Streamlined Synthesis of C(sp3)-Rich N-Heterospirocycles Enabled by Visible-Light-Mediated Photocatalysis

Article abstract of DOI:10.1021/jacs.9b03372

We report a general visible-light-mediated strategy that enables the construction of complex C(sp³)-rich N-heterospirocycles from feedstock aliphatic ketones and aldehydes with a broad selection of alkene-containing secondary amines. Key to the

Full text of DOI:10.1021/jacs.9b03372

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Communication
Streamlined synthesis of C(sp3)–H rich N-heterospirocycles
enabled by visible-light-mediated photocatalysis
Nils J. Floden, Aaron Trowbridge, Darren Willcox, Scarlett M. Walton, Yongjoon Kim, and Matthew J. Gaunt
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b03372 • Publication Date (Web): 09 May 2019
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Journal of the American Chemical Society
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Streamlined synthesis of C(sp3)–H rich N-heterospirocycles enabled
by visible-light-mediated photocatalysis
Nils J. Flodén1, Aaron Trowbridge1, Darren Willcox1, Scarlett M. Walton1,2, Yongjoon Kim1 & Matthew J.
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Gaunt*1
1Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom, UK
2 Medicinal Chemistry, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, UK
Supporting Information Placeholder
include dearomatization-based strategies, using Pd, Ir or Fe
catalysts,6a-c which harness the intrinsic reactivity of teth-
ered (hetero)arene building blocks for the generation of a
selection of spirocyclic N-heterocycles with different ring
sizes. Bode and co-workers produced a range of spirocy-
clic N-heterocycles using their SnAP technology;6d,e imin-
ium ion formation between amino-stannane reagents and
cyclic ketones enables a stoichiometric copper(II)-
ABSTRACT: We report a general visible light-mediated
strategy that enables the construction of complex C(sp3)-
rich N-heterospirocycles from feedstock aliphatic ketones
and aldehydes with a broad selection of alkene-containing
secondary amines. Key to the success of this approach was
the utilization of a highly-reducing Ir-photocatalyst and or-
chestration of the intrinsic reactivities of 1,4-cyclohexadi-
ene and Hantzsch ester. This methodology provides
streamlined access to complex C(sp3)-rich N-heterospiro-
cycles displaying structural and functional features rele-
vant to fragment-based lead identification programs.
Figure 1. The evolution of the cyclization strategy
(a)
N
Me
N
F
O
CO2H
O
N
N
O
N
Growing evidence suggests that an increasing number of
aromatic rings in lead compounds can result in greater at-
trition rates amongst pharmaceutical candidates due to
poor solubility, bioavailability and pharmacokinetics.1
However, libraries of lead-like structures often comprise
compounds with predominantly C(sp2)-rich scaffolds.
Consequently, the assessment of structurally distinct li-
braries of C(sp3)-rich small molecules displaying diverse
polar functionality could help to identify new lead candi-
dates in fragment-based screening approaches that may ex-
hibit enhanced physical and biological properties.2 In con-
sidering the design of novel C(sp3)-rich small molecules
for fragment-based approaches,3 it is noticeable that con-
formationally restricted scaffolds show highly reproduci-
ble results in in silico screening programmes; the well-de-
fined spatial orientation of molecular features in a candi-
date compound often leads to increased binding affinities.
