Concise access to indolizidine and pyrroloazepine skeleta via intramolecular Schmidt reactions of azido 1,3-diketones

Article abstract of DOI:10.1039/b608801e

Readily prepared 2-alkyl-2-azidopropylcycloalkyl-1,3-diones undergo intramolecular Schmidt rearrangement with a range of hard Lewis acids, leading to indolizidinediones and pyrroloazepinediones. Chiral aluminium-based Lewis acids could also be used to mediate this symmetry-breaking transformation, but no significant asymmetric induction was observed. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b608801e

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Concise access to indolizidine and pyrroloazepine skeleta via intramolecular
Schmidt reactions of azido 1,3-diketones†
Duanpen Lertpibulpanyaa and Stephen P. Marsden*b
Received 21st June 2006, Accepted 12th July 2006
First published as an Advance Article on the web 3rd August 2006
DOI: 10.1039/b608801e
Readily prepared 2-alkyl-2-azidopropylcycloalkyl-1,3-diones undergo intramolecular Schmidt
rearrangement with a range of hard Lewis acids, leading to indolizidinediones and
pyrroloazepinediones. Chiral aluminium-based Lewis acids could also be used to mediate this
symmetry-breaking transformation, but no significant asymmetric induction was observed.
for enantioselective variants of the reaction utilising chiral Lewis
acids to discriminate between the prochiral ketones was also a key
Introduction
Indolizidine alkaloids containing quaternary asymmetric centres
consideration.
at the carbon ring-fusion position are widely distributed in nature,
A generalised summary of the proposed chemistry is shown in
exemplified by structures such as lepadiformine C 11 and the
Fig. 1. Lewis acid activation of one of the ketones of 4 initiates
Lycopodium alkaloid serratine 2.2 Compounds containing the ho-
mologous pyrroloazepine skeleton are also known, with perhaps
nucleophilic attack by the pendant azide. Rearrangement of the
resulting intermediate 5 can potentially occur to yield the desired
the most important examples being esters of cephalotaxine 3,3
fused bicyclic product 6 (path a), or the bridged bicyclic amide 7
which show efficacy as anti-leukaemic agents.4
(path b). All available literature precedent supports the exclusive
formation of 6 (either due to conformational requirements, or due
to the instability of the bridged amide in 78), but this remained to be
verified in the current system. In particular, we had concerns that
the presence of the inductively-withdrawing acyl substituent on the
migrating carbon in path a might disfavour this pathway, leading
either to the competing reaction through path b, or the shutdown
of the Schmidt pathway altogether. At the outset of this work,
there was only a single example of the intramolecular Schmidt
reaction of an azidopropyl-substituted 1,3-diketone, promoted
by a Brønsted acid (trifluoroacetic acid).8 We therefore needed
to demonstrate that the reactions could be promoted effectively
by Lewis acids (and in particular by Lewis acids amenable to
substitution with chiral ligands) as well as defining more clearly
the scope of the reaction. We report herein the results of these
studies.
The traditional Schmidt reaction involves insertion of hydrazoic
acid into a C–H or C–C bond adjacent to an aldehyde or
ketone carbonyl group, leading to amide formation and loss of
dinitrogen.5 Attempts to use alkyl azides in the reaction (leading
to substituted amides) have met with mixed results. Intermolecular
reactions of simple alkyl azides are known but are not reliably
successful.6 Aube´ et al. have, however, pioneered intramolecular
variants of the reaction with great success,7,8 leading to appli-
cations in the total synthesis of the alkaloidal natural products
indolizidine 209B,9 aspidospermine,10 sparteine,11 dendrobatid
alkaloid 251F12 and stenine,13 as well as the homoerythrina
alkaloid skeleton.14
As part of our interest in the desymmetrisation of prochiral
azidodiketones of general structure 4,15 we considered that facile
entry to the above ring systems would be achieved by way of an
intramolecular Schmidt reaction of the alkyl azide with one of
the ketones; usefully the two carbonyl groups in the ketoamide
product would be distinguishable in subsequent chemoselective
reactions, facilitating further elaboration of the basic skeleton and
paving the way for applications in target synthesis. The potential
aDepartment of Chemistry, Imperial College, London, UK SW7 2AY
bSchool of Chemistry, University of Leeds, Leeds, UK LS2 9JT. E-mail:
s.p.marsden@leeds.ac.uk; Fax: 44 113 343 6565; Tel: 44 113 343 6425
† Electronic supplementary information (ESI) available: Copies of 1H
and 13C NMR for compounds 4a–c, 6a–c and 10/11a–c. See DOI:
10.1039/b608801e
Fig. 1 Potential pathways in the intramolecular Schmidt reaction of 4.
3498 | Org. Biomol. Chem., 2006, 4, 3498–3504
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Table 1 Schmidt rearrangement of diketoazides 4a–c by Lewis acids
Results and discussion
Entry
Azide
Lewis acid (eq.)
Time/h
Product Yield
The requisite azidodiketones 4a–c were prepared from 2-
methylcyclopentane-1,3-dione and cyclohexane-1,3-dione as
shown in Scheme 1. Hydroboration of the 2-alkyl-2-allyl diketones
8a–c16,17 was carried out with an iodinative work-up according to
the general method of Kabalka et al.18 to give primary iodides 9a–
c. Nucleophilic displacement of the iodide with sodium azide in
aqueous acetone gave the desired azidodiketones 4a–c. The azides
could be readily prepared in this manner on a multi-gram scale
(caution: although we have not experienced any problems with
these materials, all preparations, purifications and reactions of
the azides were carried out behind a blast shield with appropriate
precautions).19
1
2
3
4
5
6
7
8
9
4a
4a
4a
4a
4a
4a
4b
4b
4b
4b
4b
4c
BF3·OEt2 (4)
TiCl4 (2.5)
24
1
6
72
72
72
24
24
1
6a
6a
6a
6a
6a
6a
6b
6b
6b
6b
6b
6c
65%
89%
83%
n. r.
n. r.
n. r.
52%b
85%
67%
60%
80%
87%
EtAlCl2 (2.5)
Cu(OTf)2 (2.5)a
ZnCl2 (2.5)
a
Yb(OTf)3
BF3·OEt2 (2.5)
BF3·OEt2 (4)
TiCl4 (1.1)
EtAlCl2 (1.1)
EtAlCl2 (2.5)
EtAlCl2 (2.5)
10
11
12
24
6
24
a THF used as solvent in place of Et2O. b Starting material (20%) also
recovered.
to use with external chiral ligands; disappointingly, the use of
copper(II) triflate, zinc chloride and ytterbium(III) triflate all
returned clean starting material (>90% recovery in all cases) after
72 hours. The failure of zinc chloride to promote the reaction was
particularly disappointing given that this reagent had successfully
been used in intramolecular Schmidt reactions of azidoaldehydes,8
giving an indication of the demanding nature of the present
transformations.
