Catalytic Ring Expansions of Cyclic Alcohols Enabled by Proton-Coupled Electron Transfer

Article abstract of DOI:10.1021/jacs.9b03973

We report here a catalytic method for the modular ring expansion of cyclic aliphatic alcohols. In this work, proton-coupled electron transfer activation of an allylic alcohol substrate affords an alkoxy radical intermediate that undergoes subsequent C-C bond cleavage to furnish an enone and a tethered alkyl radical. Recombination of this alkyl radical with the revealed olefin acceptor in turn produces a ring-expanded ketone product. The regioselectivity of this C-C bond-forming event can be reliably controlled via substituents on the olefin substrate, providing a means to convert a simple N-membered ring substrate to either n+1 or n+2 ring adducts in a selective fashion.

Full text of DOI:10.1021/jacs.9b03973

Subscriber access provided by ALBRIGHT COLLEGE
Communication
Catalytic Ring Expansions of Cyclic Alcohols
Enabled by Proton-Coupled Electron Transfer
Kuo Zhao, Kenji Yamashita, Joseph Carpenter, Trevor C. Sherwood,
William R Ewing, Peter T.W. Cheng, and Robert R Knowles
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 22 May 2019
Downloaded from http://pubs.acs.org on May 22, 2019
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 6
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Catalytic Ring Expansions of Cyclic Alcohols Enabled by Proton-
Coupled Electron Transfer
Kuo Zhao†‡, Kenji Yamashita†‡, Joseph E. Carpenter§, Trevor C. Sherwood§, William R. Ewing§, Peter
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
T. W. Cheng§, and Robert R. Knowles†*
†Department of Chemistry, Princeton University, Princeton, New Jersey 08544, United States
§Discovery Chemistry, Bristol-Myers Squibb Co., Princeton, New Jersey 08543, United States
Supporting Information Placeholder
ABSTRACT: We report here a catalytic method for the modular
ring expansion of cyclic aliphatic alcohols. In this work, proton-
coupled electron transfer (PCET) activation of an allylic alcohol
substrate affords an alkoxy radical intermediate that undergoes sub-
sequent C–C bond cleavage to furnish an enone and a tethered alkyl
radical. Recombination of this alkyl radical with the revealed olefin
acceptor in turn produces a ring-expanded ketone product. The re-
gioselectivity of this C–C bond-forming event can be reliably con-
trolled via substituents on the olefin substrate, providing a means
to convert a simple N-membered ring substrate to either n+1 or n+2
ring adducts in a selective fashion.
Aliphatic rings are key structural elements in functional mole-
cules ranging from pharmaceuticals and natural products to ligands
and polymers.1 Accordingly, methods that enable direct intercon-
version between ring-size isomers are important technologies that
can provide useful retrosynthetic disconnections and facilitate the
evaluation of structure-function studies (Figure 1a and 1b). While
appealing in principle, the development of general catalytic meth-
Figure 1. (a) Development of general methods for ring-size mod-
ods for ring-size modulation remains limited in practice, as suc-
ulation; (b) access to structurally distinct cores via ring-size mod-
cessful transformations require orchestrating non-degenerate C−C
ulation; (c) PCET-enabled ring-expansion methods of cyclic alco-
bond-breaking and bond-forming events to occur in a controlled
hols.
and sequential fashion. Moreover, conversion of readily accessible
5- and 6-membered ring starting materials to either medium- or
small-ring compounds is often thermodynamically challenging due
to a concomitant increase in ring-strain.2 Significant and enabling
advances in this area have been realized by Dong, Zuo, Beckwith,
and others,3 which have demonstrated the value of this strategy.
However, the discovery and development of complementary meth-
ods are necessary to further expand the reach and generality of this
approach.
readily accessible cyclic allylic alcohol-based substrates derived
from the addition of vinyl nucleophiles to simple ketones (Figure
1c). In this scheme, the alkoxy radical formed via excited-state
PCET would undergo ring-opening b-scission to reveal a new a,b-
unsaturated ketone and a tethered alkyl radical. The alkyl radical
could then recombine with the revealed enone to form a new C−C
bond within the framework of a ring-expanded carbocycle. By var-
ying the regioselectivity of this olefin addition step, such a strategy
could provide access to homologated products incorporating either
both olefinic carbons (n+2 expansion) or only a single carbon (n+1
expansion) into the new ring structure. Such methods would pro-
vide a useful complement to classical radical ring expansion reac-
tions developed by Beckwith, Dowd and Saegusa.3m–3q Here we re-
port the successful development of both variants, providing a mod-
ular means to take simple and readily accessible cyclic alcohols di-
rectly to medium-ring ketones through a common PCET-based
mechanism. The design, optimization, and scope of these processes
are presented below.
