Pyrrolidinones derived from (S)-pyroglutamic acid. Part 4. α, β-diaminopyrrolidinones

Article abstract of DOI:10.1039/b106783b

The electrophilic amination of a β-aminolactam to provide direct acess to conformationally constrained diamines was discussed. The β-aminolactams was found to be derived from the conjugate addition of O,N-dibenzylhydroxylamine to a highly activated α,β-un

Full text of DOI:10.1039/b106783b

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Pyrrolidinones derived from (S)-pyroglutamic acid. Part 4.
ꢀ, ꢁ-Diaminopyrrolidinones
Philip W. H. Chan,a Ian F. Cottrellb and Mark G. Moloney*a
1
a The Department of Chemistry, Dyson Perrins Laboratory, The University of Oxford,
South Parks Road, Oxford, UK OX1 3QY. E-mail: mark.moloney@chem.ox.ac.uk
b Department of Process Research, Merck Sharp and Dohme Research Laboratories,
Hertford Rd, Hoddesdon, Herts., UK EN11 9BU
Received (in Cambridge, UK) 26th July 2001, Accepted 19th September 2001
First published as an Advance Article on the web 25th October 2001
The electrophilic amination of a β-aminolactam, itself derived from the conjugate addition of O,N-dibenzyl-
hydroxylamine to a highly activated α,β-unsaturated bicyclic lactam, provides direct access to conformationally
constrained diamines. Sequential deprotection allows the synthesis of 3,4-diaminopyroglutaminols.
There has been substantial recent interest in the use of
highly functionalised pyrrolidinones as excitatory amino acid
analogues1 and as conformationally controlling peptido-
mimetics,2–5 and we have reported that the bicyclic lactam 1,
readily obtained from pyroglutamic acid,6,7 provides a useful
template for the preparation of conformationally restricted
substituted pyrrolidinones.8,9 Our recent work has also shown
that suitable modification of the hemiaminal ether moiety of
this bicyclic template can be used to control the diastereo-
selectivity of enolate alkylations by using competing steric and
stereoelectronic effects to advantage.10 Of particular interest
was extension of this approach to allow the synthesis of con-
formationally constrained diamines from lactam 1, since similar
diamines11,12 have found application as ligands13,14 and chiral
auxiliaries.15 In general, amino functionalised pyrrolidines
are not especially well known, although examples of natural
products include (Ϫ)-cucurbitine 2,16 3-aminoproline 3,17 and
viomycidine 4.18 However, aminopyrrolidines have become
increasingly important for their biological and pharmacological
properties, and examples include the neuroexcitatory compound
(2R,4R)-4-aminopyrrolidine-2,4-dicarboxylic acid (APDC) 5,19
aminoprolinol 620 and 4-aminoproline 7.21 Surprisingly, there
appear to be no natural products containing a 3,4-diamino-
pyrrolidinone functionality, and perhaps for this reason there
has been little interest in developing synthetic routes to this
class of compounds, although Eckstein et al.22 reported the
isolation of trans-3,4-diaminopyrrolidin-2-one 8 as a reaction
by-product. However, since such compounds could be of con-
siderable interest for diverse applications, we decided to examine
the conversion of enone 1 to enantiopure diamino products, a
sequence which was expected to be rapid and direct.
Results and discussion
Initial investigations
On the basis of favourable literature precedent for the Diels–
Alder reaction of maleic anhydride with N,NЈ-bis(p-methoxy-
phenyl)ethylenediimine 9,23 and of our own work indicating
that lactam 1 exhibited good reactivity in cycloaddition reac-
tions,24 we attempted reaction of the enone 1 in toluene with
diimine 9, but none of the desired product could be observed
by either 1H NMR or mass spectroscopy after 18 hours at
reflux (Scheme 1). Extension of the reaction time to 36 hours
or changing the solvent to xylene gave no improvement.
DOI: 10.1039/b106783b
J. Chem. Soc., Perkin Trans. 1, 2001, 3007–3012
This journal is © The Royal Society of Chemistry 2001
3007

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In an alternative approach, the formation of the aziridine 10a
from enone 1 was examined: ring opening of this compound
with amine nucleophiles was expected to provide access to a
variety of 3,4-diamino functionalised pyrrolidinones.25 How-
ever, reaction of α,β-unsaturated lactam 1 with toluene-p-
sulfonamide–(diacetyloxyiodo)benzene, recently shown to be
applicable to aziridination of electron rich26 and electron
poor27 double bonds, was unsuccessful. Furthermore, intra-
molecular cyclisation of N,N-dimethylhydrazino derivative
11a28 as a route to the aziridine 10b was also examined; quatern-
isation (MeI) of the amine function of 11a and base treatment
(NaH) was expected to give the aziridine directly. However, the
only product obtained from this process was the unsaturated
lactam 12 as an inseparable mixture of two diastereomers in a
ratio of 1 : 1; this compound has previously been isolated from
attempted alkylation reactions of lactam 1.28 Intramolecular
cyclisation of hydroxylamine 11b to the corresponding aziridine
using the conditions of Cardillo et al.,29 as well as collapse of
the triazoline ring of 13 under photolytic conditions, a well
known process,30–33 was also unsuccessful.