One approach towards limiting structural flexibility within
C(sp3)-rich small molecules is through the introduction of
a spirocycle.4 In comparison to aromatic scaffolds, fine-
tuning the structural and functional features in these frame-
works offers an alternative means through which to probe
interactions with target binding sites by variation of ring
size, adjusting electronic properties and manipulating sub-
stituent effects.5 As a result, spirocyclic motifs displaying
polar functionality are emerging in pharmaceutical agents
and lead compounds (Figure 1a).4
N
O
O
OMe
melanin-concentrating hormone
AstraZeneca lead compound
anti-diabetic compound
MSD lead compound
(b)
radical
cyclization
Me
intuitive
O
disconnection
N
R
BocN
H
N
BocN
R
condensation
C(sp3)–rich &
polar products
rigid & topologically1
diverse scaffolds
(c)
Me
Ir-photocatalyst
O
R
+
N
H
N
HAT reagent
R
alkenyl-amine 1
ketone 2
N-heterospirocycle 3
HAT
condensation
R
R
ΔG = –1.1
kcal mol–1
N
N
SET
small driving force
N
R
α-amino radical
int-II
iminium ion
int-I
1° alkyl radical
int-III
HAT needs to be selective
for 1° alkyl radical over
α-amino radical
undesired
HAT
SET to tetra-alkyl
iminium ion requires strongly
reducing photocatalyst
BDE α-amino radical
= 92 kcal mol–1
Despite the attractive properties offered by rigid satu-
rated polar spirocyclic scaffolds, access to diversely func-
tionalized variants mainly relies on multistep alkyl- and ac-
ylative methods.5 Notable advances on these approaches
R
N
E1/2red ~ 1.95 V vs SCE
BDE 1° alkyl radical
= 101 kcal mol–1
‘reductive amination’ product
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Journal of the American Chemical Society
Page 2 of 7
process.9 Using amine 1a and cyclobutanone (2a) as sub-
strates, 1mol% of Ir(ppy)3 and 2.0 equivalents of Hantzsch
ester, we were encouraged by the formation of spirocycle
3a in 30% yield and only trace amounts of the correspond-
ing reductive amination product (Table 1, entry 1). Follow-
ing extensive optimization, we found that the use of 1,4-
cyclohexadiene as an additive (entry 2) and a more reduc-
ing photocatalyst Ir(dMeppy)3 ([E1/2red(IrIV/*IrIII)]= –1.86
V vs SCE in CH2Cl2) (entry 3) improved the yield to
97%.12 We reasoned that the use of 1,4-CHD as a HAT-
donor in high concentration would restrict the role of
Hantzsch ester to turning over the Ir(IV) species formed
after single-electron reduction of the iminium ion, while
the more reducing photocatalyst would provide a stronger
driving-force for the reduction step. A series of control ex-
periments showed that the yield of the reaction dropped to
24% in the absence of 1,4-CHD (entry 4); to 43% without
the Hantzsch ester (entry 5); and to trace amounts without
photocatalyst or light or in the absence of both 1,4-CHD
and Hantzsch ester (entries 6,7).
Gibbs free energy calculated by DFT-methods (UPW6B95-
1
2
3
4
5
6
7
8
D3BJ/def2-QZVP). Hydrogens removed for clarity.
cyclization to access free(NH)-secondary amino-spirocy-
clic products. To complement these approaches, we rea-
soned that a photocatalytic strategy7 based on an intuitive
retrosynthetic disconnection of tertiary amine-based N-het-
erospirocycles directly to feedstock ketones and readily
available alkenyl-derived secondary amines could be real-
ized through the intermediacy of an a-amino radical (Fig-
ure 1b).8 The structurally distinct C(sp3)-rich polar N-het-
erospirocycles generated by such a catalytic transformation
could be of interest to synthetic and medicinal chemists.
We envisioned that visible-light-mediated photocatalytic
single-electron reduction of an alkyl-iminium ion (int-I,
Figure 1c), formed from the condensation of a saturated
cyclic ketone with a secondary alkyl amine, would form a
cyclic-tertiary a-amino radical (int-II). Addition of this a-
amino radical to an appended alkene on the amine compo-
nent would give rise to a substituted pyrrolidine-based spi-
rocyclic scaffold. Recent work from our group established
a photocatalytic platform for the addition of nucleophilic
a-amino radicals (formed from the corresponding iminium
ions) to electron-deficient olefins.9 Critically, however, a
catalytic manifold for the addition of all-alkyl substituted
a-amino radicals to unactivated alkenes remains an un-
solved problem, principally due to the mismatched elec-
tronics and low thermodynamic driving force for such a re-
action. The lone pair on the nitrogen atom stabilizes the a-
amino radical but also renders it nucleophilic. Therefore,
its addition to an unactivated alkene is polarity-mis-
matched and produces an alkyl radical (int-III) with no sta-
bilizing substituents that, in turn, can undergo the reverse
reaction to reform the a-amino radical via C–C bond b-
scission. Indeed, the use of SmI2, a strong stoichiometric
reductant, was required to trap related alkyl radicals via or-
ganosamarium intermediates following addition to unacti-
vated alkenes.10 However, the metal waste produced in
these reactions and frequent need for highly dilute condi-
tions has hindered the wider application of this type of pro-
cess.11 We, therefore, questioned whether an alkyl radical
could be selectively intercepted in a milder fashion by way
of a hydrogen-atom transfer (HAT) reaction and in prefer-
ence to HAT to the a-amino radical.
