Carbamoyl radical-mediated synthesis and semipinacol rearrangement of β-lactam diols

Article abstract of DOI:10.1002/chem.201304982

In an approach to the biologically important 6-azabicyclo[3.2.1]octane ring system, the scope of the tandem 4-exo-trig carbamoyl radical cyclization - dithiocarbamate group transfer reaction to ring-fused β-lactams is evaluated. β-Lactams fused to five-,

Full text of DOI:10.1002/chem.201304982

DOI: 10.1002/chem.201304982
Full Paper
&
Organic Synthesis
Carbamoyl Radical-Mediated Synthesis and Semipinacol
Rearrangement of b-Lactam Diols
Marie Betou,[a] Louise Male,[a] Jonathan W. Steed,[b] and Richard S. Grainger*[a]
Abstract: In an approach to the biologically important 6-
azabicyclo[3.2.1]octane ring system, the scope of the
tandem 4-exo-trig carbamoyl radical cyclization—dithiocar-
bamate group transfer reaction to ring-fused b-lactams is
evaluated. b-Lactams fused to five-, six-, and seven-mem-
bered rings are prepared in good to excellent yield, and
with moderate to complete control at the newly formed di-
thiocarbamate stereocentre. No cyclization is observed with
an additional methyl substituent on the terminus of the
double bond. Elimination of the dithiocarbamate group
gives a,b- or b,g-unsaturated lactams depending on both
the methodology employed (base-mediated or thermal) and
the nature of the carbocycle fused to the b-lactam. Fused b-
lactam diols, obtained from catalytic OsO4-mediated dihy-
droxylation of a,b-unsaturated b-lactams, undergo semipina-
col rearrangement via the corresponding cyclic sulfite or
phosphorane to give keto-bridged bicyclic amides by exclu-
sive N-acyl group migration. A monocyclic b-lactam diol un-
dergoes Appel reaction at a primary alcohol in preference to
semipinacol rearrangement. Preliminary investigations into
the chemo- and stereoselective manipulation of the two
carbonyl groups present in a representative 7,8-dioxo-6-
azabicyclo[3.2.1]octane rearrangement product are also
reported.
Introduction
b-Lactams, both naturally occurring and synthetic, play a pre-
eminent role as medicinally important compounds, particularly
as antibiotics.[1,2] The inherent ring strain and resultant reactivi-
ty of the four-membered ring also renders b-lactams useful in-
termediates for organic synthesis, particularly through ring-
opening reactions at the amide bond.[2,3] As a consequence of
these dual roles in medicinal chemistry and synthesis, a wide
range of methodologies have been developed for the prepara-
tion and subsequent transformation of b-lactams, both mono-
cyclic and fused to other ring systems.[2,4]
We have previously reported a high yielding synthesis of
fused b-lactam 2 through simple irradiation of readily prepared
carbamoyl diethyldithiocarbamate 1 (Scheme 1).[5] 4-Exo-trig
cyclization of carbamoyl radical 3 is followed by dithiocarba-
mate group transfer from 1 to the cyclohexyl radical 4 on the
less hindered convex face of the bicyclic ring system.[6] In relat-
ed research we have employed the regioselective cyclization of
Scheme 1. Tandem carbamoyl radical cyclization—dithiocarbamate group
transfer mediated synthesis of cis-fused b-lactams and 6-azabicyclo-
[3.2.1]octane ring system.
[a] Dr. M. Betou, Dr. L. Male, Dr. R. S. Grainger
School of Chemistry, University of Birmingham
Edgbaston, Birmingham B15 2TT (UK)
E-mail: r.s.grainger@bham.ac.uk
[b] Prof. J. W. Steed
carbamoyl dithiocarbamate 5 to synthesize the bridged 6-
azabicyclo[3.2.1]octane ring system 6 of aphanorphine, an alka-
loid isolated from a blue–green algae.[7]
Department of Chemistry, Durham University
South Road, Durham DH1 3LE (UK)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201304982.
The 6-azabicyclo[3.2.1]octane ring system is found within
a range of synthetic[8–10] and naturally occurring,[7,11–18] biologi-
cally active compounds (Figure 1). The former include 7 (“azap-
rophen”), a synthetic muscarinic anatagonist,[9] and 8, a synthet-
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Scheme 3. Semipinacol rearrangement of b-lactams with N-acyl group mi-
gration. PPTS=pyridinium p-toluenesulfonate.
col-like ring expansions of non-fused b-lactams to g-lactams
have been reported in the literature, and notably all occur
with exclusive migration of the N-acyl group rather than the
methylene or methine carbon atom (Scheme 3).[21–23] Our ap-
proach was also inspired by the X-ray crystal structure of b-
lactam 2, in which the cyclohexane ring adopts a boat-like ar-
rangement to accommodate the cis-ring fusion, placing the di-
ethyldithiocarbamate group axial with the CÀS bond approxi-
mately antiperiplanar with the CÀC(O) bond of the b-lactam
(C1-C2-C7-S1 torsion angle À173.2 (2)8) (Figure 2).[24] In as
much as 2 can be regarded as a model for the proposed rear-
rangement precursor 10, migration of the N-acyl group of the
b-lactam was expected to be preferred both electronically and
stereoelectronically over migration of the N-alkyl group.