yields (quantitative and 67% respectively, Scheme 1). However,
whilst the isolation of the dibenzylcarbamate derivative 16b
could be readily achieved by flash column chromatography,
this was not the case for hydrazine 16a. Once again, the
stereochemistry of both alcohols 16a and 16b could not be
1
determined by NOE analysis. However, as shown by H and
13C NMR spectroscopy, both of these products were single
diastereomers, and it is assumed that both compounds were
obtained with C-3–C-4 trans-stereochemistry.
Hydrogenolysis of the hydrazine 16a with 10% Pd/C in glacial
acetic acid under a 4 bar pressure of hydrogen furnished the
expected 3,4-diaminopyroglutaminol in excellent yield (77%),
but with some epimerisation (ratio of products 17 : 18 = 6 : 1,
Scheme 1). Similarly, the dibenzylcarbamate derivative 16b was
converted to the same products in excellent yield (75%), as a
mixture of isomers in a ratio of 17 : 18 = 5 : 1. Once again,
X-ray crystal structure analysis or NOE spectroscopic analysis
was not possible to rigorously assign stereochemistry, but
some of our earlier work9 had shown that lactams with the
trans-configuration at C-3 and C-4 possessed larger coupling
constants than their cis-counterparts. The relative stereo-
chemistry of the major adduct 17 was therefore assigned as
trans, since the coupling constant of the C(3)H signal (8.8 Hz)
was found to be larger than that for the minor product 18
(7.9 Hz).
Amination reactions
In view of the above difficulties, our attention turned to electro-
philic amination34 as a means of effecting carbon–nitrogen
bond formation, although noteworthy was that such a process
has not previously been used in lactam systems. Lactam 14 was
chosen for this purpose, since this substrate was readily pre-
pared as a single diastereomer28 and the bulky exo-substituent
at C-6 was expected to promote addition of the electrophile
from the endo-face of the bicyclic system, thereby allowing
diastereocontrolled access to a vicinal diamine product.
We were unable to achieve direct electrophilic amination
of 14 with lithium tert-butyl-N-tosyloxycarbamate as recently
reported by Armstrong and co-workers,35 but deprotonation
with LDA gave the corresponding enolate, which, when
quenched with either di-tert-butyl azodicarboxylate or dibenzyl
azodicarboxylate, afforded the corresponding diaminolactams
15a and 15b in excellent yields (70 and 85% respectively)
and as single diastereomers after purification by flash column
chromatography. However, as both products 15a and 15b were
obtained as gums, single crystal X-ray crystallography was not
possible and neither was NOE analysis, since the NMR spectra
were complicated by rotameric equilibria. The stereochemistry
at C-6 and C-7 was assumed to be trans since this would give
the most thermodynamically stable product (Scheme 1).
Epimerisation studies
The epimerisation observed during the final hydrogenolytic
deprotection step of 16a, b (Scheme 1) was surprising, and
warranted further investigation. The most likely explanation
was that one of the intermediates generated during the reaction
underwent epimerisation at C-3 in the acidic deprotection con-
ditions;28 this was later shown to be the case as follows.
Chemoselective deprotection of the carefully purified 3,4-
diamine 15b (i.e. as a single diastereoisomer) using milder
hydrogenolysis conditions was examined, by changing the
reaction solvent from glacial acetic acid to ethyl acetate. Under
these conditions, the hemiaminal ether protecting group was
expected to be unaffected, leaving the bicyclic ring system
intact, which was then expected to allow either X-ray crystal
structure or NOE analysis to be performed. Under these
conditions, hydrogenolysis of lactam 15b was found to give
three different products depending on the reaction time, corre-
sponding to successive deprotection of each of the hydrazine
protecting groups, followed by N–N bond cleavage. Thus, if the
reaction was allowed to proceed for 22 hours, then the partially
deprotected hydrazine 19a was obtained in good yield along
Acid-mediated deprotection of both adducts 15a and 15b
furnished the corresponding lactams 16a and 16b in excellent
Scheme 1 Reagents and conditions: (i) LDA, then BocN᎐NBoc for 15a, or CbzN᎐NCbz for 15b; (ii) TFA, DCM, RT; (iii) H2, Pd/C, HOAc, 4 bar,
᎐
᎐
RT.