9
10
11
12
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Table 1. Selected optimization dataa
Me
Ir photocatalyst (1 mol%)
O
40 W blue LED
Bn
+
N
H
N
HAT reagents
propionic acid (20 mol%)
4Å MS, CH2Cl2, r.t., 24 h
Bn
homoallyl amine 1a
ketone 2a
spirocycle 3a
Hantzsch
1,4-CHD
(equiv)
Entry
Catalyst
Yield %
(equiv)
2.0
2.0
2.0
2.0
–
1
2
Ir(ppy)3
Ir(ppy)3
Ir(dMeppy)3
Ir(dMeppy)3
Ir(dMeppy)3
–
–
30
45
97
24
43
7.5
7.5
–
7.5
7.5
–
3
4
5
6
7
2.0
–
trace
trace
Ir(dMeppy)3
aReactions employed a 40 W Blue Kessil lamp & yields calculated
by GC assay with dodecane as internal standard.
Having evaluated the reaction conditions, a range of com-
mercially available ketones (Table 2) were reacted to af-
ford N-heterospirocycles 3a-3i. Aldehydes also reacted to
afford the corresponding pyrrolidines (3j-3m), with the
syn-isomer of 3k being the major diastereomer. The reac-
tion was amenable to heterocyclic ketones, with a series of
saturated N-heterocyclic readily transformed into rigid,
C(sp3)-rich and polar bis-N-heterospirocyclic scaffolds
with orthogonal protecting groups on the two nitrogen at-
oms (3n-t), facilitating further derivatization. The reaction
to form azetidine-derived spirocycle 3p could be per-
formed on a gram-scale, even with a reduced catalyst load-
ing of 0.5 mol%, forming the product in a 63% yield; the
N-groups in 3p could also be selectively deprotected for
further derivatization.13 Such derivatives are frequently
employed as b-turn mimetics for GPCR protein binding
where the orthogonality of the two nitrogen substituents is
key to achieve the desired turn-characteristics.14 While the
Ir(dMeppy)3 photocatalyst had proven optimal for reac-
tions using electron-rich ketones (to form 3a-3e, 3i, 3l),
higher yields were observed for electron-deficient ketones
(to form 3f-3h, 3j-3k & 3m-3t) using the less-reducing
[Ir(dMeppy)2{dtbbpy}]PF6 photocatalyst.
Herein, we detail the successful realization of these ideas
through the development of a streamlined strategy for the
synthesis of complex C(sp3)-rich N-heterospirocycles from
readily available secondary amines and ketones enabled by
visible-light photocatalysis. Key to the success of this strat-
egy was the utilization of a highly reducing Ir-photocata-
lyst and orchestrating the intrinsic reactivities of 1,4-cyclo-
hexadiene and Hantzsch ester, which facilitated controlled
generation and fate of the radical intermediates present in
the reaction. Under optimized conditions, the process com-
bines a range of feedstock aliphatic ketones and aldehydes
with alkene-containing secondary amines to forge complex
C(sp3)-rich N-heterospirocycles displaying structural,
functional and physical features that are likely to be attrac-
tive in fragment-based lead identification programs.
We began our investigations by testing reaction condi-
tions based on our previously established photocatalytic
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Journal of the American Chemical Society
Table 2. Scope of photocatalytic synthesis of N-heterospirocycles.