Figure 1. Representative natural and non-natural products containing the 6-
azabicyclo[3.2.1]octane ring system.
ic cocaine analogue and inhibitor of dopamine reuptake.[10]
Representative natural products containing the 6-azabicyclo-
[3.2.1]octane ring system include aphanorphine,[7,11] members
of the Securinega alkaloids, for example securinine,[12] actino-
bolamine,[13] members of the hetisine alkaloids, for example
nominine,[14] lyconadin A,[15] peduncularine,[16] calyciphilline D[17]
and sarain A.[18] Hence this ring system has been the focus of
intense synthetic interest, with a number of approaches report-
ed in addition to those applied in target synthesis.[19]
A challenge that must be addressed in the synthesis of
many of the natural products shown in Figure 1 is the func-
tionalization at C-8 of the 6-azabicyclo[3.2.1]octane ring
system. Although potentially accessible through modification
of our previous approach by incorporation of additional func-
tionality in radical precursors, such as 5, we instead sought to
exploit the simpler, high-yielding synthesis of b-lactam 2
(Scheme 1). In principle, the bridged bicyclic amide 11, bearing
a ketone at C-8, could be prepared through a semipinacol rear-
rangement[20] of an oxygenated b-lactam 10, in turn derived
from dithiocarbamate 9, the product of a group-transfer carba-
moyl radical cyclization reaction (Scheme 2). Related semipina-
Figure 2. Crystal structure of b-lactam 2 with ellipsoids drawn at the 50%
probability level. The group N2, C8–C12 is disordered over two positions.
Only the major component has been shown for clarity.
Scheme 2. Proposed semipinacol rearrangement approach to keto-bridged
6-azabicyclo[3.2.1]octane ring system 11. LG=leaving group.
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In this paper, we report the successful implementation of
this strategy through conversion of fused b-lactams of general
structure 9 in three or four steps to keto-bridged bicyclic lac-
tams 11. We also report studies on the scope and limitation of
this methodology in our attempts to apply it to structurally re-
lated systems.[25]
signed based on the close spectral similarity of 14 with 2, and
the expected dithiocarbamate group transfer to the intermedi-
ate cyclohexyl radical (analogous to 4, Scheme 1). More gener-
ally, N-PMP systems were found to display favourable spectro-
scopic and practical features, including increased crystallinity,
compared with N-alkylated systems.
Our initial approach to convert b-lactam 14 into a suitable
substrate for the proposed semipinacol rearrangement was
based on incorporation of a hydroxyl group at the ring junc-
tion, and then employ the dithiocarbamate group as a latent
leaving group.[26] Unfortunately attempts to deprotonate b-
lactam 14 and quench the corresponding enolate with an elec-
trophilic oxidant, a reaction that has precedent in non-fused
systems,[27] met with failure.
Results and Discussion
Methodology development
Methodology development was carried on N-para-methoxy-
phenyl (PMP) substituted lactams (Scheme 4). The PMP deriva-
tive 13 was prepared through a similar sequence to that for
the N-benzyl system 1.[5,25a] Treatment of p-methoxyaniline 12,
readily prepared through alkylation of p-anisidine with 3-bro-
mocyclohexene, with triphosgene gave an isolable carbamoyl
chloride intermediate of sufficient purity to be carried through
Attention therefore turned to elimination of the dithiocarba-
mate group to form a ring-fused a,b-unsaturated b-lactam
suitable for further oxidation. At the outset of this work we
were unsure as to the feasibility of incorporating a double
bond at the ring-junction of a [4.2.0] fused bicyclic b-lactam, al-
though the analogous [5.2.0] bicyclic system had been previ-
ously prepared through a palladium-catalyzed carbonylation
reaction.[28] Indeed, our previous studies on the thermal elimi-
nation of the dithiocarbamate group from 2 had shown exclu-
sive elimination to the non-conjugaged alkene, and the same
reaction conditions applied to the N-PMP b-lactam 14 gave
alkene 16 regioselectively (Scheme 4).[29]
A screen of some common bases identified NaHMDS to be
the most promising for further optimization, although avoid-
ance of aqueous work-up proved necessary for the isolation of
a,b-unsaturated b-lactam 15 (Scheme 4 and Table 1, entries 1–
6). Increasing the equivalents of base or running the reaction
at higher temperature resulted in inseparable mixtures of 15
and 16 (entries 7 and 8). Independent subjection of alkene 15
to 1.1 equivalents of NaHMDS in THF at room temperature for
6 h showed conversion to a 1:1 mixture of 15 and 16, whereas
under the same conditions no change occurred starting from
16. This suggested that the formation of 16 in the base-medi-
ated elimination reaction occurs through isomerization of 15
rather than a competing elimination pathway from 14.
Scheme 4. Preparation and dithiocarbamate group elimination of N-PMP b-
lactam 14. mCPBA=meta-chloroperbenzoic acid; NMO=N-methylmorpho-
line N-oxide.
to the next step without the
need for further purification.
Table 1. Base-mediated elimination of dithiocarbamate 14.[a]
Chloride displacement with com-
mercially available sodium dieth-
Entry
Reagent[b] (equiv)
T [8C]
t [h]
Result
yldithiocarbamate
salt
was
1
2
3
4
5
6
7
8
LDA (1.1)
À78 to RT
120
RT
18
18
26
6
4.5
4.5
1
7.5 then 18
5.75
4
2.75
2.5
6.5
14
14
14
found to require more forcing
conditions for an N-PMP sub-
stituent than for the analogous
N-benzyl system 1 (refluxing ace-
tone rather than room tempera-
ture), but the radical precursor
13 could nevertheless be pre-
pared in similarly high yield. Irra-
diation of 13 gave the fused b-
lactam 14 as a single diastereo-
isomer in 84% yield. The stereo-
chemistry at the new dithiocar-
bamate stereocentre was as-
quinoline[c]
NaH (1.1)
tBuOK (1.1)
RT
22% 14, 37% 15
22% 14, 46% 15
47% 15
42% 15 + 16
46% 15 + 16
60% 15
61% 15
16% 15
39% 15
99% 15
NaHMDS (1)
NaHMDS (1.5)
NaHMDS (3)
NaHMDS (1.5)
KHMDS (1.1)
LHMDS (1.1)
LHMDS (1.1)
LHMDS (1.1)
LHMDS (1.05)+MeI (1.05)
À78
À78
À78
À78 to RT
À78
À78
0
9
10
11
12
13
À40
À78
[a] All reactions were carried out in THF unless otherwise stated. [b] LDA=lithium diisopropylamide; K/Na/
LHMDS=potassium/sodium/lithium hexamethyldisilazide. [c] Quinoline was used as solvent.