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Table 1 Yields and diastereomeric ratios of hydrogenolysis products 19–21
Product
R
Reaction time/h
Yield (%)
Diastereomeric ratioa a : b
19a, b
20a, b
21a, b
20a, b
21a, b
NHCBZ
NH2
H
NH2
H
22
48
48
168
168
49
52
8
38
62
6 : 1
8 : 1
8 : 1
8.5 : 1
8 : 1
a Estimated from the 1H NMR spectrum.
the stage in which the α-hydrazine function of 19 and/or 20 was
generated.
Conclusion
In summary, the development of a route to a conformationally
restricted pyrrolidinone was shown to be possible through
the electrophilic amination at C-7 of lactam 14. Subsequent
elaboration of compounds 15a and 15b was then shown to
provide a route to the 3,4-diaminopyroglutaminol 17–18 in
excellent yield, although the diastereoselectivity was com-
promised by about 14% epimerisation in the deprotection
step, due to the unexpected lability of hydrazine 20. These
3,4-diaminopyroglutaminols are conformationally constrained
diamines, and may find application as organometallic ligands
or as azasugar analogues.
Fig. 1
with a minor amount of 19b (Scheme 1 and Table 1). Careful
1H NMR examination of 19a, b using deutero-DMSO under
a nitrogen atmosphere showed that the terminal hydrazine
nitrogen carried the Cbz protecting group; no evidence for an
NH2 group, which would have arisen from the removal of the
benzyl carboxylate protecting group, of the terminal nitrogen
was observed. Furthermore, we found that if the reaction time
was extended to two days then an inseparable mixture of two
products, consisting predominantly of hydrazinolactam 20a, b,
but with a minor amount of aminolactam 21a, b, was obtained.
If the reaction was allowed to proceed for one week, a reverse
in the ratios of these analogues was observed; this time the
fully deprotected aminolactam 21a, b was obtained in good
yield as the major product, again as a mixture of inseparable
isomers.
Experimental
For general experimental procedures and the preparation of
lactam 1, see our earlier reports.24
(؉)-(2R,5S,6R,7S)-7-[1,2-Bis(tert-butoxycarbonyl)hydrazino]-
6-O,N-dibenzylhydroxyamino-8-oxo-2-phenyl-3-oxa-1-aza-
bicyclo[3.3.0]octane 15a
To a stirred solution of n-butyllithium (0.53 ml, 2.00 M,
1.06 mmol) in THF (5 ml) under an inert N2 atmosphere at 0 ЊC
was added diisopropylamine (0.16 ml, 1.17 mmol) and the
mixture was allowed to stir for 15 min. The freshly prepared
solution of LDA was then cooled to Ϫ78 ЊC and the bicyclic
lactam 14 (220 mg, 0.53 mmol) dissolved in THF (5 ml) was
added slowly via cannula and the reaction mixture was allowed
to stir for 30 min. Di-tert-butyl azodicarboxylate (244 mg,
1.06 mmol) dissolved in THF (5 ml) was then added slowly via
cannula to the reaction mixture and allowed to stir at Ϫ78 ЊC
for 8 h. The reaction mixture was then quenched at Ϫ78 ЊC with
saturated sodium bicarbonate (10 ml) and allowed to slowly
warm up to RT. Filtration through Celite and removal of
solvent in vacuo gave the crude product. Purification by flash
column chromatography and evaporation in vacuo of the com-
bined fractions furnished the title compound 15a as a colourless
gum (240 mg, 70%); Rf 0.34 (3 : 1 petrol–EtOAc); [α]2D5 ϩ39.2
(c 0.6, CHCl3); νmax(film)/cmϪ1 3282 (w), 2979 (m), 1722 (s), 1368
(s), 1153 (s); δH (400 MHz, CDCl3) 1.42, 1.43, 1.44, 1.46, 1.48,
1.52 and 1.55 (18H, 7 × s, rotameric 6 × CH3), 3.56–3.77 (2H,
br m, C(4)Hendo and C(5)H), 3.98–4.19, 4.20–4.30, 4.31–4.43
(9H, 4 × br m, CH2Ph, OCH2Ph, C(4)Hexo, C(6)H and C(7)H),
5.53, 5.70, 6.43 and 6.51 (1H, 4 × br s, rotameric NH), 6.33 (1H,
br s, C(2)H), 6.93–7.07 (2H, m, ArCH), 7.20–7.26 (3H, m,
ArCH), 7.29–7.42 (8H, m, ArCH), 7.46–7.53 (2H, m, ArCH);
δC (100.7 MHz, CDCl3) 27.62, 28.03 and 28.18 (6 × CH3), 58.70
and 59.10 (C-5), 61.85 and 62.10 (NCH2Ph), 69.99 (C-6), 71.62
(C-4), 76.69 (NOCH2Ph), 86.96 (C-2), 125.99, 127.43, 127.58,
128.20, 128.33, 128.51, 128.81, 129.11 and 130.09 and 130.36
(ArCH), 136.20, 137.50 and 137.82 (3 × ArC), 154.7, 155.12
and 170.60 (3 × CO); m/z (electrospray) 645 (M ϩ Hϩ, 100%),
667 (M ϩ Naϩ, 42); HRMS 645.3288, C36H45N4O7 (M ϩ Hϩ)
requires 645.3288.
