Concise synthesis of bicyclic aminals and their evaluation as precursors to the sarain core

Article abstract of DOI:10.1039/b806031b

A number of bicyclic aminals have been prepared in a stereospecific manner as potential precursors to the core structure of the sarain alkaloids. Rearrangement of these aminals to new diazabicyclic and diazatricyclic systems has been observed under various conditions. The Royal Society of Chemistry.

Full text of DOI:10.1039/b806031b

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Concise synthesis of bicyclic aminals and their evaluation as precursors
to the sarain core
Anne J. Price Mortimer, Pui Shan Pang, Abil E. Aliev, Derek A. Tocher and Michael J. Porter*
Received 10th April 2008, Accepted 16th May 2008
First published as an Advance Article on the web 19th June 2008
DOI: 10.1039/b806031b
A number of bicyclic aminals have been prepared in a stereospecific manner as potential precursors to
the core structure of the sarain alkaloids. Rearrangement of these aminals to new diazabicyclic and
diazatricyclic systems has been observed under various conditions.
Introduction
Sarains A (1), B (2) and C (3) (Fig. 1) are alkaloids with an
unprecedented polycyclic structure which were isolated from a
Bay of Naples sponge, Reniera sarai, in the mid 1980s.1 Common
to the three alkaloids is a diazatricyclic core, which incorporates
an unusual “proximity effect” between a tertiary amine and an
aldehyde.
Scheme 1 Retrosynthesis of the sarain core.
Recognising that 8 is not only an enol ether but also an enamine, we
Fig. 1 The sarain alkaloids.
can envisage its preparation through intramolecular condensation
of a secondary amine with an aldehyde in an intermediate such as
9; this would in turn arise through protonation and ring-opening
of bicyclic aminal 10.
As both potential routes involve bicyclic aminals bearing a
substituent on the endo-face, the initial task was to develop a
method for the synthesis of such compounds.4
The sarains have attracted significant attention as synthetic
targets; five groups have reported syntheses of the core structure,2,3
and a total synthesis of sarain A has been reported by Overman
et al.3
Our projected approaches to the core of the sarain alkaloids are
outlined in Scheme 1. The tricyclic target 4 should be obtainable
by a transannular cyclisation of zwitterion 5; this, in turn would
arise from heterolytic C–N bond cleavage in an ammonium ylid,
6 (alternatively, a homolytic mechanism, proceeding through an
intermediate diradical, could be envisaged for the conversion of 6
to 4). Ammonium ylid 6 would be obtained through the reaction
of a metal carbenoid, derived from diazoketone 7, with the more
nucleophilic of the two nitrogen atoms of the aminal moiety.
A related approach would be to prepare the tricycle 4 by
cyclisation of the silyl enol ether moiety of 8 onto the iminium ion.
Results and discussion
Synthesis of bicyclic aminals
The route adopted for the establishment of the correct relative
stereochemistry in 7 and 10 was based on the Claisen rearrange-
ment of N,O- or N,S-ketene acetals derived from pyrrolidin-2-one.
While the use of an N,O-ketene acetal, as described by Stevenson
et al.,5 gave the desired product with good stereoselectivity,4 we
were unable to obtain high yields and thus chose to explore instead
the use of N,S-ketene acetals.6
Department of Chemistry, University College London, Christopher Ingold
Building, 20 Gordon Street, London, UK WC1H 0AJ. E-mail: m.j.porter@
ucl.ac.uk; Fax: +44 20 7679 7463; Tel: +44 20 7679 4710
1-Benzylpyrrolidine-2-thione 117 was alkylated with 4-(tert-
butyldimethylsilyloxy)crotyl bromide 128 to afford the salt 13 as
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=
Scheme 2 Preparation of bicyclic aminals. (a) (E)-TBSOCH2CH CHCH2Br (12), CH2Cl2, 3 h then Et3N, CH2Cl2, 16 h, 22% 15 + 22% 16; (b)
(E)-HOCH2CH CHCH2Br (18), MeCN, 3 d then Et3N, 40 ◦C, 2 h, 67%; (c) TBAF, THF, 3 d, 84% 17; (d) p-O2NC6H4COCl, pyridine, 82%; (e) MeI,
=
K2CO3, THF, H2O, 69% 20 + 9% 21; (f) MsCl, Et3N, CH2Cl2, 0 ◦C, 99%; (g) NaN3, DMSO, 60 ◦C, 83%; (h) NaN3, DMSO, 60 ◦C, 75%; (i) Bu3P, THF
then LiAlH4, 77% 23 after alumina column; (j) TsCl, i-Pr2NEt, CH2Cl2 then scavenge with polymer-bound tris(2-aminoethyl)amine, 77% 25.
a ca. 2 : 1 mixture with its desilylated analogue 14 (Scheme 2).
Upon treatment of this mixture with triethylamine, deprotonation,
thia-Claisen rearrangement and further partial deprotection took
place to give thiolactams 15 and 16, each in 22% yield (see below
for confirmation of the stereochemical assignment). Attempts to
convert 15 into 16 by deprotection with tetra-n-butylammonium
fluoride (TBAF) were unsuccessful as epimerisation also took
place, leading to a 1 : 4.7 mixture of 16 and its diastereomer
17, from which 17 could be isolated in 84% yield. The same 1 :
4.7 mixture was obtained when pure 16 was treated with TBAF,
indicating that it was indeed the basic fluoride ion that was causing
the loss of stereochemical integrity. The fact that 15 and 16 have
the same relative stereochemistry, as shown, was proved by the
reaction of 16 with tert-butyldimethylsilyl chloride to afford 15.
As the tert-butyldimethylsilyl group had proven to be labile
under the alkylation and deprotonation conditions, we decided to
dispense with the protecting group and to carry out the alkylation–
rearrangement using the free alcohol 18.9
The stereochemistry of thiolactam 16 was confirmed by X-
ray crystallography of its p-nitrobenzoate 19,† which showed the
relative configuration to be, as expected, that arising from a chair
transition state in the thia-Claisen step (Fig. 2).
Fig. 2 Thermal ellipsoid plot of 19. Ellipsoids are drawn at 50%
probability level and the H atoms have an arbitrary radius.
Hydrolysis of thiolactam 16 to the corresponding lactam 20 was
effected with methyl iodide and potassium carbonate in aqueous
tetrahydrofuran; the expected alcohol product was accompanied
by a small amount of iodide 21. Both compounds were then
converted to azide 22.
Cyclisation of azide 22 to a bicyclic aminal was carried out using
the tri-n-butylphosphine–lithium aluminium hydride protocol
previously developed within the group.4 Analysis of the crude
Following extensive experimentation, it was found that the
optimal conditions for the preparation of 16 consisted of stirring
a concentrated solution of bromide 18 and thiolactam 11 in
acetonitrile for 3 d, before dilution with further acetonitrile,
heating to 40 ◦C, and addition of triethylamine. Under these
conditions, 16 and 17 were produced in a >50 : 1 ratio (determined
1
from H NMR of the crude reaction mixture), and 16 could be
isolated in 67% yield. If the rearrangement was carried out at a
higher temperature, a less diastereoselective reaction, with more
side products, was observed.
† CCDC reference number 681439. For crystallographic data in CIF or
other electronic format see DOI: 10.1039/b806031b
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Table 1 NMR assignment of stereochemistry. The predicted values are
reaction mixture indicated that the stereochemical integrity of
the azide had been maintained, and that aminal 23 was present
in >98% de. However, following chromatography on silica gel,
the isolated product was an inseparable 1 : 3 mixture of the
desired endo-isomer 23 and exo-isomer 24, formed through acid-
catalysed ring-opening and enamine formation, followed by re-
protonation and cyclisation.10 This undesired stereoisomerisation
process could be suppressed by conducting chromatography on
basic alumina, allowing isolation of aminal 23 in 77% yield.
Tosylation of the secondary amine of 23 afforded sulfonamide
25, which showed an even greater tendency to stereoisomerisation
than 23; in this case, chromatography even on basic alumina gave
a product with substantial contamination by the undesired exo-
stereoisomer 26 (25 : 26 = 3.4 : 1). Pure 25 could be obtained
only by avoiding chromatography entirely, and instead using
a scavenger resin to effect preliminary purification; thus addi-
tion of polymer-bound tris(2-aminoethyl)amine to the reaction
mixture removed excess tosyl chloride, and 25 was obtained by
crystallisation.11
3
for the B3LYP/6-31G(d) optimised geometries. Vicinal JHH couplings
were predicted using a Karplus-type equation,15 accounting for the
3
dependence of JHH on both the dihedral angle and the substituent
electronegativities
Coupling
constants/Hz
NOE ratio Dihedral angles/◦
ꢀ
g1→5/g1→6 H6CCH7 H6CCH7 J6,7
J6,7
ꢀ
Predicted for 25 4.3
Predicted for 26 25.7
167
90
46
30
11.6
1.2
11.9
5.8
7.0
6.9
Observed
4.5
The relative stereochemistry of 25 was confirmed by a detailed
analysis of 1H-1H coupling constants and nuclear Overhauser
enhancements (NOE) in conjunction with molecular mechanics
calculations using the MMX force field12 followed by DFT
calculations using the B3LYP/6-31G(d) level of theory.13 Com-
putational studies allowed prediction of the NOE ratios, dihedral
angles and coupling constants for both the endo- and exo-
stereoisomers depicted in Table 1, and comparison with the
experimental results clearly indicated that the vinyl group had
the desired endo-orientation. In particular, on selective excitation
of proton 1-H the corresponding enhancement ratio for protons
5-H and 6-H (g1→5/g1→6) was found to be 4.5. From the B3LYP/6-
31G(d) optimised geometry, the internuclear distances, r, between
The problems of undesired stereoisomerisation observed in 23
and 25 proved unavoidable in further transformations of these
materials, and no subsequent functionalisation of 25 could be
carried out without substantial isomerisation occurring. Thus a
modification to the strategy was adopted, which would prevent
this unwanted process.
It was decided that a “blocking group” should be installed at the
junction between the two five-membered rings; this would preclude
formation of an enamine and thus stereoisomerisation. While an
ideal blocking group would be readily removable at the end of the
synthesis, initial studies were carried out using a methyl group as
this was felt to be least likely to interfere with the chemistry of
interest.
˚
˚
protons 1–5 and 1–6 in 25 are 2.42 A and 3.09 A, respectively.
Thus using the initial rate approximation,14 which is based
on the r−6 dependence of NOEs, the expected enhancement
ratio is 4.34. This compares well with the measured value
of 4.5.