In this context, we became interested in developing new ring-
expansion methods based on our recent work in the ring-opening
isomerization of cyclic alcohols.4a,4b In these reactions, proton-cou-
pled electron transfer (PCET) activation of the strong O–H bond in
an aliphatic alcohol substrate is jointly catalyzed by an excited-state
oxidant and weak Brønsted base to form a key alkoxy radical inter-
mediate. This O-centered radical can then mediate the b-scission of
an adjacent C−C bond to furnish a new carbonyl group and a teth-
ered alkyl radical, which can either be reduced by a thiol H-atom
donor catalyst or trapped by a variety of other stoichiometric rea-
gents. We questioned whether a similar series of elementary steps
might be adapted for use in a ring-expansion protocol utilizing
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 6
As depicted in Figure 1c, we envisioned a prospective mech-
Table 1. Optimization studiesa
1
2
3
4
5
6
7
8
anism for the n+2 ring expansion wherein excited-state O–H PCET
and subsequent ring-opening b-scission would result in the for-
mation of a nascent enone acceptor and tethered alkyl radical. Rad-
ical 1,4-conjugate addition between these partners would lead to
the formation of a new ring structure that incorporates both carbons
of the exocyclic olefin. Following C−C bond formation, the result-
ing a-acyl radical can be reduced by the Ir(II) state of the photo-
catalyst to furnish an enolate intermediate and then protonated by
the conjugate acid of the Brønsted base catalyst to close the cycle.
9
Our initial efforts in n+2 ring expansion focused on piperidine-
based alcohol substrate 1. Adapting previously established O−H
PCET conditions, we were pleased to find that treatment of 1 with
3 mol% of [Ir(dF(CF3)ppy)2(5,5′-d(CF3)bpy)]PF6 (A) and 40 mol%
of a diphenyl phosphate base under blue light irradiation in CH2Cl2
directly afforded the 8-membered ring ketone 1a in 27% yield (Ta-
ble 1, entry 1).4b Further optimization revealed that aromatic sol-
vents (entries 4–7) were generally more effective than non-aro-
matic solvents (entries 1–3), with α,α,α-trifluorotoluene and tolu-
ene proving optimal (entries 6, 7). In addition, we found that the
use of trifluoroacetate as the Brønsted base for the PCET event (en-
try 8) was more effective than the use of diaryl or dialkyl phos-
phates despite their comparable basicities (entries 7, 9, 10).5 Inter-
estingly, the counter-cation of the anionic base was also found to
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
influence reaction performance, with PBu4 (PhO)2P(O)O– (entry 7)
+
+
+
and PBu4 CF3CO2– (entry 8) outperforming NBu4 (PhO)2P(O)O–
+
–
(entry 11) and NBu4 CF3CO2 (entry 12), respectively – an out-
come that may be due to the improved solubility of the phospho-
nium salt in toluene. Finally, control experiments indicated that
there was no conversion in the absence of photocatalyst or visible
light irradiation (entries 13, 14) while low conversion (15%) was
observed in the absence of the Brønsted base co-catalyst (entry 15).
Notably, 1a is the sole product isomer detected by 1H-NMR analy-
sis of the crude reaction mixture, indicating that both b-scission of
the alkoxy radical and the subsequent 1,4-conjugate addition step
are highly regioselective.
a Optimization reactions were performed on 0.05 mmol scale.
b
Internal temperature of the reaction mixture under LED irra-
c
1
diation (see SI for details). Yields were determined by H
NMR analysis of crude reaction mixtures relative to an internal
standard.