As all three products 19–21 were obtained as gums, X-ray
crystallography to determine their structure could not be
performed. Furthermore, NOE analysis of the adducts 19
and 20 was not possible since the signals corresponding to
the protons of interest overlapped with each other in their
1
respective H NMR spectra. However, NOE analysis of the
amino analogue 21a was possible (Fig. 1); the cis-relationship of
the H-2 H-4endo H-6 triad was evident from their mutual
enhancement upon irradiation, and similarly the cis-relation-
ship of H-5, the C-6 hydroxylamine substituent and H-7 was
established. The stereochemistry of amino compound 21a was
therefore deduced to be the (R,S,S,S)-configuration, indicating
that the initial electrophilic amination of substrate 14 most
likely occurred exclusively from the endo-face of the bicyclic
structure, giving the trans-6,7-diamino stereochemistry of
lactam 15 as shown.
Epimerisation at C-7 of 15b during deprotection might have
been due to stepwise cleavage of protecting groups in the
hydrogenolysis deprotection. Since the partially deprotected
adducts 20 and 21 were readily available, the epimerisation of
these derivatives was therefore examined. Thus, both com-
pounds were dissolved in a 1 : 1 mixture of deuterobenzene and
D2O and allowed to stand for 24 hours at room temperature.
Using 1H NMR spectroscopic analysis, it was found that whilst
no change in the isomeric ratio of the amino analogue 21 could
be detected, a significant change in the diastereomeric ratio of
the hydrazine adduct 20 was indeed observed; the ratio of the
major product 20a to that of the minor compound 20b
decreased from 8 : 1 to 2 : 1. These results indicated that facile
epimerisation during the course of the deprotection occurred at
J. Chem. Soc., Perkin Trans. 1, 2001, 3007–3012
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(؉)-(2R,5S,6R,7S)-7-[1,2-Bis(benzyloxycarbonyl)hydrazino]-6-
O,N-dibenzylhydroxyamino-8-oxo-2-phenyl-3-oxa-1-azabicyclo-
[3.3.0]octane 15b
137.83 (ArC), 155.73 and 156.75 (acyclic CO), 171.89 (cyclic
CO); m/z (APCIϩ) 625 (M ϩ Hϩ, 100%); HRMS 625.2659,
C35H37N4O7 (M ϩ Hϩ) requires 625.2662.
To a stirred solution of n-butyllithium (0.97 ml, 2.5 M,
2.42 mmol) in THF (10 ml) under an inert N2 atmosphere at
0 ЊC was added diisopropylamine (0.37 ml, 2.66 mmol) and
allowed to stir for 15 min. The freshly prepared solution
of LDA was then cooled to Ϫ78 ЊC and the bicyclic lactam 14
(500 mg, 1.21 mmol) dissolved in THF (15 ml) was added
slowly via cannula and the reaction mixture was allowed to stir
for 30 min. Dibenzyl azodicarboxylate (800 mg, 2.42 mmol)
dissolved in THF (15 ml) was then added slowly via cannula to
the reaction mixture which was allowed to stir at Ϫ78 ЊC for
8 h. The reaction mixture was then quenched at Ϫ78 ЊC with
saturated sodium bicarbonate (10 ml) and allowed to slowly
warm up to RT. Filtration through Celite and removal of
the solvent in vacuo gave the crude product. A mixture of
EtOAc (50 ml) and water (50 ml) was then added to the gum
and the organic layer was separated. The aqueous layer was
further extracted using EtOAc (50 ml) and the combined
organic layers were washed with water (100 ml), dried over
MgSO4, filtered and concentrated in vacuo. Purification by flash
column chromatography and evaporation in vacuo of the com-
bined fractions furnished the title compound 15b as a colour-
less gum (728 mg, 85%); Rf 0.19 (3 : 1 petrol–EtOAc);
[α]2D5 ϩ44.6 (c 0.5, CHCl3); νmax(film)/cmϪ1 3500 (m), 3270 (m),
3032 (m), 2958 (m), 2879 (m), 1724 (s), 1219 (s); δH (400 MHz,
CDCl3) 3.45–3.67 (1H, br m, C(4)Hendo), 3.67–3.81 (1H, br m,
C(5)H), 4.01–4.23 (5H, br m, C(4)Hexo, C(6)H, NCH2Ph and
NOCHHPh), 4.44 (1H, br d, J 9.5, NOCHHPh), 5.01–5.31
(5H, br m, C(7)H and 2 × OCH2Ph), 5.61 and 5.79 (1H,
2 × br s, rotameric NH), 6.33 (1H, br s, C(2)H), 6.81–7.57
(25H, m, ArCH); δC (50.3 MHz, CDCl3) 58.05 (C-5), 61.83
(NCH2Ph), 67.96 (OCH2Ph), 68.79 (OCH2Ph), 69.82 (C-6),
71.52 (C-4), 77.03 (NOCH2Ph), 86.99 (C-2), 126.01, 127.59,
128.13, 128.30, 128.51, 128.59, 128.87, 129.05 and 130.20
(ArCH), 135.35, 136.26 and 137.02 (ArC), 156.06 (acyclic
CO), 174.61 (cyclic CO); m/z (APCIϩ) 713 (M ϩ Hϩ, 100%),
735 (M ϩ Naϩ, 5); HRMS 713.2975, C42H40N4O7 (M ϩ Hϩ)
requires 713.2975.