Hence 1-benzyl-3-methylpyrrolidine-2-thione 27 (prepared by
thionation of the corresponding lactam16 with Lawesson’s
reagent17) was carried through an equivalent synthetic sequence
to 11 (with minor modifications), to afford bicyclic aminal 28
and thence sulfonamide 29 (Scheme 3). As expected, both 28 and
Scheme 3 Preparation of methylated bicycles. (a) 18, MeCN, 4 d; Et3N, 40 ◦C, 6 h, 75%; (b) mCPBA, CH2Cl2, 0 ◦C, 2.5 h, 93%; (c) MsCl, Et3N,
CH2Cl2, 0 ◦C, 1 h; (d) NaN3, DMSO, 60 ◦C, 21 h, 87% (2 steps); (e) Bu3P, THF, rt, 1 h; LiAlH4, 2 h, 75%; (f) TsCl, pyridine, 0 ◦C to rt, 16 h, 87%;
(g) pinacolborane, (Ph3P)3RhCl, THF, rt, 20 h; (h) NaBO3, H2O, 0 ◦C to rt, 5 h, 86% from 29; (i) Dess–Martin periodinane, pyridine, CH2Cl2, 0 ◦C to rt,
16 h, 80%; (j) NaClO2, KH2PO4, 2-methylbut-2-ene, t-BuOH, H2O, 0 ◦C, 3 h, 85%; (k) i-BuOCOCl, Et3N, THF, −10 ◦C, 1 h; TMSCHN2, −10 ◦C to rt,
18 h, <62%; (l) MeMgBr, THF, 0 ◦C to rt, 3 h, 78%; (m) Dess–Martin periodinane, pyridine, CH2Cl2, 0 ◦C to rt, 5 h, 79%; (n) LiHMDS, THF, −78 ◦
then CF3CO2CH2CF3, −78 ◦C to rt.
C
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Scheme 4 Formation of tricycle 42. (a) TBSCN, LiCl, CH2Cl2, rt, 2 d, 88%; (b) DIBAL, toluene, −78 ◦C, 1.5 h, 42%; (c) AcOH, MeOH, rt to 65 ◦C,
46 h, 47%.
29 were stereochemically robust, with chromatography on silica
proving straightforward.
and reduction of the nitrile to aldehyde 38 was carried out with
DIBAL (Scheme 4).
Aldehyde 38 was subjected to a variety of acidic conditions
(acetic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid,
Dowex-50, hydrochloric acid) in a number of solvents (methanol,
dichloromethane, 1,4-dioxane, water). From none of these reac-
tions could any of the desired tricyclic product be isolated or
identified; however, a different tricyclic system 42 could be isolated
in moderate yie◦ld from the reaction of 38 with acetic acid in
methanol at 65 C for an extended period. This product clearly
arises through opening of the aminal system in the undesired
direction—through heterolysis of the C–NTs bond rather than
the C–NBn bond—giving iminium ion 39. Reaction of the
sulfonamide with the aldehyde could then form a six-membered
cyclic enesulfonamide 40, which would react with the iminium
ion to give 41 and, after hydration, the observed tricycle 42.
Alternatively, it may be the enol tautomer of 39 which cyclises
in a Mannich reaction, with subsequent hemiaminal formation by
cyclisation of the sulfonamide onto the product aldehyde.
While it is conceivable that the processes leading to the
formation of 42 are reversible, and that either 42 or the desired
tricycle could be the thermodynamic product of acid-catalysed
rearrangement of 38, we have been unable to identify any
conditions under which a compound corresponding to tricycle
4 is formed.
Attempts to prepare diazoketones
The next task was the conversion of the vinyl group in 29 to either
a diazomethyl ketone or a silyloxyaldehyde in order to test the
chemistry in Scheme 1. While uncatalysed hydroboration of the
alkene proved ineffective, hydroboration with pinacolborane in the
presence of Wilkinson’s catalyst afforded the boronate 30 in good
yield (Scheme 3).18 This boronate could be isolated and oxidised
in a subsequent step, but it proved more convenient to carry out
the oxidation to alcohol 31 without prior isolation of 30. Sodium
perborate was the most effective oxidant for this transformation.19
Further oxidation to aldehyde 32 was effected with Dess–Martin
periodinane,20 and Pinnick oxidation afforded carboxylic acid 33.21
Activation of the carboxylic acid followed by treatment with dia-
zomethane or TMS-diazomethane was then expected to afford the
desired diazomethyl ketone; however, on attempted activation of
33 with oxalyl chloride, isobutyl chloroformate, carbonyl diimida-
zole, DCC–pentafluorophenol or DCC–N-hydroxysuccinimide,
bicyclic lactam 34 was formed. This compound is presumed to
arise from acid-catalysed ring opening of the aminal, cyclisation
of the resulting secondary amine onto the activated carboxylic
acid, and trapping of the N-sulfonyliminium ion with water. All
efforts to avoid the acid-catalysed ring opening by carrying out the
activation in the presence of a base, or by activation of the sodium
or potassium salts of acid 33, were unsuccessful as lactam 34 was
again generated.
Conclusions
A concise route for the stereospecific construction of bicyclic
aminals such as 32 has been developed, using thia-Claisen
rearrangement and reductive cyclisation as key steps. While it
has not yet been possible to convert these aminals to the desired
tricyclic sarain core, other modes of reactivity, generating novel
bicyclic and tricyclic structures, have been observed.
An alternative approach to the synthesis of diazomethyl ketones
is through the detrifluoroacetylating diazo transfer approach
developed by Danheiser et al.22 Conversion of aldehyde 32 to
the methyl ketone 36 was carried out through the intermediacy of
secondary alcohol 35; however, all attempts to convert this ketone
to the desired diketone 37 were unsuccessful.
Experimental
Preparation and rearrangement of an a-silyloxyaldehyde
General procedures
The conversion of bicycle 33 to lactam 34, while not in itself useful,
seemed to indicate that acid-catalysed ring-opening of the bicyclic
aminal framework through cleavage of the C–NBn bond was a very
straightforward process. Hence conversion of a compound such
as 10, through the ring-opened form 9 to enamine 8 (Scheme 1)
was also expected to proceed readily.
In our efforts to synthesise compounds with the structure 10,
we chose to exploit cyanohydrin chemistry. Thus aldehyde 32 was
reacted with tert-butyldimethylsilyl cyanide and lithium chloride
to afford a silylated cyanohydrin as a mixture of diastereomers,23
All reactions involving non-aqueous reagents were carried out
under argon or nitrogen in flame-dried apparatus. 4-Tolylsulfonyl
chloride was recrystallised from toluene–petrol prior to use.
Ethyldiisopropylamine and triethylamine were distilled from
potassium hydroxide; 2,2,2-trifluoroethyl trifluoroacetate, pyri-
dine and DMSO were distilled from calcium hydride; t-BuOH was
distilled from magnesium. THF, acetonitrile, toluene and CH2Cl2
were dried by passage through alumina columns under nitrogen.
All other chemicals were used as obtained from commercial
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sources. Where petrol is specified, this refers to the fraction that
boils in the range 40–60 ◦C.
Column chromatography was carried out on BDH silica gel
(Kieselgel 60) or Acros basic alumina (50–200 micron), deactivated
to Brockmann Grade III prior to use.
IR spectra were recorded using a SHIMADZU FT-IR 8700
spectrometer. NMR spectra were recorded on Bruker AMX-300,
Bruker AMX-400 or Bruker AVANCE-500 spectrometers. Proton
and 13C chemical shifts are reported in parts per million (ppm) and
are referenced to the residual solvent signal. Peaks were assigned
with the aid of COSY, DEPT-135, HMQC and HMBC analysis
where applicable. Proton–proton coupling constants are reported
in Hz.
petrol 1 : 4) afforded the title compound 16 as a pale yellow oil
(2.14 g, 67%); mmax/cm−1 (film) 3408br (OH), 2924, 2877 (CH),
1504, 1454, 1078, 1030; dH (500 MHz; CDCl3) 1.88 (1H, m)
and 2.18 (1H, m, NCH2CH2), 2.68 (1H, br s, OH), 3.02 (1H,
=
=
m, CH2 CHCH), 3.34 (1H, m, CHC S), 3.41–3.54 (2H, m,
CH2CH2N), 3.72 (1H, m) and 3.86 (1H, m, CH2OH), 4.90 (1H, d,
J 14.3) and 5.05 (1H, d, J 14.3, NCH2Ph), 5.10 (1H, dd, J 10.3,
=
1.0) and 5.18 (1H, d, J 17.2 CH CH2), 5.64 (1H, ddd, J 17.2, 10.3,
=
8.7, CH CH2), 7.24–7.34 (5H, m, ArH); dC (125 MHz; CDCl3)
=
23.1 (NCH2CH2), 49.3 (CHCH CH2), 51.8 (NCH2Ph), 52.8
(CH2CH2N), 55.1 (CHC S), 62.9 (CH2OH), 118.4 (CH CH2),
128.1, 128.3, 128.8 (aromatic CH), 134.9 (aromatic C), 135.6
(CH CH2), 202.9 (C S); m/z (CI , CH4) 290 ([M + C2H5] ,
22%), 262 (MH+, 100), 244 ([M − OH]+, 32), 191 (25). HRMS
found 262.1260. Calc. for C15H20NOS (MH+) 262.1266.
=
=
+
+
=
=
Melting points were measured on a Reichert-Jung THER-
MOVAR instrument and are uncorrected.
Mass measurements were carried out using VG70-SE or
Thermo MAT 900 instruments. Elemental analyses were deter-
mined on a Perkin Elmer 2400 CHN elemental analyser.
(3RS,2ꢀRS)-1-Benzyl-3-(1-hydroxybut-3-en-2-yl)pyrrolidine-2-
thione 17. A solution of thioamide 16 (50 mg, 0.19 mmol) in THF
(3 mL) was cooled to 0 ◦C and TBAF (1 M in THF, 0.23 mmol,
2.3 mL) was added dropwise. The resulting solution was allowed
to warm to room temperature and stirred for 72 h. Saturated
aqueous NaHCO3 (10 mL) was added and the organic material
extracted with EtOAc (3 × 20 mL). The combined organic extracts
were dried (MgSO4) and concentrated, affording a 4.7 : 1 mixture
of thioamides 17 and 16. Flash chromatography (SiO2; EtOAc–
petrol 1 : 4) afforded the title compound 17 (41 mg, 82%) as a pale
yellow oil; (Found C, 68.6; H, 7.35; N, 5.3. Calc for C15H19NOS
C, 68.9; H, 7.3; N, 5.4%); mmax/cm−1 (film) 3379br (OH), 2924,
2876 (CH), 1512, 1450, 1316; dH (300 MHz; CDCl3) 1.90 (1H, m)
and 2.10 (1H, m, NCH2CH2), 2.39 (1H, br s, OH), 3.13 (1H,
(3RS,2ꢀSR)-1-Benzyl-3-[1-(tert-butyldimethylsilanyloxy)but-3-
en-2-yl]pyrrolidine-2-thione 15. 1-Benzylpyrrolidine-2-thione 117
(102 mg, 0.53 mmol) and bromide 128 (153 mg, 0.58 mmol)
were combined, with the addition of the minimum volume of
CH2Cl2 (0.5 mL) required to give a homogeneous mixture, and the
resulting mixture was stirred at room temperature for 3 h. Further
CH2Cl2 (5 mL) was added, followed by triethylamine (0.11 mL,
0.80 mmol) and the resulting solution was stirred overnight. The
mixture was diluted with further CH2Cl2 (30 mL) and washed
with aqueous citric acid (2% w/v, 2 × 15 mL), dried (MgSO4) and
concentrated. Flash chromatography (SiO2; EtOAc–petrol 3 : 97)
afforded the title compound 15 (44 mg, 22%) as a colourless oil;
=
=
m, CH2 CHCH), 3.31 (1H, m, CHC S), 3.48 (2H, app t, J
7.3, CH2CH2N), 3.66 (1H, dd, J 11.0, 6.9) and 3.88 (1H, dd, J
11.0, 6.1, CH2OH), 4.87 (1H, d, J 14.3, NCHHPh), 5.08–5.21
mmax/cm−1 (film) 2953, 2928, 2856 (CH), 1639 (C C), 1504, 1256
=
=
(C S), 1101, 837; dH (300 MHz; CDCl3) −0.01 (3H, s, CH3Si),
=
0.04 (3H, s, CH3Si), 0.85 (9H, s, C(CH3)3), 2.00–2.19 (2H, m,
(3H, m, CH CH2 and NCHHPh), 5.66 (1H, ddd, J 17.6, 10.1,
=
=
=
NCH2CH2), 3.01 (1H, m, CH2 CHCH), 3.27 (1H, m, CHC S),
3.44 (1H, ddd, J 11.0, 8.5, 6.4) and 3.53 (1H, ddd, J 11.0, 8.6,
6.3 CH2CH2N), 3.74 (1H, dd, J 10.2, 5.4) and 3.87 (1H, dd, J
10.2, 5.8, CH2O), 4.89 (1H, d, J 14.3, NCHHPh), 5.09–5.21 (3H,
7.8, CH CH2), 7.26–7.31 (5H, m, ArH); dC (75 MHz; CDCl3)