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Increased yields of 15 were obtained using KHMDS and
LHMDS at low temperatures (Table 1, entries 9 and 10), with
higher temperatures resulting in reduced yields (entries 11 and
12). Addition of MeI to activate the dithiocarbamate group to-
wards elimination[26] caused a dramatic increase in yield, with
alkene 15 the exclusive product formed in nearly quantitative
yield (entry 13).
The strain inherent in alkene 15 is evident in the X-ray crys-
tal structure (Figure 3).[24] There is a notable deviation from pla-
narity in the alkene, as evidenced in the C1-C2-C3-C4 torsion
angle (À145.14(16)8). The C3-C2-C1 bond angle (138.30(13)8) is
also larger than expected. This strain may account for the iso-
merisation of 15 to the non-conjugated alkene 16 under cer-
tain conditions.
Figure 4. Crystal structure of hydrate 23 with ellipsoids drawn at the 50%
probability level.
selective activation of the secondary over the tertiary alcohol
proved to be challenging. Attempted mesylation gave pre-
dominantly the dimesylate 25, alongside 24, the product of
mesylation of the tertiary alcohol, with dimesylation favoured
even in the presence of starting diol. Treatment of 18 with
tosyl chloride, DMAP and triethylamine also showed the prefer-
ence for reaction at the tertiary alcohol, with tosylate 26 isolat-
ed in 71% yield. Switching to pyridine as base partially re-
versed this selectivity, with the desired secondary tosylate 27,
clearly structurally distinct from its epimer 20, isolated in 50%
yield alongside ditosylate 28. Tosylate 27 underwent the de-
sired rearrangement to 21 in refluxing toluene in the presence
of pyridine, and 21 could be prepared in 58% yield in one
step from 18 without isolation of the tosylate (Scheme 5). At-
Figure 3. Crystal structure of alkene 15 with ellipsoids drawn at the 50%
probability level. Selected bond lengths and angles: C3-C2-C1 138.30(13),
C3-C2-C7 125.47(12), C2-C3-C4 120.17(13), C7-C2-C3-C4 À5.1(2), C1-C2-C3-C4
À145.14(16)8.
Treatment of alkene 15 with mCPBA gave epoxide 17 in rea-
sonable yield as long as a non-aqueous work-up was em-
ployed.[30] Osmium tetraoxide-catalyzed dihydroxylation gave
diol 18 stereoselectively (Scheme 4).[31] Both 17 and 18 were
assigned as cis-fused b-lactams. The corresponding trans-fused
b-lactams would be considerably more strained and hence un-
likely to form under these conditions.[32]
The semipinacol rearrangement of epoxide 17 was first at-
tempted. Treatment of 17 with BF3 gave no reaction at low
temperature (À788C, CH2Cl2), and decomposition upon warm-
ing to room temperature. The use of TiCl4 resulted in ring-
opening of the epoxide to chloroalcohol 19. However, treat-
ment of 17 with PPTS in refluxing toluene gave tosylate 20 in
42% yield after 2.25 h, and encouragingly the desired rear-
rangement product 21 when the reaction time was increased
to 18 h, albeit in a moderate 33% yield.
Structural assignment of the semipinacol rearrangement
product as ketone 21 rather than the alternative 1,2-dicarbonyl
22 arising from methine carbon migration could not be made
unambiguously by NMR spectroscopic analysis. However X-ray
crystallography confirmed the formation of the 6-azabicyclo-
[3.2.1]octane ring system. Surprisingly the corresponding hy-
drate 23 crystallized rather than ketone 21 from acetone solu-
tion (Figure 4). Intermolecular hydrogen bonding is evident in
the solid state, which presumably stabilizes the hydrate struc-
ture.[24]
The more robust diol 18 offered a wider variety of potential
conditions to affect the semipinacol rearrangement; however,
Scheme 5. Attempted semipinacol rearrangement of epoxide 17 and diol
18. DMAP=4-dimethylaminopyridine; py=pyridine.
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tempted direct pinacol rearrangement of diol 18 using PPTS in
toluene at 808C gave only starting material, and recourse to
a stronger acid (TsOH) gave either no reaction, or degradation
at higher temperatures.
raphy, and the stereochemistry at the sulfinyl group initially as-
1
signed on the basis of the H NMR chemical shift of the proton
in the cyclic sulfite ring, which appears at d=5.41 ppm for 30
and 5.04 ppm for 31. The anisotropy of the sulfinyl (S=O)
group results in a downfield shift for the appropriately aligned
proton adjacent to oxygen in 30.[37] Subsequent X-ray crystal-
lography of both 30 and 31 confirmed the stereochemical as-
signment (Figure 5).[24]
The apparent higher reactivity of the tertiary over the secon-
dary alcohol in 18 may be a consequence of the conformation
adopted by the bicyclic ring system. Analogous to 2, the cyclo-
hexane ring of 18 is forced to adopt a boat-like conformation
to accommodate the cis-ring fusion of the b-lactam. As a conse-
quence the secondary alcohol is in a more hindered flagstaff
position and the tertiary alcohol is pseudo-equatorial and rela-
tively exposed. Hence reaction at the tertiary alcohol, or migra-
tion of groups from secondary to tertiary, is feasible.
