2. Radical Relay Carbo- and Heterocyclizations
With the basic reactivity and cyclization selectivity
established, we sought to investigate the substrate scope of
this transformation (Table 2). Simple cyclopentane derivative
6a could be isolated in high yields as a 75:25 mixture of cis
to trans isomers (entry 1). The syntheses of cyclohexanes
using homologated N-alkoxyphthalimides provided only
moderate amounts of cyclized product (<30% isolated yield)
in poor diastereoselectivity. Analysis of the crude reaction
by NMR spectroscopy revealed a 79:21 ratio of cyclohexane
to 9-decen-1-ol, presumably arising from quenching the
radical prior to cyclization. Attempts to synthesize 8- and
9-membered rings using this methodology were unsuccessful
and provided only linear alcohols.
Secondary and tertiary N-alkoxyphthalimides (entries 2 and
3) were also viable substrates for the radical relay cyclization.
Secondary oxygen-centered radical precursor 1b provided
an 80:20 mixture of cis to trans cyclopentane isomers in
66% yield. The corresponding tertiary oxygen-centered
radical precursor (1c) provided comparable ratios of cyclized
product to straight-chain alcohol. The yield and diastereo-
selectivities for both cyclizations were also comparable.
We then studied how the cyclization was affected by aryl
substituents on the olefinic acceptor (entries 4 and 5).
Cyclization of 1d, containing a terminally substituted phenyl
group (entry 4),17 afforded cyclopentane derivative 6d in
comparable conversion and diastereoselectivity to cycliza-
tions with terminal alkenes (entries 1-3). The isolated yield
is lower because an additional silylation step was needed to
allow for separation from tin byproduct 2. Geminally
substituted alkene 1e (entry 5) resulted in a 6-endo cycliza-
tion to form cyclohexane 6e in a 65:35 mixture of trans to
cis isomers.
For this radical relay methodology to have broader
synthetic utility, it would be valuable to access additional
functional handles after cyclization. One possibility is to
cyclize onto silyl enol ethers, as the reaction provides a
protected alcohol in the product. Siloxy-substituted olefin
1f (entry 6) proved to be an excellent acceptor, providing
cyclopentane derivative 6f in 63% yield and moderate
diastereoselectivity. Another valuable functionality is a
carbonyl group on the cyclopentane ring. Cyclization of
ketone 1g primarily provided the straight-chain hydrogen-
quenched product (7g); thus, very low yields of cyclopen-
tanone 6g were obtained. However, the ketal can be readily
a Reactions were carried out on a >0.25mmol scale. b The relative
stereochemistry was determined by NOE experiments. c Isolated yields of
the mixture of diastereomers after flash chromatography. d The diastereo-
meric ratio was determined by 1H NMR spectroscopy. e Ph3SnH was used
as a metal hydride source to facilitate purification of the cyclized product.
f Substrate 1d was cyclized using the standard procedure and then converted
to the silyl ether. See the Supporting Information for details. g The isolated
yield corresponds to a two-step cyclization/silylation procedure.
cyclized to the corresponding protected cyclopentanone (6h)
in good yield and in a 58:42 ratio of cis- to trans-fused
isomers.
(13) The cyclized product was obtained in 50% yield. The diastereomeric
ratio was not reported. See ref 11b.
(14) (a) Kim, S.; Lee, T. A.; Song, Y. Synlett 1998, 471–472. (b) Okada,
K.; Okamoto, K.; Oda, M. J. Am. Chem. Soc. 1998, 110, 8736–8738. (c)
Barton, D. H. R.; Blundell, P.; Jaszberenyl, J. C. Tetrahedron Lett. 1989,
30, 2341–2344.
(15) For the development of tris(trimethylsilyl)silane as a radical
reducing agent, see: Chatgilialoglu, C.; Griller, D.; Lesage, M. J. Org. Chem.
1988, 53, 3641–3642.
(16) For the use of tris(trimethylsilyl)silane in the generation of oxygen-
centered radicals, see ref 14a.
With the successful application of this radical relay
methodology to the formation of cyclopentane derivatives,
we next focused on the formation of heterocycles. Nitrogen-
containing substrate 1i readily cyclized to pyrrolidine 6i in
63% yield and in moderate diastereoselectivity (entry 9).
1
Uncyclized aminoalcohol 7i was not observed by H NMR
(17) The E/Z ratio is 3:1. See the Supporting Information for details.
spectroscopic analysis of crude reaction mixtures. Similar
Org. Lett., Vol. 11, No. 9, 2009
2021

to the carbon analogue, piperidine derivatives could only be
isolated in poor selectivity.