=
21.9 (NCH2CH2), 48.3 (CHCH CH2), 51.8 (NCH2Ph), 52.7
(CH2CH2N), 54.8 (CHC S), 63.9 (CH2OH), 118.9 (CH CH2),
128.0, 128.3, 128.8 (aromatic CH), 135.0 (aromatic C), 135.1
(CH CH2), 203.8 (C S); m/z (FAB ) 262 (MH , 100%), 244
([M − OH]+, 20), 228 (21), 207 (21), 191 (44). HRMS found
262.1267. Calc. for C15H20NOS (MH+) 262.1266.
=
=
+
+
=
=
=
m, CH2 CH and NCHHPh), 5.91 (1H, ddd, J 17.3, 10.3, 8.0,
=
CH CH2), 7.29–7.34 (5H, m, ArH); dC (125 MHz; CDCl3) −5.4
(Si(CH3)2), 18.2 (C(CH3)3), 22.9 (NCH2CH2), 25.9 (C(CH3)3),
=
48.7 (CHCH CH2), 51.6 (NCH2Ph), 52.7 (CH2CH2N), 55.8
(3RS,2ꢀSR)-1-Benzyl-3-[1-(4-nitrobenzoyloxy)but-3-en-2-yl]pyr-
rolidine-2-thione 19. To a solution of alcohol 16 (100 mg,
0.38 mmol) in pyridine (1.5 mL) at 0 ◦C was added para-
nitrobenzoyl chloride (142 mg, 0.77 mmol). The resulting mixture
was allowed to warm to room temperature and stirred for 18 h,
then diluted with CH2Cl2 (30 mL). The solution was washed
successively with saturated aqueous CuSO4 (2 × 20 mL), aqueous
HCl (1 M, 20 mL), saturated aqueous NaHCO3 (20 mL) and
brine (20 mL); it was then dried (MgSO4) and concentrated.
Flash chromatography (SiO2; EtOAc–petrol 3 : 17) afforded
the ester 19 (125 mg, 75%) as a yellow solid; mp 113 ◦C (from
=
=
(CHC S), 63.2 (CH2O), 116.8 (CH CH2), 127.9, 128.3, 128.8
=
(aromatic CH), 135.2 (aromatic C), 137.5 (CH CH2), 203.3
+
+
+
=
(C S); m/z (CI , CH4) 376 (MH , 17%), 375 (M , 24), 318 ([M −
tBu]+, 35), 191 (75), 91 (100). HRMS found 376.2131. Calc. for
C21H34NOSiS (MH+) 376.2130.
Further elution (EtOAc–petrol 1 : 1) afforded alcohol 16 (30 mg,
22%).
(3RS,2ꢀSR)-1-Benzyl-3-(1-hydroxybut-3-en-2-yl)pyrrolidine-2-
thione 16. 1-Benzylpyrrolidine-2-thione 117 (2.33 g, 12.2 mmol)
and (E)-4-bromobut-2-en-1-ol 189 (2.03 g, 13.4 mmol) were
dissolved in MeCN (24 mL) and the mixture was stirred for
3 d. Further MeCN (100 mL) was added and the mixture was
warmed to 40 ◦C. Et3N (1.87 mL, 13.4 mmol) was added and
the resulting mixture was stirred at 40 ◦C for 2 h. After cooling to
room temperature, the mixture was diluted with CH2Cl2 (300 mL),
washed with aqueous citric acid (2% w/v, 2 × 100 mL), dried
(MgSO4) and concentrated. Flash chromatography (SiO2; EtOAc–
CH2Cl2–petrol); mmax/cm−1 (KBr disc) 2868 (CH), 1719 (C O),
=
1522 (NO2), 1346 (NO2), 1273; dH (300 MHz; CDCl3) 1.90 (1H,
=
m) and 2.23 (1H, m, NCH2CH2), 3.29 (1H, m, CH2 CHCH),
=
3.41–3.57 (3H, m, CH2CH2N and CHC S), 4.59–4.64 (2H, m,
CH2O), 4.93 (1H, d, J 14.3) and 5.01 (1H, d, J 14.3, NCH2Ph),
=
5.19 (1H, d, J 10.4) and 5.26 (1H, dt, J 17.2, 1.2, CH CH2), 5.87
=
(1H, ddd, J 17.2, 10.4, 8.1, CH CH2), 7.28–7.35 (5H, m, ArH),
This journal is
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8.17–8.29 (4H, m, ArH); dC (75 MHz; CDCl3) 22.7 (NCH2CH2),
91%) as a colourless oil; (Found: C, 59.6; H, 6.7; N, 4.3. Calc. for
45.5 (CH2 CHCH), 51.8, 52.4 (CH2CH2N and NCH2Ph), 55.4
C16H21NO4S: C, 59.4; H, 6.5; N, 4.3%); mmax/cm−1 (film) 2936 (CH),
=
=
=
=
(CHC S), 65.3 (CH2O), 118.4 (CH CH2), 123.5 (aromatic CH
1682 (C O), 1356 (SO2), 1175 (SO2), 953; dH (300 MHz; CDCl3)
=
o- to C O), 128.1, 128.3, 128.9 (aromatic CH), 130.8 (aromatic
CH o- to NO2), 134.9, 135.6 (aromatic C), 135.7 (CH CH2),
150.6 (aromatic C), 164.6 (C O), 201.9 (C S); m/z (EI) 410
(M+, 7%), 244 (68), 243 (77), 242 (65), 241 (67), 167 (32), 152 (48),
150 (62), 91 (100). HRMS found 410.1311. Calc. for C22H22N2O4S
(M+) 410.1300.
1.82 (1H, dq, J 13.0, 8.4) and 2.10 (1H, m, NCH2CH2), 2.73–2.89
=
=
=
(2H, m, CH2 CHCH and CHC O), 3.04 (3H, s, SCH3), 3.15–
3.27 (2H, m, CH2CH2N), 4.38 (1H, d, J 14.6, NCHHPh), 4.43
(1H, m, CHHOMs), 4.46 (1H, d, J 14.6, NCHHPh), 4.67 (1H,
=
=
=
dd, J 9.8, 8.0, CHHOMs), 5.24–5.29 (2H, m, CH CH2), 5.65
=
(1H, ddd, J 17.4, 9.8, 9.1, CH CH2), 7.19–7.36 (5H, m, ArH); dC
=
A single crystal suitable for X-ray diffraction was obtained by
slow diffusion of petrol into an EtOAc solution of 19.†
(75 MHz; CDCl3) 21.9 (NCH2CH2), 37.2 (SCH3), 41.3 (CHC O),
45.1 (NCH2CH2), 45.5 (CH2 CHCH), 46.7 (NCH2Ph), 70.6
(CH2OMs), 120.8 (CH CH2), 127.7, 128.1, 128.7 (aromatic CH),
133.3 (CH CH2), 136.3 (aromatic C), 174.1 (C O); m/z (CI ,
CH4) 323 (MH+, 35%), 244 (22), 228 ([M − OMs]+, 51), 174 (100),
118 (13).
=
=
(3RS,2ꢀSR)-1-Benzyl-3-(1-hydroxybut-3-en-2-yl)pyrrolidin-2-
one 20 and (3RS,2ꢀSR)-1-benzyl-3-(1-iodobut-3-en-2-yl)pyrrolidin-
2-one 21. To a stirred solution of thioamide 16 (1.50 g,
5.75 mmol) in THF (50 mL) were added water (10 mL), potassium
carbonate (1.59 g, 11.5 mmol) and MeI (1.78 mL, 28.8 mmol) and
the resulting mixture was stirred at room temperature for 1 week.
The reaction mixture was diluted with CH2Cl2 (200 mL) and
washed with water (2 × 100 mL), dried (MgSO4) and concentrated.
Purification by flash chromatography (SiO2; EtOAc–petrol 1 : 1)
afforded the iodide 21 (185 mg, 9%) as a yellow oil; (Found C,
50.9; H, 5.3; N, 3.8. Calc. for C15H18INO: C 50.7, H 5.1, N 3.9%);
+
=
=
To a solution of this mesylate (130 mg, 0.40 mmol) in DMSO
(1.5 mL) was added sodium azide (78 mg, 1.21 mmol) and the
resulting mixture was heated to 60 ◦C for 2.5 h. The solution
was allowed to cool to room temperature and water (15 mL)
was added. The organic material was extracted with EtOAc (3 ×
30 mL). The combined organic extracts were dried (MgSO4) and
concentrated. Flash chromatography (SiO2; EtOAc–petrol 1 : 4)
afforded the azide 22 (77 mg, 71%) as a colourless oil; (Found:
C, 66.4; H, 6.7; N, 20.4. Calc. for C15H18N4O: C, 66.6; H, 6.7; N,
mmax/cm−1 (film) 2945 (CH), 1682br (C O), 1433br; dH (500 MHz;
=
CDCl3) 1.75 (1H, m) and 2.08 (1H, m, NCH2CH2), 2.56 (1H,
20.7%); mmax/cm−1 (film) 2874 (CH), 2097 (N3), 1682 (C O); dH
=
=
=
m, CH2 CHCH), 2.89 (1H, td, J 9.0, 3.3, CHC O), 3.11–3.17
(2H, m, CH2CH2N), 3.41 (1H, dd, J 9.7, 7.1) and 3.72 (1H, dd,
J 9.7, 7.6, CH2I), 4.35 (1H, d, J 14.6) and 4.45 (1H, d, J 14.6,
(300 MHz; CDCl3) 1.79 (1H, dq, J 12.9, 8.4) and 2.09 (1H, m,
=
NCH2CH2), 2.58 (1H, m, CH2 CHCH), 2.75 (1H, td, J 9.0, 3.3,
=
CHC O), 3.12–3.21 (2H, m, CH2CH2N), 3.60 (1H, dd, J 12.2,
=
NCH2Ph), 5.13–5.20 (2H, m, CH CH2), 5.64 (1H, dt, J 17.0,
7.9) and 3.69 (1H, dd, J 12.2, 7.1, CH2N3), 4.36 (1H, d, J 14.6)
=
9.8, CH CH2), 7.18–7.32 (5H, m, ArH); dC (125 MHz; CDCl3)
=
and 4.48 (1H, d, J 14.6, NCH2Ph), 5.20–5.25 (2H, m, CH CH2),
=
9.8 (CH2I), 22.4 (NCH2CH2), 44.6 (CHC O), 44.8 (CH2CH2N),
46.6 (NCH2Ph), 49.1 (CH2 CHCH), 119.3 (CH CH2), 127.5,
128.1, 128.6 (aromatic CH), 136.32 and 136.34 (CH CH2 and
aromatic C), 174.0 (C O); m/z (CI , CH4) 384 ([M + C2H5] ,
6%), 356 (MH+, 88), 228 ([M − I]+, 100), 175 (34). HRMS found
356.0502. Calc. for C15H19INO (MH+) 356.0511.
=
5.71 (1H, ddd, J 17.0, 10.3, 9.1, CH CH2), 7.20–7.35 (5H, m,
=
=
=
ArH); dC (125 MHz; CDCl3) 21.8 (NCH2CH2), 42.5 (CHC O),
44.9 (NCH2CH2), 45.7 (CH2 CHCH), 46.5 (NCH2Ph), 52.8
(CH2N3), 119.3 (CH CH2), 127.5, 128.0, 128.6 (aromatic CH),
135.5 (CH CH2), 136.3 (aromatic C), 174.1 (C O); m/z (FAB )
271 (MH+, 100%), 243 ([MH − N2]+, 5), 228 ([M − N3]+, 7), 215
([M − CH2N3]+, 18).
