Alkene Ozonolysis in the Presence of Diazo Functionality: Accessing an Intermediate for Squalestatin Synthesis

Article abstract of DOI:10.1055/s-0039-1690180

Studies on both the propensity for intramolecular cycloaddition between diazo and alkene functionality, and the tolerance of α-substituted α-diazoesters towards ozone in the presence of an alkene, led to chemoselective alkene ozonolysis of an ?-unsaturated-α-diazoester to give a key racemic diazoketone for the synthesis of 6,7-dideoxysqualestatin H5.

Full text of DOI:10.1055/s-0039-1690180

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–H
paper
A
en
H. A. A. Almohseni et al.
Paper
Synthesis
Alkene Ozonolysis in the Presence of Diazo Functionality:
Accessing an Intermediate for Squalestatin Synthesis
Hasanain A. A. Almohseni1
MeO2C
TMSO
MeO2C
TMSO
EtO2C
I
Younes Fegheh-Hassanpour
Tanzeel Arif
O3
OBn
OBn
OBn
O
EtO2C
N2
then
Et3N
N2
David M. Hodgson*
Department of Chemistry, Chemistry Research Laboratory,
University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
david.hodgson@chem.ox.ac.uk
HO2C
HO2C
O
Ph
O
CO2H
OH
Received: 08.07.2019
Accepted after revision: 26.07.2019
Published online: 13.09.2019
created by stereoselective alkylation of dimethyl tartrate
acetonide (8), with five to six steps being subsequently re-
quired to produce the diazoketones 4. In principle, a more
concise approach to such cycloaddition precursors 4 could
proceed by aldol reaction between a diazoacetate anion 2
and an unsaturated -ketoester 1, followed by chemoselec-
tive alkene ozonolysis of the resulting unsaturated diazodi-
ester 3 (Scheme 1). Here, we report the realisation of this
latter strategy, despite concerns over both intrinsic instabil-
ity of the aldol product to spontaneous intramolecular cyc-
loaddition between the diazo and alkene functionality, and
of undesired conversion of diazo into keto functionality by
ozone.
DOI: 10.1055/s-0039-1690180; Art ID: ss-2019-z0383-op
Abstract Studies on both the propensity for intramolecular cycloaddi-
tion between diazo and alkene functionality, and the tolerance of -
substituted -diazoesters towards ozone in the presence of an alkene,
led to chemoselective alkene ozonolysis of an -unsaturated--di-
azoester to give a key racemic diazoketone for the synthesis of 6,7-dide-
oxysqualestatin H5.
Key words 6,7-dideoxysqualestatin H5, squalestatin synthesis, alkene
ozonolysis, intramolecular cycloaddition, diazo stability, pyrazoline
We recently reported two syntheses of 6,7-dideox-
ysqualestatin H5 (DDSQ) 7 (Scheme 1).2,3 Both syntheses
proceeded through diazoketones 4, which underwent rho-
dium(II)-catalysed tandem carbonyl ylide formation–inter-
molecular dipolar cycloadditions (4→5→6),4 followed by
acid-catalysed rearrangement to generate the characteristic
2,8-dioxabicyclo[3.2.1]octane core of the squalestatins /
zaragozic acids at the correct tricarboxylic acid oxidation
level. Also, in both cases, the silyloxyester stereocentre was
Before embarking on the above route (1→3→4), it was
considered prudent to first establish on simpler substrates
the proclivity of -diazoester functionality to engage in in-
tramolecular cycloaddition with an electron-rich alkene to
form bicyclic pyrazolines.5
Unsaturated hydrazones 9a,b6 underwent Et3N-induced
diazo formation7 in CH2Cl2 at room temperature (Scheme
2). As anticipated from Dauben’s studies,5b this led hydra-
zone 9a to form 1-pyrazoline 11a, in 92% yield (Scheme 2).
R'O2C
R'O2C
MeO2C
O
[Si]O
CO2Me
[Si]O
[Si]O
O3
–
cat Rh(II)
(R' = Me)
[3+2]
O
R"
R"
R"
MeO2C
O
R"
MeO2C
[Si]O
R'O2C
R'O2C
O
N2
N2
N2
O
this
work
4
3
5
CO2Me
MeO2C
–
6
R'O2C
R'O2C
2
MeO2C
O
OBn [Ref 2]
R" =
R" =
HO2C
HO2C
O
Ph
O
MeO2C
O
O
Ph
CO2H
R"
[Ref 3]
OH
8
Br
DDSQ 7
1
Scheme 1 Approaches to 6,7-dideoxysqualestatin H5 (7)
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
H. A. A. Almohseni et al.
Paper
Synthesis
However, intramolecular cycloaddition was minimised
with the 2,2-dialkyl-substituted terminal alkene 9b, to give
a mixture (52%), mainly consisting of unsaturated di-
azoester 10b together with only small amounts of bicycle
11b (10b/11b, 91:9).
O3/O2
CH2Cl2
–78 °C
recovered 16a
R
R
+
+
EtO2C
16a–c
N2
OTBS
O
OTBS
then Et3N
rt, 4 h
EtO2C
17b,c
O
14
15
TMSO
COCO2Et,
C4H9,
16b
R =
Et3N
EtO2C
R
R
R
+
EtO2C
EtO2C
N2
N
16a
16c
CH2Cl2
N
NHTs
N
Scheme 4 Examining the tolerance of -substituted -diazoesters 16
towards ozone
9a (R = H)
11a (R = H)
9b (R = Me)
10b (R = Me)
11b (R = Me)
Scheme 2 Propensity for diazoalkenes to undergo intramolecular cyc-
loaddition
Following the above observations, we focused on a syn-
thesis of the racemic DDSQ intermediate 4 (Scheme 1, R′′ =
OBn), through diazoacetate anion addition to homoallylic
-ketoester 20 (Scheme 5). Although many methods are
known for the synthesis of -ketoesters,13 only a limited
number of organometallic additions to oxalates are suitable
for the synthesis of homoallylic -ketoesters.14 When the
freshly prepared Grignard reagent from bromide 18a (avail-
able from the corresponding alcohol,2 see experimental)
was added to a solution of dimethyl oxalate (19) in THF at
–65 °C, only a low yield of -ketoester 20 was obtained
(11%). Halogen–lithium exchange of iodide 18b2 using
t-BuLi (2 equiv) at –78 °C15 and dropwise addition of the
resulting organolithium to a solution of oxalate 19 in Et2O
(at –78 °C) gave a similar yield (ca. 15%). The low yield could
be due to the limited solubility of dimethyl oxalate in Et2O
at –78 °C, because switching from Et2O to THF led to an im-
proved yield of -ketoester 20 (37%). Next, diazo-alcohol 21
was prepared through the addition of lithiated ethyl diazo-
acetate 2 to -ketoester 20 (78%).