Although disappointed by the lack of scope of potential Lewis
acids, we were encouraged by the clean nature of the reactions
and aware of the potential for chiral Lewis acids based upon
titanium, boron and aluminium. Before embarking on screens
for enantioselective variants, we needed to identify an assay for
enantiomeric purity. The lack of a potent chromophore in products
6a–c coupled with their likely low volatility prompted us to con-
sider non-chromatographic options. In the event, chemoselective
sodium borohydride reduction of the ketoamides gave a mixture
of diastereomeric alcohols 10/11a–c (Scheme 3). The identity
of the diastereomers was not unambiguously established but is
tentatively assigned as shown based upon the literature precedent
for stereoselective reductions in the corresponding carbocyclic
series.20 Chromatographic separation of the diastereomers and
derivatisation of the major diastereomers as their Mosher’s esters
allowed resolution of the antipodal alcohols by 1H or 19F NMR.
Scheme 1 Reagents, conditions and yields: (i) 5 M NaOH, MeI or BnBr,
65 ◦C or 100 ◦C respectively; (ii) 1 N NaOH, 1% Bu4NI, allyl bromide,
r.t. (8a 84%, step 2 only; 8b 52% and 8c 43% over 2 steps); (iii) 1.2 eq.
BH3·Me2S, 2.5 eq. cyclohexene, THF, 0 ◦C then 8a–c, 0 ◦C to r.t., then
NaOAc–MeOH, I2, r.t. (9a 35%, 9b 55%, 9c 42%); (iv) NaN3, 1% Bu4NI,
acetone–H2O, r.t. (4a 85%, 4b 87%, 4c 79%).
With the substrates in hand, attention then turned to an
investigation of the Schmidt reaction promoted by various Lewis
acids. The results of our screening are summarised in Scheme 2 and
Table 1. The hard Lewis acids boron trifluoride and titanium(IV)
chloride had previously been shown to be effective promoters of
the intramolecular Schmidt reactions of azidoketones, and we were
pleased to find that these reagents were also effective in the current
programme, giving good yields of the rearranged bicyclic products
6a and 6b. No trace of the bridged lactams 7 was observed in any
of the reactions. Super-stoichiometric Lewis acid was required
for the reaction to proceed at an acceptable rate, likely because
of sequestration of the first equivalent of reagent by the strongly
Lewis-basic lactam in products 6. Ethylaluminium dichloride was
also found to be an excellent reagent for the transformation. We
next attempted to utilise Lewis acids which might be amenable
Scheme 3 Reagents and conditions: (i) NaBH4, MeOH, r.t.
We then commenced screening of chiral Lewis acids. Initial
attempts focused on boron and titanium-based Lewis acids, in the
form of Corey’s N-tosyl-L-tryptophan-derived oxazaborolidine21
and Mikami et al.’s (S)-BINOLTiCl2 respectively.22 After 72 hours
at room temperature, only starting material was observed.
However, more encouraging results were obtained with chiral
aluminium-based Lewis acids, namely L-menthyloxyaluminium
Scheme 2 Schmidt rearrangement of diketoazides 4a–c.
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Table 2 Attempted asymmetric Schmidt rearrangements
Entry
Azide
Lewis acid
Product
Conv. (%)a
Yield (%)b
ee (%)c
1
2
3
4
5
6
4a
4a
4b
4b
4c
4c
12
13
12
13
12
13
5a
5a
5b
5b
5c
5c
40
22
67
50
40
14
35
18
50
25
27
10
0
6
5
4
0
0
a Conversion measured from crude 1H NMR spectrum. b Isolated yield. c Determined by ketone reduction and Mosher’s ester derivatisation.
dichloride 12 and (S)-BINOLAlCl 13. These reagents proved
competent enough Lewis acids to promote the reaction, although
as seen in Table 2, the conversions after 72 hours were far from
complete. In three cases, a small optical rotation was observed for
the products but on derivatisation by reduction–esterification to
the Mosher’s derivative as outlined above, asymmetric induction
was found to be less than 10% in all cases.
2-Methyl-1,3-cyclohexanedione17
1,3-Cyclohexanedione (16.8 g, 150 mmol) was dissolved in 5 M
aqueous NaOH (30 ml, 150 mmol) at 0 ◦C. Iodomethane (42.6 g,
300 mmol) was added to the resulting red/brown solution in one
portion. The ice bath was removed and the mixture was heated
at 65 ◦C for 24 h, then allowed to cool to room temperature.
The beige/orange solid was filtered, and washed with petrol
(100 ml) and a minimum amount of cold water until a pale beige
solid was obtained. This was dried in vacuo to give 2-methyl-1,3-
cyclohexanedione (12.3 g, 97.5 mmol, 65%) which was used in the
next◦step without further purification: mp 198–200 ◦C (lit.17 204–
Conclusions
Prochiral 2-(3-azidopropyl)-1,3-diketones, readily prepared from
commercial cycloalkyldiones, undergo completely regioselective
Schmidt rearrangement yielding desymmetrised racemic bicyclic
ketoamides. Attempts at asymmetric variants of the reaction
resulted in modest conversions to product with aluminium-based
Lewis acids, but with negligible asymmetric induction. Future
exploration of this process will require the identification of
more active catalyst systems which will be amenable to ligand
optimisation to maximise asymmetric induction.
1
205 C). H NMR (270 MHz; DMSO-d6; 100% enol tautomer)
dH 1.53 (3H, s, CH3), 1.80 (2H, quintet, J 6.5, 5-H) and 2.29 (4H,
t, J 6.5, 4-H and 6-H). 13C NMR (67.5 MHz; DMSO-d6) dC 7.7
(CH3), 21.0 (5-C), 33.0 (br, 4-C and 6-C) and 110.0 (1-C and 3-C)
(C2 signal not observed).
2-Benzyl-1,3-cyclohexanedione
Prepared by the same procedure as above from 1,3-
cyclohexanedione (14.0 g, 125 mmol), benzyl bromide (32.0 g,
187.5 mmol) and 5 M aqueous NaOH (25 ml, 125 mmol), except
that the mixture was heated at 100 ◦C for 3 h. The solid formed was
filtered and washed successively with petrol (150 ml), a minimum
amount of cold water and cold ether until a pale beige solid was
obtained (19.2 g, 94.9 mmol, 76%). This was used in the next step
Experimental
All dry glassware was oven-dried at 150 ◦C overnight or flame-
dried prior to use. All reactions in anhydrous solvent were
carried out under a dry nitrogen atmosphere. Analytical thin layer
chromatography was performed on pre-coated glass backed plates
(Merck Kieselgel 60 F254). Visualisation was accomplished with
UV light (254 nm), acidic ammonium molybdate(IV) or potassium
permanganate. Flash column chromatography was performed on
Merck Kieselgel 60 (200–300 mesh) under gentle pressure from
hand bellows.