1
Me
Me
[Ir(dMeppy)2{dtbpy}]PF6
Me
2
3
4
5
6
7
8
9
–
PF6
Ir photocatalyst (1 mol%)
40 W blue LED
O
N
Ir
Me
Me
tBu
N
+
Hantzsch ester, 1,4-cyclohexadiene
propionic acid (20 mol%)
N
H
N
N
Me
Ir+
N
N
N
4Å MS, CH2Cl2, r.t., 24-72 h
N
Me
tBu
Me
homoallyl amine 1
a carbonyl scope
Me
carbonyl 2
pyrrolidine 3
Ir(dMeppy)3
Me
Me
Me
Me
Me
Me
Me
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
O
O
N
N
N
N
N
N
tBu
Bn
Bn
Bn
Bn
Bn
Bn
62%a (1.5:1 d.r.), 3e
71%,a 3a
76%,a 3b
72%,a 3c
34%,a 3d
71%,a 3f
Me
Me
Me
Me
Me
Me
Me
Me
O
Et
F
O
N
N
N
N
N
2
N
S
Me
F
O
Bn
Bn
Bn
71%,a 3i
Me
Bn
Bn
82%b (1.8:1 d.r.), 3k
Me
Bn
72%b (2.3:1 d.r.), 3j
44%a (1.2:1 d.r.), 3l
87%,b 3g
50%,b 3h
Me
Me
Me
Me
N
BocN
N
O
BocN
2
N
N
N
N
N
O
BocN
Bn
Bn
Bn
Bn
Bn
Bn
73%b
70%b (3.7:1 d.r.), 3q
67%,b 3n
75%,b 3o
49%,b 3r
60%b (1.3:1 d.r.), 3m
63% (10 mmol),b,c 3p
b amine scope
Me
Me
Me
Me
Me
Me
OMe
OMe
BocN
BocN
N
O
N
N
N
O
O
N
Bn
N
N
S
CN
Bn
Me
2
53%,a 3w
64%,b 3s
78%,b 3t
77%,a 3u
60%,a 3v
77%,a 3x
c homoallyl amine scope
Me
Me
Me
Me
Me
Me
O
N
N
N
N
N
N
NBoc
H
N
N
Tol
N
S
N
Bn
S
2
O
O
53%,a 3y
29%,a 3z
69%,a 3aa
52%,a 3ab
25%,b 3ac
37%,a 3ad
CO2Et
Me
F
Ph
Me
Me
Me
F
i-Bu
N
O
O
N
N
N
N
O
N
OTIPS
Bn
Bn
Bn
Bn
Bn
Bn
54%,a 3af
46%b (1.6:1 d.r.), 3ag
51%b (4.9:1 d.r.), 3ah
84%b (1.1:1 d.r.), 3aj
40%,b 3ai
39%,b 3ae
d bis-α-tertiary amines
Me
Me
Me
Me
Me
Me
NBoc
n-Pr
i-Bu
n-Pr
O
BocN
O
N
N
N
N
N
N
S
NCbz
Bn
Bn
Bn
Bn
Bn
Bn
45%b (3:1 dr), 3ak
80%b (1.6:1 d.r.), 3al
65%b (>20:1 d.r.), 3am
78%b (>20:1 d.r.), 3an
49%,b 3ao
47%,b 3ap
aReaction using Ir(dMeppy)3. bReaction using [Ir(dMeppy)2{dtbpy}]PF6. c0.5mol% [Ir].
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Journal of the American Chemical Society
Page 4 of 7
We next assessed N-substituted alkenylamines, (3u-3an),
72% yield, whose structure comprises three different sized
ring-systems and two adjacent spirocyclic centres, as well
as different oxidative transformations (5 & 7, Figure 2b).17
Figure 3. Mechanistic studies
1
2
3
4
5
6
7
8
where useful functional groups such as sulfonamide, N-
Boc-piperidine, heteroaryl motifs (3u-3ab) and a less nu-
cleophilic aniline (3ac) could be built into the spirocycle
products. Substitution on the alkene was tolerated (3ad-
3ah), introducing valuable functionality such the ester and
gem-difluoro in useful yields. Whilst no cyclized product
was observed from attempts at reacting N-benzyl allyl
amine (to afford azetidine-based spirocycles), a piperidine
scaffold 3ai could be assembled via a 6-exo cyclization,
further expanding scope of the process. Homoallylic
amines containing a–substitutents were effective in the cy-
clization process with both aldehydes and functionalized
alicyclic ketones, in some cases with surprisingly high di-
astereoselectivities 3aj-3an. We found that the exception-
ally hindered spirocycles 3ao & 3ap could be accessed in
49% & 47% yield respectively, affording access to a class