Pleasingly, and following the trend seen with the model
studies (Scheme 2), no undesired intramolecular cycloaddi-
tion was observed for diazo-alcohol 21. At this stage, we
proceeded to protect the OH group, since otherwise it
would be highly likely to undergo problematic -lactolisa-
tion with the ketone subsequently generated on ozonoly-
sis.16 A silyl group was the protecting group of choice for
this purpose. Interestingly, when diazo-alcohol 21 was
treated with TBSOTf in the presence of 2,6-lutidine (CH2Cl2,
48 h), a mixture of desired TBS ether 22a along with cyc-
loadduct 23a (as a single diastereomer)17 was obtained
(22a/23a, 1:2). Using DMAP or pyridine as the base was not
successful in preventing the 1,3-dipolar cycloaddition,
whereas using Et3N led to retro-aldolisation. The partial for-
mation of cycloadduct 23a on silylation could be ra-
tionalised by a Thorpe–Ingold effect, from the bulky silyl
group. With this in mind, it was considered that minimising
the steric effect by using a less-hindered silyl group might
reduce the bicyclic product formation; indeed, on trimeth-
ylsilylation, the ratio of silyl ether 22b to cycloadduct 23b
was 4:3 in favour of the desired non-cyclic product. Finally,
ozonolysis of silyl ethers 22a and 22b led to diazoketones
24a and 24b (58% and 61%, respectively). The silyl ethers
The stability of the -diazoester motif towards ozone
was next examined. The diazo moiety could be oxidised to a
carbonyl group by ozone.6,8 Model compounds 13a,b
(Scheme 3), which contain the diazo moiety in a similar en-
vironment to diazodiester 3 (Scheme 1), were prepared by
aldol reaction between ethyl pyruvate (12) and the anion of
ethyl diazoacetate (2),9 followed by silylation. Equimolar
solutions of -diazoesters 13a,b and alkene 14, the latter
mimicking the alkene portion of 3, were exposed to ozone
at –78 °C in CH2Cl2, followed by addition of Et3N.10 Pleasing-
ly, these conditions gave ketone 15, with diazoesters 13a,b
being recovered intact (Scheme 3, see also the Supporting
Information, Figure S1).
EtO2C
12
EtO2C
1. LDA
THF, 78%
O
+
[Si]O
recovered
13a,b
+
EtO2C
N2
2. [Si]OTf
2,6-lutidine
CH2Cl2
EtO2C
N2
O3/O2
CH2Cl2
13a,b
2
+
then
Et3N
13a ([Si] = TBS) 76%
13b ([Si] = TES) 77%
O
OTBS
OTBS
15
14
Scheme 3 Preparation and stability of -diazoesters 13a,b towards
ozone
The presence of further electron-withdrawing function-
ality on the diazocarbonyl likely reduces the reactivity of
the diazo group towards ozone.11 For example, -diazo--
ketoester 16a12 (Scheme 4) was stable to ozone even at –
15 °C for 1 h (alkene 14 converted into ketone 15 within 5
min at –78 °C), whereas, the diazo moiety in 13a (Scheme 3,
CO2Me instead of CO2Et) is converted into the correspond-
ing ketone on ozonolysis at –15 °C.6 -Substituted -di-
azoesters 16b,c (Scheme 4) were also examined to study
the effect of different substitution on the stability of the di-
azo moiety to ozonolysis; however, they were both reactive
to ozonolysis at –78 °C, being converted into the corre-
sponding ketones 17b,c after addition of Et3N.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H

C
H. A. A. Almohseni et al.
Paper
Synthesis
MeO2C
HO
t-BuLi
MeO2C
X
EtO2C
N2
Et2O, –78 °C
2
O
OBn
OBn
OBn
EtO2C
N2
LDA, THF
20
MeO2C
19
21
OMe
–78 °C, 78%
18a (X = Br)
18b (X = I)
O
TBSOTf, 2,6-lutidine
CH2Cl2 (for 22a and 23a),
THF, –78 °C
4 h, 37% (from 18b)
HMDS, imidazole, THF
(for 22b and 23b)
MeO2C
MeO2C
[Si]O
MeO2C
[Si]O
O3/O2
[Si]O
CH2Cl2, –78 °C
EtO2C
OBn
O
EtO2C
OBn
+
EtO2C
N2
OBn
N2
N
N
then, Et3N
(from 22a,b)
22a ([Si] = TBS), 18%
22b ([Si] = TMS), 40%
24a ([Si] = TBS), 58%
24b ([Si] = TMS), 61%
23a ([Si] = TBS), 37%
23b ([Si] = TMS), 31%
Scheme 5 Synthesis of -diazo--ketoesters 24a,b
22a,b should be directly subjected to ozonolysis following
their isolation because they undergo intramolecular cycli-
sation to cycloadducts 23a,b with the rate being slower for
22b (see the Supporting Information, Figure S2).
doublets (dd), triplet of triplets (tt), doublet of doublet of doublets
(ddd), doublet of quartets (dq), or multiplet (m). The 13C signal of CN2
was often not observed due to quadrupolar relaxation. High-resolu-
tion mass spectra were obtained by electrospray ionization, with a
Thermo Fisher Orbitrap Exactive mass spectrometer.
In summary, we have developed a strategy for the syn-
thesis of -diazo--ketoesters, for application in squalesta-
tin synthesis, based on chemoselective ozonolysis of unsat-
urated -diazoesters. To survive ozonolysis, -diazoester
functionality requires to be either further substituted with
a -carbonyl group or be sterically shielded by substituents
at the -position. Further studies will focus on construction
of the enantiomerically enriched intermediate for the natu-
ral product (DDSQ).
Procedures
(a) Propensity of Diazoalkenes to Undergo Intramolecular Cyc-
loaddition
Ethyl 3a,4,5,6-Tetrahydrocyclopenta[c]pyrazole-6a(3H)-carboxyl-
ate (11a)
To a solution of hydrazone 9a6 (500 mg, 1.42 mmol) in CH2Cl2 (2 mL)
was added Et3N (0.62 mL, 4.4 mmol) and stirred at r.t. After 3 h, the
mixture was passed through a short pad of silica (ca. 2 cm), and
washed through with CH2Cl2 (20 mL). The eluent was evaporated un-
der reduced pressure and the mixture was purified by column chro-
matography (30% Et2O in petrol) to give 1-pyrazoline 11a.
All reactions requiring anhydrous conditions were carried out under
an atmosphere of nitrogen in flame-dried glassware. Tetrahydrofuran
(THF), dichloromethane and dimethylformamide (DMF) were ob-
tained from Grubbs’ drying stills.18 Flash column chromatography
was carried out using silica gel (VWR chemicals, BDH), monitored by
thin-layer chromatography (TLC) (Merck 60 F254) plates. TLC plates
were viewed using ultraviolet light (max = 254/365 nm) and immer-
sion in KMnO4, followed by heating. Except where stated otherwise,
commercially available reagents were used as received. Infrared spec-
tra were obtained with a PerkinElmer FTIR spectrometer (Universal
ATR Sampling Accessory), with absorption maxima quoted in wave-
numbers (cm–1). Peak intensities are described as broad (br), weak
(w), medium (m) or strong (s). Nuclear magnetic resonance (1H NMR
and 13C NMR) spectra were recorded with Bruker Avance AVIIIHD 400,
NEO 400, and AVIIIHD 500 spectrometers in CDCl3 (referenced to re-
sidual CHCl3 singlet at  = 7.27 ppm for 1H NMR spectra, and to the
central line of CDCl3 triplet at  = 77.16 ppm for 13C NMR spectra).
Chemical shifts are quoted in parts per million (ppm). Coupling con-
stants (J) are measured to the nearest 0.5 Hertz (Hz). The splittings
are quoted as singlet (s), doublet (d), triplet (t), quartet (q), doublet of
Yield: 240 mg (92%); yellow oil; Rf = 0.52 (30% EtOAc in petrol).
IR (film): 296 (w), 2871 (w), 1730 (s), 1556 (w), 1267 (s), 1222 (s),
1094 (s) cm–1
.