1H and 13C NMR spectra were recorded on Bruker ARX250,
JEOL-GSL270 and Bruker DRX300 spectrometers. Chemical
shifts are expressed in parts per million (d) relative to tetramethyl-
silane, and are referenced to (residual protic) solvent; coupling
constants (J) are expressed in Hertz. 19F NMR spectra were
recorded on Bruker ARX250 spectrometer. Infrared spectra were
recorded on a Perkin Elmer 683 Infrared Spectrometer. Mass
spectra were recorded on a VG Autospec Q or Micromass Platform
II spectrometer under chemical ionisation (CI) with ammonia.
Optical rotations were measured with a Perkin-Elmer 141 and
an Optical Activity AA1000 polarimeter with a path length of
1 dm at 598 nm and concentration c measured in g per 100 ml.
Melting points were measured using a Gallenkamp melting point
apparatus and are uncorrected.
◦
without further purification: mp 178–180 C (lit.23 184–185 ◦C
from toluene). IR mmax(KBr)/cm−1 3500–3000br, 2958w, 2927w,
1
=
1710s (C O), 1602w, 1232w, 1180w. H NMR (270 MHz; DMSO-
d6 + acetone-d6; 100% enol tautomer) dH 1.88 (2H, quintet, J 6.0,
5-H), 2.38 (4H, t, J 6.0, 4-H and 6-H), 3.55 (2H, s, CH2Ph) and
7.00–7.30 (5H, m, Ph). 13C NMR (67.5 MHz; DMSO-d6 + acetone-
d6) dC 21.0 (5-C), 27.5 (CH2Ph), 33.0 (br, 4-C and 6-C), 114.8 (1-C
and 3-C), 125.2 (Ar CH), 127.9 (Ar CH), 128.7 (Ar CH) and 142.5
(Ar C) (C2 signal not observed).
2-Allyl-2-methyl-1,3-cyclopentanedione17 8a
Allyl bromide (14.5 g, 120 mmol) and Bu4NI (222 mg, 0.6 mmol)
was added to a solution of 2-methyl-1,3-cyclopentanedione
(Aldrich; 7.0 g, 60 mmol) in 1 M aqueous NaOH (60 ml, 60 mmol).
The mixture was stirred vigorously for 72 h. The organic layer
was separated and the aqueous layer was extracted with DCM
(2 × 35 ml). The combined organic layers were washed with
brine, dried (MgSO4) and evaporated. Vacuum distillation of
the crude material gave the title compound (7.7 g, 50.6 mmol,
Tetrahydrofuran and diethyl ether for use as reaction solvents
were dried by prolonged heating under reflux over and distillation
from sodium–benzophenone ketyl.
◦
84%) as a colourless oil: bp 88–90 C (4 mmHg) (lit.17 65 ◦C,
2 mmHg). IR mmax(KBr/film)/cm−1 3079w, 2979s, 2931s, 2873w,
3500 | Org. Biomol. Chem., 2006, 4, 3498–3504
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=
1764w, 1725s (C O), 1641w, 1452m, 1419m, 1068s and 1029s.
solution of iodine (1.1 eq.) in methanol (1 ml per mmol of iodine),
both via a cannula. The resulting red/brown solution was stirred
at room temperature for 18 h and then quenched by a slow
addition of saturated aqueous sodium thiosulfate until the mixture
turned pale yellow. This was stirred for 15 minutes, then diluted
with water (5 ml per mmol of 8) and extracted with ether. The
combined organic layers were washed with brine, dried (MgSO4)
and evaporated. The residue was purified by flash chromatography
(gradient elution, 10% petroleum ether–DCM to DCM).
1H NMR (270 MHz; CDCl3) dH 0.95 (3H, s, CH3), 2.19 (2H,
=
d, J 7.5, CH2CH CH2), 2.47–2.70 (4H, m, 2 × CH2CO), 4.87–
=
4.94 (2H, m, CH CH2) and 5.44 (1H, ddt, J 16.0, 11.0 and 7.5,
CH CH2). 13C NMR (67.5 MHz; CDCl3) dC 18.6 (CH3), 35.3
=
=
=
=
(CH2CO), 40.0 (CH2CH ), 56.6 (C), 119.7 ( CH2), 131.5 (CH )
and 216.2 (C O).
=
2-Allyl-2-methyl-1,3-cyclohexanedione 8b
Prepared as for 8a from allyl bromide (23.6 g, 195 mmol), Bu4NI
(362 mg, 0.98 mmol), 2-methyl-1,3-cyclohexanedione (12.3 g,
97.5 mmol) and 1 M aqueous NaOH (97.5 ml, 97.5 mmol).
Vacuum distillation of the crude material gave the title compound
(12.9 g, 77.6 mmol, 80%) as a pale yellow oil: bp 100–102 ◦C
(1 mmHg) (lit.24 63 ◦C, 0.23 mmHg). IR mmax(KBr/film)/cm−1
2-(3-Iodopropyl)-2-methyl-1,3-cyclopentanedione 9a. Prepared
and purified according to the general procedure from 8a (2.5 g,
16.4 mmol), cyclohexene (3.39 g, 41.3 mmol), BH3·SMe2 (9.85 ml
of 2.0 M solution in THF, 19.7 mmol), sodium acetate (3.23 g,
39.4 mmol) and iodine (4.58 g, 18.0 mmol), except that the
reaction mixture was stirred at 0 ◦C for 3 h after the addition
of 8a to dicyclohexylborane. The product was obtained as a pale
=
=
3079w, 2967s, 2940s, 2877s, 1724m (C O), 1693s (C O), 1454m,
1321m, 1025m and 921m. H NMR (270 MHz; CDCl3) dH 1.22
1
yellow oil (1.5 g, 5.7 mmol, 35%). IR mmax(KBr/film)/cm−1 2924s,
1
=
(3H, s, CH3), 1.78–2.07 (2H, m, CH2CH2CO), 2.52 (2H, dt, J 7.0
1716s (C O), 1451m, 1418m, 1231m, 1074m and 991m. H NMR
=
and 1.0, CH2CH CH2), 2.55–2.72 (4H, m, 2 × CH2CO), 5.00–
(270 MHz; CDCl3) dH 1.08 (3H, s, CH3), 1.12–1.32 (2H, br m,
CH2), 1.59–1.72 (2H, m, CH2), 2.64–2.84 (4H, m, 2 × CH2CO)
and 3.00–3.06 (2H, m, CH2I). 13C NMR (67.5 MHz; CDCl3) dC
=
5.08 (2H, m, CH CH2) and 5.56 (1H, ddt, J 17.5, 9.5 and 7.0,
CH CH2). 13C NMR (67.5 MHz; CDCl3) dC 17.5 (CH2CH2CO),
=
=
19.3 (CH3), 38.1 (CH2CO), 41.2 (CH2CH ), 65.1 (C), 119.1
( CH2), 132.2 (CH ) and 209.8 (C O).