of compounds that are challenging to synthesize using clas-
sical C–N bond-forming methods.6e,15,16
(a)
Me
Ir(dMeppy)3 (1 mol%)
amine 1a, 40 W blue LED
O
no additive: 97%a
with TEMPO: 13%a
Hantzsch ester, 1,4-CHD
propionic acid (20 mol%)
4Å MS, CH2Cl2, r.t., 24 h
N
Bn
2a
3a
9
Ir(dMeppy)3 (1 mol%), 40 W blue LED
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
Et
O
BnHN
1r
50% (83%)b, 3aq
Hantzsch ester, 1,4-CHD
propionic acid (20 mol%)
4Å MS, CH2Cl2, r.t., 24 h
N
Bn
2a
H
H
(b)
EtO2C
Me
CO2Et
Ir(III)(dMeppy)3* / Ir(IV)(dMeppy3)+
E1/2red = –1.86 V vs SCE
N
H
Me
[Ir(III)(dMeppy3)]
Figure 2. Cyclization on alkynes & amine derivatizations
Ir photocatalyst (1 mol%)
O
40 W blue LED
+
SET
Ph
N
Hantzsch ester, 1,4-CHD
propionic acid (20 mol%)
4Å MS, CH2Cl2, r.t., 24 h
Z
N
H
H
H
Z
Bn
EtO2C
CO2Et
Me
photocatalytic
cycle
homopropargyl amine 1o carbonyl 2
pyrrolidine 4
Me
N
H
[Ir(III)(dMeppy3)]*
(acts as reductant)
[Ir(IV)(dMeppy3)]+
BocN
N
N
N
O
Bn
Bn
Bn
SET
73%,a 4a
55%,a 4b
72%,b 4c
X-ray 4a
(2 mmol scale)
iminium
reduction
Ph
Ph
Br
N
N
Bn
Bn
5-exo
O
N
BocN
N
trig
cyclization
BocN
O
Int-II
Int-I
N
N
Bn
Bn
Stern-Volmer quenching of Ir(III)(dMeppy3)*
Bn
Bn
iminium ion
Et
Et
57%,a 4d
54%a 1:1 E:Z, 4e
53%a 1:1 E:Z, 4f
70%a >20:1 Z:E, 4g
Hantzsch ester
N
–
PF6
Int-III
N
4d
Bn
8
H
H
H
HAT
H
K2[OsO2(OH)4] (4 mol%)
NaIO4, THF-H2O, 5 °C, 60 h
Me3SiCF3, NaI
THF, 65 °C, 2h
K2[OsO2(OH)4] (2 mol%), NMO
THF/Me2CO/H2O/t-BuOH, 18 h
Me
3a
N
HO
OH
O
[Quencher] (mM)
F
F
Bn
aYield determined by GC assay with dodecane as internal standard.
bYield determined by 1H NMR with 1,1,2,2-tetrachloroethane as inter-
nal standard.
O
N
O
N
O
N
72%, 6
68%, 7
60%, 5
Bn
Bn
Bn
aReaction
using
Ir(dMeppy)3.
bReaction
using
[Ir(dMeppy)2{dtbpy}]PF6.
We found that the addition of TEMPO, as a radical trap,
significantly inhibited the reaction (Figure 3a). A reaction
with cyclopropyl-substituted alkenyl amine 1r led to the
ring opened product, supporting the existence of a cyclized
radical intermediate (c.f. Int-III). Stern-Volmer studies on
a representative iminium ion 8 showed effective quenching
of the excited state of the Ir(dMeppy)3 photocatalyst in
comparison to Hantzsch ester (Figure 3c). As a result of
Next, we questioned whether we could apply the a-amino
radical to a cyclization process with simple alkynes, afford-
ing N-heterospirocycles carrying a useful alkenyl handle
for further functionalization. N-benzyl 4-aminobutyne de-
rivatives smoothly reacted with a range of cyclic ketones
furnishing the desired spirocycles 4a-g in 53–73% yield
(Figure 2a). Finally, the alkenyl handle of 4d could be deri-
vatized through a difluorocyclopropanation to afford 6 in
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Journal of the American Chemical Society
these studies and those outlined in our optimization (Table
C. M. The utilization of spirocyclic scaffolds in novel drug
discovery. Expert Opin. Drug Discov. 2016, 11, 831-834.