1H NMR (500 MHz; CDCl3):  = 4.67 (dd, J = 18.5, 9 Hz, 1 H, CH-
CHHN=N), 4.40 (dd, J = 18.5, 3 Hz, 1 H, CHCHHN=N), 4.23–4.15 (m,
2 H, CH2CH3), 2.64 (tt, J = 9, 3 Hz, 1 H, CHCH2N=N), 2.40–2.34 (m, 1 H,
CHHCCO2Et), 2.32–2.24 (m, 1 H, CHHCCO2Et), 1.85–1.76 (m, 1 H, CH-
CHHCH2), 1.69–1.61 (m, 1 H, CHCH2CHH), 1.40–1.34 (m, 1 H, CHCH-
HCH2), 1.25 (t,
CHCH2CHH).
J = 8 Hz, 3 H, COCH2CH3), 1.12–1.02 (m, 1 H,
13C NMR (125 MHz; CDCl3):  = 170.5 (CO2Et), 106.8 (quat. CCO2Et),
86.1 (CH2N=N), 61.8 (COCH2CH3), 39.3 (CHCH2N=N), 34.3
(CH2CCO2Et), 34.2 (CHCH2CH2), 24.0 (CHCH2CH2), 14.2 (COCH2CH3).
HRMS m/z [M + Na]+ calcd for C9H14N223NaO2: 205.0948; found:
205.0949.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H

D
H. A. A. Almohseni et al.
Paper
Synthesis
Ethyl 2-Diazo-6-methylhept-6-enoate (10b) and Ethyl 3a-Methyl-
3a,4,5,6-tetrahydrocyclopenta[c]pyrazole-6a(3H)-carboxylate
(11b)
HRMS: m/z [M + Na]+ calcd. for C9H14O5N223Na: 253.0794; found:
253.0795.
To a solution of hydrazone 9b6 (45 mg, 0.13 mmol) in CH2Cl2 (3 mL)
was added Et3N (53.0 L, 0.38 mmol) and the solution was stirred at
r.t. After 3 h, the mixture was passed through a short pad of silica (ca.
2 cm), and washed through with CH2Cl2 (20 mL). The eluent was evap-
orated under reduced pressure and the mixture was purified by col-
umn chromatography (30% Et2O in petrol) to give an inseparable mix-
ture of diazoalkene 10b and cycloadduct 11b (13 mg, 52%, 91:9 re-
spectively, by integration at 10b [ C=CH2] and 11b [ CH2N=N]
peaks), as a yellow oil; Rf = 0.54 (30% Et2O in petrol).
Diethyl 2-[(tert-Butyldimethylsilyl)oxy]-3-diazo-2-methylsucci-
nate (13a)
TBSOTf (0.4 mL, 1.7 mmol) was added to 2,6-lutidine (0.3 mL, 2.6
mmol) in CH2Cl2 (1 mL) and the solution was stirred for 10 min at
0 °C. A solution of diethyl 3-diazo-2-hydroxy-2-methylsuccinate (25)
(200 mg, 0.87 mmol) in CH2Cl2 (2 mL) at 0 °C was then added. The
mixture was warmed to r.t. and stirred for 48 h. The reaction was
quenched with water (4 mL), and the mixture was extracted with
CH2Cl2 (3 × 10 mL), washed with brine (10 mL) and dried (MgSO4). Af-
ter evaporation under reduced pressure, the residue was purified by
column chromatography (10% Et2O in petrol) to give TBS ether 13a.
IR (film): 2934 (w), 2361 (w), 2078 (s), 1688 (s), 1447 (m), 1371 (m),
1304 (m), 1157 (s), 1110 (s) cm–1
.
+
Na]+ calcd for C10H16N223NaO2: 219.1109; found:
Yield: 227 mg (76%); Rf = 0.3 (20% Et2O in petrol).
HRMS [M
219.1106.
IR (film): 2956 (m), 2931 (m), 2858 (m), 2096 (s), 1745 (s), 1698 (s),
1464 (m), 1309 (s), 1255 (s), 1144 (s), 1069 (s), 839 (w) cm–1
.
Data for diazoalkene 10b
1H NMR (400 MHz; CDCl3):  = 4.25–4.14 (m, 4 H, 2 × OCH2CH3), 1.66
(s, 3 H, Me), 1.30–1.22 (m, 6 H, 2 × OCH2CH3), 0.86 [s, 9 H, OSiC(CH3)3],
0.11 and 0.08 [2 × s, 6 H, OSi(CH3)2].
13C NMR (100 MHz; CDCl3):  = 172.0 (CO2Et), 165.0 (CO2Et), 73.7
(quat. C), 61.9 (OCH2), 60.9 (OCH2), 25.9 (Me), 25.7 [SiC(CH3)3], 18.4
[SiC(CH3)3], 14.6 (OCH2CH3), 14.2 (OCH2CH3), –3.0 (OSiCH3), –3.5
(OSiCH3).
1H NMR (500 MHz, CDCl3):  = 4.73 (s, 1 H, C=CHH), 4.68 (s, 1 H,
C=CHH), 4.22 (q, J = 7 Hz, 2 H, COCH2CH3), 2.30 (t, J = 7.5 Hz, 2 H,
CH2C=CH2), 2.07 (t, J = 7.5 Hz, 2 H, CH2CN=N), 1.71 (s, 3 H, CH3C=CH2),
1.66 (m, 2 H, CH2CH2CN=N), 1.27 (t, J = 7 Hz, 3 H, COCH2CH3).
13C NMR (125 MHz; CDCl3):  = 169.7 (CO2Et), 144.9 (C=CH2), 110.7
(C=CH2), 60.9 (COCH2CH3), 36.9 (CH2CN=N), 25.7 (CH2CH2CN=N), 22.9
(CH2C=CH2), 22.4 (CH3C=CH2), 14.7 (COCH2CH3).
HRMS: m/z [M + Na]+ calcd for C15H28O5N228Si23Na: 367.1659; found:
Data for cycloadduct 11b
367.1656.
1H NMR (500 MHz; CDCl3):  = 4.53 (d, J = 18 Hz, 0.1 H, CHHN=N),
4.34 (d, J = 18 Hz, 0.1 H, CHHN=N), 2.52–2.41 (CHH), 1.11 (s, 0.3 H,
quat. CCH3).
Diethyl 3-Diazo-2-methyl-2-[(triethylsilyl)oxy]succinate (13b)
By following the procedure for silyl ether 13a above, but using
TESOTf, diethyl 3-diazo-2-hydroxy-2-methylsuccinate (25) (200 mg,
0.87 mmol) gave, after column chromatography (10% Et2O in petrol),
TES ether 13b.
13C NMR (125 MHz; CDCl3):  = 167.8 (CO2Et), 105.7 (quat. CCO2Et),
91.7 (CH2N=N), 61.7 (COCH2CH3), 47.2 (quat. CCH3), 42.5 (CH2CCO2Et),
34.0 (CH2CH2CCO2Et), 23.3 (CH2CCH3), 22.2 (quat. CCH3).
Yield: 230 mg (77%); yellow oil; Rf = 0.3 (20% Et2O in petrol).
(b) Preparation and Stability of -Substituted -Diazoesters to-
wards Ozone
IR (film): 2956 (m), 2931 (m), 2858 (m), 2096 (s), 1745 (s), 1698 (s),
1464 (m), 1309 (s), 1255 (s), 1144 (s), 1069 (s), 839 (w) cm–1
.