and modular approach to the syntheses of this prominent family of
alkaloid targets.9
With these optimized conditions in hand, we next set out to in-
vestigate the generality of the n+2 ring expansion (Table 2). On
preparative scale, a variety of alkene partners, including terminal
olefins (1), 1,2- disubstituted olefins (2, 3, and 4), trisubstituted ole-
fins (5, 6), and allenes (9) were all well tolerated. Similarly, various
ring substitution patterns were also accommodated, including 4-
methylated piperidine (7, 8), hexahydropyrimidine (10), N-Cbz pi-
peridine (11), 2-azabicyclo[2.2.1]heptane (12), azepane (13), 1,4-
diazepane (14), and 2-aminocyclohexanol (15, 16). Notably, all the
products presented in Table 2 are formed as single regioisomers,
consistent with a selective b-scission event to form more stabilized
a-amino radical intermediates. In reactions forming diastereo-
meric products, (5, 6, and 7) high stereoselectivities were observed
in enolate protonation (d.r. >20:1) – a likely consequence of the
strong conformational preferences of 8-membered ring ketone eno-
lates as originally suggested by Still.6 In the case of allene deriva-
tive 9, non-conjugated olefin 9a was the only product detected, sug-
gesting a highly a-regioselective protonation of the intermediate
1,3-dienolate, in accord with literature precedent.7 While this reac-
tion functions well with aza-heterocyclic substrates, n+2 ring ex-
pansions of analogous oxygen heterocycles and simple carbocyclic
alcohols proved less efficient. As prior work indicates that the ni-
trogen substituent is not required for efficient b-scission,4a this ob-
servation may suggest that these aza-cyclic substrates are privi-
leged as a result of the enhanced nucleophilicity of the a-amino
radical in the conjugate addition step. In terms of applications, the
aminoketone heterocycles produced in this reaction have been used
previously as starting points for the synthesis of pyrrolizidine and
indolizidine structures via transannular reductive amination.8 As
such, we are optimistic that these methods will provide a simple
We next questioned whether we could adapt this method to
achieve a complementary n+1 type ring expansion. Based on recent
work from Sparling and Lovett, we anticipated that the regioselec-
tivity of the C–C bond forming step might be reversed upon incor-
poration of an aryl group at the terminal position of the substrate
olefin (Figure 2a).10 These authors demonstrated that intermolecu-
lar addition of a-amino radicals to cinnamates occurs regioselec-
tively at the olefinic carbon proximal to the carbonyl to form stabi-
lized benzylic radical intermediates. Accordingly, we reasoned that
reactions employing cinnamyl analogs of 1 might alter the pre-
ferred cyclization mode from 8-endo to 7-exo, delivering a 7-mem-
bered cyclic ketone product through a formal n+1 ring expansion.
However, the viability of this approach was complicated by the
fact that the Ir(II) state of photocatalyst A is insufficiently reducing
to transfer an electron to the benzylic radical (E1/2 [IrIII/IrII] = –1.07
–
V vs Fc+/Fc in MeCN; E1/2 [PhCH2•/PhCH2 ] = –1.92 V vs Fc+/Fc
in MeCN) and close the catalytic cycle.4a,11 To overcome this issue,
we proposed to introduce an aryl thiol co-catalyst to the reaction,
which could reduce the benzylic radical intermediate via H-atom
transfer to deliver the desired n+1 product. The resulting aryl thiyl
radical could then be reduced to its corresponding thiolate by the
Ir(II) state of A (E1/2[ArS•/ArS–] = –0.22 V vs Fc+/Fc in MeCN;
E1/2[IrIII/IrII] = –1.07 V vs Fc+/Fc in MeCN).12 This aryl thiolate
could then be protonated by the conjugate acid of the Brønsted base
to return the active forms of all three catalysts.4c
The success of this proposal hinged on the ability of the proposed
exo-trig cyclization to kinetically outcompete bimolecular HAT re-
duction of the alkyl radical initially formed in the b-scission event
ACS Paragon Plus Environment

Page 3 of 6
Journal of the American Chemical Society
Table 2. Scope of n+2 ring expansiona
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a
Reactions were run on 0.5 mmol scale. Reported yields are for isolated and purified material and represent the average of two
experiments. Diastereomeric ratios were determined by 1H NMR of the crude reaction mixtures. b PhMe was used as the reaction solvent.
c PhCF3 was used as the reaction solvent. d Relative configuration was determined by X-ray crystallographic analysis (see SI for details).
e 5 mol% photocatalyst and 0.1 M concentration were used. f PBu4+ (PhO)2P(O)O– (25 mol%) was used as the base.
by the thiophenol co-catalyst – a typically rapid elementary step (k
~ 108 M–1s–1) (Figure 2b).13 To probe this question directly, we con-
ducted a competition experiment using our n+2 model substrate 1
in the presence of 25 mol% 2,4,6-triisopropyl thiophenol (TRIP-
SH) under otherwise standard conditions, wherein the ratio of cy-
clized to uncyclized products (1a and 1b, Figure 2b) would report
on the kinetic partitioning of the key alkyl radical intermediate.