(c) Johansson, L.; Anders, M. Azetidine derivatives for
treatment of melanin related disorders. Patent WO
2013/011285 A1, 2013. (d) Chen, H.; Colletti, S. L.; De-
mong, D.; Guo, Y.; Miller, M.; Nair, A.; Plummer, C.;
Xiao, D.; Yang, D.-Y. Antidiabetic bicyclic compounds.
Patent WO 2016/022742 A1, 2016.
1
2
3
4
5
6
7
8
1), we propose a tentative mechanism for the reaction
which begins with visible-light excitation of Ir(dMeppy)3
to Ir(dMeppy)3* (Figure 3c). Single-electron reduction of
the iminium ion (Int-I) by Ir(dMeppy)3* forms the a-amino
radical (Int-II), which engages the pendant alkene in a 5-
exo-trig cyclization to form an alkyl radical (Int-III); HAT
from 1,4-CHD to the alkyl radical then forms N-heterospi-
rocycle 3. The oxidized Ir(IV)(dMeppy)3 species is re-
duced to the active catalyst by single-electron transfer from
the Hantzsch ester, closing the catalytic cycle.
(5) (a) Carreira, E. M.; Fessard, C. T. Four-membered ring-
containing spirocycles: synthetic strategies and opportuni-
ties. Chem. Rev. 2014, 114, 8257-8322. (b) Rios, R. Enan-
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Scalable synthesis of biologically relevant spirocyclic pyr-
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In summary, we have developed a visible-light mediated
process to enable the facile synthesis of heterospirocyclic
compounds from readily available starting materials. The
photoredox strategy offers an intuitive retrosynthetic dis-
connection for difficult-to-access C(sp3)-rich N-heterospi-
rocyclic scaffolds that may be of interest to practitioners of
both synthetic and medicinal chemistry.
ASSOCIATED CONTENT
The Supporting Information is available free of charge on the
ACS Publications website. Experimental procedures and spec-
tral data (PDF); crystallographic data (CIF)
(6) (a) Rousseaux, S.; Garcia-Fortanet, J.; Angel Del
Aguila Sanchez, M.; Buchwald, S. L. J. Am. Chem. Soc.
2011, 133, 9282-9285. (b) Zhu, M.; Zheng, C.; Zhang, X.;
You, S-L. Synthesis of cyclobutane-fused angular tetracy-
clic spiroindolines via visible-light-promoted intramolecu-
lar dearomatization of indole derivatives. J. Am. Chem.
Soc. 2019, 141, 2636-2644. (c) Adams, K.; Ball, A. K.;
Birkett, J.; Brown, L.; Chappell, B.; Gill, D. M.; Tony Lo,
P. K.; Patmore, N. P.; Rice, C. R.; Ryan. J.; Raubo, P.;
Sweeney, J. B. An iron-catalysed C-C bond forming spiro-
cyclization cascade providing sustainable access to new
3D heterocyclic frameworks. Nat. Chem. 2017, 9,
396-401. (d) Siau, W.-Y.; Bode, J. W. One-step synthesis
of saturated spirocyclic N‑heterocycles with stannyl amine
protocol (SnAP) reagents and ketones. J. Am. Chem. Soc.
2014, 51, 17726-17729. (e) Saito, F.; Trapp, N.; Bode, J.
W. Iterative assembly of polycyclic saturated heterocycles
from monomeric building blocks. J. Am. Chem. Soc. 2019,
141, 5544-5554.
AUTHOR INFORMATION
Corresponding Author
*mjg32@cam.ac.uk
ACKNOWLEDGMENT
We are grateful to the Gates Cambridge Trust (N. J. F.) and
Herschel Smith Scholarship Scheme (A. T.) for student-
ships, the EPSRC (EP/S020292/1 & EP/N031792/1), Am-
bitious Leader's Program, Hokkaido University, Japan (J.
K.) and the Royal Society for a Wolfson Merit Award
(M.J.G.). S. M. W. is a Fellow of the AstraZeneca Postdoc-
toral program. We are grateful to the EPSRC UK National
Mass Spectrometry Facility at Swansea University for
HRMS analysis.
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50 examples of functionally diverse products C(sp3)-rich polar
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