-Diazo--ketoester 16a was prepared according to a reported proce-
dure12 and -diazoester 16b was prepared by following a procedure
reported by Wang and co-workers.19
1H NMR (400 MHz; CDCl3):  = 4.25–4.13 (m, 4 H, 2 × OCH2CH3), 1.67
(s, 3 H, Me), 1.27 (t, J = 7 Hz, 3 H, OCH2CH3), 1.24 (t, J = 7 Hz, 3 H,
OCH2CH3), 0.93 [t, J = 8 Hz, 9 H, OSi(CH2CH3)3], 0.62 [q, J = 8 Hz, 6 H,
OSi(CH2CH3)3].
Diethyl 3-Diazo-2-hydroxy-2-methylsuccinate (25)
The procedure of Padwa and co-workers5h was followed with slight
modifications. A solution of LDA [prepared from n-BuLi (3.1 mL, 1.4 M
in hexanes, 4.6 mmol) and i-Pr2NH (600 L, 4.6 mmol) in THF (5 mL)
at –78 °C] was added dropwise to a stirred solution of ethyl diazoace-
tate (2) (525 mg, 4.60 mmol) and ethyl pyruvate (12) (534 mg, 4.60
mmol) in THF (20 mL) at –78 °C. The solution was warmed to r.t. and
stirred for 3 h, and then AcOH (0.26 mL, 4.6 mmol) was added drop-
wise. The mixture was extracted with Et2O (2 × 15 mL), the combined
organic layers washed with brine (10 mL), dried (MgSO4), and evapo-
rated under reduced pressure. The residue was purified by column
chromatography (10% Et2O in petrol) to give diethyl 3-diazo-2-hy-
droxy-2-methylsuccinate (25) (825 mg, 78%), as a yellow liquid; Rf =
0.27 (30% Et2O in petrol).
13C NMR (100 MHz; CDCl3):  = 172.0 (CO2Et), 165.1 (CO2Et), 73.6
(quat. C), 61.9 (OCH2), 60.9 (OCH2), 25.9 (Me), 14.6 (OCH2CH3), 14.2
(OCH2CH3), 6.9 [OSi(CH2CH3)3], 6.1 [OSi(CH2CH3)3].
HRMS: m/z [M + Na]+ calcd for C15H28O5N223Na28Si: 367.1659; found:
367.1656.
Ethyl 2-Diazo-2-{1-[(trimethylsilyl)oxy]cyclopentyl}acetate (16c)
TMSCl (127 L, 1.0 mmol) was added slowly to a solution of ethyl 2-
diazo-2-(1-hydroxycyclopentyl)acetate5h (100 mg, 0.50 mmol) and
imidazole (170 mg, 2.50 mmol) in DMF (1.4 mL) at 0 °C. After 4 h at
r.t., Et2O (5 mL) was added, the organic layer was washed with water
(2 × 2 mL), brine (2 mL) and dried (Na2SO4). After evaporation under
reduced pressure, the residue was purified by column chromatogra-
phy (0–10% Et2O in petrol) to give silyl ether 16c.
IR (film): 3380 (br), 2956 (m), 2096 (s), 1745 (s), 1698 (s) cm–1
.
1H NMR (400 MHz; CDCl3):  = 4.29–4.16 (m, 4 H, 2 × OCH2Me), 4.13
(s, 1 H, OH), 1.56 (s, 3 H, Me), 1.30–1.22 (m, 6 H, 2 × OCH2CH3).
13C NMR (100 MHz; CDCl3):  = 173.8 (CO2Et), 165.7 (CO2Et), 71.6
(quat. C), 62.9 (OCH2), 61.3 (OCH2), 23.8 (Me), 14.5 (OCH2CH3), 14.2
(OCH2CH3).
Yield: 118 mg (87%); yellow liquid; Rf = 0.59 (10% Et2O in petrol).
IR (film): 2960 (m), 1714 (s), 1370 (w), 1204 (m), 1040 (m) cm–1
.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H

E
H. A. A. Almohseni et al.
Paper
Synthesis
1H NMR (400 MHz; CDCl3):  = 4.22 (q, J = 7 Hz, 2 H, OCH2CH3), 2.05–
1.99 (m, 2 H, CH2), 1.94–1.86 (m, 2 H, CH2), 1.84–1.78 (m, 2 H, CH2),
1.70–1.63 (m, 2 H, CH2), 1.28 (t, J = 7.0 Hz, 3 H, OCH2CH3), 1.10 [s, 9 H,
OSi(CH3)3].
1H NMR (400 MHz; CDCl3):  = 4.31 (q, J = 7 Hz, 2 H, OCH2CH3), 2.26–
2.15 (m, 2 H, 2 × H of CH2), 1.93–1.87 (m, 2 H, 2 × H of CH2), 1.85–1.78
(m, 2 H, 2 × H of CH2), 1.77–1.69 (m, 2 H, 2 × H of CH2), 1.36 (t, J =
7 Hz, 3 H, OCH2CH3), 0.13 [s, 9 H, OSi(CH3)3].
13C NMR (100 MHz; CDCl3):  = 165.7 (CO2Et), 81.0 (COTMS), 60.6
(OCH2CH3), 40.1 (2 × CH2), 22.8 (2 × CH2), 14.7 (OCH2CH3), 1.5
[OSi(CH3)3].
13C NMR (100 MHz; CDCl3):  = 200.0 (C=O), 165.2 (CO2Et), 88.8
(COTMS), 61.9 (OCH2CH3), 39.0 (2 × CH2), 24.7 (2 × CH2), 14.2
(OCH2CH3), 1.8 [OSi(CH3)3].
HRMS: m/z [M + Na]+ calcd. for C12H22O3N223Na28Si: 293.1291; found:
HRMS: m/z [M + Na]+ calcd for C12H22O423Na28Si: 281.1179; found:
293.1292.
281.1180.
General Procedure for Ozonolysis
(c) Synthesis of -Diazo--ketoesters 24a,b
A stream of O3/O2 was bubbled through a mixture of -diazoester (1
mmol) and alkene 1420 (1 mmol) in CH2Cl2 at –78 °C until the colour
of the reaction mixture changed from yellow to blue (ca. 5 min). Then
the excess of O3 was removed by bubbling N2 through the reaction
mixture, followed by addition of Et3N (3 mmol). After 4 h at r.t., the
reaction mixture was evaporated under reduced pressure and the res-
idue was analysed by 1H NMR (see the Supporting Information, Figure
S1).
{[(5-Bromo-3-methylenepentyl)oxy]methyl}benzene (18a)
Ph3P (365 mg, 1.39 mmol) and CBr4 (577 mg, 1.74 mmol) were added
to a solution of 5-(benzyloxy)-3-methylenepentan-1-ol2 (240 mg,
1.16 mmol) in CH2Cl2 (8 mL) at r.t. After 10 min, the reaction mixture
was poured into sat. aq. NaHCO3 (5 mL) and the aq. layer was extract-
ed with CH2Cl2 (2 × 5 mL). The combined organic layers were washed
with brine (5 mL), dried (MgSO4), concentrated under reduced pres-
sure and purified by column chromatography (5% Et2O in petrol) to
give bromide 19a.
Ethyl 2-Oxohexanoate (17b)
By following the general ozonolysis procedure above, -diazoester
16b (100 mg, 0.58 mmol) was oxidised to give after column chroma-
tography (5% EtOAc in petrol) an inseparable mixture of -ketoester
17b and the corresponding trioxane trimer 26 (66 mg, 73%, ca. 60:40,
respectively, by integration at 17b [ CH2CH2CO] and 26 [ CH2CH2CO]
peaks), as a colourless liquid; Rf = 0.56 (5% EtOAc in petrol).