Gratifyingly, under standard conditions cyclized product 1a was
obtained in 60% yield, while the product resulting from HAT re-
duction of the alkyl radical intermediate (1b) was formed in 23%
yield. Formation of the acyclic product could be further suppressed
by lowering the loading of TRIP-SH to 5 mol% to provide 1a in
88% yield along with 11% of 1b.
Adapting these findings to the proposed n+1 ring expansion, we
were pleased to find that treatment of styrene derivative 17 under
standard n+2 conditions (Table 1, entry 8) with the addition of 5
mol% of TRIP-SH provided the desired n+1 product 17a in 80%
Figure 2. (a) Unconventional regioselectivity in radical addi-
tions to cinnamates. (b) Results of competition experiments.
yield and with only trace amounts of the acyclic side product
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 6
Table 3. Scope of n+1 Ring Expansiona
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a
Reactions run on 0.5 mmol scale. Reported yields are for isolated and purified material and are the average of two experiments. Dia-
stereomeric ratios were determined by 1H NMR of the crude reaction mixtures. b PhCF3 was used as the reaction solvent. c PBu4+ CF3CO2
–
(25 mol%) as the base. d PhMe was used as the reaction solvent. e 20 mol% of TRIP-SH was used. Collidine (3 equiv.) as the base. g
f
Without TRIP-SH. h Relative or absolute configuration was determined by NOESY analysis (see SI for details). i Relative configuration
was determined by X-ray crystallographic analysis (see SI for details). j See SI for detailed reaction conditions.
resulting from premature HAT (Table 3, entry 18). This encourag-
ing result led us to examine the scope of n+1 ring expansion in
greater detail. On preparative scale, we found that 5- to 7-mem-
bered N-heterocycles underwent efficient ring expansion (17–22),
and the reaction tolerates aryl substituents with varying electronic
character (17–19). Spirocyclic ketone 21a could be accessed from
2-indenyl derivative 21 in good yield. Meanwhile, olefin substrates
bearing β-electron withdrawing groups, including ketones (23) and
electron deficient N-heterocycles, such as 2-pyridyl (24) and 2-py-
rimidinyl (25), were also found to be efficient for n+1 ring expan-
sion. In these cases, the intrinsic selectivity of ring closure favors
7-exo over 8-endo, and the HAT reagent is not required as direct
reduction of the radical intermediate by the Ir(II) state of photocata-
lyst A is viable. This n+1 protocol also tolerates both 5- and 6-
membered cyclic ether substrates (26, 27) as well as a variety of
carbocyclic substrates (28–31). Of particular note, we discovered
that simple derivatives of (+)-camphor (30) and trans-androsterone
(31) underwent highly regioselective and diastereoselective n+1
expansion, suggesting that this method may prove useful in the
preparation of non-natural terpenoid derivatives that might prove
more difficult to access by other means.14 However, unsubstituted
1-alkenylcycloalkanols are not efficient substrates in this chemis-
try, presumably as b-scission is not kinetically competitive with
charge recombination between the alkoxy radical and the reduced
Ir(II) state of the photocatalyst. Lastly, during the development of
this n+1 process, we observed that reaction efficiency was sensitive
to the identity of the solvent, the reaction concentration, the struc-
ture and loading of the Brønsted base and HAT co-catalysts, and
reaction temperature. As such, any variation from the standard pro-
tocol are listed in the footnotes to Table 3.
In conclusion, we have developed a new method for the con-
struction of valuable medium-sized ring ketones from readily ac-
cessible cyclic allylic alcohols through catalytic ring expansion.
The key C–C bond-breaking b-scission event is enabled by excited-
state PCET activation of a strong alcohol O−H bond, while the sub-
sequent ring closure can selectively deliver either n+1 or n+2 ring-
expanded products by varying the substitution pattern of the olefin
acceptor. We note that the outcomes presented here stand in con-
trast to several previous studies on alkoxy radicals derived from 1-
vinylcycloalkanols, where spiroepoxide products are formed pre-
dominantly.15 Future efforts will seek to understand the factors
leading to this unexpected selectivity for b-scission. These reac-
tions further highlight the ability of excited-state redox events to
drive challenging isomerization chemistry under mild catalytic
conditions and provide further support for the synthetic utility of
PCET-based C–C bond functionalization.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website.