The moderate yields of 21 from epoxide 17 and diol 18,
coupled with the difficulties in selectively activating the secon-
dary alcohol of 18, led us to investigate cyclic systems. At-
tempted rearrangement via a cyclic orthoester through treat-
ment of diol 18 with trimethylorthoformate and a Lewis acid
gave the formate ester 29 in 41% yield (Scheme 6).[33] Suspect-
Scheme 6. Attempted semipinacol rearrangement through cyclic activation.
Figure 5. Crystal structures of 30 (top) and 31 (bottom) with ellipsoids
drawn at the 50% probability level. Selected bond lengths and torsion
angles: 30: C2ÀC7: 1.542(2), C2ÀC3: 1.558(2), C1ÀO2: 1.4559(18) ꢁ, O2-C1-
C2-C7: 140.95(13), O2-C1-C2-C3: À117.46(14)8; 31: C2ÀC7: 1.5394(17), C2À
C3: 1.5617(17), C1ÀO2 1.4670(15) ꢁ; O2-C1-C2-C7 147.23(11), O2-C1-C2-C3
À108.61(12)8.
ing that the difficulty might lie in forming a five-membered
ring intermediate with a carbon linking the two alcohols, at-
tention turned to the use of a heteroatom linker offering a po-
tential driving force for rearrangement.[34] Although less prece-
dented in the literature, we were drawn to reports on the rear-
rangements of cyclopropyl diols to cyclobutanones by in situ
formation of cyclic sulfites or sulfates, occurring at or below
room temperature.[35,36]
Heating a solution of cyclic sulfites 30 and 31 in diphenyl
ether at 1908C effected the desired semipinacol rearrangement
to the target bridged bicyclic ketone 21, which was isolated in
excellent yield by direct column chromatography of the reac-
tion mixture (Scheme 6). Other solvents at comparable or
lower temperatures were less effective, and attempts to cata-
lyze the process with a Lewis acid resulted in lower yields (see
Treatment of diol 18 with thionyl chloride and pyridine gave
a 1:1 mixture of cyclic sulfites 30 and 31 in 91% yield
(Scheme 6). The sulfites were separable by column chromatog-
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the Supporting Information). Qualitatively, 31 required a longer
reaction (135 min) time than 30 (45 min) for the semipinacol
rearrangement to go to completion, with the yield of ketone
21 also lower (87 vs. 100%). Although the crystal structures
show that the migrating C2ÀC7 bond in 31 is shorter than in
30 (1.5394(17) vs. 1.542(2) ꢁ), conversely the leaving group
and the migrating group is better aligned in 31 than in 30
(O2-C1-C2-C7 torsion angle 147.23(11) vs. 140.95(13)8). Reduc-
tion in the overall dipole moment might also rationalize the
faster and higher yielding rearrangement of 30 compared to
31: the S=O and C=O dipoles in 30 are more closely aligned
than in 31. However, in the absence of additional examples
and knowledge of the concertedness of the rearrangement
with release of SO2 at relatively high temperatures, these ra-
tionales should be regarded as speculative at best.
Table 2. 4-Exo-trig carbamoyl radical cyclization—dithiocarbamate group
transfer mediated synthesis of b-lactams.[a]
Entry
Radical precursor
b-Lactam
Yield [%][b]
1
2
a: 80
b: 91
3
92
Although the rearrangement of cyclic sulfites 30 and 31
overcame the need to selectively activate the secondary alco-
hol of 18, and provided 21 in much higher overall yield than
previously achieved, we were keen to reduce both the temper-
ature and the additional step required. To this end we investi-
gated the use of cyclic phosphoranes. These can be prepared
through reaction of diols with Ph3PCl2, conveniently generated
in situ through reaction of Ph3P with a suitable chlorine
source.[38] We[39] and others[40] have used in-situ-generated
cyclic phosphoranes to achieve related rearrangements with
1,2-hydride migration (Meinwald-like rearrangement). In prac-
tice, treatment of diol 18 with 1.5 equivalents of Ph3P and
C2Cl6 in refluxing acetonitrile gave the target ketone 21 in an
excellent 94% yield through the presumed rearrangement of
an intermediate cyclic phosphorane 32 (Scheme 6). In contrast
to the use of similar methodology for the rearrangement of
diols to ketones with 1,2-hydride migration,[39,40] the addition
of a base such as iPr2NEt to neutralize the HCl formed in the
cyclic phosphorane formation is not necessary, and in fact
proved detrimental to the yield of 21. The formation of triphe-
nylphosphine oxide as a byproduct did not prove problematic
for the purification of 21 by column chromatography. This rep-
resents the first use of cyclic phosphoranes to affect semipina-
col-like rearrangement with carbon–carbon bond migration.
39
29
4[c]
65
16
5
6
7
55
86
Methodology scope and limitations
8
9[c]
no reaction
degradation
0
0
With a successful route from fused b-lactam 14 to bridged bi-
cyclic ketone 21 by the semipinacol rearrangement of cyclic
derivatives of diol 18 in hand, attention turned to determining
the scope and limitations of the methodology.
[a] Conditions: hu, 500 W Halogen lamp, Pyrex, cyclohexane (0.1m),
reflux, 2–5 h. [b] Isolated yield after column chromatography. [c] Chloro-
benzene as the reaction solvent.
Carbamoyl radical mediated synthesis of b-lactams: The 4-
exo-trig carbamoyl radical cyclization has been previously in-
vestigated to a limited extent for the synthesis of b-lac-
tams.[41–45] However, at the outset of this work we were aware
of only one additional example in the literature, related to the
cyclization of 3 to 4, for the synthesis of a ring-fused system.[42]
A range of carbamoyl radical precursors 33–39 were pre-
pared in two steps (one purification) from the corresponding
amine by using our previously described methodology: forma-
tion of a carbamoyl chloride using triphosgene and pyridine in
toluene, followed by chloride displacement with sodium dieth-
yldithiocarbamate in acetone (Table 2). Yields were generally
>80% over two steps.