Yield: 225 mg (72%); colourless oil; Rf = 0.41 (5% Et2O in petrol).
IR (film): 2858 (w), 1646 (m), 1453 (m), 1208 (m), 1098 (s), 901 (s),
736 (s), 697 (s) cm–1
.
1H NMR (400 MHz; CDCl3):  = 7.40–7.25 (m, 5 H, ArH), 4.94 (s, 1 H,
C=CHH), 4.89 (s, 1 H, C=CHH), 4.53 (s, 2 H, CH2Ph), 3.59 (t, J = 7 Hz,
2 H, CH2OBn), 3.47 (t, J = 7 Hz, 2 H, CH2Br), 2.62 (t, J = 7 Hz, 2 H,
CH2CH2Br), 2.36 (t, J = 7.0 Hz, 2 H, CH2CH2OBn).
13C NMR (100 MHz; CDCl3):  = 143.7 (C=CH2), 138.4 (ArC), 128.5
(ArCH), 127.8 (ArCH), 127.7 (ArCH), 113.4 (C=CH2), 73.1 (CH2Ph), 68.9
(CH2OBn), 39.7 (CH2CH2Br), 35.9 (CH2CH2OBn), 31.0 (CH2Br).
IR (film): 2961 (m), 2935 (m), 1750 (s), 1727 (s), 1466 (s), 1275 (m),
1246 (m), 1142 (m), 1120 (m), 1048 (s), 856 (m) cm–1
.
Data for -Ketoester 17b
1H NMR (400 MHz; CDCl3):  = 4.30 (q, J = 7 Hz, 2 H, OCH2CH3), 2.81 (t,
J = 7 Hz, 2 H, CH2CH2CO), 1.68–1.55 (m, 2 H, CH2CH2CO), 1.42–1.27
(m, 5 H, CH2 and CO2CH2CH3), 0.91 (t, J = 7 Hz, 3 H, CH2CH3).
HRMS: m/z [M + Na]+ calcd for C13H17O79Br23Na: 291.0355; found:
291.0354.
13C NMR (100 MHz; CDCl3):  = 194.9 (C=O), 161.5 (CO2Et), 62.5
(CO2CH2CH3), 39.1 (CH2CO), 25.2 (CH2CH2CO), 22.2 (CH3CH2CH2), 14.1
(OCH2CH3), 13.9 (CH2CH3).
HRMS: m/z [M + Na]+ calcd for C8H14O323Na: 181.0835; found:
181.0836.
Methyl 7-(Benzyloxy)-5-methylene-2-oxoheptanoate (20)
To a solution of {[(5-iodo-3-methylenepentyl)oxy]methyl}benzene
(18b)2 (100 mg, 0.31 mmol) in Et2O (3 mL) at –78 °C was added t-BuLi
(0.44 mL, 1.7 M in pentane, 0.75 mmol) dropwise. After 1 h, the reac-
tion mixture was transferred slowly by cannula to a solution of di-
methyl oxalate (19) (186 mg, 1.58 mmol) in THF (0.5 mL) at –78 °C
and stirred for 4 h. Then, sat. aq. NH4Cl (2 mL) was added and the mix-
ture was allowed to warm to r.t. The aq. layer was extracted with Et2O
(2 × 5 mL) and the combined organic layers were washed with water
(5 mL), brine (5 mL), dried (MgSO4), and concentrated under reduced
pressure. Purification of the residue by column chromatography (20%
Et2O in petrol) gave -ketoester 20.
Data for Triethyl 2,4,6-Tributyl-1,3,5-trioxane-2,4,6-tricarboxylate
(26)
1H NMR (400 MHz; CDCl3):  = 4.27–4.21 (m, 2 H, OCH2CH3), 2.10–
1.91 (m, 2 H, CH2CH2CO), 1.42–1.27 (m, 5 H, 2 × CH2 and CO2CH2CH3),
0.88 (t, 3 H, J = 7 Hz, 2 H, OCH2CH3).
13C NMR (100 MHz; CDCl3):  = 168.2 (CO2Et), 107.6 (quat. C), 62.1
(CO2CH2CH3), 31.6 (CH2CO), 25.0 (CH2CH2CO), 22.6 (CH3CH2CH2), 14.2
(OCH2CH3), 13.8 (CH2CH3).
Yield: 32 mg (37%); colourless liquid; Rf = 0.15 (20% Et2O in petrol).
IR (film): 2931 (m), 1743 (s), 1452 (w), 1276 (m), 1099 (m), 716
(w) cm–1
.
Ethyl 2-Oxo-2-{1-[(trimethylsilyl)oxy]cyclopentyl}acetate (17c)
1H NMR (500 MHz; CDCl3):  = 7.40–7.26 (m, 5 H, ArH), 4.84 (s, 1 H,
C=CHH), 4.80 (s, 1 H, C=CHH), 4.51 (s, 2 H, CH2Ph), 3.86 (s, 3 H,
CO2Me), 3.58 (t, 2 H, J = 7 Hz, CH2OBn), 3.00 (t, J = 7 Hz, 2 H, CH2C=O),
2.42–2.33 (m, 4 H, CH2C(=CH2)CH2).
By following the general ozonolysis procedure above, TMS ether 16c
(47 mg, 0.17 mmol) was oxidised to give, after column chromatogra-
phy (10% Et2O in petrol), -ketoester 17c.
13C NMR (125 MHz; CDCl3):  = 193.6 (C=O), 161.5 (CO2Me), 144.7
(C=CH2), 138.4 (ArC), 128.5 (ArCH), 127.8 (ArCH), 127.7 (ArCH), 111.5
(C=CH2), 73.1 (CH2Ph), 68.9 (CH2OBn), 53.1 (CO2CH3), 37.7
(CH2CH2OBn), 36.5 (CH2CH2C=O), 29.3 (CH2CH2C=O).
Yield: 17 mg (39%); colourless liquid; Rf = 0.5 (10% Et2O in petrol).
IR (film): 2958 (m), 1727 (s), 1251 (s), 1216 (m), 1066 (s), 1028 (m),
917 (m), 839 (s) cm–1
.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H

F
H. A. A. Almohseni et al.
Paper
Synthesis
HRMS: m/z [M + Na]+ calcd for C16H20O423Na: 299.1264; found:
HRMS: m/z [M + H]+ calcd for C26H41O6N228Si: 505.2728; found:
299.1254.
505.2729.
Second eluted cycloadduct 23a (14 mg, 37%), as a pale-yellow oil; Rf =
0.34 (20% Et2O in petrol).
4-Ethyl 1-Methyl 2-[5-(Benzyloxy)-3-methylenepentyl]-3-diazo-2-
hydroxysuccinate (21)
IR (film): 2928 (m), 2855 (m), 1741 (s), 1454 (m), 1365 (w), 1313 (m),
1253 (s), 1100 (m), 1056 (m), 838 (s), 779 (m) cm–1
.
A solution of LDA [prepared from n-BuLi (90 L, 2.5 M in hexanes,
0.22 mmol) and i-Pr2NH (30 L, 0.22 mmol) in THF (1 mL) at −78 °C]
was added dropwise to a solution of ethyl diazoacetate (2) (23 L,
0.22 mmol) and -ketoester 20 (36 mg, 0.13 mmol) in THF (350 L) at
–78 °C. After 2 h, the reaction was quenched with NH4Cl (2 mL), and
the mixture was extracted with Et2O (2 × 5 mL), and dried (MgSO4).
