Conformationally Driven Two- and Three-Photon Cascade Processes in the Stereoselective Photorearrangement of Pyrroles

Article abstract of DOI:10.1021/acs.orglett.6b02829

A TBSO group has been shown to exert a high degree of stereocontrol during the two-photon photocycloaddition/rearrangement of N-butenylpyrroles to complex tricyclic aziridines. Moreover, this and other bulky groups have been shown to change the outcome of the reaction, promoting a new two-photon sequence to tricyclic imines and an unprecedented stereoselective three-photon sequence to azabicyclo[3.3.1]nonanes.

Full text of DOI:10.1021/acs.orglett.6b02829

Letter
pubs.acs.org/OrgLett
Conformationally Driven Two- and Three-Photon Cascade Processes
in the Stereoselective Photorearrangement of Pyrroles
Paul J. Koovits, Jonathan P. Knowles, and Kevin I. Booker-Milburn*
School of Chemistry, University of Bristol, Cantock’s Close, Bristol BS8 1TS, U.K.
S
* Supporting Information
ABSTRACT: A TBSO group has been shown to exert a high
degree of stereocontrol during the two-photon photocycloaddi-
tion/rearrangement of N-butenylpyrroles to complex tricyclic
aziridines. Moreover, this and other bulky groups have been shown
to change the outcome of the reaction, promoting a new two-
photon sequence to tricyclic imines and an unprecedented
stereoselective three-photon sequence to azabicyclo[3.3.1]-
nonanes.
hotochemistry is largely unrivaled in its ability to access
complex molecular structures from simple starting
excited states remains highly challenging due to the very short
lifetimes involved. Only recently have effective organocatalysts
for asymmetric photochemistry been developed as exemplified
by the very elegant host−guest sensitizer work of Bach et al.7
Successful enantioselective photochemical reactions induced by
chiral auxiliaries have been reported. However, despite notable
successes, diastereomeric ratios (dr) in these auxiliary-
controlled reactions can often be lower than ideal8 as the
rapid reaction of excited-state intermediates can thwart the
establishment of key auxiliary-controlled transition states.
Against this backdrop, we wished to explore whether
functional groups (R2/R3) on the butenyl side chain of pyrrole
4 would influence the outcome of this complex photochemical
sequence and lead to single diastereomers of sp3-rich aziridines
as reactive scaffolds9 for use in drug discovery. Initially, we
focused on synthesizing a range of 2-substituted pyrroles (R1 =
CO-Aux) bearing common chiral auxiliaries such as (+)-men-
thol, Evans’ auxiliary, camphor sultam, borneol, and various
chiral amines. All attempts gave aziridines (R1 = CO-Aux; R2/
R3 = H) with very little or no observed diastereoselection. This
result was surprising given the likely proximity of the butenyl
double bond to the 2-acyl unit bearing the chiral auxiliary
during the initial [2 + 2] cycloaddition. Moving to substituents
on the butenyl side chain, we initially studied the β-
methylpyrrole 4 (R1 = CONHEt, R2 = H, R3 = Me). Although
the aziridine 6 (R1 = CONHEt, R2 = H, R3 = Me) was obtained
in 56% yield, the exo/endo diastereoselectivity was low at 4:1,
although still better than the R1 auxiliary approach (Scheme 1).
We therefore decided to study a range of α-substituted
pyrrole examples 7. Moving the methyl group to the α-position
(Table 1, entry 1) gave excellent diastereoselectivity (≥98:2 dr)
during the two-photon process. Pleasingly, this high level of
stereocontrol was maintained for a range of α-substituted
examples bearing even more bulky alkyl groups (entries 2−5).
P
materials. Part of this is due to reaction types specific to the
photochemical excited state such as alkene−alkene [2 + 2],1
arene m-photocycloaddition,2 di-π-methine rearrangements,3
and various Norrish−Yang4-type hydrogen abstraction−recom-
bination sequences to name but a few. Useful sequences
involving a second photon-mediated step are rare5 but do offer
the promise of large increases in molecular complexity due to
massive reorganization of the original starting material
structure. We recently6 described an example of a general
two-photon cascade sequence of pyrroles 1 to give structurally
complex aziridines 3 via a second photon-mediated rearrange-
ment step of the initially formed cyclobutane 2 (Scheme 1).
Scheme 1. Photocycloaddition−Rearrangement Reactions of
Pyrroles
Herein, we describe the unusually high diastereoselectivity
observed in the photocycloaddition/rearrangement of N-
butenylpyrroles bearing bulky groups and how these groups
change the course of the reaction to uncover unprecedented
two- and three-photon-mediated processes.