General hydrogenolysis method
To a vigorously stirred solution of the starting material dis-
solved in absolute ethanol, EtOAc or glacial acetic acid in a
Fischer–Porter apparatus was added palladium supported on
carbon (Pd/C). The heterogeneous solution was then evacuated
and flushed with H2 six times at RT. The reaction mixture was
subjected to H2 at the given pressure and time. The mixture was
filtered through Celite and the resultant filtrate was concen-
trated in vacuo. Purification of the crude product was carried
out by either flash column chromatography or ion-exchange
chromatography.
(3S,4S,5S)-3,4-Diamino-5-hydroxymethyl-2-oxopyrrolidine 17
and (3R,4S,5S)-3,4-diamino-5-hydroxymethyl-2-oxopyrrolidine
18
Using the above general method, lactam 16a (192 mg, 0.54
mmol) was dissolved in glacial acetic acid (15 ml) and reacted
with palladium supported on carbon (Pd/C) (384 mg,
10%) under a hydrogen atmosphere (4 bar) for 72 h. Standard
work-up and purification of the crude product by ion-exchange
chromatography (water and then 2 M ammonia in water as
eluent) gave the gummy product (60 mg, 77%) as an inseparable
diastereomeric mixture of 17–18 (6 : 1); νmax(film)/cmϪ1 3348
(br), 1693 (s), 1379 (w); data for major isomer only δH (500
MHz, D2O) 3.06 (1H, t, J 8.2, C(4)H), 3.36 (1H, d, J 8.8,
C(5)H), 3.38–3.42 (1H, m, C(3)H), 3.61 (1H, dd, J 12.2 and
5.1, CHHOH), 3.72 (1H, dd, J 12.2 and 2.6, CHHOH);
δC (125.8 MHz, D2O) 56.96 (C(4)H), 60.16 (C(5)H and C(3)H),
61.08 (CH2OH), 178.28 (CO); m/z (APCIϩ) 146 (M ϩ Hϩ,
100%); HRMS 146.0932, C5H12N3O2 (M ϩ Hϩ) requires
146.0930.
Using the same general method, the lactam 16b (450 mg,
0.72 mmol) was dissolved in glacial acetic acid (40 ml) and
reacted with Pd/C (450 mg, 10%) and H2 (4.5 bar) for 72 h.
Purification by ion-exchange chromatography (water and then
2 M ammonia in water as eluent) gave the gummy product
(78 mg, 75%) as an inseparable diastereomeric mixture of 17–18
(5 : 1) with identical data to those above.
(3S,4R,5S)-4-O,N-Dibenzylhydroxyamino-3-hydrazino-5-
hydroxymethyl-2-oxopyrrolidine 16a
Trifluoroacetic acid (0.5 ml) was added to adduct 15a (240 mg,
0.37 mmol) dissolved in DCM (10 ml) at RT and allowed to stir
for 1 h. Concentration in vacuo gave the crude product as a dark
orange gum (188 mg, 100%). However, purification of the crude
product by standard techniques was found to be unsuccessful;
m/z (APCIϩ) 106 (100%), 357 (M ϩ Hϩ, 14).