After evaporation under reduced pressure, the residue was purified by
a short column chromatography (10% EtOAc in petrol) to give diazo-
alcohol 21.
1H NMR (500 MHz; CDCl3):  = 7.38–7.27 (m, 5 H, ArH), 4.73 (d, J =
18.5 Hz, 1 H, CHHN=N), 4.52–4.43 (m, 3 H, CH2Ph and CHHN=N),
4.21–4.14 (m, 2 H, CO2CH2CH3), 3.79 (s, 3 H, CO2Me), 3.57–3.48 (m,
2 H, CH2OBn), 2.41–2.32 [m, 1 H, CHHC(OTBS)], 2.09–2.02 [m, 1 H,
CHHCH2C(OTBS)], 1.88–1.78 [m, 2 H, CHHC(OTBS) and CHHCH2OBn],
1.65–1.60 (m, 1 H, CHHCH2OBn), 1.57–1.50 [m, 1 H, CHHCH2C(OTBS)],
1.25 (t, J = 7 Hz, 3 H, CO2CH2CH3), 0.82 (s, 9 H, OSiCMe3), 0.05 [2 × s,
6 H, OSi(CH3)2].
13C NMR (125 MHz; CDCl3):  = 172.0 (CO2Me), 168.2 (CO2Et), 138.1
(ArC), 128.6 (ArCH), 127.9 (ArCH), 127.7 (ArCH), 110.5 (quat. CCO2Et),
90.9 (CH2N=N), 87.1 [quat. C(OTBS)CO2Me], 73.4 (CH2Ph), 67.8
(CH2OBn), 61.9 (CO2CH2CH3), 52.3 (CO2CH3), 49.6 (quat. CCH2N=N),
37.4 [CH2C(OTBS)], 35.3 (CH2CH2OBn), 34.5 [CH2CH2C(OTBS)], 25.7
[SiC(CH3)3], 18.5 [SiC(CH3)3], 14.2 (CO2CH2CH3), –3.1 and –4.0
(2 × SiCH3).
Yield: 40 mg (78%); yellow oil; Rf = 0.25 (50% Et2O in petrol).
IR (film): 3390 (br), 3027 (w), 2920 (m), 1732 (s), 1453 (m), 1261 (s),
1097 (s), 739 (m), 699 (m) cm–1
.
1H NMR (500 MHz; CDCl3):  = 7.39–7.26 (m, 5 H, ArH), 4.82 (s, 1 H,
C=CHH), 4.80 (s, 1 M, C=CHH), 4.50 (s, 2 H, CH2Ph), 4.28–4.16 (m, 2 H,
CO2CH2CH3), 3.78 (s, 3 H, CO2Me), 3.56 (t, J = 7 Hz, 2 H, CH2OBn), 2.34
(t, J = 7 Hz, 2 H, CH2CH2OBn), 2.32–2.26 [m, 1 H, CHHC(OH)], 2.02–
1.97 [m, 1 H, CHHC(OH)], 1.96–1.90 [m, 2 H, CH2CH2C(OH)], 1.27 (t, J =
7 Hz, 3 H, CO2CH2CH3).
HRMS: m/z [M + H]+ calcd for C26H41O6N228Si: 505.2728; found:
505.2732.
13C NMR (125 MHz; CDCl3):  = 173.6 (CO2Me), 165.9 (CO2Et), 145.2
(C=CH2), 138.5 (ArC), 128.5 (ArCH), 127.8 (ArCH), 127.7 (ArCH), 111.5
(C=CH2), 73.8 (quat. C(OH)CO2Me), 73.1 (CH2Ph), 68.9 (CH2OBn), 61.4
(CO2CH2CH3), 53.6 (CO2CH3), 36.4 and 34.6 (CH2C(=CH2)CH2), 29.7
(CH2C(OH)), 14.5 (CO2CH2CH3).
4-Ethyl 1-Methyl 2-[5-(Benzyloxy)-3-methylenepentyl]-3-diazo-2-
[(trimethylsilyl)oxy] Succinate (22b) and 6a-Ethyl 6-Methyl
(3aR,6S,6aR)-3a-[2-(Benzyloxy)ethyl]-6-[(trimethylsilyl)oxy]-
3a,4,5,6-tetrahydrocyclopenta[c]pyrazole-6,6a(3H)-dicarboxylate
(23b)
HRMS: m/z [M + H]+ calcd for C20H27O6N2: 391.1863; found: 391.1882.
Hexamethyldisilazane (66 L, 0.32 mmol) was added to a solution of
diazo alcohol 21 (30 mg, 0.076 mmol) and imidazole (11 mg, 0.16
mmol) in THF (0.8 mL) at r.t. After 48 h, the reaction mixture was con-
centrated by blowing nitrogen, followed by purification of the residue
by column chromatography (0–10% Et2O in petrol).
4-Ethyl 1-Methyl 2-[5-(Benzyloxy)-3-methylenepentyl]-2-[(tert-
butyldimethylsilyl)oxy]-3-diazosuccinate (22a) and 6a-Ethyl 6-
Methyl (3aR,6S,6aR)-3a-[2-(Benzyloxy)ethyl]-6-[(tert-butyldi-
methylsilyl)oxy]-3a,4,5,6-tetrahydrocyclopenta[c]pyrazole-
6,6a(3H)-dicarboxylate (23a)
First eluted TMS ether 22b (14 mg, 40%), as a yellow oil; Rf = 0.26 (20%
Et2O in petrol).
TBSOTf (35 L, 0.15 mmol) was added to a solution of 2,6-lutidine (26
L, 0.22 mmol) in CH2Cl2 (200 L) at 0 °C and stirred for 15 min. A
solution of diazo-alcohol 21 (30 mg, 0.076 mmol) in CH2Cl2 (200 L)
was added and the reaction mixture was stirred for 48 h at r.t., then
water (1 mL) was added, and the mixture was extracted with CH2Cl2
(2 × 5 mL), dried (MgSO4) and evaporated under reduced pressure.
The crude mixture was purified by column chromatography (0–20%
Et2O in petrol).
IR (film): 2954 (m), 2096 (s), 1744 (s), 1701 (s), 1454 (m), 1369 (m),
1304 (s), 1251 (s), 1135 (m), 844 (s) cm–1
.
1H NMR (400 MHz; CDCl3):  = 7.37–7.27 (m, 5 H, ArH), 4.80 (s, 2 H,
C=CH2), 4.51 (s, 2 H, CH2Ph), 4.26–4.11 (m, 2 H, CO2CH2CH3), 3.73 (s,
3 H, CO2Me), 3.56 (t, J = 7 Hz, 2 H, CH2OBn), 2.34 (t, J = 7 Hz, 2 H,
CH2CH2OBn), 2.22–1.92 [m, 4 H, CH2CH2C(OTBS)], 1.25 (t, J = 7 Hz, 3 H,
CO2CH2CH3), 0.13 [s, 9 H, OSi(CH3)3].
13C NMR (100 MHz; CDCl3):  = 171.8 (CO2Me), 164.9 (CO2Et), 145.6
(C=CH2), 138.5 (ArC), 128.5 (ArCH), 127.8 (ArCH), 127.7 (ArCH), 111.1
(C=CH2), 76.2 [quat. C(OTMS)CO2Me], 73.1 (CH2Ph), 68.9 (CH2OBn),
61.0 (CO2CH2CH3), 52.8 (CO2CH3), 36.7 and 36.5 [CH2C(=CH2)CH2], 30.2
[CH2C(OTMS)], 14.6 (CO2CH2CH3), 1.4 [OSi(CH3)3].