ACS Paragon Plus Environment

Page 5 of 6
Journal of the American Chemical Society
Expansion to γ-Keto Esters. J. Am. Chem. Soc., 1987, 109, 3493–3494. (n)
Dowd, P.; Choi, S.-C. Free Radical Ring Expansion by Three and Four Car-
bons. J. Am. Chem. Soc. 1987, 109, 6548- 6549. (o) Beckwith, A. L. J.;
O’Shea, D. M.; Wetswood, S. W. Rearrangement of Suitably Constituted
Aryl, Alkyl, or Vinyl Radicals by Acyl or Cyano Group Migration. J. Am.
Chem. Soc. 1988, 110, 2565-2572. (p) Ito, Y.; Fujii, S.; Saegusa, T. Reac-
tion of 1-Silyloxybicyclo[n.1.0] alkanes with Iron(III) Chlorides. A Facile
Synthesis of 2-Cycloalkenones via Ring Enlargement of Cyclic Ketones. J.
Org. Chem. 1976, 41, 2073-2074. (q) Dowd, P.; Zhang, W. Free Radical-
Mediated Ring Expansion and Related Annulations. Chem. Rev. 1993, 93,
2091-2115. (r) Song, Z.; Fan, C.; Tu, Y. Semipinacol Rearrangement in
Natural Product Synthesis. Chem. Rev. 2011, 111, 7523–7556.
(4) (a) Ota, E.; Wang, H.; Frye, N. L.; Knowles, R. R. A Redox Strategy
for Light-Driven, Out-of-Equilibrium Isomerizations and Application to
Catalytic C–C Bond Cleavage Reactions. J. Am. Chem. Soc. 2019, 141,
1457–1462. (b) Yayla, H. G.; Wang, H.; Tarantino, K. T.; Orbe, H. S.;
Knowles, R. R. Catalytic Ring-Opening of Cyclic Alcohols Enabled by
PCET Activation of Strong O–H Bonds. J. Am. Chem. Soc. 2016, 138,
10794–10797. (c) Zhu, Q.; Graff, D. E.; Knowles, R. R. Intermolecular
Anti-Markovnikov Hydroamination of Unactivated Alkenes with Sulfona-
mides Enabled by Proton-Coupled Electron Transfer. J. Am. Chem. Soc.,
2018, 140, 741–747.
(5) pKa (trifluoroacetic acid) = 12.65 in MeCN; pKa (BINOL/diphenyl
phosphoric acid) = 12-13 in MeCN, see: (a) Muckerman, J. T.; Skone, J.
H.; Ning M.;.Wasada-Tsutsui, Y. Toward the accurate calculation of pKa
values in water and acetonitrile. Biochimica et Biophysica Acta. 2013, 1827,
882–891. (b) Rueping, M.; Nachtsheim, B. J.; Ieawsuwan, W.; Atodiresei,
I. Modulating the Acidity: Highly Acidic Brønsted Acids in Asymmetric
Catalysis. Angew. Chem., Int. Ed., 2011, 50, 6706-6720.
(6) Still, W. C.; Galynker, I. Chemical consequences of conformation in
macrocyclic compounds: An effective approach to remote asymmetric in-
duction. Tetrahedron 1981, 37, 3981-3996.
(7) For a-regioselective dienolate electrophilic reactions, see: (a) Cargill,
R. L.; Bushey, D. F.; Good, J. J. Alkylation of 1-cyanocyclohexene. J. Org.
Chem., 1979, 44, 300–301. (b) Gesson, J.; Jacuesy, J.; Mondon, M. Regi-
oselective dienolate formation and alkylation of alkyl 2-methyl cyclohex-
ene-1 carboxylate. Tetrahedron Lett. 1980, 21, 2509-2512. (c) Davies, S.