Synthesis of (-)-amphidinolide K fragment 9 began with
the epoxide ring-opening of commercially available, enan-
tiomerically enriched trityl-protected glycidol 11 to afford
chiral alcohol 12 in 95% yield (Scheme 2). Ether formation,
Oxygen-containing heterocycles could also be accessed
using this new cyclization methodology. Ether 1j cyclized
to afford tetrahydrofuran derivative 6j in 62% yield and a
90:10 ratio of diastereomers (entry 10). The yield of the 6-exo
cyclization for oxygen-containing substrate 1k (41% yield)
was higher than for the carbon analog (<30% yield), although
the diastereoselectivity was still modest (entry 11). Cycliza-
tion of racemic substrate 1l, containing an existing stereo-
center, provided trisubstituted tetrahydrofuran 6l in 64% yield
and a 86:14 ratio of the cis isomer to all other diastereomers
(entry 12).
Scheme 2
.
Concise Synthesis of the Tetrahydrofuran Fragment
within (-)-Amphidinolide K
Substituted tetrahydrofurans are common substitution
patterns in many bioactive polyketide natural products.18 One
example is amphidinolide K (Figure 1, 8), isolated from the
followed by TBAF-mediated removal of the silyl protecting
groups, resulted in free alcohol 14 in 45% yield over two
steps. Installation of the phthalimide was achieved using a
Mitsunobu reaction to provide N-alkoxyphthalimide 15 in
67% yield. The key radical relay cyclization gave (-)-
amphidinolike K fragment 16 in 64% yield and an 89:11
ratio of cis to trans isomers. Overall, the core was synthesized
in only five steps from commercially available material.
In summary, we have demonstrated a general and versatile
radical methodology for the rapid construction of carbo- and
heterocycles from simple linear precursors. The cyclizations
are effective for the synthesis of a wide range of cyclopen-
tane, pyrrolidine, tetrahydropyran, and tetrahydrofuran de-
rivatives. The synthetic generality of these new heterocy-
clizationswasdemonstratedinthesynthesisofthetetrahydrofuran
fragment in (-)-amphidinolide K. Studies toward the con-
struction of new, complex heterocyclic frameworks are
currently underway. We are also currently investigating the
use of this methodology in several natural product syntheses.
Figure 1. Retrosynthetic analysis of (-)-amphidinolide K.
Okinawan flatworm Amphiscolops sp,19-22 which contains
a 2,3,5-trisubstituted tetrahydrofuran in the macrocyclic core.
Our synthesis of trisubstituted tetrahydrofuran 6l (entry 12)
suggests that we can utilize our radical methodology for the
synthesis of the tetrahydrofuran in amphidinolide K as they
both contain the same 2,5-cis-substitution pattern. Tetrahy-
drofuran fragment 9 can easily be accessed using our
methodology by replacing the alkene acceptor with an alkyne
(10). Furthermore, the resulting functionality provides handles
for future fragment couplings.
(18) For representative reviews, see: (a) Rupprecht, J. K.; Hui, Y.-H.;
McLaughlin, J. L. J. Nat. Prod. 1990, 53, 237–278. (b) Kobayashi, J.; Tsuda,
M. Nat. Prod. Rep. 2004, 21, 77–93.
Acknowledgment. This work was supported by the
University of British Columbia, Merck-Frosst, and the
Natural Sciences and Engineering Research Council of
Canada (NSERC).
(19) Ishibashi, M.; Sato, M.; Kobayashi, J. J. Org. Chem. 1993, 58,
6928–6929
.
(20) For a synthesis of (+)-amphidinolide K, see: Williams, D. R.;
Meyer, K. G. J. Am. Chem. Soc. 2001, 123, 765–766
(21) For a synthesis of (-)-amphidinolide K, see: Ko, H. M.; Lee, C. W.;
Kwon, H. K.; Chung, H. S.; Choi, S. Y.; Chung, Y. K.; Lee, E. Angew.
.
Supporting Information Available: Complete experi-
mental procedures and characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
Chem. Int. Ed. 2009, 48, 2364–2366
.
(22) For synthetic efforts toward the synthesis of (-)-amphidinolide K,
see: (a) Williams, D. R.; Meyer, K. G. Org. Lett. 1999, 1, 1303–1305. (b)
Andreou, T.; Costa, A. M.; Esteban, L.; Gonza`lez, L.; Mas, G.; Vilarrasa,
J. Org. Lett. 2005, 7, 4083–4086
.
OL900481E
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Org. Lett., Vol. 11, No. 9, 2009