=
=
+
+
=
=
+
=
=
Further elution afforded alcohol 20 (0.97 g, 69%) as a colourless
oil; mmax/cm−1 (film) 3418br (OH), 2922, 2874 (CH), 1663br (C O);
=
(ii) From iodide 21. To a solution of iodide 21 (237 mg,
0.67 mmol) in DMSO (3 mL) was added sodium azide (130 mg,
2.0 mmol) and the resulting mixture stirred at 60 ◦C for 3 h. The
mixture was allowed to cool to room temperature, water (30 mL)
was added and the organic material extracted with EtOAc (3 ×
40 mL). The combined organic extracts were washed with brine
(80 mL), dried (MgSO4) and concentrated. Flash chromatography
(SiO2; EtOAc–petrol 15 : 85) afforded the azide 22 as a colourless
oil (135 mg, 75%).
dH (300 MHz; CDCl3) 1.87 (1H, dq, J 12.9, 8.6) and 2.10 (1H,
=
m, NCH2CH2), 2.47 (1H, m, CH2 CHCH), 2.86 (1H, td, J 9.1,
=
3.1, CHC O), 3.18–3.23 (2H, m, CH2CH2N), 3.76–3.93 (2H,
m, CH2OH), 4.35 (1H, br s, OH), 4.39 (1H, d, J 14.6) and
=
4.49 (1H, d, J 14.6, NCH2Ph), 5.13–5.21 (2H, m, CH CH2),
=
5.85 (1H, ddd, J 16.9, 10.5, 9.4, CH CH2), 7.19–7.36 (5H, m,
=
ArH); dC (75 MHz; CDCl3) 22.2 (NCH2CH2), 45.3 (CHC O),
45.6, 47.0 (CH2CH2N and NCH2Ph), 48.0 (CH2 CHCH), 65.9
(CH2O), 118.9 (CH CH2), 127.7, 128.1, 128.7 (aromatic CH),
135.3 (CH CH2), 136.1 (aromatic C), 175.0 (C O); m/z (FAB )
=
=
+
=
=
(1RS,5RS,6SR)-2-Benzyl-6-vinyl-2,8-diazabicyclo[3.3.0]octane
23. To a solution of azide 22 (100 mg, 0.37 mmol) in THF
(3 mL) was added tributylphosphine (0.11 mL, 0.44 mmol) and
the resulting mixture was stirred at room temperature for 1 h.
Lithium aluminium hydride (1 M in THF, 0.22 mL, 0.22 mmol)
was added dropwise and the resulting mixture was stirred at room
temperature for a further 40 min. Aqueous sodium potassium
tartrate solution (0.5 M, 10 mL) was added and the mixture
was stirred for a further 1 h. Brine (10 mL) was added and
the organic material extracted with EtOAc (3 × 15 mL). The
combined organic extracts were washed with water (25 mL), brine
(25 mL), dried (MgSO4) and concentrated. Flash chromatography
246 (MH+, 100%), 228 ([M − OH]+, 7), 154 (13).
(3RS,2ꢀSR)-3-(1-Azidobut-3-en-2-yl)-1-benzylpyrrolidin-2-one
22. (i) From alcohol 20. To a solution of alcohol 20 (108 mg,
0.44 mmol) in CH2Cl2 (2 mL) at 0 ◦C were added Et3N (0.122 mL,
8.8 mmol) and methanesulfonyl chloride (0.068 mL, 8.8 mmol)
dropwise. The resulting solution was stirred at 0 ◦C for 3 h, then
water (10 mL) was added. The organic material was extracted
with CH2Cl2 (3 × 20 mL). The combined organic extracts
were dried (MgSO4) and concentrated. Flash chromatography
(SiO2; EtOAc–petrol 1 : 2) afforded (3RS,2ꢀSR)-1-benzyl-3-
[1-(methanesulfonyloxy)but-3-en-2-yl]pyrrolidin-2-one (130 mg,
2946 | Org. Biomol. Chem., 2008, 6, 2941–2951
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(grade III basic Al2O3; EtOAc–petrol 1 : 19) afforded the bicycle
petrol 2 : 3, removed the polar impurities. Further purification
by flash chromatography (SiO2; EtOAc–petrol 1 : 19 → 1 :
9) provided thioamide 27 (16.0 g, 91%) as a pale yellow oil;
23 (65 mg, 77%, 97% de) as a colourless oil; mmax/cm−1 (film)
=
3298br (NH), 2963, 2928, 2866, 2793 (CH), 1639 (C C), 1450,
914, 698; dH (500 MHz; CDCl3) 1.59–1.68 (2H, m, BnNCH2CH2),
1.89 (1H, br s, NH), 2.31 (1H, app q, J 8.0, NCHHCH2), 2.61
mmax/cm−1 (film) 2966, 2927, 2872 (CH), 1452, 1232 (C S); dH
=
(400 MHz; CDCl3) 1.39 (3H, d, J 7.0, CH3), 1.62 (1H, m) and 2.27
(1H, m, BnNCH2CH2), 2.95 (1H, m, CHMe), 3.40–3.55 (2H, m,
BnNCH2), 4.95 (1H, d, J 14.5) and 5.04 (1H, d, J 14.5, NCH2Ph),
7.24–7.38 (5H, m, ArH); dC (75 MHz; CDCl3) 19.5 (CH3), 28.3
(BnNCH2CH2), 48.9 (CHMe), 51.8 and 51.9 (PhCH2NCH2),
128.0, 128.2, 128.8 (aromatic CH), 135.2 (aromatic C), 206.7
=
(1H, m, CHCH CH2), 2.68 (1H, app quintet, J 8.1, NCHNCH),
2.76–2.80 (2H, m, BnNCHHCH2 and NHCHH), 2.87 (1H, dd,
J 10.2, 6.4, NHCHH), 3.65 (1H, d, J 13.0) and 3.84 (1H, d, J
13.0, NCH2Ph), 4.14 (1H, d, J 7.0, NCHN), 5.02–5.06 (2H, m,
=
=
CH CH2), 5.83 (1H, ddd, J 17.6, 10.2, 7.1, CH CH2), 7.20–
7.32 (5H, m, ArH); dC (125 MHz; CDCl3) 24.7 (NCH2CH2),
+
+
+
=
(C S); m/z (CI ) 234 ([M + C2H5] , 23%), 206 (MH , 100).
45.7 (NCHNCH), 47.8 (CHCH CH2), 49.0 (NHCH2), 52.4
HRMS found 206.1005. Calc. for C12H16NS (MH+) 206.1003.
=
=
(BnNCH2), 57.5 (NCH2Ph), 83.6 (NCHN), 115.9 (CH CH2),
(1RS,5RS,6SR)-2-Benzyl-5-methyl-6-vinyl-2,8-diazabicyclo-
[3.3.0]octane 28.
=
126.8, 128.2, 128.9 (aromatic CH), 136.6 (CH CH2), 139.4
(aromatic C); m/z (EI+) 228 (M+, 48%), 198 (50), 158 (17), 108
(50), 91 (100). HRMS found 228.1424. Calc. for C15H20N2 (MH+)
228.1626.
(3RS,2ꢀSR)-1-Benzyl-3-(1-hydroxybut-3-en-2-yl)-3-methylpy-
rrolidine-2-thione. A solution of 1-benzyl-3-methylpyrrolidine-2-
thione 27 (13.6 g, 66.4 mmol) and (E)-4-bromobut-2-en-1-ol 189
(11.2 g, 74.3 mmol) in MeCN (10 mL) was stirred at room
temperature for 4 d. After dilution with further MeCN (350 mL),
the mixture was heated to 40 ◦C then Et3N (10.2 mL, 73.1 mmol)
was added. After 6 h, the mixture was cooled to room temperature,
diluted with CH2Cl2 (750 mL) and washed with aqueous citric acid
(10% w/v, 2 × 150 mL) and brine (150 mL), and dried (MgSO4).
Concentration and purification by flash chromatography (SiO2;
EtOAc–petrol 1 : 9 → 3 : 7) afforded the title thiolactam (13.7 g,
75%) as a pale yellow solid; mp 49–50 ◦C; (Found C, 69.6; H,
7.9; N, 5.0. Calc. for C16H21NOS: C, 69.8; H, 7.7; N, 5.1%);
mmax/cm−1 (KBr disc) 3337br (OH), 2872 (CH), 1504, 1448, 1232
(1RS,4SR,5RS)-8-Benzyl-2-(4-tolylsulfonyl)-4-vinyl-2,8-diaza-
bicyclo[3.3.0]octane 25. To a solution of amine 23 (261 mg,
1.14 mmol) in CH2Cl2 (8 mL) was added ethyldiisopropylamine
(0.59 mL, 3.42 mmol) and the resulting mixture was cooled to
0
◦C. 4-Tolylsulfonyl chloride (262 mg, 1.37 mmol) was added
and the resulting solution was stirred at 0 ◦C for 1 h, then
allowed to warm to room temperature and stirred for 48 h.