G.; Easton, R. J. C.; Sutton, K. H.; Walker, J. C.; Jones, R. H. Chiral Dieno-
lates: Formation and Stereoselective a-Alkylation of the Lithium
Dienolate Derived from (Z)-[(η5-C5H5)Fe(CO)(PPh3)COCH=CHMe]. X-
Ray Crystal Structure of (RS)-(Z)-[(η5-C5H5)Fe(CO)(PPh3)COCH=CH
Me]. J. Chem. Soc. Perkin Trans. 1 1987, 489-493.
(8) (a) Garst, M. E.; Bonfiglio, J. N.; Marks, J. Hydroboration-carbon
monoxide insertion of bis-olefinic amine derivatives. Synthesis of .delta.-
coniceine, pyrrolizidine, (±)-heliotridane, and (±)-pseudoheliotridane. J.
Org. Chem. 1982, 47, 1494-1500. (b) Garst, M. E.; Bonfiglio, J. N. Hydrob-
oration-carbonylation of bisolefinic amines: a facile synthesis of δ-co-
niceine. Tetrahedron Lett., 1981, 22, 2075-2076.
1
2
3
4
5
6
7
8
Experimental details, characterization data, and spectra (PDF).
Crystallographic data for 5a (CIF).
Crystallographic data for 6a (CIF).
Crystallographic data for 7a (CIF).
Crystallographic data for 31a (CIF).
AUTHOR INFORMATION
Corresponding Author
9
rknowles@princeton.edu
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Author Contributions
‡These authors contributed equally.
Notes
The authors declare no competing financial interests. Crystallo-
graphic data are deposited with the Cambridge Crystallographic
Data Centre (CCDC) under the following accession numbers: 5a
(1900667), 6a (1900665), 7a (1900666), and 31a (1900668).
ACKNOWLEDGMENT
Funding for the work was provided by the NIH (NIGMS R01
113105) and Bristol-Myers Squibb. K.Y. thanks the Uehara Me-
morial Foundation for a postdoctoral fellowship.
REFERENCES
(1) (a) Stephen, J. C.; Cutler, H. G.; Biologically Active Natural Prod-
ucts: Pharmaceuticals; CRC Press: Boca Raton, FL, 2000. (b) Mander, L.
N. Comprehensive Natural Products II: Chemistry and Biology; Elsevier:
Amsterdam, 2010. (c) Allen, G.; Bevington, J. C.; Booth, C.; Price, C. Com-
prehensive Polymer Science: The Synthesis, Characterization, Reactions &
Applications of Polymers; Pergamon: Oxford, 1989.
(2) Galli, C.; Mandolini, L. The Role of Ring Strain on the Ease of Ring
Closure of Bifunctional Chain Molecules. Eur. J. Org. Chem. 2000, 3117–
3125.
(3) (a) Sun, T.; Zhang, Y.; Qiu, B.; Wang, Y.; Qin, Y.; Dong, G.; Xu, T.
Rhodium(I)-Catalyzed Carboacylation/Aromatization Cascade Initiated by
Regioselective C−C Activation of Benzocyclobutenones. Angew. Chem.
Int. Ed. 2018, 57, 2859–2863. (b) Deng, L.; Jin, L.; Dong, G. Fused-Ring
Formation via an Intramolecular "Cut-and-Sew" Reaction between Cyclo-
butanones and Alkynes. Angew. Chem. Int. Ed. 2018, 57, 2702–2706. (c)
Zhou, X.; Dong, G. Nickel-Catalyzed Chemo- and Enantioselective Cou-
pling between Cyclobutanones and Allenes: Rapid Synthesis of [3.2.2] Bi-
cycles. Angew. Chem. Int. Ed. 2016, 55, 15091–15095. (d) Xia, Y.; Lu, G.;
Liu, P.; Dong, G. Catalytic Activation of Carbon–carbon Bonds in Cyclo-
pentanones. Nature, 2016, 539, 546–550. (e) Deng, L; Xu, T.; Li, H.; Dong,
G. Enantioselective Rh-catalyzed Carboacylation of C=N Bonds via C−C
Activation of Benzocyclobutenones. J. Am. Chem. Soc. 2016, 138, 369–
374. (f) Xu, T.; Dong, G. Rh-Catalyzed Regioselective Carboacylation of
Olefins: A C−C Activation Approach to Access Fused-Ring Systems." An-
gew. Chem., Int. Ed. 2012, 51, 7567-7571. (g) Hu, A.; Chen, Y.; Guo, J.;
Yu, N.; An, Q., Zuo, Z. Cerium-Catalyzed Formal Cycloaddition of Cyclo-
alkanols with Alkenes through Dual Photoexcitation. J. Am. Chem. Soc.