First eluted TBS ether 22a (7 mg, 18%), as a yellow oil; Rf = 0.23 (20%
Et2O in petrol).
IR (film): 2953 (m), 2857 (m), 2096 (s), 1745 (s), 1701 (s), 1454 (w),
1369 (m), 1304 (s), 1254 (m), 1135 (s), 838 (s), 780 (m) cm–1
.
1H NMR (400 MHz; CDCl3):  = 7.37–7.26 (m, 5 H, ArH), 4.80 (s, 2 H,
C=CH2), 4.50 (s, 2 H, CH2Ph), 4.26–4.11 (m, 2 H, CO2CH2CH3), 3.72 (s,
3 H, CO2Me), 3.55 (t, J = 7 Hz, 2 H, CH2OBn), 2.33 (t, J = 7 Hz, 2 H,
CH2CH2OBn), 2.24–1.94 [m, 4 H, CH2CH2C(OTBS)], 1.24 (t, J = 7 Hz, 3 H,
CO2CH2CH3), 0.88 (s, 9 H, OSiCMe3), 0.11 and 0.05 [2 × s, 6 H,
OSi(CH3)2].
13C NMR (100 MHz; CDCl3):  = 173.6 (CO2Me), 145.6 (C=CH2), 138.5
(ArC), 128.5 (ArCH), 127.8 (ArCH), 127.7 (ArCH), 111.2 (C=CH2), 76.0
[quat. C(OTBS)CO2Me], 73.1 (CH2Ph), 68.9 (CH2OBn), 61.1
(CO2CH2CH3), 52.8 (CO2CH3), 36.9 and 36.4 [CH2C(=CH2)CH2], 30.2
[CH2C(OH)], 25.9 [SiC(CH3)3], 18.6 [SiC(CH3)3], 14.6 (CO2CH2CH3), –3.4
and –3.08 (2 × SiCH3).
HRMS: m/z [M + H]+ calcd for C23H35O6N228Si: 463.2258; found:
463.2258.
Second eluted cycloadduct 23b (11 mg, 31%), as a pale-yellow oil; Rf =
0.34 (20% Et2O in petrol).
IR (film): 2951 (m), 2928 (m), 1741 (s), 1455 (m), 1254 (s), 1101 (m),
1056 (m), 839 (s), 779 (m) cm–1
.
1H NMR (500 MHz; CDCl3):  = 7.38–7.27 (m, 5 H, ArH), 4.72 (d, J =
18.5 Hz, 1 H, CHHN=N), 4.53–4.42 (m, 3 H, CH2Ph and CHHN=N),
4.21–4.14 (m, 2 H, CO2CH2CH3), 3.80 (s, 3 H, CO2CH3), 3.56–3.47 (m,
2 H, CH2OBn), 2.33 [dt, J = 13.5, 7.5 Hz, 1 H, CHHC(OTBS)], 2.12–2.04
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H

G
H. A. A. Almohseni et al.
Paper
Synthesis
[m, 1 H, CHHCH2C(OTBS)], 1.85 (dt, J = 13.5, 5.5 Hz, 1 H, CHHCH2OBn),
1.75 [ddd, J = 13.5, 7.5, 6.5, 1 H, CHHC(OTBS)], 1.64–1.52 [m, 1 H, CH-
HCH2OBn and CHHCH2C(OTBS)], 1.24 (t, J = 7 Hz, 3 H, CO2CH2CH3),
0.10 [s, 9 H, OSi(CH3)3].
13C NMR (125 MHz; CDCl3):  = 172.4 (CO2Me), 167.8 (CO2Et), 138.2
(ArC), 128.6 (ArCH), 127.8 (ArCH), 127.7 (ArCH), 110.1 (quat. CCO2Et),
91.9 (CH2N=N), 87.0 (quat. C(OTBS)CO2Me), 73.4 (CH2Ph), 67.7
(CH2OBn), 61.8 (CO2CH2CH3), 52.3 (CO2CH3), 49.6 (quat. CCH2N=N),
37.5 [CH2C(OTBS)], 35.5 (CH2CH2OBn), 34.8 [CH2CH2C(OTBS)], 14.2
(CO2CH2CH3), 1.6 [Si(CH3)3].
Funding Information
We thank the Higher Committee for Education Development in Iraq,
the EPSRC and the Higher Education Commission of Pakistan for stu-
dentship support (to H.A.A.A., Y.F.H. and T.A., respectively).()
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690180.
S
u
p
p
orit
n
gInformati
o
n
S
u
p
p
orit
n
gInformati
o
n
HRMS: m/z [M + H]+ calcd for C23H35O6N228Si: 463.2258; found:
463.2251.
References and Notes
4-Ethyl 1-Methyl 2-[5-(Benzyloxy)-3-oxopentyl]-2-[(tert-butyldi-
methylsilyl)oxy]-3-diazosuccinate (24a)
(1) Permanent address: University of Kufa, Najaf Governorate, Iraq.
(2) Fegheh-Hassanpour, Y.; Arif, T.; Sintim, H. O.; Al-Mamari, H. A.;
Hodgson, D. M. Org. Lett. 2017, 19, 3540; corrigendum 2018, 20,
5528.
(3) Almohseni, H. A. A.; Al-Mamari, H. A.; Valade, A.; Sintim, H. O.;
Hodgson, D. M. Chem. Commun. 2018, 52, 5354.
By following the general procedure for ozonolysis above, TBS ether
22a (4 mg, 0.008 mmol) gave, after column chromatography (0–40%
Et2O in petrol), diazoketone 24a.
Yield: 2.3 mg (58%); yellow oil; Rf = 0.53 (50% Et2O in petrol).
(4) Hodgson, D. M.; Labande, A. H.; Muthusamy, S. Org. React. 2013,
80, 133.
IR (film): 2931 (m), 2856 (m), 2095 (s), 1747 (s), 1700 (s), 1456 (w),
1305 (m), 1256 (m), 1132 (m), 838 (m) cm–1
.
(5) For intramolecular cycloadditions between diazo and alkene
functionality, see: (a) Padwa, A.; Ku, H. J. Org. Chem. 1980, 45,
3756. (b) Dauben, W. G.; Hendricks, R. T.; Luzzio, M. J.; Ng, H. P.
Tetrahedron Lett. 1990, 31, 6969. (c) Jung, M. E.; Huang, A. Org.
Lett. 2000, 2, 2659. (d) Taber, D. F.; Guo, P. J. Org. Chem. 2008, 73,
9479. (e) Liu, H.; O’Connor, M. J.; Sun, C.; Wink, D. J.; Lee, D. Org.
Lett. 2013, 15, 2974. (f) Barroso, R.; Escribano, M.; Cabal, M.-P.;
Valdés, C. Eur. J. Org. Chem. 2014, 1672. (g) Xia, Y.; Wang, J.