Unlike thermal chemistry, and outside of photoredox
catalysis, asymmetric bond formation from photochemically
Received: September 21, 2016
© XXXX American Chemical Society
A
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Letter
Table 1. Exploring the Effects of Stereocontrol with Various
α-Substituents during the Photochemical Rearrangement of
Pyrroles
Scheme 2. Scope of the OTBS as a Chiral Auxiliary in the
Diasteresoselective Photochemical Rearrangement of
Pyrroles
a
,b
a
entry
R1
R2
Me
9 (%)
dr
1
2
3
4
5
6
7
8
9
CONHEt
CONHEt
CONHEt
CONHEt
CONHEt
CN
39
51
46
60
38
37
40
50
39
70
≥98:2
≥98:2
≥98:2
≥98:2
≥98:2
5:1
Et
Pr
iBu
iPr
Me
Pr
CN
5:1
CN
OAc
OTBS
2:1
CN
8:1
10
CONHEt
OTBS
b
≥98:2
a
Reactions performed in MeCN. All products are racemic.
Interestingly, however, on switching from an amide activating
group (R1) to nitrile a significant drop in diastereocontrol was
observed that was not improved by switching from Me to Pr
(entries 6 and 7). Use of more functionally useful groups led to
interesting results. Although R2 = OAc (entry 8) gave very poor
dr, the use of R2 = OTBS gave high selectivity (8:1). The lower
yields obtained with the nitrile activating group are a reflection
of the known competing 2- to 3-cyano photorearrangement10
of pyrroles. In all of these examples, NMR and X-ray
experiments indicated that the endo product (9) was the
major diastereomer formed, where the R2 group was placed in
the concave face of the “bowl” generated by the three new rings
(vide infra).
a
b
All products except 11d were synthesized as racemates; Concurrent
irradiation at 312 nm was employed using a dual lamp system (see the
SI).
We were keen to exploit this unusually high level of
stereoselectivity observed by the OTBS group, especially since
the aziridine products would possess a useful functional group
(R2) for further elaboration. The requisite pyrrole carbinols (7,
R2 = OH) have been described by Evans as remarkably stable
and have been frequently used as masked aldehydes.11 Using
this methodology, we synthesized a range of substituted
pyrroles containing OTBS ethers at the α-substituted carbon
and investigated their two-photon rearrangement (Scheme 2).
All 12 examples gave excellent levels of selectivity, with
essentially the endo-isomer of the aziridines 11a−l being
formed as the single product in each case. In examples
possessing two electron-withdrawing groups (11g−l), better
yields were obtained with a dual lamp system at 254 and 312
nm, where the longer wavelength was a better match for the
now conjugated cyclobutane intermediates. Only the nitrile
example 11a showed less than optimal selectivity at 8:1 dr.
With the exception of 11k, the yields of these rearrangements
can be considered moderate to good; i.e., this is a complex
cascade process involving two photons of very high energy (254
nm), generating very strained tricyclic products of high
reactivity.9,12 As the stereogenic center bearing the OTBS
group had such a profound and consistent level of stereocontrol
during rearrangement, we were keen to prove that an
asymmetric synthesis of 11 could be achieved in high ee
from enantiopure 10. Synthesis of S-10d (R1 = CONHEt, R2 =
OTBS) gave enantioenriched 11d (98% ee) with no erosion of
chirality observed during the photochemical process (see the
Supporting Information).
Initially, we found it curious that the products were formed
as the most hindered isomers; i.e., the large OTBS group was
placed on the concave face of the tricyclic aziridine ring system.
The origin of this high selectivity is very likely to arise during
the first step in the formation of the cyclobutane ring.13 If a
simple diradical-like mechanism is considered, then after initial
excitation a Beckwith radical cyclization transition-state
model14 could be adopted (Scheme 3).
Here, the diradical could adopt one of two equilibrating
chairlike transition states 12 and 13, where the former,
pseudoequatorial disposition of the OTBS group would be
greatly favored. On cyclization of 12, the cyclobutane 14 would
result, which in turn would lead to the endo-isomer of 11. This
Scheme 3. Stereochemical Model To Explain Endo-
Selectivity during Cycloaddition/Rearrangement of Pyrroles
B
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Letter
well-documented Beckwith model for stereoselective cycliza-
tion neatly explains why in our case the more sterically
congested endo-isomers of the aziridines are obtained in every
case (Scheme 2). This also explains the exo selectivity obtained
for β-substituted methyl isomer 6 (R1 = CONHEt, R2 = H, R3
= Me).
While attempting to increase the dr of the 2-cyano-
substituted pyrroles (Table 1, entries 6−9), we explored a
range of alkyl substituents of increasing steric bulk. During the
course of this, we uncovered a novel mode of reactivity that we
had not previously observed. For example, irradiation of the iBu
substrate 16 (Table 2, entry 1, R1 = CN, R2 = iBu) gave the
cyclobutanes (8) led to aziridine formation and small amounts
of the starting pyrrole. However, irradiation of the aziridines
showed no sign of the reverse rearrangement to the
cyclobutanes. We believe that the formation of 19 likely occurs
directly from an excited state of 8, which influenced by R2,
adopts a conformation that favors fragmentation to 19. It is also
possible that in 20 the large R2 now dictates a conformation
that disfavors radical recombination to 18 and so equilibrates
back to 8. This 3,4,7-fused ring system is novel and stable, and
the X-ray structure of the crystalline adamantyl derivative 17
(R1 = CN, R2 = Ad) shows the interesting fusion of 3-, 4-, and
7-membered rings. The two-photon process represents an
entirely novel photochemical reaction, and further studies are
ongoing to determine its generality. In particular, the ability to
influence very complicated two-photon pathways by choice of
R2 group size introduces the exciting prospect of control of
short-lived reactive species.