2018, 140, 13580–13585. (h) Jin, S.; Nguyen, V. T.; Dang, H. T.; Nguyen,
D. P.; Arman, H. D.; Larionov, O. V. Photoinduced Carboborative Ring
Contraction Enables Regio- and Stereoselective Synthesis of Multiply Sub-
stituted Five-Membered Carbocycles and Heterocycles. J. Am. Chem.
Soc. 2017, 139, 11365–11368. (i) Wang, N.; Gu, Q.; Li, Z.; Guo, Y.; Kiu,
X. Angew. Chem., Int. Ed. 2018, 57, 14225–14229. (j) Chen, P.; Billett B.
A.; Tsukamoto T.; Dong, G. “Cut and Sew” Transformations via Transi-
tion-Metal-Catalyzed Carbon–Carbon Bond Activation. ACS Catal. 2017,
7, 1340–1360. (k) Fumagalli, G., Stanton S., Bower, J. F., Recent Method-
ologies That Exploit C−C Single-Bond Cleavage of Strained Ring Systems
by Transition Metal Complexes. Chem. Rev. 2017, 117, 9404–9432. (l)
Donald, J. R., Unsworth, W. P., Ring-Expansion Reactions in the Synthesis
of Macrocycles and Medium-Sized Rings. Chem. Eur. J. 2017, 23, 8780-
8799. (m) Dowd, P.; Choi, S.-C,. A New Tri-n-butyltin Hydride Based Re-
arrangement of Bromomethyl b-Keto Esters. A Synthetically Useful Ring
(9) (a) Roberston, J.; Stevens, K. Pyrrolizidine alkaloids. Nat. Prod. Rep.,
2014, 31, 1721-1788. (b) Michael, J. P. Indolizidine and Quinolizidine Al-
kaloids. Nat. Prod. Rep., 2008, 25, 139–165.
(10) Lovett, G. H.; Sparling, B. A. Decarboxylative Anti-Michael Addi-
tion to Olefins Mediated by Photoredox Catalysis. Org. Lett., 2016, 18,
3494–3497.
(11) Sim, B. A.; Griller, D.; Wayner, D. D. M. Reduction potentials for
substituted benzyl radicals: pKa values for the corresponding toluenes. J.
Am. Chem. Soc., 1989, 111, 754–755.
(12) Romero, N.; Nicewicz, D. A. Mechanistic Insight into the Photore-
dox Catalysis of Anti-Markovnikov Alkene Hydrofunctionalization Reac-
tions. J. Am. Chem. Soc., 2014, 136, 17024–17035.
(13) Dénès, F.; Pichowicz, M.; Povie, G.; Renaud, P. Thiyl Radicals in
Organic Synthesis. Chem. Rev. 2014, 114, 2587−2693.
(14) Urabe, D.; Asaba, T.; Inoue, M. Convergent Strategies in Total Syn-
theses of Complex Terpenoids. Chem. Rev. 2015, 115, 9207–9231.
(15) (a) Galatsis, P.; Millan, S. D.; Faber, T. 1-Alkenylcycloalkoxy Rad-
ical Chemistry. A Two-Carbon Ring Expansion Methodology. J. Org.
Chem. 1993, 58, 1215-1220. (b) Galatsis, P.; Millan, S. D. Use of Iodoben-
zene Diacetate for the Synthesis of α-Iodoepoxides. Tetrehedron. 1991, 51,
7493–7496. (c) Aureliano Antunes, C. S.; Bietti, M.; Lanzalunga, O.; Sala-
mone, M. Photolysis of 1-Alkylcycloalkanols in the Presence of (Diacetox-
yiodo)benzene and I2. Intramolecular Selectivity in the β-Scission Reac-
tions of the Intermediate 1-Alkylcycloalkoxyl Radicals. J. Org. Chem.
2004, 69, 5281-5289.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 6
Ph
OH
Me
Ph
1
Me
O
2
3
4
5
Me
H
H
5
Me
H
H
6
via O–H
PCET
H
H
H
H
MeO
>20:1 dr
MeO
6
Catalytic Ring Expansion of Cyclic Alcohols
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
6
ACS Paragon Plus Environment