Chem. Soc. Rev. 2017, 46, 2306. (h) See also: Padwa, A.; Kulkarni,
Y. S.; Zhang, Z. J. Org. Chem. 1990, 55, 4144.
1H NMR (500 MHz; CDCl3):  = 7.37–7.27 (m, 5 H, ArH), 4.50 (s, 2 H,
CH2Ph), 4.24–4.12 (m, 2 H, CO2CH2CH3), 3.75–3.68 (m, 5 H, CO2CH3
and CH2OBn), 2.69 (t, J = 6 Hz, 2 H, CH2CH2OBn), 2.67–2.61 [m, 1 H,
CHHC(OTBS)], 2.51–2.44 [m, 1 H, CHHC(OTBS)], 2.27–2.21 [m, 2 H,
CH2CH2C(OTBS)], 1.24 (t, J = 7 Hz, 3 H, OCH2CH3), 0.86 [s, 9 H,
OSiC(CH3)3], 0.09 and 0.04 [2 × s, 6 H, OSi(CH3)2].
13C NMR (125 MHz; CDCl3):  = 207.7 (C=O), 171.4 (CO2Me), 164.8
(CO2Et), 138.2 (ArC), 128.5 (ArCH), 127.8 (ArCH), 127.8 (ArCH), 75.6
[quat. C(OTBS)CO2Me], 73.4 (CH2Ph), 65.4 (CH2OBn), 61.2
(CO2CH2CH3), 52.9 (CO2CH3), 43.2 (O=CCH2), 37.8 (O=CCH2), 32.2
[CH2C(OTBS)], 25.9 [SiC(CH3)3], 18.6 [SiC(CH3)3], 14.6 (CO2CH2CH3), –
3.5 and –3.9 (2 × SiCH3).
(6) Fegheh-Hassanpour, Y.; Ebrahim, F.; Arif, T.; Sintim, H. O.;
Claridge, T. D. W.; Amin, N. T.; Hodgson, D. M. Org. Biomol.
Chem. 2018, 16, 2876.
HRMS: m/z [M + Na]+ calcd for C25H38O7N223Na28Si: 529.2340; found:
529.2341.
(7) (a) House, H. O.; Blankley, C. J. J. Org. Chem. 1968, 33, 53.
(b) Blankley, C. J.; Sauter, F. J.; House, H. O. Org. Synth. Coll. Vol.
V; John Wiley & Sons: London, 1973, 258.
(8) For examples of ozonolysis of diazo compounds to give ketones,
see: (a) Erickson, R. E.; Andrulis, P. J. Jr.; Collins, J. C.; Lungle, M.
L.; Mercer, G. D. J. Org. Chem. 1969, 34, 2961. (b) Sekiguchi, A.;
Ando, W. J. Chem. Soc. 1979, 575. (c) Ursini, A.; Pellicciari, R.;
Tamburini, B.; Carlesso, R.; Gaviraghi, G. Synthesis 1992, 363.
(9) (a) Schöllkopf, U.; Frasnelli, H. Angew. Chem. Int. Ed. Engl. 1970,
9, 301. (b) Wenkert, E.; McPherson, C. A. J. Am. Chem. Soc. 1972,
94, 8084.
(10) Hon and co-workers report that, for ozonolysis of alkenes (for
example, 2,2-disubstituted-1-alkenes), Et3N typically gives
better yields and proceeds faster compared to Me2S. Me2S also
proved viable in the current transformation, but the crude reac-
tion mixture was not as clean as with Et3N. See: Hon, Y.-S.; Lin,
S.-W.; Lu, L.; Chen, Y.-J. Tetrahedron 1995, 51, 5019.
(11) (a) Poschenrieder, H.; Stachel, H.-D. Arch. Pharm. (Weinheim,
Ger.) 1989, 322, 301. (b) Hodgson, D. M.; Man, S. Chem. Eur. J.
2011, 17, 9731. (c) Hodgson, D. M.; Moreno-Clavijo, E.; Day, S.
E.; Man, S. Org. Biomol. Chem. 2013, 11, 5362.
(12) Jiang, Y.; Khong, V. Z. Y.; Lourdusamy, E.; Park, C.-M. Chem.
Commun. 2012, 48, 3133.
4-Ethyl 1-Methyl 2-[5-(Benzyloxy)-3-oxopentyl]-3-diazo-2-
[(trimethylsilyl)oxy]succinate (24b)
By following the procedure for ozonolysis above, TMS ether 22b (6
mg, 0.013 mmol) gave, after column chromatography (0–40% Et2O in
petrol), diazoketone 24b.
Yield: 3.7 mg (61%); yellow oil; Rf = 0.51 (50% Et2O in petrol).
IR (film): 2953 (w), 2871 (w), 2096 (s), 1747 (s), 1702 (s), 1455 (w),
1369 (m), 1305 (s), 1251 (s), 1135 (m), 845 (s) cm–1
.
1H NMR (500 MHz; CDCl3):  = 7.37–7.27 (m, 5 H, ArH), 4.50 (s, 2 H,
CH2Ph), 4.27–4.11 (m, 2 H, CO2CH2CH3), 3.75–3.71 (m, 5 H, CO2CH3
and CH2OBn), 2.70 (t, J = 6.5 Hz, 2 H, CH2CH2OBn), 2.66–2.58 [m, 1 H,
CHHC(OTMS)], 2.48–2.41 [m, 1 H, CHHC(OTMS)], 2.26–2.20 [m, 2 H,
CH2CH2C(OTMS)], 1.25 (t, J = 7 Hz, 3 H, OCH2CH3), 0.11 (s, 3 H, OTMS).
13C NMR (125 MHz; CDCl3):  = 207.8 (C=O), 171.5 (CO2Me), 164.8
(CO2Et), 138.2 (ArC), 128.6 (ArCH), 127.8 (ArCH), 127.8 (ArCH), 75.8
[quat. C(OTMS)CO2Me], 73.4 (CH2Ph), 65.4 (CH2OBn), 61.2
(CO2CH2CH3), 53.0 (CO2CH3), 43.2 (O=CCH2), 37.7 (O=CCH2), 32.2
[CH2C(OTMS)], 14.6 (CO2CH2CH3), 1.3 (OTMS).
HRMS: m/z [M + Na]+ calcd for C22H32O7N223Na28Si: 487.1871; found:
487.1867.
(13) (a) Eftekhari-Sis, B.; Zirak, M. Chem. Rev. 2015, 115, 151. (b) de
las Heras, M. A.; Vaquero, J. J.; García-Navio, J. L.; Alvarez-Builla,
J. J. Org. Chem. 1996, 61, 9009. (c) Weinstock, L. M.; Currie, R. B.;
Lovell, A. V. Synth. Commun. 1981, 11, 943.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H

H
H. A. A. Almohseni et al.
Paper
Synthesis
(14) For examples, see: (a) Macritchie, J. A.; Silcock, A.; Willis, C. L.
Tetrahedron: Asymmetry 1997, 8, 3895. (b) Vickers, T. D.; Keay,
B. A. Synlett 2003, 1349.
(15) Bailey, W. F.; Punzalan, E. R. J. Org. Chem. 1990, 55, 5404.
(16) On a similar motif, -lactolisation of a -hydroxy--oxo--
diazoester was observed, see: Villalonga-Barber, C. D Phil Thesis;
University of Oxford: UK, 2002.
(17) The stereochemistry of pyrazolines 23a,b were supported by
NOESY experiments.
(18) Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.;
Timmers, F. J. Organometallics 1996, 15, 1518.
(19) Peng, C.; Wang, Y.; Wang, J. J. Am. Chem. Soc. 2008, 130, 1566.
(20) Siu, J. C.; Parry, J. B.; Lin, S. J. Am. Chem. Soc. 2019, 141, 2825.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H