Table 2. Discovery of a New Conformationally Controlled
c
Two-Photon Cycloaddition−Rearrangement Sequence
During the extensive work with the TBSO derivatives
(Scheme 2), we became aware that traces of a new product
were being formed in addition to the aziridine. Prolonged
irradiation of 10c showed the appearance of the aziridine 11c,
which over time was consumed to give a new product, the
lactam 22a, in 50% yield as essentially a single diastereomer.
This remarkable product would appear to be a three-photon
process involving pyrrole → cyclobutane → aziridine → lactam.
Further excitation of the ketone in the initially formed aziridine
11c leads to a Norrish Type II hydrogen atom abstraction
sequence 23 to 24. The resulting biradical 24 then undergoes
fragmentation to 25 and upon protonation and desilylation
yields 22a (Scheme 5). This is the first time that we have
a
entry
R1
CN
R2
17 (%)
18 (%)
dr (18)
1
2
3
4
5
iBu
Cy
iPr
tBu
19
8
35
27
7
11:1
>98:2
>98:2
>98:2
CN
CN
CN
22
52
47
23
13
10
29
CN
CO2Et
1
Ad
tBu
b
>98:2
>98:2
c
b
6
a
Determined by H NMR. Reaction performed in cyclohexane. All
products are racemic.
Scheme 5. Novel Three-Photon Conversion of Pyrroles to
Bicyclic Lactams and Proposed Mechanism
aziridine 18 (R1 = CN, R2 = iBu) with an improved dr of 11:1.
However, along with this we isolated the remarkable tricyclic
imine 17 (R1 = CN, R2 = iBu) as a single isomer. We then
synthesized a variety of pyrroles with more sterically
demanding R1 groups. In all cases, this unusual tricyclic
product was observed, and indeed, with very bulky groups this
was the main product (entries 3−5). It is also interesting to
note that that as the steric bulk of R2 increased so too did the
dr, to the point that no other isomers of the aziridine 18 were
detected.
It is likely that this is a two-photon process proceeding via
the initial cyclobutane 8 as a common intermediate. As
previously discussed, aziridine formation (18) is thought to
proceed from rearrangement of 8 via the diradical species 20.
Clearly, the large R2 group is exerting a degree of conforma-
tional control that favors fragmentation of 8 to the imine
diradical 19, which then cyclizes to 17 (Scheme 4). In our
previous work, we proved that irradiation of intermediate
observed fragmentation of this particular aziridine bond;
reactions with nucleophiles, organometallics, and internal H
atom-transfer processes have all proceeded with cleavage of the
alternative N−C bond. We believe that the OTBS group
performs two crucial roles in directing this alternative pathway.
First, the endo stereochemistry places the key H atom in close
proximity to the excited ketone in 23. Second, the radical
center resulting from abstraction is additionally stabilized by
virtue of the α-oxygen atom, explaining why this mode has not
been observed in other 2-acylpyrrole systems.
Scheme 4. Mechanism of Tricyclic Imine Formation
It was interesting to note that enol−keto tautomerization of
25 would appear to proceed by protonation from the amide/
OTBS side of the molecule to give predominantly one
diastereoisomer. As the resulting ketone proved stable to
epimerization during isolation and purification by flash
chromatography, this is likely a kinetic protonation to the
stereoisomer observed. Although we were never able to observe
the silyloxy imine motif in 25, such species are very labile15 and
C
DOI: 10.1021/acs.orglett.6b02829
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
would likely undergo rapid hydrolysis to the amide in the
hygroscopic MeCN solvent used.
An optimization study showed that a ketone in the 2-position
of the pyrrole was essential to enable lactam formation (Table
3, entries 1−5) and that a second ketone was actually
Synthesis procedures; additional spectral and character-
1
ization data, including H and 13C NMR (PDF)
X-ray data for 17 (CIF)
X-ray data for 22a (CIF)
AUTHOR INFORMATION
Corresponding Author
■
Table 3. Discovery of a Novel Three-Photon Rearrangement
Cascade Sequence of 2-Acylpyrroles to 2-
Azabicyclo[3.3.1]nonanes
*E-mail: k.booker-milburn@bristol.ac.uk.
Notes
b
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the Engineering and Physical Sciences Research
Council (EP/K006053/1 and EP/L003325/1) for funding.
■
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a
■
entry
product
R1
R2
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43
dr
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̈
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acylpyrroles, OTBS substitution facilitates an unprecedented
and highly stereoselective three-photon cascade sequence
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underlines the versatility of photochemistry for the synthesis
of highly complex molecules from simple starting materials.
The ability to select a desired reaction manifold through
substituent choice allows access to broad areas of molecular
space from a common structural starting point, potentially
making it of considerable value in drug discovery.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02829.
D
DOI: 10.1021/acs.orglett.6b02829
Org. Lett. XXXX, XXX, XXX−XXX