Tris(2-aminoethyl)amine-PS (518 mg, active loading 1.1 mmol g−1,
0.57 mmol) was added and the resulting suspension was stirred
for 3 h. The mixture was diluted with CH2Cl2 (50 mL) and
filtered then washed with saturated aqueous NaHCO3 (20 mL) and
brine (20 mL), dried (MgSO4), and concentrated. Recrystallisation
(MeOH–H2O) afforded the title compound 25 (337 mg, 77%)
as white needles; mp 97–98 ◦C (from MeOH–H2O); (Found C,
69.4; H, 7.0; N, 7.1. Calc. for C22H26N2O2S: C, 69.1; H 6.85; N
=
(C S); dH (400 MHz; CDCl3) 1.23 (3H, s, CH3), 1.74 (1H, ddd, J
12.8, 8.0, 4.7, BnNCH2CHH), 1.90 (1H, br dd, J 6.6, 3.8, OH),
2.16 (1H, ddd, J 12.8, 9.1, 8.0, BnNCH2CHH), 2.93 (1H, dt, J
9.9, 6.6, CHCH2OH), 3.40–3.53 (2H, m, BnNCH2), 3.55–3.70
(2H, m, CH2OH), 4.99 (1H, d, J 14.3) and 5.03 (1H, d, J 14.3,
7.3%); mmax/cm−1 (KBr disc) 2928, 2810 (CH), 1641 (C C), 1333
=
(SO2), 1159 (SO2), 1088, 885, 833, 715; dH (500 MHz; CDCl3)
=
NCH2Ph), 5.24–5.32 (2H, m, HC CH2), 5.64 (1H, dt, J 17.0,
=
1.59–1.65 (2H, m, BnNCH2CH2), 2.18 (1H, m, CHCH CH2),
=
9.9, HC CH2), 7.27–7.37 (5H, m, ArH); dC (100 MHz; CDCl3)
2.43 (3H, s, CH3), 2.49 (1H, dt, J 9.1, 6.8) and 2.62 (1H,
dt, J 9.1, 6.2, BnNCH2CH2), 2.73 (1H, app quintet, J 7.9,
NCHNCH), 3.16 (1H, t, J 12.0) and 3.61 (1H, dd, J 12.1,
6.9, TsNCH2), 4.04 (1H, d, J 13.9) and 4.07 (1H, d, J 13.9,
NCH2Ph), 4.91 (1H, dt, J 17.4, 1.5) and 5.05 (1H, dt, J 10.6, 1.4,
27.1 (CH3), 28.6 (BnNCH2CH2), 51.1 and 52.0 (PhCH2NCH2),
=
54.5 (CHCH2OH), 56.6 (CMe), 63.1 (CH2OH), 120.1 (HC CH2),
128.1, 128.2, 128.9 (aromatic CH), 135.1 (aromatic C), 135.5
+
+
=
=
(HC CH2), 208.6 (C S); m/z (CI ) 304 ([M + C2H5] , 20%),
276 (MH+, 100), 258 (16), 205 (19). HRMS found 276.1424. Calc.
for C16H22NOS (MH+) 276.1422.
=
CH CH2), 5.14 (1H, d, J 6.7, NCHN), 5.64 (1H, ddd, J 17.4,
=
10.6, 6.5, CH CH2), 7.21–7.29 (7H, m) and 7.74–7.76 (2H, m,
(3RS,2ꢀSR)-1-Benzyl-3-(1-hydroxybut-3-en-2-yl)-3-methylpyr-
rolidin-2-one. To a stirred solution of (3RS,2ꢀSR)-1-benzyl-
3-1-hydroxybut-3-en-2-yl-3-methylpyrrolidine-2-thione (13.7 g,
50.0 mmol) in CH2Cl2 (600 mL) at 0 ◦C was added mCPBA (70%
by weight, 27.7 g, 112 mmol) in 3 g portions every 10 min. After
a further 1 h at 0 ◦C, the reaction was allowed to warm to room
temperature, poured into saturated aqueous NaHCO3 (400 mL)
and the layers were separated. The aqueous layer was extracted
with CH2Cl2 (2 × 400 mL), then the combined organic extracts
were dried (MgSO4) and concentrated. Flash chromatography
(SiO2; EtOAc–petrol 4 : 6 → 8 : 2) afforded the title lactam
(12.0 g, 93%) as a white solid; mp 53–55 ◦C; (Found: C, 74.0;
H, 8.2; N, 5.3. Calc. for C16H21NO2: C, 74.1; H, 8.2; N, 5.4%);
ArH); dC (125 MHz; CDCl3) 21.5 (ArCH3), 24.0 (NCH2CH2),
=
45.0 (CHCH CH2), 46.2 (NCHNCH), 50.7 (BnNCH2), 50.9
=
(TsNCH2), 55.5 (NCH2Ph), 84.9 (NCHN), 117.2 (CH CH2),
=
126.7, 127.2, 128.6, 128.8, 129.8 (aromatic CH), 134.6 (CH CH2),
137.2, 139.1, 143.3 (aromatic C); m/z (CI+) 383 (MH+, 3%), 227
([M − Ts]+, 28), 199 (100), 158 (12), 108 (14). HRMS found
383.1788. Calc. for C22H27N2O2S (MH+) 383.1793.
1-Benzyl-3-methylpyrrolidine-2-thione 27. A solution of 1-
benzyl-3-methylpyrrolidin-2-one16 (16.2 g, 85.6 mmol) and Lawes-
son’s reagent17 (20.8 g, 51.4 mmol) in THF (400 mL) was heated
at 40 ◦C for 2 h. After cooling to room temperature, the reaction
mixture was quenched by addition of H2O (250 mL), then stirred
for 10 min. The organic products were extracted with EtOAc
(3 × 200 mL), and the combined extracts were washed with
brine (250 mL), dried (MgSO4) and concentrated. Filtration
through a short column of flash silica, eluting with EtOAc–
mmax/cm−1 (KBr disc) 3371br (OH), 2862 (CH), 1676 (C O), 1496,
=
1450; dH (500 MHz; CDCl3) 1.23 (3H, s, CH3), 1.62 (1H, ddd, J
12.8, 7.9, 3.5) and 2.13 (1H, dt, J 12.8, 8.5, BnNCH2CH2), 2.26
(1H, dt, J 10.0, 4.4, CHCH2OH), 3.10–3.23 (2H, m, BnNCH2),
This journal is
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Org. Biomol. Chem., 2008, 6, 2941–2951 | 2947
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3.62 (1H, dd, J 11.3, 4.4) and 3.90 (1H, ddd, J 11.3, 4.4, 1.6,
CH2OH), 3.97 (1H, br s, OH), 4.40 (1H, d, J 14.7) and 4.45 (1H,
concentrated. Flash chromatography (SiO2; MeOH–CH2Cl2 1 :
49 → 1 : 9) provided the bicycle 28 (1.27 g, 75%) as a pale yellow
oil; dH (400 MHz; CDCl3) 1.15 (3H, s, CH3), 1.21 (1H, ddd, J
12.3, 5.5, 2.0) and 1.82 (1H, ddd, J 12.3, 10.4, 7.1, BnNCH2CH2),
2.31 (1H, dt, J 10.4, 7.4, HNCH2CH), 2.47 (1H, m) and 2.84 (1H,
m, HNCH2), 2.93–3.03 (2H, m, BnNCH2), 3.68 (1H, d, J 13.0,
PhCHH), 3.79 (1H, s, NCHN), 3.92 (1H, d, J 13.0, PhCHH),
=
d, J 14.7, PhCH2), 5.14–5.21 (2H, m, HC CH2), 5.78 (1H, dt,
=
J 17.0, 10.0, HC CH2), 7.16–7.35 (5H, m, ArH); dC (75 MHz;
CDCl3) 22.8 (CH3), 29.7 (BnNCH2CH2), 44.1 (BnNCH2), 46.8
(CMe), 47.0 (NCH2Ph), 53.1 (CHCH2OH), 63.0 (CH2OH), 119.2
=
(HC CH2), 127.7, 128.1, 128.7 (aromatic CH), 136.1 (aromatic
+
+
=
=
=
C), 136.2 (HC CH2), 178.8 (C O); m/z (CI ) 260 (MH , 100%),
242 (32), 229 (17), 190 (45), 91 (28). HRMS found 260.1640. Calc.
for C16H22NO2 (MH+) 260.1645.
5.02–5.10 (2H, m, CH CH2), 5.74 (1H, ddd, J 17.1, 10.7, 7.4,
=
HC CH2), 7.20–7.37 (5H, m, ArH); dC (100 MHz; CDCl3) 25.1
(CH3), 32.0 (BnNCH2CH2), 49.3 (BnNCH2), 51.3 (HNCH2), 51.9
(CMe), 54.4 (HNCH2CH), 57.7 (NCH2Ph), 90.1 (NCHN), 116.9
(3RS,2ꢀSR)-3-(1-Azidobut-3-en-2-yl)-1-benzyl-3-methylpyrroli-
din-2-one. To a stirred solution of (3RS,2ꢀSR)-1-benzyl-3-1-hy-
droxybut-3-en-2-yl-3-methylpyrrolidin-2-one (11.9 g, 45.9 mmol)
in CH2Cl2 (150 mL) at 0 ◦C were added Et3N (12.8 mL, 92 mmol)
and methanesulfonyl chloride (7.1 mL, 92 mmol). After 1 h, the
reaction was allowed to warm to room temperature, diluted with
CH2Cl2 (100 mL), washed successively with H2O (2 × 100 mL)
and brine (2 × 100 mL), then dried (MgSO4). Concentration
provided the desired mesylate (17.7 g) as a colourless oil which was
used without further purification. The oil was dissolved in DMSO
(50 mL), NaN3 (8.9 g, 140 mmol) was added and the mixture was
stirred at 60 ◦C for 21 h. The reaction mixture was cooled to room
temperature, then diluted with H2O (400 mL) and the organic
material extracted with EtOAc (4 × 50 mL). The combined
organic extracts were washed with brine (50 mL), dried (MgSO4)
and concentrated. Purification by flash chromatography (SiO2;
EtOAc–petrol 1 : 9 → 2 : 8) provided the title azide (11.3 g, 87%)
as white crystals; mp 40–42 ◦C; (Found: C, 67.5; H, 7.2; N, 19.4.
Calc. for C16H20N4O: C, 67.6; H, 7.1; N, 19.7%); mmax/cm−1 (KBr
=
=
(HC CH2), 126.9, 128.2, 128.8 (aromatic CH), 135.1 (HC CH2),
139.1 (aromatic C); m/z (CI+) 243 (MH+, 100%), 214 (34), 173 (27).
HRMS found 243.1854. Calc. for C16H23N2 (MH+) 243.1856.