The bridged bicyclic amine 42 was prepared from the
known dibromide 40 through a sequence of allylic substitu-
tion[46] followed by reductive lithiation to remove the vinyl bro-
mide. Attempts to employ vinyl bromide 41a in a palladium-
mediated cyclocarbonylation to a,b-unsaturated b-lactam 43,
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a
reaction reported for the corresponding non-bridged
system,[28] were unsuccessful.
The novel 1,4-cyclohexadiene 44 was prepared as an insepa-
rable 5:3 mixture with conjugated diene 45 through photoad-
dition of isopropylamine to benzene.[47] Treatment of the mix-
ture of aminodienes with triphosgene gave a mixture of carba-
moyl chlorides, from which the skipped diene 37 could be iso-
lated in 48% yield over two steps after reaction with sodium
diethyldithiocarbamate (Scheme 7).
Figure 6. Crystal structure of 48 with ellipsoids drawn at the 50% probability
level.
quent derivative of the minor isomer 51 (vide infra). Hence the
major isomer in the cyclization of both 35 and 36 results from
group transfer syn to the hydrogen atoms at the b-lactam ring
junction (as it does in the cyclization of 1, 13, 33, 34, and 37),
although the diastereoselectivity is higher for 36, presumably
due to the additional rigidity in the tricyclic ring system ren-
dering the face syn to the one-carbon bridge less accessible.
Carbamoyl dithiocarbamate 39 did not provide any of the
expected cyclization product under our standard conditions,
with extensive degradation occurring when the higher boiling
chlorobenzene was instead used in place of cyclohexane as re-
action solvent (Table 2, entries 8 and 9). Cyclization of 39, if it
occurred, would generate tertiary alkyl radical 54 (Figure 7).
Scheme 7. Preparation of allylic amines through reductive debromination
and amine–benzene photoaddition.
4-Exo-trig carbamoyl radical cyclization of carbamoyl dithio-
carbamates 33–38 proceeded in reasonable to excellent yield
under our standard conditions (irradiation with a 500 W halo-
gen lamp; Table 2, entries 1–7). Although the cis-ring junction
in the b-lactam products is ensured due to the constraint of
the tether in the cyclization, the stereochemistry at the dithio-
carbamate stereocentre depends on the facial selectivity in the
group transfer to the intermediate carbon-centred radical. The
cyclization of 33a–b, 34, and 37 gave rise to single b-lactam
products (Table 2, entries 1–3 and 6). As for 14, the stereo-
chemistry of b-lactams 46a and 46b was assigned based on
the close spectral similarity to the previously reported b-lactam
2.[24] The stereochemistry in 47 and 52 was assigned on the
basis of the expected dithiocarbamate group transfer to the
less-hindered face of the bicyclic radical intermediate, but has
not been unambiguously determined.
Figure 7. Effect of substitution on carbamoyl radical cyclization—dithiocar-
bamate group transfer.
We have previously observed lower yields in the 5-exo-trig car-
bamoyl radical cyclization onto a trisubstituted alkene to pro-
duce 55b compared with a terminal alkene to produce 55a.[5b]
This situation is exacerbated in the case of the 4-exo-trig cycli-
zation, with lactam 56b only isolated in 5% yield from a com-
plex reaction mixture, compared to 56a lacking the methyl
groups.[5a,48] A combination of a slower cyclization[45] of the nu-
cleophilic carbamoyl radical onto a more electron-rich double
bond, and a slower group-transfer reaction,[49] may accounts
for these trends, and the lack of product formation from 39.
The cyclization of the seven-membered carbocylic systems
35 and 36 gave rise to mixtures of diastereomers (Table 2, en-
tries 4 and 5). The structure of the major diastereomer 48 from
the cyclization of 35 was confirmed by X-ray crystallography
(Figure 6).[24] The relative stereochemistry in the bridged sys-
tems 50 and 51 was confirmed by X-ray analysis of a subse-
Dithiocarbamate elimination: Elimination of the dithiocarba-
mate group from b-lactams 46a and 2 bearing N-benzylic
groups to form a,b-unsaturated b-lactams 57a and 57c oc-
curred in excellent yield (Table 3, entries 1 and 2). The N-octyl
lactam 46b required a larger excess of LHMDS and MeI to
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Table 3. Base-mediated and thermal elimination of the dithiocarbamate functional group.
Entry
b-Lactam
Base-mediated elimination[a]
Yield [%][b]
Thermal elimination[c]
Yield [%][b]
1
2
3
a: 88
b: 67
c: 93
a: 80
b: not determined
c: 79[29]
4
5
9[d]
77
85
10
no reaction
–
6
7
8
93
78
82
89
degradation
no reaction, recovered starting material
9
10
11
2+98 rsm[e]
65+22 rsm[f]
89+11 rsm[g]
34
12
95
not determined
[a] Conditions: MeI (1.1–5 equiv), LHMDS (1.1–5 equiv), THF, À788C, 5–8 h. [b] Isolated yield after column chromatography. [c] Conditions: Ph2O, reflux, 1–
7 h. [d] Conditions: MeI (5 equiv), LHMDS (5 equiv), THF, À788C to RT, 18 h. [e] Conditions: MeI (10 equiv), LHMDS (10 equiv), À788C to RT, 18 h. [f] Condi-
tions: MeI (1.1 equiv), LDA (1.1 equiv), THF, À788C to RT, 18 h. [g] Conditions: LHMDS (1.5 equiv), Davis oxaziridine (1.5 equiv), 08C to RT, 18 h.
drive the reaction to completion, with a,b-unsaturated lactam
57b obtained in lower yield (entry 2). Thermal elimination of
46a gave alkene 58a in a similar yield to 16 and that previous-
ly reported for 58c.[29]
Attempted base-mediated elimination of the cyclopentyldi-
thiocarbamate 47 was unsuccessful, with only starting material
returned. The use of five equivalents each of LHMDS and MeI
gave mainly starting material alongside small quantities of the
C-methylated b-lactam 59, which suggests that deprotonation
occurs but presumably the a,b-unsaturated b-lactam is too
strained to form. Thermal elimination of 47 gave the expected
alkene 60 in good yield (Table 3, entry 4).