5.2 (CH2I), 19.2 (CH3), 28.4 (CH2), 35.1 (CH2), 35.8 (CH2CO),
+
=
=
=
=
56.1 (C) and 215.9 (C O). LRMS (CI /NH3): m/z (%) = 298 ([M
+ NH4]+, 100), 172 (38), 153 (75), 142 (25) and 125 (21). HRMS
(CI+/NH3): m/z calcd for [M + NH4]+: C9H17INO2 = 298.0304.
Found 298.0302.
2-Allyl-2-benzyl-1,3-cyclohexanedione 8c
Prepared as for 8a from allyl bromide (9.6 g, 79.2 mmol),
Bu4NI (148 mg, 0.4 mmol), 2-benzyl-1,3-cyclohexanedione (8.0 g,
39.6 mmol) and 1 M aqueous NaOH (39.6 ml, 39.6 mmol).
Recrystallisation of the crude material from ether yielded the title
compound (5.4 g, 22.3 mmol, 56%) as a pale yellow crystalline
solid: mp 57–59 ◦C (lit.25 62 ◦C). IR mmax(KBr/film)/cm−1 3059w,
2-(3-Iodopropyl)-2-methyl-1,3-cyclohexanedione 9b. Prepared
and purified according to the general procedure from 8b (5.0 g,
30.1 mmol), cyclohexene (6.24 g, 75.9 mmol), BH3·SMe2 (18.1 ml
of 2.0 M solution in THF, 36.1 mmol), sodium acetate (5.92 g,
72.2 mmol) and iodine (8.4 g, 33.1 mmol). The product
was obtained as a yellow oil (4.85 g, 16.5 mmol, 55%). IR
=
=
3034w, 2960w, 2934w, 2884w, 1720m (C O), 1694s (C O),
1457m, 1340m, 930s and 705s. H NMR (270 MHz; CDCl3) dH
1
mmax(KBr/film)/cm−1 2958m, 1725s (C O), 1694s (C O), 1456m,
1426m, 1375m, 1218m and 1025m. 1H NMR (270 MHz; CDCl3)
dH 1.23 (3H, s, CH3), 1.54–1.65 (2H, m, 1-H or 2-H), 1.79–2.02
(4H, m, CH2CH2CO and 1-H or 2-H), 2.55–2.73 (4H, m, CH2CO)
and 3.08 (2H, t, J 6.5, CH2I). 13C NMR (67.5 MHz; CDCl3) dC 5.9
=
=
1.05–1.20 (1H, m, CH2CH2CO), 1.52–1.68 (1H, m, CH2CH2CO),
2.07 (2H, ddd, J 17.0, 8.0 and 5.0, CH2CO), 2.33 (2H, ddd, J 17.0,
=
8.5 and 5.0, CH2CO), 2.62 (2H, d, J 7.5, CH2CH CH2), 3.08
=
(2H, s, CH2Ph), 5.02 (1H, d, J 10.0, CH CH2 cis), 5.04 (1H, d,
=
J 17.0, CH CH2 trans) and 5.53 (1H, ddt, J 17.0, 10.0 and 7.5,
(CH2I), 17.7 (CH2CH2CO), 20.2 (CH3), 28.7 (CH2), 37.2 (CH2),
CH CH2), 6.93–7.05 (2H, m, Ph) and 7.15–7.25 (3H, m, Ph). 13C
37.9 (2 × CH2CO), 65.0 (C) and 209.9 (C O). LRMS (CI /NH3):
+
=
=
NMR (67.5 MHz; CDCl3) dC 14.9 (CH2CH2CO), 40.6 (CH2CO),
m/z (%) = 312 ([M + NH4]+, 100), 172 (55) and 167 (100). HRMS
(CI+/NH3): m/z calcd for [M + NH4]+: C10H19INO2 = 312.0461.
Found 312.0474.
=
42.3 (CH2), 43.9 (CH2), 68.7 (C), 118.9 ( CH2), 126.6, 128.0, 129.4
=
=
(CH of Ph), 132.0 (CH ), 136.1 (C of Ph) and 211.1 (C O).
2-Benzyl-2-(3-iodopropyl)-1,3-cyclohexanedione 9c. Prepared
and purified according to the general procedure from 8c (5.28 g,
21.8 mmol), cyclohexene (4.52 g, 55.0 mmol), BH3·SMe2 (13.1 ml
of 2.0 M solution in THF, 26.2 mmol), sodium acetate (4.30 g,
52.3 mmol) and iodine (6.10 g, 24.0 mmol). The product
was obtained as a yellow oil (3.40 g, 9.2 mmol, 42%): IR
General procedure for the preparation of iododiketones
A 2.0 M solution of BH3·SMe2 in THF (1.2 eq.) was carefully
added via a syringe to a solution of freshly distilled cyclohexene
(2.52 eq.) in dry THF (0.6 ml per mmol of BH3·SMe2) at 0 ◦C. A
thick white precipitate appeared after ca. 5–10 minutes, indicating
the formation of dicyclohexylborane. The mixture was stirred at
that temperature for 1 h, then a solution of alkene 8 (1.0 eq.) in
dry THF (0.5 ml per mmol of 8) at 0 ◦C was added dropwise via a
cannula (followed by a THF rinse, 0.3 ml per mmol of 8). Stirring
was continued at 0 ◦C for 1.5 h and then at room temperature
for 1.5 h, during which time the precipitate was consumed. The
mixture was then cooled again to 0 ◦C and a solution of sodium
acetate (2.4 eq.) in methanol (1 ml per mmol of NaOAc) was
slowly added, immediately followed by dropwise addition of a
mmax(KBr/film)/cm−1 3061w, 3027w, 2949w, 2887w, 1717s (C O),
=
1
=
1690s (C O), 1438m, 1176m, 761s and 706s. H NMR (270 MHz;