(1RS,4SR,5RS)-8-Benzyl-5-methyl-2-(4-tolylsulfonyl)-4-vinyl-
2,8-diazabicyclo[3.3.0]octane 29. 4-Tolylsulfonyl chloride (2.00 g,
10.5 mmol) was added to a stirred solution of amine 28 (1.27 g,
◦
5.6 mmol) in pyridine (8.5 mL, 105 mmol) at 0 C. The reaction
was slowly allowed to warm to room temperature and stirred
for 16 h. The mixture was diluted with EtOAc (50 mL) then
washed with H2O (20 mL) and saturated aqueous CuSO4 (3 ×
20 mL). The aqueous washes were re-extracted with EtOAc (3 ×
30 mL), and the combined organic extracts washed with brine
(2 × 10 mL) then dried (MgSO4) and concentrated. Purification by
flash chromatography (SiO2; EtOAc–petrol 1 : 9 → 2 : 8) afforded
the sulfonamide 29 (1.81 g, 87%) as a pale yellow solid; (Found:
C, 69.4; H, 7.1; N, 7.0. Calc. for C23H28N2O2S: C, 69.7; H, 7.1;
N, 7.1%); mmax/cm−1 (CHCl3 cast) 2923, 2878 (CH), 1599 (C C),
=
1448, 1348, 1157; dH (400 MHz; CDCl3) 0.96 (3H, s, NCHCCH3),
1.20 (1H, ddd, J 12.8, 6.4, 5.1, BnNCH2CHH), 1.75–1.88 (2H, m,
TsNCH2CH and BnNCH2CHH), 2.43 (3H, s, ArCH3), 2.58–2.72
(2H, m, BnNCH2), 3.23 (1H, t, J 12.0) and 3.66 (1H, dd, J 12.0,
7.1, TsNCH2), 4.05 (2H, s, NCH2Ph), 4.68 (1H, s, NCHN), 4.91
=
disc) 2968, 2893 (CH), 2085 (N3), 1680 (C O), 1497, 1433; dH
(500 MHz; CDCl3) 1.14 (3H, s, CH3), 1.60 (1H, ddd, J 13.1, 7.8,
3.9) and 2.03 (1H, ddd, J 13.1, 8.7, 7.8, BnNCH2CH2), 2.53 (1H,
td, J 9.7, 4.3, CHCH2N3), 3.06–3.16 (2H, m, BnNCH2), 3.30 (1H,
dd, J 12.2, 9.7) and 3.44 (1H, dd, J 12.2, 4.3, CH2N3), 4.40 (1H,
d, J 14.7) and 4.43 (1H, d, J 14.7, NCH2Ph), 5.23–5.28 (2H, m,
=
(1H, d, J 17.4) and 5.06 (1H, d, J 10.5, HC CH2), 5.57 (1H, ddd,
=
J 17.4, 10.5, 7.1, HC CH2), 7.20–7.36 (7H, m, ArH), 7.77 (2H,
=
=
HC CH2), 5.57 (1H, dt, J 17.4, 9.7, HC CH2), 7.14–7.34 (5H,
m, ArH); dC (125 MHz; CDCl3) 23.2 (CH3), 28.1 (BnNCH2CH2),
43.3 (BnNCH2), 45.7 (CMe), 46.8 (NCH2Ph), 50.2 (CHCH2N3),
d, J 8.2, ArH o- to SO2); dC (100 MHz; CDCl3) 21.6 (ArCH3),
24.8 (NCHCCH3), 31.1 (BnNCH2CH2), 50.4 (BnNCH2), 51.7
(TsNCH2CH), 52.0 (TsNCH2), 52.9 (NCHCMe), 55.6 (NCH2Ph),
=
51.6 (CH2N3), 120.2 (HC CH2), 127.6, 128.1, 128.7 (aromatic
=
90.7 (NCHN), 118.0 (HC CH2), 126.7, 127.2, 128.1, 128.7, 129.7
=
=
CH), 135.2 (HC CH2), 136.3 (aromatic C), 177.1 (C O); m/z
(CI+) 285 (MH+, 43%), 257 (67), 242 (100), 228 (35), 188 (18),
152 (22), 117 (21). HRMS found 285.1706. Calc. for C16H21N4O
(MH+) 285.1710.
=
(aromatic CH), 133.8 (HC CH2), 137.2, 139.2, 143.3 (aromatic
C); m/z (CI+) 425 ([M + C2H5]+, 21%), 397 (MH+, 100), 241 (16),
213 (21), 172 (16), 125 (52), 93 (44). HRMS found 397.1950. Calc.
for C23H29N2O2S (MH+) 397.1941.
(1RS,5RS,6SR)-2-Benzyl-5-methyl-6-vinyl-2,8-diazabicyclo-
[3.3.0]octane 28. A solution of (3RS,2’SR)-3-(1-azidobut-3-en-
2-yl)-1-benzyl-3-methylpyrrolidin-2-one (2.00 g, 7.0 mmol) and
tributylphosphine (3.2 mL, 12.7 mmol) in THF (60 mL) was stirred
at room temperature for 1 h then LiAlH4 (0.27 g, 7.0 mmol) was
slowly added. After 1 h, further LiAlH4 (0.27 g, 7.0 mmol) was
added and stirring was continued for a further 1 h. After quenching
by addition of aqueous sodium potassium tartrate (0.5 M, 60 mL)
the mixture was stirred for 30 min. The product was then extracted
with EtOAc (3 × 60 mL), washed with H2O (2 × 60 mL) and
brine (2 × 60 mL), then dried (MgSO4) and concentrated. The
residue was redissolved in CH2Cl2 (20 mL) and the amine product
extracted with 2 M HCl (3 × 20 mL). The combined aqueous
extracts were cooled in an ice bath and basified to pH 11 with
3 M NaOH. The organic material was extracted with EtOAc
(3 × 50 mL), washed with brine (50 mL), dried (MgSO4) and
2-[(1RS,4SR,5RS)-8-Benzyl-5-methyl-2-(4-tolylsulfonyl)-2,8-
diazabicyclo[3.3.0]oct-4-yl]ethanol 31. A solution of alkene 29
(1.75 g, 4.4 mmol) and tris(triphenylphosphine)rhodium(I) chlo-
ride (0.12 g, 0.13 mmol) in THF (40 mL) was degassed by pump-
filling with argon. Pinacolborane (1.9 mL, 13.2 mmol) was added
slowly and the mixture degassed again, then stirred for 20 h.
The reaction was cooled to 0 ◦C and treated successively with
H2O (40 mL) and NaBO3·4H2O (2.42 g, 13.2 mmol), stirred at
0
◦C for 15 min then allowed to warm to room temperature.
After a further 5 h, the product was extracted with EtOAc (3 ×
40 mL) and the combined organic extracts washed with H2O (2 ×
40 mL), brine (2 × 40 mL) and dried (MgSO4). Concentration
and purification by flash chromatography (SiO2; EtOAc–petrol 1 :
4 → 3 : 2) afforded alcohol 31 (1.51 g, 86%) as a pale yellow
oil; mmax/cm−1 (CHCl3 cast) 3449br (OH), 2930, 2876 (CH), 1334,
2948 | Org. Biomol. Chem., 2008, 6, 2941–2951
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1155; dH (500 MHz; CDCl3) 0.92 (3H, s, NCHCCH3), 1.26–1.35
(3H, m, CHHCH2OH, TsNCH2CH, and BnNCH2CHH), 1.51
(1H, m, CHHCH2OH), 1.58 (1H, br s, OH), 1.75 (1H, dt, J 12.6,
7.7, BnNCH2CHH), 2.40 (3H, s, ArCH3), 2.59 (1H, ddd, J 9.0,
7.6, 6.5) and 2.67 (1H, ddd, J 9.0, 7.3, 4.3, BnNCH2), 2.99 (1H,
t, J 12.0, TsNCHH), 3.44–3.55 (2H, m, CH2OH), 3.74 (1H, dd, J
12.0, 6.7, TsNCHH), 3.99 (1H, d, J 13.9) and 4.07 (1H, d, J 13.9,
NCH2Ph), 4.60 (1H, s, NCHN), 7.18–7.32 (7H, m, ArH), 7.75
(2H, d, J 8.2, ArH o- to SO2); dC (125 MHz; CDCl3) 21.5 (ArCH3)
24.5 (NCHCCH3), 30.2 (CH2CH2OH), 30.7 (BnNCH2CH2), 45.2
(TsNCH2CH), 50.4 (BnNCH2), 52.7 (TsNCH2), 52.8 (NCHCMe),
55.8 (NCH2Ph), 61.7 (OCH2), 90.7 (NCHN), 126.7, 127.2, 128.1,
128.8, 129.6 (aromatic CH), 137.5, 139.1, 143.2 (aromatic C); m/z
(ESI+) 453 (MK+, 14%), 437 (MNa+, 14), 415 (MH+, 100). HRMS
found 415.2050. Calc. for C23H31N2O3S (MH+) 415.2051.
Aqueous workup and flash chromatography (SiO2; EtOAc–
petrol 1 : 19 → 1 : 4) prior to addition of the perborate allowed
isolation of the boronate 30 as a white solid; (Found: C, 66.3; H,
7.9; N, 5.3. Calc. for C29H41BN2O4S: C, 66.4; H, 7.9; N, 5.3%); dH
(500 MHz; CDCl3) 0.50 (1H, ddd, J 15.8, 10.3, 5.8) and 0.61 (1H,
ddd, J 15.8, 11.0, 5.8, BCH2), 0.89 (3H, s, NCHCCH3), 1.02 (1H,
m, TsNCH2CH), 1.18 (6H, s) and 1.19 (6H, s, (CH3)2CC(CH3)2),
1.10–1.25 (2H, m, BCH2CH2), 1.33 (1H, m) and 1.76 (1H, dt,
J 12.6, 7.5, BnNCH2CH2), 2.39 (3H, s, ArCH3), 2.58 (1H, m)
and 2.64 (1H, m, BnNCH2), 2.92 (1H, t, J 12.0) and 3.68 (1H,
dd, J 12.0, 6.9, TsNCH2), 4.01 (1H, d, J 14.0) and 4.05 (1H,
d, J 14.0, NCH2Ph), 4.58 (1H, s, NCHN), 7.16–7.32 (7H, m,
ArH), 7.72 (2H, d, J 8.2, ArH o- to SO2); dC (125 MHz; CDCl3)
10.2 (br, BCH2), 21.3 (BCH2CH2), 21.5 (ArCH3), 24.7, 24.8
(NCHCCH3 and (H3C)2CC(CH3)2), 30.5 (BnNCH2CH2), 50.4
(TsNCH2CH), 50.5 (BnNCH2), 52.5 (TsNCH2), 52.8 (NCHCMe),
55.6 (NCH2Ph), 83.1 ((H3C)2CC(CH3)2), 91.4 (NCHN), 126.6,
127.2, 128.8, 129.5 (aromatic CH), 137.4, 139.2, 143.0 (C); m/z
(CI+) 525 (MH+, 69%), 371 (16), 171 (31), 125 (100), 93 (88).
HRMS found 525.2945. Calc. for C29H42BN2O4S (MH+) 525.2958.
(TsNCH2CH), 50.1 (BnNCH2), 52.2 (TsNCH2), 52.4 (NCHCMe),
55.4 (NCH2Ph), 90.1 (NCHN), 126.8, 127.3, 128.1, 128.8, 129.7
=
(aromatic CH), 137.1, 138.8, 143.4 (aromatic C), 199.9 (C O);
m/z (CI+) 413 (MH+, 100%), 257 (17), 229 (20), 157 (27), 91 (67).
HRMS found 413.1895. Calc. for C23H29N2O3S (MH+) 413.1899.
2-[(1RS,4SR,5RS)-8-Benzyl-5-methyl-2-(4-tolylsulfonyl)-2,8-
diazabicyclo[3.3.0]oct-4-yl]ethanoic acid 33. To a solution of
aldehyde 32 (0.62 g, 1.5 mmol) in t-BuOH (10 mL) and H2O
(6 mL) at 0 ◦C was added 2-methyl-2-butene (1.9 mL, 18.1 mmol),
followed by a solution of NaClO2 (0.68 g, 7.6 mmol) and KH2PO4
(1.0 g, 7.6 mmol) in H2O (14 mL). The mixture was stirred at
0
◦C for 3 h then allowed to warm to room temperature. The
reaction was quenched by the addition of aqueous Na2S2O3 (5%
w/v, 16 mL), and then the mixture acidified to pH 6.0 with 1%
aqueous HCl. The organic material was extracted with EtOAc
(3 × 20 mL), then the combined extracts dried (MgSO4) and
concentrated. The brown solid residue was dissolved in EtOAc
(20 mL), then extracted with aqueous NaOH (0.1 M, 3 × 20 mL).