The epimeric dithiocarbamates 48 and 49 showed divergent
behaviour towards thermal and basic elimination conditions
(Table 3, entries 5 and 6). Whereas 48 proved surprisingly re-
sistant to base-mediated elimination, thermal elimination gave
predominantly the conjugated alkene 61, presumably the
larger ring size better accommodating the double bond at the
Chem. Eur. J. 2014, 20, 6505 – 6517
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ring junction. In contrast, thermal elimination of 49 gave non-
conjugated alkene 62, consistent with the concerted Chugaev-
like mechanism of the process.[29] Previous studies in our group
have shown that, despite the high temperatures required for
thermal elimination of the dithiocarbamate group, equilibra-
tion between alkene regioisomers does not occur under the
reaction conditions. Product outcome is determined by the
availability of a suitable b-H syn to the dithiocarbamate group,
hence only 62 forms from thermolysis of 49. Base-mediated
elimination was successful in the case of 49, providing the
target alkene 61 in an excellent 93% yield. Hence both 48 and
49 could be converged to the desired alkene 61 under appro-
priate conditions.
Tricyclic dithiocarbamate 50 was successfully converted to
alkene 63 under basic conditions, but degraded upon attempt-
ed thermolysis (Table 3, entry 7). The minor epimer 51 could
not be utilized—it underwent clean C-methylation to provide
64 in high yield under basic conditions, and unsurprisingly
could not be eliminated under thermal conditions given that
this would generate an anti-Bredt alkene (entry 8). The struc-
ture of 64 was proven by X-ray crystallography (Figure 8),[24]
which, given that the deprotonation and resulting methylation
of the b-lactam does not affect the dithiocarbamate stereocen-
tre, also confirmed that the major diastereoisomer formed in
the cyclization of 36 was 50 (Table 2, entry 5).
Scheme 8. Base-mediated and thermal elimination of dithiocarbamate 52.
Thermolysis of 52 also generated a surprising result. In this
case the urea 66 was isolated from the reaction mixture in
34% yield (Table 3, entry 9). The formation of 66 can be ration-
alized according to the sequence shown in Scheme 8. At the
high temperatures involved, conjugated diene 69, generated
in situ, undergoes pyrolytic ring fission to benzene and isopro-
pylisocyanate.[51] The dithiocarbamic acid byproduct of the di-
thiocarbamate group elimination fragments to diethylamine
and carbon disulfide,[29] and whereas normally these are lost at
high temperature, the amine reacts with the isocyanate to
form urea 66.
Base-mediated elimination of the dithiocarbamate group in
the simple monocyclic b-lactam 53 gave alkene 67 in excellent
yield (Table 3, entry 12). We have previously found the analo-
gous monocyclic N-Bn b-lactam degrades under thermal elimi-
nation conditions,[29] and hence overall this route provides effi-
cient access to exo-methylene b-lactams in combination with
our high-yielding radical cyclization methodology. Alkene 67
has previously been synthesized in a palladium-catalyzed car-
bonylation of a 2-bromoallylamine, albeit in low yield.[28]
mCPBA-mediated epoxidation of alkene 16 provided
a means to introduce additional functionality on the cyclohex-
anone ring of bicyclic lactam 21 (Scheme 9). The stereochemis-
Figure 8. Crystal structure of 64 with ellipsoids drawn at the 50% probability
level.
Attempted base-mediated elimination of 52 gave mainly
starting material and small amounts of N-isopropylbenzamide
(65) (Table 3, entry 9). The yield of 65 increased slightly with
a change of base to LDA (entry 10), and dramatically when MeI
was replaced with the Davis oxaziridine in an attempt to trap
out the putative deprotonated b-lactam with an oxygen
source (entry 11). Although the role of the oxaziridine in this
process is not known,[50] the formation of 65 in all cases is con-
sistent with a presumably facile base-mediated fragmentation
of the target diene 68, generated in situ (Scheme 8).
Scheme 9. Functionalization of alkene 16.
try of epoxide 70 was assigned based on the expected prefer-
ential attack on the convex face of the bicyclic ring system. Re-
gioselective base-mediated ring-opening of epoxide 70 gave
a,b-unsaturated b-lactam 71. The liberated alcohol was pro-
tected as the benzoate ester 72.
Chem. Eur. J. 2014, 20, 6505 – 6517
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molysis of the mixture. In general yields are comparable or
slightly better using method B, but in some cases this method
fails, despite the milder conditions.
Table 4. Dihydroxylation and semipinacol rearrangement of b-lactams.
Entry Diol (% yield from
alkene dihydroxylation)[a]
Method[b] Product(s)
Yield [%]
b-Lactams fused to six-membered rings rearranged under
both conditions (Table 4, entries 1–8). Notably the epoxide ste-
reochemistry, established in 70, is translated into the axially-
orientated benzoate in 80. The lack of a large axial–axial cou-
pling for the proton adjacent to oxygen in 80 is consistent
with the axial orientation, and confirms the expected stereose-
lectivity of the epoxidation step (Scheme 9).