CDCl3) dH 1.19–1.34 (1H, m, CH2CH2CO), 1.40–1.70 (3H, m,
CH2CH2CO and 1-H or 2-H), 1.95–2.00 (2H, m, 1-H or 2-H),
2.09 (2H, ddd, J 17.0, 9.0 and 5.0, CH2CO), 2.40 (2H, ddd, J
17.0, 7.5 and 4.5, CH2CO), 3.03 (2H, t, J 7.0, CH2I), 3.04 (2H, s,
CH2Ph), 6.93–6.99 (2H, m, Ph) and 7.15–7.26 (3H, m, Ph). 13C
NMR (67.5 MHz; CDCl3) dC 4.8 (CH2I), 15.4 (CH2CH2CO), 29.1
(CH2), 38.3 (CH2), 40.4 (CH2CO), 44.8 (CH2Ph), 68.2 (C), 126.9,
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=
128.2, 129.4 (CH of Ph), 135.7 (C of Ph) and 211.4 (C O). LRMS
CH2CH2CO and 1-H or 2-H), 1.57–1.71 (1H, m, CH2CH2CO),
1.92–1.98 (2H, m, 1-H or 2-H), 2.13 (2H, ddd, J 17.0, 9.0 and
5.0, CH2CO), 2.43 (2H, ddd, J 17.0, 7.5 and 5.0, CH2CO), 3.06
(2H, s, CH2Ph), 3.20 (2H, t, J 7.0, CH2N3), 6.96–7.01 (2H, m,
Ph) and 7.20–7.28 (3H, m, Ph). 13C NMR (67.5 MHz; CDCl3) dC
15.6 (CH2CH2CO), 24.8 (CH2), 34.3 (CH2), 40.6 (CH2CO), 45.3
(CI+/NH3): m/z (%) = 388 ([M + NH4]+, 100), 262 (86) and 243
(8). HRMS (CI+/NH3): m/z calcd for [M + NH4]+: C16H23INO2 =
388.0774. Found: 388.0768.
General procedure for the preparation of azidodiketones 4a–c
(CH2Ph), 51.1 (CH2N3), 68.7 (C), 127.1, 128.4, 129.6 (CH of Ph),
Caution: azides are potentially explosive and should be handled
and treated with appropriate precautions.19 All reactions and
manipulations of azides were carried out behind a blast shield.
A solution of sodium azide (5 eq.) in water (1.25 ml per mmol
of sodium azide) was added to the solution of iodopropyl
cycloalkyldione 9 (1 eq.) and Bu4NI (0.1 eq.) in acetone (7.3 ml
per mmol of 9). The resulting homogeneous mixture was stirred at
room temperature for 72 h—if the mixture was not homogeneous,
an additional amount of water and/or acetone was slowly added
until the mixture became homogeneous. The mixture was then
diluted with water (6 ml per mmol of 9) and extracted with ether.
The combined ether layers were washed with brine, dried (MgSO4)
and evaporated. The residue was purified by flash chromatography
(50% ether–petroleum ether).
+
=
135.8 (C of Ph) and 211.7 (C O). LRMS (CI /NH3): m/z (%) =
303 ([M + NH4]+, 100) and 258 (96). HRMS (CI+/NH3): m/z
calcd for ([M + NH4]+) C16H23N4O2 = 303.1821. Found 303.1823.
General procedure for the Schmidt rearrangement of
azidodiketones 4 utilising achiral Lewis acids
Lewis acid (2.5 eq. unless otherwise stated) was added to a solution
of an azidodiketone 4 (1.0 eq.) in dry ether (10 ml per mmol of 4)
and the reaction was stirred at ambient temperature. The progress
of the reaction was monitored by the disappearance of the azide
stretch in the IR spectrum. After the reaction was complete (or at
72 hours, whichever was sooner), saturated NaHCO3 solution was
slowly added to quench the excess Lewis acid and the resulting
mixture was extracted with DCM. The combined organic layers
were washed with brine, dried (Na2SO4) and evaporated. The
residue was purified by flash chromatography (methanol–DCM).
2-(3-Azidopropyl)-2-methyl-1,3-cyclopentanedione 4a. Prepared
and purified according to the general procedure from 9a (1.5 g,
5.7 mmol), sodium azide (1.85 g, 28.5 mmol) and Bu4NI (22 mg,
0.06 mmol). The product was obtained as a yellow oil (950 mg,
4.85 mmol, 85%). IR mmax(KBr/film)/cm−1 2929s, 2856w, 2100s
Preparation of 8a-methylhexahydroindolizine-5,8-dione 6a.
Prepared and purified according to the general procedure from
4a (100 mg, 0.51 mmol) and BF3·OEt2 (0.27 ml, 2 mmol, 4 eq.)
or EtAlCl2 (1.0 M solution in DCM, 1.28 ml) or TiCl4 (1.0 M
solution in DCM, 1.28 ml). The reaction was complete within
24, 6 and 1 h respectively. The product was obtained after flash
chromatography (56, 71 and 76 mg, 65, 83 and 89% respectively)
as an oil: IR mmax(KBr/film)/cm−1 2981m, 2933m, 2888m, 1722s
=
=
(N3), 1762w (C O), 1722s (C O), 1452m, 1421m, 1263m and
1062m. 1H NMR (270 MHz; CDCl3) dH 1.12 (3H, s, CH3), 1.36–
1.39 (2H, m, CH2), 1.65–1.71 (2H, m, CH2), 2.66–2.88 (4H, m, 2 ×
CH2CO) and 3.21 (2H, t, J 6.5, CH2N3). 13C NMR (67.5 MHz;
CDCl3) dC 19.7 (CH3), 24.0 (CH2), 31.7 (CH2), 35.1 (CH2CO),
+
=
51.2 (CH2N3), 56.2 (C) and 216.0 (C O). LRMS (CI /NH3): m/z
(%) = 213 ([M + NH4]+, 100), 185 (40) and 168 (84). HRMS
(CI+/NH3): m/z calcd for ([M + NH4]+) C9H17N4O2 = 213.1352.
Found 213.1366.
=
=
(C O ketone), 1654s (C O amide), 1430m, 1191m, 1141m and
1118m. 1H NMR (300 MHz; CDCl3) dH 1.34 (3H, s, CH3), 1.86–
2.02 (4H, m, CH2), 2.58–2.66 (3H, m, CH2), 2.71–2.85 (1H, m,
CH2), 3.49–3.58 (1H, m, 3-H) and 3.61–3.70 (1H, m, 3-H). 13C
NMR (67.5 MHz; CDCl3) dC 20.7 (CH2), 23.6 (CH3), 30.0 (CH2),
34.3 (CH2), 35.7 (CH2), 45.0 (3-C), 69.1 (8a-C), 168.2 (5-C) and
209.6 (8-C). LRMS (CI+/NH3): m/z (%) = 185 ([M + NH4]+, 80),
168 ([M + H]+, 100). HRMS (CI+/NH3): m/z calcd for ([M + H]+)
C9H14NO2 = 168.1025. Found 168.1020.