The combined aqueous extracts were acidified to pH 6.0 with
1% aqueous HCl, then extracted with EtOAc (3 × 50 mL). The
combined organic extracts were dried (MgSO4) and concentrated
to afford the acid 33 (0.55 g, 85%) as a peach-coloured foamy
solid; mmax/cm−1 (CHCl3 cast) 3412br (OH), 2928, 2878 (CH), 1719
=
(C O), 1597, 1452, 1346, 1159; dH (500 MHz; CDCl3) 0.84 (3H, s,
NCHCCH3), 1.20 (1H, ddd, J 12.5, 6.2, 4.0, BnNCH2CHH), 1.56
(1H, m, TsNCH2CH), 1.73 (1H, dt, J 12.5, 7.5, BnNCH2CHH),
2.11 (1H, dd, J 16.4, 10.7) and 2.27 (1H, dd, J 16.4, 3.6,
CH2CO2H), 2.39 (3H, s, ArCH3), 2.62 (1H, m) and 2.75 (1H,
ddd, J 9.1, 7.5, 4.0, BnNCH2), 3.06 (1H, t, J 12.2) and 3.93
(1H, dd, J 12.2, 6.9, TsNCH2), 4.03 (1H, d, J 13.8) and 4.09
(1H, d, J 13.8, NCH2Ph), 4.58 (1H, s, NCHN), 7.19–7.35 (7H,
m, ArH), 7.68 (1H, br s, CO2H), 7.76 (2H, d, J 8.2, ArH o- to
SO2); dC (125 MHz; CDCl3) 21.5 (ArCH3), 24.0 (NCHCCH3),
30.6 (BnNCH2CH2), 32.7 (CH2CO2H), 43.7 (TsNCH2CH), 50.1
(BnNCH2), 52.2 (NCHCMe), 52.6 (TsNCH2), 55.3 (NCH2Ph),
89.9 (NCHN), 127.0, 127.3, 128.2, 129.2, 129.8 (aromatic CH),
2-[(1RS,4SR,5RS)-8-Benzyl-5-methyl-2-(4-tolylsulfonyl)-2,8-
diazabicyclo[3.3.0]oct-4-yl]ethanal 32. To a solution of alcohol
31 (1.48 g, 3.6 mmol) in CH2Cl2 (50 mL) at 0 ◦C were added
pyridine (2.9 mL, 36 mmol) and 1,1,1-triacetoxy-1,1-dihydro-1,2-
benziodoxol-3(1H)-one (3.8 g, 8.9 mmol). The reaction mixture
was allowed to warm to room temperature, and after 16 h, was
quenched by addition of saturated aqueous Na2S2O3 (40 mL) and
saturated aqueous NaHCO3 (40 mL). After vigorously stirring
for 1 h, the organic materials were extracted with CH2Cl2 (2 ×
50 mL), washed with saturated aqueous CuSO4 (3 × 40 mL), brine
(40 mL) and then dried (MgSO4) and concentrated. Purification
by flash chromatography (SiO2; EtOAc–petrol 3 : 7) afforded
aldehyde 32 (1.18 g, 80%) as a pale yellow oil; mmax/cm−1 (CHCl3
+
=
136.9, 138.0, 143.5 (aromatic C), 177.0 (C O); m/z (CI ) 429
(MH+, 100%), 273 (24), 186 (39). HRMS found 429.1841. Calc.
for C23H29N2O4S (MH+) 429.1848.
(1RS,7SR)-4-Benzyl-8-hydroxy-7-methyl-9-(4-tolylsulfonyl)-4,9-
diazabicyclo[5.3.0]decan-3-one 34. To a stirred solution of acid
33 (0.11 g, 0.25 mmol) in THF (2 mL) at −10 ◦C were added Et3N
(0.046 mL, 0.33 mmol) and isobutyl chloroformate (0.043 mL,
0.33 mmol). After 1 h, TMSCHN2 (2 M in Et2O, 0.25 mL,
0.50 mmol) was added, and after an additional 2 h, further
TMSCHN2 (2 M in Et2O, 0.25 mL, 0.50 mmol) was added, and
the mixture was allowed to warm to room temperature. After
a further 16 h, the mixture was concentrated and purified by
flash chromatography (SiO2; EtOAc–petrol 1 : 4 → 3 : 2) to
afford slightly impure lactam 34 (0.066 g, <62%) as a white
solid; mmax/cm−1 (KBr disc) 3350br (OH), 2927, 2881 (CH), 1630
=
cast) 2928, 2822 (CH), 1724 (C O), 1599, 1454, 1334, 1155; dH
(500 MHz; CDCl3) 0.87 (3H, s, NCHCCH3), 1.20 (1H, ddd, J
11.0, 6.5, 4.6, BnNCH2CHH), 1.54–1.74 (2H, m, BnNCH2CHH
and TsNCH2CH), 2.22 (1H, ddd, J 17.8, 10.1, 1.0) and 2.39 (1H,
m, CH2CHO), 2.41 (3H, s, ArCH3), 2.60 (1H, m) and 2.68 (1H,
m, BnNCH2), 2.95 (1H, t, J 12.2) and 3.87 (1H, dd, J 12.2, 6.9,
TsNCH2), 4.00 (1H, d, J 13.9) and 4.08 (1H, d, J 13.9, NCH2Ph),
4.57 (1H, s, NCHN), 7.19–7.33 (7H, m, ArH), 7.78 (2H, d, J 8.3,
ArH o- to SO2), 9.64 (CHO); dC (125 MHz; CDCl3) 21.5 (ArCH3),
24.4 (NCHCCH3), 30.9 (BnNCH2CH2), 41.5 (CH2CHO), 41.9
=
(C O), 1342, 1169; dH (500 MHz; CDCl3) 0.83 (1H, dd, J 14.2,
11.5, BnNCH2CHH), 1.04 (3H, s, CH(OH)CCH3), 1.10 (1H,
dd, J 14.2, 6.2, BnNCH2CHH), 2.39 (1H, m, TsNCH2CH),
2.44 (3H, s, ArCH3), 2.50 (1H, dd, J 14.8, 7.2) and 2.77 (1H,
=
d, J 14.8, O CCH2), 2.82 (1H, dd, J 15.6, 6.2, BnNCHH),
2.91 (1H, m, TsNCHH), 3.32 (1H, dd, J 15.6, 11.5, BnNCHH),
3.38 (1H, br s, OH), 3.60 (1H, m, TsNCHH), 3.77 (1H, d, J
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14.7, NCHHPh), 4.80 (1H, s, NCH(OH)), 4.86 (1H, d, J 14.7,
NCHHPh), 7.10–7.35 (7H, m, ArH), 7.74 (2H, d, J 8.1, ArH o- to
SO2); dC (125 MHz; CDCl3) 18.5 (CH(OH)CCH3), 21.6 (ArCH3),
(3H, s, COCH3), 2.11 (1H, dd, J 17.6, 10.5) and 2.34 (1H,
dd, J 17.6, 3.2, CH2COMe), 2.39 (3H, s, ArCH3), 2.58 (1H,
m) and 2.65 (1H, ddd, J 9.0, 7.5, 4.6, BnNCH2), 2.89 (1H,
t, J 12.2) and 3.88 (1H, dd, J 12.2, 6.9, TsNCH2), 4.00 (1H,
d, J 13.8) and 4.08 (1H, d, J 13.8, NCH2Ph), 4.50 (1H, s,
NCHN), 7.18–7.35 (7H, m, ArH), 7.78 (2H, d, J 8.2, ArH o- to
SO2); dC (125 MHz; CDCl3) 21.5 (ArCH3), 24.4 (NCHCCH3),
=
32.6 (BnNCH2CH2), 33.1 (O CCH2), 38.6 (TsNCH2CH), 42.7
(BnNCH2), 46.5 (TsNCHCMe), 49.0 (TsNCH2), 50.4 (NCH2Ph),
90.0 (NCH(OH)), 127.3, 127.6, 128.0, 128.7, 129.8 (aromatic
+
=
CH), 135.5, 136.9, 143.7 (aromatic C), 172.1 (C O); m/z (FAB )
429 (MH+, 5%), 307 (44), 289 (14), 154 (100). HRMS found
429.1846. Calc. for C23H29N2O4S (MH+) 429.1848.
30.1 (O CCH3), 31.0 (BnNCH2CH2), 41.4 (CH2COMe), 42.7
=
(TsNCH2CH), 50.1 (BnNCH2), 52.1 (NCHCMe), 52.6 (TsNCH2),
55.3 (NCH2Ph), 90.2 (NCHN), 126.7, 127.4, 128.1, 128.8, 129.7
3-[(1RS,4SR,5RS)-8-Benzyl-5-methyl-2-(4-tolylsulfonyl)-2,8-
diazabicyclo[3.3.0]oct-4-yl]propan-2-ol 35. To a stirred solution
of aldehyde 32 (0.63 g, 1.5 mmol) in THF (18 mL) at 0 ◦C
was added MeMgBr (1.0 M in THF, 3.1 mL, 3.1 mmol). The
temperature was maintained at 0 ◦C for 15 min then the flask
was stirred at room temperature for 3 h and quenched by
addition of saturated aqueous NH4Cl (20 mL). The product was
extracted into EtOAc (3 × 20 mL), washed with brine (20 mL),
and then dried (MgSO4) and concentrated. Purification by flash
chromatography (SiO2; EtOAc–petrol 3 : 7 → 2 : 3) afforded
a 3 : 2 mixture of diastereoisomeric alcohols 35 (0.51 g, 78%)
as a pale yellow oil; mmax/cm−1 (film) 3449br (OH), 2982, 2877
(CH), 1454, 1336, 1157; dH (500 MHz; CDCl3) 0.89 (1.2H, s)
and 0.91 (1.8H, s, NCHCCH3), 1.04 (1.8H, d, J 6.2) and 1.08
(1.2H, d, J 6.2, CH(OH)CH3), 1.10–1.20 (2H, m, BnNCH2CHH
and TsNCH2CH), 1.20–1.38 (2H, m, CH2CH(OH)), 1.65 (1H,
br s, OH), 1.68–1.77 (1H, m, BnNCH2CHH), 2.40 (3H, s,
ArCH3), 2.56–2.62 (1H, m) and 2.63–2.69 (1H, m, BnNCH2),
2.96 (0.4H, t, J 12.1) and 3.00 (0.6H, t, J 12.1, TsNCHH), 3.56–
3.60 (0.6H, m) and 3.61–3.67 (0.4H, m, CH(OH)), 3.76 (0.4H,
dd, J 12.2, 6.7) and 3.79 (0.6H, dd, J 12.2, 6.7, TsNCHH),
3.98–4.09 (2H, m, NCH2Ph), 4.59 (1H, s, NCHN), 7.18–7.32
(7H, m, ArH),7.75 (1.2H, d, J 8.3) and 7.76 (0.8 H, d, J 8.3,
ArH o- to SO2); dC (125 MHz; CDCl3) 21.5 (ArCH3), 23.9, 24.0
(CH(OH)CH3), 24.3, 24.6 (NCHCCH3), 30.7 (BnNCH2CH2),
36.3, 36.7 (CH2CH(OH)), 43.8, 46.0 (TsNCH2CH), 50.3, 50.4
(BnNCH2), 52.5, 52.8 (NCHCMe), 52.7, 53.2 (TsNCH2), 55.6
(NCH2Ph), 66.2, 67.6 (CH(OH)), 90.3, 90.7 (NCHN), 126.7,
127.0, 127.2, 127.3, 128.1, 128.8, 129.6 (aromatic CH), 137.4,
137.5, 139.1, 143.1, 143.2 (aromatic C); m/z (ESI+) 451 (MNa+,
100%), 429 (83), 258 (56). HRMS found 451.2036. Calc. for
C24H32N2O3SNa (MNa+) 451.2031.