(2R,5S,6S,7S)-7-[2-(Benzyloxycarbonyl)hydrazino]-6-O,N-
dibenzylhydroxyamino-8-oxo-2-phenyl-3-oxa-1-azabicyclo-
[3.3.0]octane 19a and (2R,5S,6S,7R)-7-[2-(benzyloxycarbonyl)-
hydrazino]-6-O,N-dibenzylhydroxyamino-8-oxo-2-phenyl-3-oxa-
1-azabicyclo[3.3.0]octane 19b
Using the general hydrogenolysis method, Pd/C (400 mg, 10%)
was reacted with compound 15b (400 mg, 0.56 mmol) dissolved
in EtOAc (40ml) and H2 (4 bar) for 22 h. Purification by flash
column chromatography (1 : 2 petrol–EtOAc as eluent) gave the
partially deprotected compound 19 as a yellow gum (160 mg,
49%) as an inseparable mixture of diastereomers in a ratio
of 19a : 19b = 6 : 1, along with the starting material 15b (88 mg);
Rf 0.22 (2 : 1 petrol–EtOAc); νmax(film)/cmϪ1 3304 (br), 2958
(m), 2880 (m), 1716 (s); m/z (APCIϩ) 579 (M ϩ Hϩ, 100%);
HRMS 579.2617, C34H35N4O5 (M ϩ Hϩ) requires 579.2607.
Data for 19a: δH (400 MHz, CDCl3) 3.44 (1H, dd, J 9.5 and
6.1, C(6)H), 3.59 (1H, t, J 7.5, C(4)Hendo), 3.80–4.40 (6H, m,
NCH2Ph, NOCHHPh, C(4)Hexo, C(5)H, and C(7)H), 4.50 (1H,
br d, J 10.1, OCHHPh), 4.59 (1H, br s, NHNH), 5.18 (2H, s,
NCO2CH2Ph), 6.31 (1H, s, C(2)H), 6.88 (1H, br s, NHNH),
7.06–7.52 (20H, m, ArCH); δC (100.7 MHz, CDCl3) 57.44
(C-5), 61.60 (NCH2Ph), 65.56 (C-7), 67.20 (NCO2), 70.53 (C-6),
71.49 (C-4), 76.58 (NOCH2Ph), 86.62 (C-2), 126.07, 127.73,
128.22, 128.29, 128.39, 128.42, 128.49, 128.53, 128.56, 128.87,
128.96, 129.16, 129.28, 129.54 and 129.91 (ArCH), 136.01,
(؊)-(3S,4R,5S)-3-(1,2-Bis[benzyloxycarbonyl]hydrazino)-4-
O,N-dibenzylhydroxyamino-5-hydroxymethyl-2-oxopyrrolidine
16b
Trifluoroacetic acid (0.5 ml) was added to adduct 15b (400 mg,
0.56 mmol) dissolved in DCM (30 ml) at RT and allowed to stir
for 2.5 h. Concentration in vacuo and subsequent purification
by flash column chromatography (1 : 2 petrol–EtOAc as eluent)
and concentration in vacuo gave the product 16b as a pale pink
foam (236 mg, 67%); Rf 0.25 (1 : 2 petrol–EtOAc); [α]2D3.5 Ϫ44.8
(c 2.9, CHCl3); νmax(film)/cmϪ1 3260 (br), 2946 (w), 1720 (s),
1220 (s), 1054 (m); δH (200 MHz, CDCl3) 2.60 (1H, br s, NH),
3.15–3.80 (5H, br m, NCH2Ph, NOCHHPh, CHOH and
C(5)H), 3.95–4.35 (3H, br m, NOCHHPh, CHOH and C(4)H),
4.95–5.25 (4H, br m, 2 × NCO2CH2Ph), 5.30–5.55 (1H, br m,
C(3)H), 6.80–7.55 (20H, m, ArCH); δC (50.3 MHz, CDCl3)
56.29 (C-5), 61.58 (NCH2Ph), 63.99 (NCO2), 66.40 (C-3), 67.78
(NCO2), 68.40 (CH2), 77.70 (NOCH2Ph), 127.38, 127.98,
128.10, 128.23, 128.53 and 130.09 (ArCH), 135.57, 136.43 and
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136.32, 136.84 and 137.69 (4 × ArC), 156.85 (acyclic CO),
172.97 (cyclic CO).
128.80, 128.91, 128.96, 129.46, 130.49 and 130.63 (ArCH),
137.20, 137.54 and 139.78 (3 × ArC), 174.70 (CO).
Data for 19b: δH (400 MHz, CDCl3) 3.44 (1H, dd, J 9.5 and
6.1, C(6)H), 3.62–3.73 (1H, m, C(4)Hendo), 3.80–4.40 (6H, m,
NCH2Ph, NOCHHPh, C(4)Hexo, C(5)H, and C(7)H), 4.50 (1H,
br d, J 10.1, OCHHPh), 4.59 (1H, br s, NHNH), 5.18 (2H, s,
NCO2CH2Ph), 6.34 (1H, s, C(2)H), 7.02 (1H, br d, J 5.0,
NHNH), 7.06–7.52 (20H, m, ArCH); δC (100.7 MHz, CDCl3)
56.84 (C-5), 61.60 (NCH2Ph), 65.56 (C-7), 67.20 (NCO2), 70.53
(C-6), 71.49 (C-4), 76.56 (NOCH2Ph), 86.96 (C-2), 126.07,
127.73, 128.22, 128.29, 128.39, 128.42, 128.49, 128.53, 128.56,
128.87, 128.96, 129.16, 129.28, 129.54 and 129.91 (ArCH),
136.01, 136.32, 136.84 and 137.69 (4 × ArC), 156.85 (acyclic
CO), 172.97 (cyclic CO).