2-(3-Azidopropyl)-2-methyl-1,3-cyclohexanedione 4b. Prepared
and purified according to the general procedure from 9b (4.82 g,
16.4 mmol), sodium azide (5.33 g, 82.0 mmol) and Bu4NI (59 mg,
0.16 mmol). The product was obtained as a pale yellow oil (3.0 g,
14.3 mmol, 87%): IR mmax(KBr/film)/cm−1 2950s, 2933s, 2875w,
=
=
2098s (N3), 1725s (C O), 1695s (C O), 1459m, 1427m, 1263m
and 1024m. H NMR (270 MHz; CDCl3) dH 1.21 (3H, s, CH3),
1
Preparation of 9a-methylhexahydropyrrolo[1,2-a]azepine-5,9-
dione 6b. Prepared and purified according to the general pro-
cedure from 4b (100 mg, 0.48 mmol) and BF3·OEt2 (0.25 ml,
1.92 mmol, 4 eq.) or EtAlCl2 (1.0 M solution in DCM, 1.2 ml)
or TiCl4 (1.0 M solution in DCM, 0.53 ml, 1.1 eq.). The reaction
was complete within 24, 6 and 1 h respectively. The product was
obtained as a pale yellow solid (74, 70 and 58 mg, 85, 80 and
1.30–1.41 (2H, m, CH2), 1.75–1.86 (2H, m, CH2), 1.88–1.97 (2H,
m, CH2), 2.63 (4H, t, J 6.5, 2 × CH2CO) and 3.20 (2H, t, J 6.5,
CH2N3). 13C NMR (67.5 MHz; CDCl3) dC 17.6 (CH2CH2CO),
20.8 (CH3), 24.4 (CH2), 33.1 (CH2), 37.9 (CH2CO), 51.3 (CH2N3),
+
=
65.1 (C) and 210.1 (C O). LRMS (CI /NH3): m/z (%) = 227 ([M
+ NH4]+, 100), 199 (75), 184 (25), 167 (87) and 153 (32). HRMS
(CI+/NH3): m/z calcd for ([M + NH4]+) C10H19N4O2 = 227.1508.
Found 227.1506.
◦
67% respectively): mp 63–65 C. IR mmax(KBr/film)/cm−1 2954s,
=
=
2921s, 2858s, 1718s (C O ketone), 1648s (C O amide), 1461m,
1407m, 1288w, 1105m and 1037m. 1H NMR (300 MHz; CDCl3)
dH 1.40 (3H, s, CH3), 1.77–1.82 (1H, m, CH2), 1.85–2.01 (4H, m,
CH2), 2.02–2.16 (1H, m, CH2), 2.26–2.40 (3H, m, CH2 and 6-H
or 8-H), 2.87 (1H, td, J 11.0 and 9.5, 6-H or 8-H), 3.51–3.63
(1H, m, 3-H) and 3.68–3.75 (1H, m, 3-H). 13C NMR (67.5 MHz;
CDCl3) dC 20.5 (CH2), 21.4 (CH3), 22.7 (CH2), 33.1 (CH2), 35.1
(CH2), 38.5 (CH2), 46.8 (3-C), 71.4 (9a-C), 170.4 (5-C) and 212.5
(9-C). LRMS (CI+/NH3): m/z (%) = 199 ([M + NH4]+, 12) 182
2-(3-Azidopropyl)-2-benzyl-1,3-cyclohexanedione 4c. Prepared
and purified according to the general procedure from 9c (3.36 g,
9.1 mmol), sodium azide (2.96 g, 45.5 mmol) and Bu4NI
(34 mg, 0.09 mmol). The product was obtained as an oil,
which solidified on standing in a freezer (2.05 g, 7.2 mmol,
79%): IR mmax(KBr/film)/cm−1 3063w, 3031w, 2933s, 2886m, 2098s
=
=
(N3), 1722s (C O), 1694s (C O), 1455m, 1259m, 1032m, 762m
and 703s. H NMR (270 MHz; CDCl3) dH 1.23–1.40 (3H, m,
1
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([M + H]+, 100), and 138 (14). HRMS (CI+/NH3): m/z calcd for
([M + H]+) C10H16NO2 = 182.1181. Found 182.1181.
Preparation of 9a-benzylhexahydropyrrolo[1,2-a]azepine-5,9-
dione 6c. Prepared and purified according to the general pro-
cedure from 4c (117 mg, 0.41 mmol) and EtAlCl2 (1.0 M solution
in DCM, 1 ml). The product was obtained as a pale yellow solid
(92 mg, 87%): mp 158–160 ◦C; IR mmax(KBr/film)/cm−1 3060w,
and 3.77–3.85 (1H, m, 3-H). 13C NMR dC (67.5 MHz; CDCl3)
18.3 (CH3), 20.7 (1-C), 21.7 (7-C), 34.1 (8-C), 37.0 (6-C), 42.1
(2-C), 49.4 (3-C), 65.2 (9a-C), 77.5 (9-C) and 173.6 (5-C). LRMS
(CI+/NH3): m/z (%) = 184 ([M + H]+, 100). HRMS (CI+/NH3):
m/z calcd for ([M + H]+) C10H18NO2 = 184.1338. Found 184.1340.
Further elution gave the minor diastereoisomer (11 mg, 20%): 1H
NMR (270 MHz; CDCl3) dH 1.35 (3H, s, CH3), 1.57–2.06 (8H, m,
1-H, 2-H, 7-H and 8-H), 2.49–2.66 (3H, m, 6-H and OH), 3.43
(1H, ddd, J 12.0, 9.5 and 7.5, 3-H) and 3.73–3.82 (2H, m, 3-H and
9-H); 13C NMR (75.5 MHz; CDCl3) dC 16.7 (CH3), 21.4 (1-C), 23.7
(7-C), 30.9 (8-C), 37.4 (6-C), 39.7 (2-C), 50.1 (3-C), 65.2 (9a-C),
72.3 (9-C) and 173.4 (5-C).
=
=
3030w, 2945m, 2886m, 1718s (C O ketone), 1649s (C O amide),
1460m, 1268m, 1035m, 765m and 702s. 1H NMR (270 MHz;
CDCl3) dH 1.36–1.59 (2H, m, CH2), 1.72–1.87 (2H, m, CH2), 1.89–
2.04 (4H, m, CH2), 2.22 (1H, dd, J 11.0 and 7.5, 6-H or 8-H), 2.78
(1H, td, J 11.5 and 8.5, 8-H), 2.86 (1H, d, J 13.5, CHaHbPh), 3.36
(1H, d, J 13.5, CHaHbPh), 3.47 (1H, ddd, J 12.5, 9.5 and 2.5, 3-H)
and 3.65 (1H, ddd, J 12.5, 9.5 and 8.5, 3-H) and 7.04–7.25 (5H,
m, Ph). 13C NMR (67.5 MHz; CDCl3) dC 20.9 (CH2), 23.0 (CH2),
32.5 (CH2), 34.9 (CH2), 38.0 (CH2), 39.6 (CH2), 47.6 (3-C), 75.5
(9a-C), 127.2 (CH of Ph), 128.6 (CH of Ph), 130.5 (CH of Ph),
136.4 (C of Ph), 171.5 (5-C) and 211.0 (9-C). LRMS (CI+/NH3):
m/z (%) = 258 ([M + H]+, 100) and 166 (14). HRMS (CI+/NH3):
m/z calcd for ([M + H]+) C16H20NO2 = 258.1494. Found 258.1498.