1
2
3
4
5
6
79a: 77
79b: 77
79c: 83
79a: 80
79b: 80
79c: 97
A
B
Rearrangement of the seven-membered ring-fused b-lactam
diol 75 gave the keto-bridged bicyclic lactam 81, again with
complete selectivity for N-acyl group migration, despite the
larger ring size (Table 4, entries 9 and 10). The 7-azabicyclo-
[4.2.1]nonane ring system 81 is found in members of the Gelse-
mium alkaloids, which have been the subject of some synthetic
interest.[53]
7
8
A
B
75
77
9
10
A
B
82
98
Treatment of the mixture of diol 76 and ketoalcohol 77 with
thionyl chloride and pyridine allowed for the separation of 77
from the cyclic sulfites derived from 76. Rearrangement of the
cyclic sulfites did not occur at 1908C, but in refluxing diphenyl
ether (b.p. 2598C) conversion to the doubly bridged ring
system 82 occurred (Table 4, entry 11). In contrast, direct sub-
jection of the mixture of 76 and 77 to Ph3P and C2Cl6 in reflux-
ing MeCN (method B) did not give any of the semipinacol rear-
rangement product 82. Instead, chloroalcohol 83 was isolated
in low yield. The conversion of alcohols to chlorides by using
Ph3P and electrophilic chlorine sources (Appel conditions) is
known in the literature.[54] The stereochemistry in 83 was as-
signed on the basis of the expected SN2 displacement by chlo-
ride, and also suggested by the lack of coupling between the
proton adjacent to chlorine with the adjacent bridgehead
proton. Molecular models showed that the dihedral angle be-
tween these protons is close to 908 when the chlorine is syn to
the one carbon bridge, as in 83. The lack of rearrangement of
76 under these conditions may suggest that the cyclic phos-
phorane does not form, although we do not have any evi-
dence for this. The higher temperature required to rearrange
the corresponding sulfite suggests that the barrier to rear-
rangement is higher for the diol 76 compared to diol 75,
which lacks the constraint imposed by the additional one-
carbon bridge, allowing other reaction pathways to compete.
Raising the temperature of the Ph3P/C2Cl6 reaction by running
the reaction in a microwave up to 1508C over 3 h still only
provided 83 in low yield, with no evidence of formation of 82.
Semipinacol rearrangement of the monocyclic b-lactam diol
78 could not be achieved under either set of conditions. Al-
though the cyclic sulfite could be prepared in 68% yield, no
rearrangement occurred upon heating at 1908C, and the reac-
tion mixture underwent decomposition in refluxing Ph2O.
High-yielding conversion to the chloroalcohol 84 occurred
upon treatment of 78 with Ph3P and C2Cl6 in refluxing acetoni-
trile. Clearly the competing SN2 substitution pathway is particu-
larly favourable at the primary alcohol of 78. More generally,
the preference for ring-fused systems to undergo semipinacol
rearrangement rather than Appel reactions can, therefore, be
ascribed to a combination of factors: the slower SN2 reaction
11
12
A[c]
64[d]
B
28[e]
13
14
A
B
no reaction[f]
–
85
[a] Dihydroxylation conditions: cat. OsO4, NMO (2.4 equiv), 5:5:2 acetone/
H2O/tBuOH, 408C, 18 h. [b] Method A: i) SOCl2, pyridine, 08C to RT;
ii) Ph2O, 1908C, 2–5 h. Method B: PPh3, C2Cl6, CH3CN, reflux, 18 h. [c] Reac-
tion conditions: ii) Ph2O, reflux, 2 h. [d] Yield over three steps from alkene
63. [e] Yield over two steps from alkene 63. [f] No reaction at 1908C in
Ph2O. Decomposition in refluxing Ph2O.
Dihydroxylation and semipinacol rearrangement: The dihy-
droxylation of a,b-unsaturated b-lactams 57a–c, 72, 61 and 67
gave diols 73a–c, 74, 75 and 78, respectively, in reasonable to
good yield (Table 4, yields of diols in parentheses). Treatment
of alkene 63 under the same conditions gave the expected
diol 76 as the major product as an inseparable mixture along
with the a-hydroxyketone 77. Attempts to minimize the forma-
tion of the unwanted byproduct 77 were unsuccessful.[52] In all
cases dihydroxylation is completely diastereoselective, re-es-
tablishing the cis-ring fusion of the b-lactam.
Semipinacol rearrangement of diols 73a–c, 74, 75 and 78
was attempted via both the corresponding cyclic sulfites in
two steps (Table 4, method A), and in one step via the cyclic
phosphorane (method B). As for 30 and 31, cyclic sulfites were
obtained as approximately 1:1 mixtures of diastereomers. For
comparison purposes yields in Table 4 for method A are over
two steps, formation of the cyclic sulfite and subsequent ther-
Chem. Eur. J. 2014, 20, 6505 – 6517
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at a secondary rather than a primary alcohol, the enforcement
of a favourable orbital alignment for bond migration, and
increased ring strain offering a greater driving force for
rearrangement.
practical methodology for the synthesis of ring-fused b-lac-
tams. Good yields of b-lactams are achieved with the excep-
tion of a system carrying double substitution at the alkene ter-
minus. Novel conditions for the base-mediated elimination of
the dithiocarbamate group have been developed, which pro-
vide access to alkene regioisomers unavailable through ther-
molysis. Dihydroxylation of a,b-unsaturated b-lactams provides
substrates which undergo semipinanol rearrangement with ex-
clusive N-acyl group migration under all conditions. This selec-
tivity is consistent with prior examples of semipinacol rear-
rangement of non-fused b-lactams in the literature and the ex-
pected better alignment of the migrating bond with the break-
ing CÀO bond, even when constrained within a heterocyclic
ring system. In situ generated cyclic phosphoranes have been
shown to undergo semipinacol rearrangement with CÀC bond
migration for the first time, and provide milder and shorter
routes to target compounds over the use of non-cyclic systems
and of cyclic sulfites, unless chloroalcohol formation competes.