Data for 21: Rf 0.31 (1 : 2 petrol–EtOAc); νmax(film)/cmϪ1
3380 (w), 3031 (w), 2878 (m), 1714 (s), 1356 (br), 1218 (w);
m/z (APCIϩ) 122 (100%), 430 (M ϩ Hϩ, 90); HRMS 430.2123,
C26H28N3O3 (M ϩ Hϩ) requires 430.2131.
Data for 21a: δH (500 MHz, C6D6) 1.19 (2H, br s, NH2), 2.86
(1H, dd, J 9.7 and 6.6, C(6)H), 3.30 (1H, t, J 7.4, C(4)Hendo),
3.69 (1H, d, J 13.4, NCHHPh), 3.76 (1H, d, J 8.8, C(7)H), 3.84
(1H, dd, J 13.1 and 6.5, C(5)H), 3.89–3.92 (1H, m, C(4)Hexo),
4.06 (1H, d, J 13.3, NCHHPh), 4.15 (1H, d, J 10.6, OCHHPh),
4.20 (1H, d, J 10.6, OCHHPh), 6.47 (1H, s, C(2)H), 6.93–7.19
(11H, m, ArCH), 7.33 (2H, d, J 7.1, ArCH), 7.55 (2H, d, J 7.4,
ArCH).
Data for 21b: δH (500 MHz, C6D6) 1.19 (2H, br s, NH2), 2.86
(1H, dd, J 9.7 and 6.6, C(6)H), 3.30 (1H, t, J 7.4, C(4)Hendo),
3.69 (1H, d, J 13.4, NCHHPh), 3.76 (1H, d, J 8.8, C(7)H), 3.84
(1H, dd, J 13.1 and 6.5, C(5)H), 3.89–3.92 (1H, m, C(4)Hexo),
4.06 (1H, d, J 13.3, NCHHPh), 4.15 (1H, d, J 10.6, OCHHPh),
4.20 (1H, d, J 10.6, OCHHPh), 6.60 (1H, s, C(2)H), 6.93–7.19
(11H, m, ArCH), 7.33 (2H, d, J 7.1, ArCH), 7.67 (2H, d, J 7.4,
ArCH); δC (100.7 MHz, C6D6) 58.49 (C-5), 58.85 (C-7), 62.17
(NCH2Ph), 71.96 (C-4), 77.02 (OCH2Ph), 77.11 (C-6), 87.69
(C-2), 126.83, 128.18, 128.29, 128.53, 128.75, 128.78, 128.93,
128.99, 129.57 and 130.51 (ArCH), 137.31, 138.02 and 139.57
(3 × ArC), 176.00 (CO).
(2R,5S,6S,7S)-6-O,N-Dibenzylhydroxyamino-7-hydrazino-8-
oxo-2-phenyl-3-oxa-1-azabicyclo[3.3.0]octane 20a, (2R,5S,6S,-
7R)-6-O,N-dibenzylhydroxyamino-7-hydrazino-8-oxo-2-phenyl-
3-oxa-1-azabicyclo[3.3.0]octane 20b, and (2R,5S,6S,7S)-7-
amino-6-O,N-dibenzylhydroxyamino-8-oxo-2-phenyl-3-oxa-1-
azabicyclo[3.3.0]octane 21a and (2R,5S,6S,7R)-7-amino-6-O,N-
dibenzylhydroxyamino-8-oxo-2-phenyl-3-oxa-1-azabicyclo-
[3.3.0]octane 21b
Reaction 1: following the general method for hydrogenolysis,
Pd/C (632 mg, 10%) was reacted with compound 15b (632 mg,
0.89 mmol) dissolved in EtOAc (30 ml) and H2 (4 bar) for 48 h.
Purification by flash column chromatography (1 : 1 petrol–
EtOAc and then EtOAc as eluent) gave the two products 20 and
21. Compound 21 was obtained as a yellow gum (29 mg, 8%)
and as a mixture of inseparable diastereomers in a ratio of 21a :
21b = 8 : 1, along with compound 20 as a yellow gum (205 mg,
52%) and as a mixture of inseparable diastereomers in a ratio of
20a : 20b = 8 : 1.
Epimerisation of lactam 20a, b. To a solution of adduct 20a, b
(30 mg, 0.07 mmol) dissolved in C6D6 (0.5 ml) was added
D2O (0.5 ml). The mixture was vigorously shaken for 30 s
and allowed to stand for 24 h. On completion, the organic
1
layer was decanted. H NMR analysis showed a change in the
diastereomeric ratio of compound 20 from 20a : 20b = 8 : 1 to
20a : 20b = 2 : 1.
Reaction 2: following the same general method, Pd/C
(132 mg, 10%) was reacted with compound 15b (132 mg, 0.19
mmol), dissolved in EtOAc (15 ml), and H2 (4 bar) for 7 days.
Purification by flash column chromatography (1 : 1 petrol–
EtOAc and then EtOAc as eluent) gave the two isolated prod-
ucts 20 and 21. Compound 20 was obtained as a yellow gum
(30 mg, 38%) and as a mixture of inseparable diastereomers in
a ratio of 20a : 20b = 8.5 : 1, with compound 21 as a yellow gum
(51 mg, 62%) and as a mixture of inseparable diastereomers in a
ratio of 21a : 21b = 8 : 1.
Attempted epimerisation of lactam 21a, b. To a solution of
adduct 21a, b (25 mg, 0.06 mmol) dissolved in C6D6 (0.5 ml)
was added D2O (0.5 ml). The mixture was vigorously shaken for
30 s and allowed to stand for 24 h. On completion, the organic
layer was decanted. 1H NMR analysis showed that there was no
change observed in the diastereomeric ratio of compound 21a,
b (21a : 21b = 8 : 1).
Acknowledgements
Data for 20: Rf 0.23 (1 : 2 petrol–EtOAc); νmax(film)/cmϪ1
3356 (w), 3283 (w), 3031 (m), 2925 (m), 2878 (m), 1707 (s), 1359
(m); m/z (APCI) 445 (M ϩ Hϩ, 100%); HRMS 445.2236,
C26H29N4O3 (M ϩ Hϩ) requires 445.2240.
We thank EPSRC and Merck Sharp and Dohme for funding
of a studentship to PWHC, and we wish to gratefully acknow-
ledge the use of the EPSRC Chemical Database Service
at Daresbury36 and the EPSRC National Mass Spectrometry
Service Centre at Swansea.
Data for 20a: δH (500 MHz, C6D6) 3.24 (2H, br s, NH2), 3.52
(1H, t, J 7.5, C(4)Hendo), 3.75 (1H, dd, J 8.7 and 5.6, C(6)H),
3.80–4.07 (4H, m, NCHHPh, C(7)H, C(5)H, C(4)Hexo), 4.20–
4.26 (2H, m, NCHHPh and OCHHPh), 4.30 (1H, d, J 10.7,
OCHHPh), 6.50 (1H, s, C(2)H), 6.88–7.28 (11H, m, ArCH),
7.30–7.43 (2H, m, ArCH), 7.47–7.71 (2H, m, ArCH); δC (100.7
MHz, C6D6) 59.25 (C-5), 61.87 (NCH2Ph), 62.56 (C-7), 68.90
(C-6), 71.77 (C-4), 77.04 (OCH2Ph), 87.47 (C-2), 126.79,
126.84, 127.96, 128.19, 128.29, 128.44, 128.53, 128.75, 128.80,
128.91, 128.96, 129.46, 130.49 and 130.63 (ArCH), 137.25,
137.54 and 138.33 (3 × ArC), 174.70 (CO).
Data for 20b: δH (500 MHz, C6D6) 2.25 (1H, dd, J 15.9
and 8.1, C(7)H), 2.59–2.77 (1H, br m, NH), 2.93 (1H, ddd,
J 14.1, 8.2 and 5.9, C(6)H), 3.24 (2H, br s, NH2), 3.31 (1H, d,
J 13.0, NCHHPh), 3.44 (1H, d, J 13.0, NCHHPh), 3.52 (1H, t,
J 7.5, C(4)Hendo), 3.89–3.97 (1H, m, C(4)Hexo), 3.89–4.07 (1H,
m, C(5)H), 4.10 (1H, d, J 10.5, OCHHPh), 4.15 (1H, d, J 10.4,
OCHHPh), 6.55 (1H, s, C(2)H), 6.88–7.28 (11H, m, ArCH),
7.30–7.7.43 (2H, m, ArCH), 7.47–7.71 (2H, m, ArCH);
δC (100.7 MHz, C6D6) 59.25 (C-5), 61.66 (NCH2Ph), 62.56
(C-7), 67.80 (C-6), 71.10 (C-4), 76.85 (OCH2Ph), 87.71 (C-2),
126.79, 126.84, 127.96, 128.19, 128.29, 128.44, 128.53, 128.75,
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