Preparation of 9a-benzyl-9-hydroxyoctahydropyrrolo[1,2-a]-
azepine-5-one 10c and 11c. Prepared according to the general
procedure from 6c (92 mg, 0.36 mmol) and NaBH4 (34 mg,
0.9 mmol). The 1H NMR spectrum of the crude material showed
a diastereomeric ratio of 71 : 29. Flash chromatography (25%
acetone–DCM) gave the major diastereoisomer (51.4 mg, 55%):
IR mmax(NaCl/film)/cm−1 3394br (O–H), 2960m, 2933m, 2869m,
1
=
1598s (C O), 1452m, 1265w, 748w and 701w. H NMR (300 MHz;
CDCl3) dH 0.32–0.50 (1H, m, 2-H), 1.26–1.40 (1H, m, 2-H), 1.65–
1.80 (1H, m, 7-H), 1.92–2.26 (5H, m, 1-H, 1 × 7-H and 8-H),
2.74–2.90 (2H, m, 6-H), 2.88 (1H, d, J 14.0, CHaHbPh), 3.21 (1H,
br s, OH), 3.31–3.41 (2H, m, 3-H), 3.39 (1H, d, J 14.0, CHaHbPh),
General procedure for the reduction of lactams 6a–c
Sodium borohydride (2.5 eq.) was added to the solution of a
bicyclic lactam 6 (1.0 eq.) in methanol (15 ml per mmol of 6)
at room temperature in one portion. The reaction was stirred for
45 minutes and then quenched with water (0.1 ml per mmol of
6). The mixture was evaporated to dryness and the residue was
pre-absorbed on silica gel. The two diastereoisomeric products 11
and 12 were separated by flash chromatography.
3.55 (1H, dt, J 10.0 and 5.0, 9-H) and 7.09–7.28 (5H, m, Ph). 13
C
NMR (75.5 MHz; CDCl3) dC 19.9 (2-C), 22.0 (7-C), 33.7 (8-C),
36.1 (CH2Ph), 37.3 (6-C), 39.0 (1-C), 50.1 (3-C), 68.7 (9a-C), 78.1
(9-C), 126.7 (CH of Ph), 128.5 (CH of Ph), 130.3 (CH of Ph),
137.4 (C of Ph) and 173.9 (5-C). LRMS (CI+/NH3): m/z (%) =
260 ([M + H]+, 100) and 168 (26). HRMS (CI+/NH3): m/z calcd
for ([M + H]+) C16H22NO2 = 260.1651. Found 260.1656. Further
elution gave the minor diastereoisomer (21.7 mg, 23%): 1H NMR
(300 MHz; CDCl3) dH 0.69–0.86 (1H, m, 2-H), 1.45–1.60 (1H, m,
2-H), 1.69–1.84 (1H, m, 7-H), 1.90–2.04 (3H, m, 1-H, 7-H and 8-
H), 2.18–2.25 (2H, m, 8-H and OH), 2.39–2.50 (1H, m, 1-H), 2.61
(1H, d, J 14.0, CHaHbPh), 2.62–2.88 (2H, m, 6-H), 3.32–3.50 (2H,
m, 3-H), 3.47 (1H, d, J 14.0, CHaHbPh), 3.80–3.97 (1H, br m, 9-H)
and 7.12–7.33 (5H, m, Ph). 13C NMR (75.5 MHz; CDCl3) dC 17.1
(7-C), 20.8 (2-C), 30.6 (8-C), 36.0 (1-C), 37.5 (6-C), 41.3 (CH2Ph),
50.6 (3-C), 68.9 (9a-C), 72.6 (9-C), 126.9 (CH of Ph), 128.5 (CH
of Ph), 130.2 (CH of Ph), 136.8 (C of Ph) and 173.4 (5-C).
Preparation of 8-hydroxy-8a-methylhexahydroindolizine-5-one
10a and 11a. Prepared according to the general procedure from
6a (31 mg, 0.185 mmol) and NaBH4 (17.5 mg, 0.463 mmol). The
1H NMR spectrum of the crude material showed a diastereomeric
ratio of ∼91 : 9. Flash chromatography (60% acetone–DCM) gave
the major diastereoisomer (26 mg, 83%): IR mmax(NaCl/film)/cm−1
=
3392br (O–H), 2973m, 2888m, 1606s (C O), 1459m, 1413m,
1099m and 1054m. H NMR (300 MHz; CDCl3) dH 1.16 (3H, s,
1
CH3), 1.66 (1H, td, J 11.5 and 8.5, 6-H), 1.87–2.00 (4H, m, 2-H
and 7-H), 2.01–2.12 (1H, m, 6-H), 2.40 (1H, ddd, J 18.5, 9.5 and
9.0, 1-H), 2.52 (1H, ddd, J 18.5, 7.5 and 2.5, 1-H), 3.38 (1H, br s,
OH), 3.41–3.56 (1H, m, 3-H) and 3.59–3.67 (2H, m, 3-H and 8-H).
13C NMR (75.5 MHz; CDCl3) dC 18.3 (CH3), 20.7 (2-C or 7-C),
25.9 (2-C or 7-C), 29.5 (1-C or 6-C), 39.3 (1-C or 6-C), 45.3 (3-C),
64.2 (8a-C), 74.3 (8-C) and 168.4 (5-C). LRMS (CI+/NH3): m/z
(%) = 170 ([M + H]+, 100) and 125 (5). HRMS (CI+/NH3): m/z
calcd for ([M + H]+) C9H16NO2 = 170.1181. Found 170.1179. The
minor isomer was not isolated following chromatography.
General procedure for desymmetrising Schmidt-type reactions
mediated by (−)-menthoxyaluminium dichloride
A 1.0 M solution of EtAlCl2 (1 eq.) was added to a solution of (−)-
menthol (1.2 eq.) in dry hexane (4.5 ml per mmol of azidodiketone
4). After stirring at room temperature for 30 minutes, a solution
of an azidodiketone 4 (1 eq.) in dry toluene (4.5 ml per mmol of 4)
was added to the mixture via a cannula. The reaction was stirred
for 72 h, then quenched with saturated aqueous NaHCO3 and
extracted with DCM. The combined organic layers were washed
with brine, dried (Na2SO4), and evaporated and the residue was
purified by flash chromatography (3% methanol–DCM).
Preparation of 9-hydroxy-9a-methyloctahydropyrrolo[1,2-a]-
azepine-5-one 10b and 11b. Prepared according to the general
procedure from 6b (54 mg, 0.3 mmol) and NaBH4 (28 mg,
0.75 mmol). The 1H NMR spectrum of the crude material showed
a diastereomeric ratio of ∼71 : 29. Flash chromatography (30%
acetone–DCM) gave the major diastereoisomer (30 mg, 55%): IR
mmax(NaCl/film)/cm−1 3389br (O–H), 2971s, 2939s, 2876s, 1601s
Reaction with 4a. The reaction was carried out according to
the general procedure from 4a (124.4 mg, 0.637 mmol), EtAlCl2
(1 M solution in DCM, 637 ll, 0.637 mmol) and (−)-menthol
(119 mg, 0.764 mmol). The 1H NMR spectrum of the crude
1
=
(C O), 1443s, 1051m and 1026m. H NMR (270 MHz; CDCl3)
dH 1.28 (3H, s, CH3), 1.48–2.12 (8H, m, 1-H, 2-H, 7-H and 8-H),
2.40–2.60 (3H, m, 6-H and OH), 3.28–3.44 (2H, m, 3-H and 9-H)
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mixture showed a 40% conversion. Flash chromatography of the
crude material yielded 6a (36.4 mg, 35%): ee = 0% determined by
1H NMR spectrum of the Mosher’s ester of alcohol 10a following
reduction: 1H NMR (270 MHz; CDCl3) dH (inter alia) 1.11 (s, CH3,
50%) and 1.41 (s, CH3, 50%).
Reaction with 4c. The reaction was carried out according to
the general procedure from 4c (100 mg, 0.35 mmol), Me2AlCl (1 M
solution in DCM, 0.35 ml, 0.35 mmol) and (S)-BINOL (120 mg,
0.42 mmol). The 1H NMR spectrum of the crude mixture showed
a 14% conversion. Flash chromatography of the crude material
yielded 6c (9 mg, 10%): ee = 0% determined by 19F NMR spectrum
of the Mosher’s esters as above.
Reaction with 4b. The reaction was carried out according to
the general procedure from 4b (200 mg, 0.96 mmol), EtAlCl2 (1 M
solution in DCM, 0.96 ml, 0.96 mmol) and (−)-menthol (180 mg,
1.15 mmol). The 1H NMR spectrum of the crude mixture showed
a 67% conversion. Flash chromatography of the crude material
Acknowledgements
We thank the IPST for a scholarship (DL) and Pfizer and Merck
for generous unrestricted support.
yielded 6b (87 mg, 50%): [a]21 +4.4 (c 1 in DCM); ee = 5%
D
determined by 19F NMR spectrum of the Mosher’s ester of alcohol
10b following reduction: 19F NMR (250 MHz; CDCl3) dF −75.32
(52.5%) and −75.20 (47.5%).
References
1 M.-P. Sauviat, J. Vercauteren, N. Grimaud, M. Juge´, M. Nabil, J.-Y.
Petit and J.-F. Biard, J. Nat. Prod., 2006, 69, 558.
2 Y. Inubushi, H. Ishii and T. Harayama, Chem. Pharm. Bull., 1967, 15,
250.
3 R. G. Powell, D. Weisleder, C. R. Smith, Jr. and I. A. Wolff, Tetrahedron
Lett., 1969, 4081.
4 R. G. Powell, D. Weisleder and C. R. Smith, Jr., J. Pharm. Sci., 1972,
61, 1227.
5 H. Wolff, Org. React., 1946, 3, 307; G. R. Krow, Tetrahedron, 1981, 37,
1283.
6 J. Aube´, G. L. Milligan and C. J. Mossman, J. Org. Chem., 1992, 57,
1635; P. Desai, K. Schildknegt, K. A. Agrios, C. Mossman, G. L.
Milligan and J. Aube´, J. Am. Chem. Soc., 2000, 122, 7226.
7 J. Aube´ and G. L. Milligan, J. Am. Chem. Soc., 1991, 113, 8965; C. J.
Mossman and J. Aube´, Tetrahedron, 1996, 52, 3403; A. Wrobleski and
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J. Aube´, Org. Lett., 2004, 6, 4993.
Reaction with 4c. The reaction was carried out according to
the general procedure from 4c (58.4 mg, 0.205 mmol), EtAlCl2
(1 M solution in DCM, 205 ll, 0.205 mmol) and (−)-menthol
(38 mg, 0.246 mmol). The 1H NMR spectrum of the crude mixture
showed a 40% conversion. Flash chromatography of the crude
material yielded 6c (14 mg, 27%); ee = 0% determined by 19F
NMR spectrum of the Mosher’s ester of alcohol 10c following
reduction: 19F NMR (250 MHz; CDCl3) dF −74.95 (50%) and
−75.02 (50%).
General procedure for desymmetrising Schmidt reaction mediated
by (S)-binaphthoxyaluminium chloride
A 1 M solution of Me2AlCl (1 eq.) was added dropwise to a
solution of (S)-BINOL (1.2 eq.) in DCM (12 ml per mmol of
azidodiketone 4). The evolution of gas and the formation of
a white precipitate were observed. The mixture was stirred at
room temperature for 2 h, after which DCM was removed via the
vacuum line and toluene (6 ml per mmol of 4) was added to the
resulting residue. Then the solution of an azidodiketone 4 (1 eq.)
in toluene (6 ml per mmol of 4) was added to the chiral Lewis acid
via a cannula and the mixture was stirred at room temperature
for 72 h. The work-up, purification and determination of the
enantiomeric excesses of the products were carried out according
to the procedure described above.
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Reaction with 4a. The reaction was carried out according to
the general procedure from 4a (100 mg, 0.51 mmol), Me2AlCl
(1 M solution in DCM, 0.51 ml, 0.51 mmol) and (S)-BINOL
(175 mg, 0.61 mmol). The 1H NMR spectrum of the crude mixture
showed a 22% conversion. Flash chromatography of the crude
material yielded 6a (15 mg, 18%): [a]24D +26.0 (c 1 in DCM); ee =
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1
6% determined by H NMR spectroscopy of the Mosher’s ester
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derivative as above.
Reaction with 4b. The reaction was carried out according to
the general procedure from 4b (150 mg, 0.72 mmol), Me2AlCl (1 M
solution in DCM, 0.96 ml, 0.96 mmol) and (S)-BINOL (247 mg,
0.86 mmol). The 1H NMR spectrum of the crude mixture showed
a 50% conversion. Flash chromatography of the crude material
yielded 6b (33 mg, 25%): [a]20 −7.1 (c 1 in DCM); ee = 4%
D
determined by 19F NMR spectrum of the Mosher’s esters as above.
3504 | Org. Biomol. Chem., 2006, 4, 3498–3504
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