=
(aromatic CH), 137.0, 139.0, 143.3 (aromatic C), 206.5 (C O);
m/z (ESI+) 449 (MNa+, 45%), 427 (MH+, 100), 242 (39). HRMS
found 427.2047. Calc. for C24H31N2O3S (MH+) 427.2055.
3-[(1RS,4SR,5RS)-8-Benzyl-5-methyl-2-(4-tolylsulfonyl)-2,8-
diazabicyclo[3.3.0]oct-4-yl]-2-(tert-butyldimethylsilanyloxy)pro-
panal 38. To a solution of aldehyde 32 (0.32 g, 0.78 mmol) and
TBSCN (0.22 g, 1.6 mmol) in CH2Cl2 (0.5 mL) was added LiCl
(0.3 M solution in CH2Cl2, prepared by sonication for 15 min,
26 lL, 7.8 lmol) and the mixture was stirred for 2 d. The mixture
was diluted with H2O (5 mL) and the organic materials were
extracted with EtOAc (3 × 5 mL), washed with brine (5 mL), dried
(MgSO4) and concentrated. Purification by flash chromatography
(SiO2; EtOAc–petrol 1 : 19 → 3 : 17) afforded a 3 : 2 diastereomeric
mixture of protected cyanohydrins (0.37 g, 88%) as a pale yellow
oil; mmax/cm−1 (CHCl3 cast) 2933 (CH), 2332 (C N), 1599, 1458,
≡
1348, 1159; dH (500 MHz, CDCl3) 0.10, 0.15 and 0.18 (6H, 3
× s, Si(CH3)2), 0.85, 0.90 and 0.91 (12H, 3 × s, NCHCCH3 and
C(CH3)3), 1.14–1.23 (1H, m, BnNCH2CHH), 1.32–1.42 (1H, m,
TsNCH2CH), 1.49–1.62 (1H, m, CHHCHOTBS), 1.63–1.75 (2H,
m, BnNCH2CHH and CHHCHOTBS), 2.39 (3H, s, ArCH3),
2.55–2.62 (1H, m) and 2.64–2.71 (1H, m, BnNCH2), 3.01 (0.4H,
t, J 12.2), 3.04 (0.6H, t, J 12.2) and 3.85–3.93 (1H, m, TsNCH2),
3.98–4.04 (1H, m), 4.08 (0.6H, d, J 14.0) and 4.09 (0.4H, d, J 14.0,
NCH2Ph), 4.28 (0.6H, t, J 6.0) and 4.44 (0.4H, t, J 4.3, CHOTBS),
4.56 (0.6H, s) and 4.57 (0.4H, s, NCHN), 7.19–7.34 (7H, m, ArH),
7.72–7.77 (2H, m, ArH o- to SO2); dC (125 MHz; CDCl3) −5.5,
−5.3, −5.2 (Si(CH3)2), 17.9, 18.0 (CMe3), 21.5 (ArCH3), 24.4
(NCHCCH3), 25.5 (C(CH3)3), 30.9 (BnNCH2CH2), 34.1, 34.7
(CH2CHOTBS), 43.8, 44.2 (TsNCH2CH), 50.1 (BnNCH2), 52.8,
53.0 (NCHCMe), 52.7, 53.5 (TsNCH2), 55.4, 55.5 (NCH2Ph),
≡
61.0, 61.5 (CHOTBS), 89.9 (NCHN), 119.0, 119.4 (C N), 126.7,
3-[(1RS,4SR,5RS)-8-Benzyl-5-methyl-2-(4-tolylsulfonyl)-2,8-
diazabicyclo[3.3.0]oct-4-yl]propan-2-one 36. To a stirred solution
of alcohols 35 (0.46 g, 1.1 mmol) in CH2Cl2 (25 mL) at 0 ◦C
were added pyridine (0.44 mL, 5.4 mmol) and 1,1,1-triacetoxy-
1,1-dihydro-1,2-benziodoxol-3(1H)-one (1.1 g, 2.7 mmol). The
reaction mixture was allowed to warm to room temperature,
and after 5 h was quenched by addition of saturated aqueous
Na2S2O3 (25 mL) and saturated aqueous NaHCO3 (25 mL). After
vigorously stirring for 30 min, the organic materials were extracted
with CH2Cl2 (3 × 30 mL), and the combined extracts were washed
with brine (30 mL), dried (MgSO4) and concentrated. Purification
by flash chromatography (SiO2; EtOAc–petrol 3 : 7 → 4 : 6)
afforded methyl ketone 36 (0.36 g, 79%) as a pale yellow oil;
126.8, 127.1, 127.2, 128.1, 128.8, 129.9 (aromatic CH), 136.9,
137.1, 139.0, 143.4, 143.6 (aromatic C); m/z (FAB+) 576 (MNa+,
93%), 554 (MH+, 78), 381 (100), 176 (58). HRMS found 576.2702.
Calc. for C30H43N3O3SSiNa (MNa+) 576.2692.
To a solution of the silylated cyanohydrin (0.28 g, 0.51 mmol)
in toluene (5 mL) at −78 ◦C was added DIBAL (20 wt% in
toluene, 0.68 mL, 0.82 mmol) dropwise. After stirring for 1.5 h
at −78 ◦C, aqueous sodium potassium tartrate (0.5 M, 5 mL)
was added and the stirring mixture was allowed to warm to room
temperature. After 30 min, the organic materials were extracted
with EtOAc (3 × 5 mL), washed with brine (5 mL), dried (MgSO4)
and concentrated. Purification by flash chromatography (SiO2;
EtOAc–petrol 1 : 19 → 1 : 9) afforded a 3 : 2 diastereomeric
mixture of aldehydes 38 (0.12 g, 42%) as a pale yellow oil; mmax/cm−1
mmax/cm−1 (CHCl3 cast) 2926, 2880 (CH), 1715 (C O), 1599,
=
=
1448, 1348, 1159; dH (500 MHz; CDCl3) 0.82 (3H, s, NCHCCH3),
1.17 (1H, ddd, J 12.5, 6.5, 4.6, BnNCH2CHH), 1.50 (1H, m,
TsNCH2CH), 1.66 (1H, dt, J 12.5, 7.5, BnNCH2CHH), 2.03
(CHCl3 cast) 2934 (CH), 1702 (C O), 1597, 1460, 1339, 1159; dH
(500 MHz, CDCl3) 0.03 (3.6H, s) and 0.07 (2.4H, s, Si(CH3)2),
0.87, 0.89, 0.91 (12H, 3 × s, NCHCCH3 and C(CH3)3), 1.09–
2950 | Org. Biomol. Chem., 2008, 6, 2941–2951
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1.21 (1.4H, m, TsNCH2CHminor and BnNCH2CHH), 1.35–1.76
(3.6H, m, BnNCH2CHH, CH2CHOTBS and TsNCH2CHmajor),
2.41 (3H, s, ArCH3), 2.54–2.61 (1H, m) and 2.64–2.71 (1H,
m, BnNCH2), 2.96 (0.4H, t, J 12.0) and 2.97 (0.6H, t, J 12.0,
TsNCHH), 3.67 (0.6H, dd, J 12.2, 6.9, TsNCHHmajor), 3.79–3.87
(0.8H, m, CHminorOTBS and TsNCHHminor), 3.89–3.92 (0.6H, m,
CHmajorOTBS), 3.96 (0.4H, d, J 13.5), and 3.98 (0.6H, d, J 13.5,
NCHHPh) 4.07 (0.6H, d, J 13.5) and 4.10 (0.4H, d, J 13.5,
NCHHPh), 4.56 (0.4H, s) and 4.58 (0.6H, s, NCHN) 7.17–7.34
(7H, m, ArH), 7.71 (1.2H, d, J 8.3) and 7.72 (0.8H, d, J 8.3,
ArH o- to SO2), 9.41 (0.6H, s) and 9.46 (0.4H, d, J 1.8, CHO); dC
(125 MHz; CDCl3) −5.0, −4.9, −4.7, −4.6 (Si(CH3)2), 18.0, 18.1
(CMe3), 21.5 (ArCH3), 24.2, 24.3 (NCHCCH3), 25.7 (C(CH3)3),
30.5, 30.7, 30.9 (CH2CHOTBS and BnNCH2CH2), 43.5, 43.8
(TsNCH2CH), 50.1, 50.3 (BnNCH2), 52.9, 53.0 (NCHCMe), 53.1,
53.4 (TsNCH2), 55.7 (NCH2Ph), 76.5, 76.6 (CHOTBS), 89.9, 90.0
(NCHN), 126.7, 127.0, 127.1, 127.2, 128.1, 128.8, 129.8, 129.9
(aromatic CH), 137.3, 137.5, 139.0, 143.1, 143.2 (aromatic C),
204.6, 205.5 (CHO); m/z (FAB+) 557 (MH+, 34%), 286 (23), 173
(100), 154 (93). HRMS found 557.2883. Calc. for C30H45N2O4SSi
(MH+) 557.2870.
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(CH), 1599, 1456, 1336, 1159 (SO2); dH (500 MHz; CDCl3) 0.11
(3H, s) and 0.15 (3H, s, Si(CH3)2), 0.86 (9H, s, C(CH3)3), 0.88
(3H, s, NCHCCH3), 1.46 (1H, dd, J 12.5, 5.8, BnNCH2CHH),
1.50–1.75 (4H, m, BnNCH2CHH, TsNCH2CH, CHHCOTBS
and OH), 2.11 (1H, d, J 11.8, CHHCOTBS), 2.33 (1H, s,
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J 9.0, 7.3, BnNCH2), 3.03 (1H, dd, J 11.3, 1.5) and 3.21 (1H, m,
TsNCH2), 3.47 (1H, d, J 13.1) and 4.04 (1H, d, J 13.1, NCH2Ph),
5.30 (1H, s, NCHOH), 7.20–7.37 (7H, m, ArH), 7.79 (2H, d, J
8.3, ArH o- to SO2); dC (125 MHz; CDCl3) −4.3, −3.9 (Si(CH3)2),
18.5 (CMe3), 21.4 (NCHCCH3), 21.5 (ArCH3), 26.1 (C(CH3)3),
33.7 (CH2COTBS), 39.4 (BnNCH2CH2), 41.1 (TsNCH2CH), 44.0
(TsNCH2), 49.3 (NCHCMe), 52.8 (BnNCH2), 62.3 (NCH2Ph),
76.4 (BnNCHCMe), 79.3 (COTBS), 84.2 (CHOH), 127.2, 127.9,
128.4, 128.6, 129.4 (aromatic CH), 136.7, 139.0, 143.3 (aromatic
C), m/z (EI+) 556 (M+, 2%), 499 (67), 269 (86), 95 (100). HRMS
found 556.2781. Calc. for C30H44N2O4SSi (M+) 556.2786.
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Acknowledgements
22 R. L. Danheiser, R. F. Miller, R. G. Brisbois and S. Z. Park, J. Org.
The authors thank Mr John Hill and Dr Lisa Harris for carrying
out mass spectrometry, and Ms Jill Maxwell for microanalysis. We
thank UCL Graduate School and EPSRC for funding.
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This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 2941–2951 | 2951
©