The resulting keto-bridged bicyclic lactams are versatile inter-
mediates in target synthesis.
Functional-group
transformations:
The
7,8-dioxo-6-
azabicyclo[3.2.1]octane ring system is a potentially versatile in-
termediate for organic synthesis. Preliminary studies have
shown that the two carbonyl groups in 21 can be chemo- and
stereoselectively functionalized (Scheme 10). Treatment with
Acknowledgements
We thank the EPSRC for funding (studentship to M.B., EP/
G031371/1). The NMR spectrometers used in this research
were obtained through Birmingham Science City: Innovative
Uses for Advanced Materials in the Modern World (West Mid-
lands Centre for Advanced Materials Project 2), with support
from Advantage West Midlands (AWM) and part funded by the
European Regional Development Fund (ERDF). We thank the
EPSRC UK National Crystallographic Service (UK NCS) at the
University of Southampton for the collection of crystallograph-
ic data[57] and Dr. Mateusz B. Pitak and Dr. Simon J. Coles at UK
NCS for X-ray crystal structure determination as previously re-
ported.[25a] Mass spectrometry data was acquired at the EPSRC
UK National Mass Spectrometry Facility at Swansea University.
Scheme 10. Reactions of lactams 21 and 57c.
l-selectride gave the axial alcohol 85 stereoselectively. Wittig
methylenation gave terminal alkene 86 in excellent yield.
Carbon–carbon bond formation at the amide carbonyl pro-
ceeded through formation of thioamide 87, activation as the
methyl sulfonium salt 88, and subsequent treatment with allyl
Grignard followed by sodium cyanoborohydride.[16a] The result-
ing diene 89 was isolated as a single diastereomer, presumed
to be the result of reduction from the less-hindered exo-face of
the intermediate imminium. Tentative assignment of the C-7
stereocentre was also based on the absence of an nOe signal
between the axial hydrogen at C-3 and the newly installed hy-
drogen at C-7.
Keywords: cyclization
·
fused-ring systems
·
nitrogen
heterocycles · ring expansion · strained molecules
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lographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif. X-ray crystal data for 2:
C19H26N2OS2, Mr =362.54. Crystal dimensions: 0.6ꢅ0.3ꢅ0.05 mm. Triclin-
ic, a=6.4252(3), b=11.5439(6), c=13.0833(7) ꢁ, a=100.156(4), b=
90.832(3), g=93.064(2)8, U=953.56(8) ꢁ3, T=220(2) K, space group
PÀ1, Z=2. 1calcd =1.263 gcmÀ3
, lMoKa =0.71073 ꢁ, 2qmax =508, m=
0.287 mmÀ1, max./min. transmission factors=0.9858/0.8464. 5316 re-
flections measured, 3311 unique (Rint =0.0824) which were used in all
calculations; 268 parameters. The final R1 was 0.0657 (I>2s(I)) and
wR(F2) was 0.1826 (all data). Max./min. residual electron density=0.529/
À0.466 eꢁ3. The group N2, C8–C12 is disordered over two positions
with the refined occupancy ratio being 0.65(1):0.35(1). Atoms C9a, C10a
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64: C22H30N2O2S2, Mr =418.60. Crystal dimensions: 0.28ꢅ0.18ꢅ0.02 mm.
Orthorhombic, a=45.85(7), b=6.260(11), c=7.640(13) ꢁ, U=2193(6) ꢁ3,
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T=100(2) K, space group Pna21, Z=4. 1calcd =1.268 gcmÀ3
1.54184 ꢁ, 2qmax =133.198, m=2.351 mmÀ1, max./min. transmission fac-
tors=0.9545/0.5589. 13394 reflections measured, 3417 unique (Rint
, lCuÀKa =
=
0.1247) which were used in all calculations. 258 parameters. The final
R1 was 0.1215 (I>2s(I)) and wR(F2) was 0.3709 (all data). Max./min. re-
sidual electron density=1.078/À0.618 eꢁ3. Further details on X-ray
crystal structure analysis of 2 and 64: Suitable crystals were selected
and datasets were measured on a Nonius Kappa CCD diffractometer for
2 and by the EPSRC UK National Crystallography Service[56] on a Rigaku
AFC11 goniometer equipped with a Saturn944+ detector mounted at
the window of a Rigaku 007 HF copper rotating anode generator for
64. Absorption corrections were applied using SCALEPACK (Z. Otwinow-
ski, W. Minor, Methods Enzymol. 1997, 276, 307–326) for 2 and Crystal-
Clear-SM Expert 2.0 r7 (Rigaku, 2011) for 64. The structures were solved
by direct methods in SHELXS-97 (G. M. Sheldrick, Acta Crystallogr. Sect.
A 2008, 64, 112–122) and were refined by a full-matrix least-squares
procedure on F2 in SHELXL-97 for 2 and SHELXL-2013 for 64. All non-
hydrogen atoms were refined with anisotropic displacement parame-
ters. The hydrogen atoms were added at calculated positions and re-
fined by use of a riding model with isotropic displacement parameters
based on the equivalent isotropic displacement parameter (Ueq) of the
parent atom. Figure were produced using OLEX2 (O. V. Dolomanov, L. J.
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2009, 42, 339–341).
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Received: December 20, 2013
Revised: February 21, 2014
Published online on April 7, 2014
Chem. Eur. J. 2014, 20, 6505 – 6517
www.chemeurj.org
6517 ꢀ 2014 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim