Stereoselective synthesis of polyhydroxylated aminocyclohexanes

Article abstract of DOI:10.1039/c0ob00619j

The stereoselective synthesis of a series of di- and tri-hydroxylated aminocyclohexane derivatives has been developed. A one-pot, two step tandem process involving an Overman rearrangement and a ring closing metathesis reaction has been utilised for the asymmetric synthesis of (1S)-1-(2′, 2′,2′-trichloromethylcarbonylamino)cyclohexa-2-ene. Oxidation of this cyclohexene derivative was then studied leading to the preparation of two diol analogues in excellent stereoselectivity. (1S)-1-(2′,2′, 2′-trichloromethylcarbonylamino)cyclohexa-2-ene was then converted to a novel allylic alcohol via a 4,5-dihydro-1,3-oxazole. Functionalisation of this allylic alcohol by Upjohn dihydroxylation conditions or by a directed epoxidation/hydrolysis sequence of reactions allowed the synthesis of two dihydroconduramines in excellent stereoselectivity. The stereochemical assignment of all compounds prepared was confirmed by NOE experiments or X-ray structure determination.

Full text of DOI:10.1039/c0ob00619j

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PAPER
Stereoselective synthesis of polyhydroxylated aminocyclohexanes†
Sajjad Ahmad, Lynne H. Thomas and Andrew Sutherland*
Received 23rd August 2010, Accepted 31st January 2011
DOI: 10.1039/c0ob00619j
The stereoselective synthesis of a series of di- and tri-hydroxylated aminocyclohexane derivatives has
been developed. A one-pot, two step tandem process involving an Overman rearrangement and a ring
closing metathesis reaction has been utilised for the asymmetric synthesis of
(1S)-1-(2¢,2¢,2¢-trichloromethylcarbonylamino)cyclohexa-2-ene. Oxidation of this cyclohexene
derivative was then studied leading to the preparation of two diol analogues in excellent
stereoselectivity. (1S)-1-(2¢,2¢,2¢-trichloromethylcarbonylamino)cyclohexa-2-ene was then converted to
a novel allylic alcohol via a 4,5-dihydro-1,3-oxazole. Functionalisation of this allylic alcohol by Upjohn
dihydroxylation conditions or by a directed epoxidation/hydrolysis sequence of reactions allowed the
synthesis of two dihydroconduramines in excellent stereoselectivity. The stereochemical assignment of
all compounds prepared was confirmed by NOE experiments or X-ray structure determination.
which form the aglycon portions of the therapeutically useful
Introduction
aminoglycoside antibiotics.2,4,5 They have also been used to prepare
a variety of natural products such as alkaloids6 and azasugars.7
The importance of conduramines and their derivatives have led
to a significant number of approaches for their preparation,
usually via functional group manipulation of carbohydrates or
other natural building blocks.1,2,5,8 The most recent stereoselective
syntheses of conduramines have involved nitroso-Diels–Alder
reactions as the key step.9 Studer and co-workers used a Cu(I)-
catalysed enantioselective nitroso-Diels–Alder reaction between
2-nitrosopyridine and cyclohexa-1,3-dienes,9a while the research
group of Liao used a homochiral nitroso dienophile derived from
10-camphorsulfonic acids with masked o-benzoquinones.9b In
both cases, the cycloadducts were obtained in excellent yields and
stereoselectivities and were easily converted to the corresponding
conduramine core.
Conduramines such as conduramine C-1 (2) and E-1 (3) are purely
synthetic aminocyclohexenetriols formally derived from conduri-
tols (1) in which one of the hydroxyl groups is exchanged for an
amino moiety (Fig. 1).1,2 They constitute an increasingly important
class of compound due to their ability to mimic oligosaccharides
and act as inhibitors of glycosidases.3 Conduramines are excellent
synthetic precursors of amino- and diaminocyclitols many of
Very recently, we developed a new one-pot tandem process that
utilises an Overman rearrangement10 and a ring closing metathesis
(RCM) reaction for the rapid and highly efficient synthesis of 5-, 6-,
7- and 8-membered carbocyclic amides.11 A stereoselective variant
has also been developed using chiral palladium(II)-catalysts for
the Overman rearrangement step resulting in application of this
tandem process for natural product synthesis.11,12 Continuing our
studies on new synthetic applications of the tandem process,
we now report in full the asymmetric synthesis of an N-
(cyclohexenyl)trichloroacetamide 7 and the subsequent investiga-
tion of the stereoselective oxidation of this synthetic intermediate
leading to the preparation of polyhydroxylated aminocyclohex-
ane derivatives (Scheme 1). In particular, we have used this
approach for the highly stereoselective synthesis of dihydrocon-
duramine E-1 4 and the enantiomer of dihydroconduramine
C-1 5.
Fig. 1 Structures of 1, 2, 3, 4 and 5.
WestCHEM, School of Chemistry, The Joseph Black Building, Univer-
sity of Glasgow, Glasgow, UK, G12 8QQ. E-mail: Andrew.Sutherland@
glasgow.ac.uk
† Electronic supplementary information (ESI) available: Figure showing
the key NOE enchancements for compounds 15, 17, 22 and 23. CIF files for
compounds 17 and 21; CCDC reference numbers 809769 and 809770. 1H
and 13C NMR spectra for all new compounds. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c0ob00619j
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emphasised that this general approach permits the highly efficient
and rapid synthesis of carbocyclic allylic amides such as 7 on a
multi-gram scale (e.g. 75% overall yield of 7 from 8).
Due to the considerable interest in the vicinal amino
diol motif19 and in particular 3-aminocyclohexane-1,2-diols,20
we next investigated the dihydroxylation of (1S)-1-(2¢,2¢,2¢-
trichloromethylcarbonylamino)cyclohexa-2-ene (7). An effective
method for the syn-selective dihydroxylation of cyclic allylic
trichloroacetamides has been reported by Donohoe and co-
workers.21 This method uses a reagent that is generated from
osmium tetroxide and N,N,N¢,N¢-tetramethylethylenediamine
(TMEDA). This reagent then forms a complex with the sub-
strate via hydrogen bonding and directed dihydroxylation occurs
forming predominantly, the all syn-isomer. Dihydroxylation of
7 using this procedure gave 1,2-syn-2,3-syn-isomer 13 in 94%
Scheme 1 Proposed route to polyhydroxylated aminocyclohexanes.
Results and discussion
The first stage of this project involved the development of
a highly efficient asymmetric synthesis of N-(cyclohexenyl)-
trichloroacetamide 7 (Scheme 2).11a The key substrate (2E)-octa-
2,7-dien-1-ol (6) was prepared in two steps from 5-hexen-1-ol
(8) using a one-pot Swern oxidation and Horner–Wadsworth–
Emmons reaction to give E-a,b-unsaturated ester 9 followed by
reduction of the ester functional group using DIBAL-H.13 Allylic
alcohol 6 was then converted to allylic trichloroacetimidate 10
using trichloroacetonitrile and a catalytic amount of DBU.14
Without purification, allylic trichloroacetimidate 10 was then
subjected to the one-pot tandem process using commercially avail-
able (S)-COP-Cl 1115,16 to catalyse the Overman rearrangement
and Grubbs first generation catalyst17 to effect the ring closing
metathesis step. This allowed the isolation of (1S)-1-(2¢,2¢,2¢-
trichloromethylcarbonylamino)cyclohexa-2-ene (7) in 90% yield
from allylic alcohol 6 and in 88% enantiomeric excess.18 The enan-
tiomeric excess of 7 was improved to >99% on recrystallisation
from a mixture of ethyl acetate and petroleum ether. It should be
1
diastereomeric excess (by H NMR spectroscopy) (Scheme 3).21
Flash column chromatography allowed isolation of 13 as a single
stereoisomer in 93% yield. Synthesis of the 1,2-syn-2,3-anti-isomer
15 was achieved using a two-step approach. Epoxidation of 7 was
carried out using meta-chloroperbenzoic acid (m-CPBA) which
gave cis-epoxide 14 via a substrate directed intermediate22 in 90%
diastereomeric excess (by 1H NMR spectroscopy). As before,
separation of the diastereomers by flash column chromatography
was easily achieved allowing isolation of 14 as a single stereoisomer
in 95% yield. Acid mediated hydrolysis of the epoxide then gave
15 in 75% yield as a single stereoisomer. The relative stereo-
chemistry of 15 was confirmed by difference NOE experiments
which clearly showed the 1,2-syn-2,3-anti-relationships of the
trichloroacetamide and hydroxyl groups.23
Scheme 3 Reagents and conditions: i. OsO4, TMEDA, CH2Cl2, -78 ◦C,
93%; ii. m-CPBA, NaHCO3, CH2Cl2, 95%; iii. 0.2 M H2SO4, 1,4-dioxane,
75%.
The next stage of our programme then focused on methods for
the stereoselective introduction of three hydroxyl groups to (1S)-
1-(2¢,2¢,2¢-trichloromethylcarbonylamino)cyclohexa-2-ene (7) that
would allow access to dihydroconduramines 4 and 5. Our proposed
strategy involved stereoselective functionalisation of the alkene
of 7 in such a way to introduce a hydroxyl group at C-2 and
a leaving group at C-3 of the cyclohexane ring. Elimination of
the leaving group and subsequent stereoselective oxidation of the
Scheme 2 Reagents and conditions: i. (COCl)2, DMSO, Et3N, CH2Cl2,
-78 ◦C to RT, then DBU, LiCl, (EtO)2POCH2CO2Et, MeCN, 88% over
the two steps; ii. DIBAL-H (2.2 eq.), Et2O, -78 ◦C to RT, 95%; iii. DBU,
Cl3CCN, CH2Cl2; iv. (S)-COP-Cl 11 (5 mol%), CH2Cl2, 45 ◦C; v. Grubbs’
1st generation catalyst (10 mol%), D, 90% from 6.
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resulting alkene would then produce the conduramine derivatives.
The first stage of this strategy was implemented by reaction
of 7 with N-iodosuccinimide to give 4,5-dihydro-1,3-oxazole 16
in 85% yield (Scheme 4).24 As 16 was found to be relatively
unstable, it was subjected immediately to hydrolysis under acidic
conditions which gave 1,2-syn-2,3-anti-iodoalcohol 17 in 76%
yield and as a single stereoisomer. The relative stereochemistry
of 17 was initially confirmed by difference NOE experiments.23
However, recrystallisation of 17 provided crystals suitable for
X-ray structural determination. Iodoalcohol 17 crystallises in
the monoclinic space group P21 (Fig. 2, see also supporting
information†) and the structure clearly shows the 1,2-syn-2,3-
anti-relationship of the trichloroacetamide, hydroxyl and iodide
substitutents.25 Thus, reaction of 7 with N-iodosuccinimide must
generate the iodonium intermediate anti to the trichloroacetamide
group followed by syn-formation of the 4,5-dihydro-1,3-oxazole
ring yielding 16. Hydrolysis then takes place at C-2 of the 4,5-
dihydro-1,3-oxazole ring to give 17. On preparation of iodoalcohol
17, elimination of the iodide to generate allylic alcohol 19 was
then investigated. However, all attempts using a number of bases
including DBU under reflux conditions returned only starting
material. Instead, (1S)-N-(cyclohexenyl)trichloroacetamide 7 was
again reacted with N-iodosuccinimide. Without purification, 4,5-
dihydro-1,3-oxazole 16 was treated with DBU and the resulting
intermediate 18 was subjected to hydrolysis under acidic condi-
tions. This allowed the isolation of allylic alcohol 19 in 60% yield
over the three steps.
With allylic alcohol 19 in hand, oxidation of the alkene moiety
was then investigated (Scheme 5). Dihydroxylation of 19 using the
Donohoe conditions gave a 3 : 1 mixture of two diastereomeric
triols in 87% yield.21 The major isomer was easily separated by
flash column chromatography in 53% yield and recrystallisation
allowed X-ray structural determination (Fig. 3, see also supporting
information†).26 Surprisingly, the X-ray structure revealed that the
major diastereomer was 1,2-syn-2,3-anti-3,4-syn isomer 21. Dono-
hoe and co-workers have studied the use of 6-membered cyclic
homoallylic trichloroacetamides as substrates for their directed
dihydroxylation and found these to have poor stereoselectivity.27
They proposed that the bulky trichloroacetamide group in these
compounds likely adopts an equatorial position which prevents
it from effectively directing the dihydroxylation. However, we
reasoned that allylic alcohol 19 should be a good substrate for the
Donohoe directed dihydroxylation. With the bulky trichloroac-
etamide group in an equatorial position, the adjacent hydroxyl
group must be axial and thus, in a position to direct the
dihydroxylation forming triol 20 as the major diastereomer. The
isolation of triol 20 as the minor diastereomer suggests that while
directed dihydroxylation via the alcohol may occur to some extent,
Scheme 5 Reagents and conditions: i. OsO4, TMEDA, CH2Cl2, -78 ◦C,
87% (1 : 3 ratio of 20 and 21, respectively); ii. OsO4, NMO, acetone, H2O,
56% (21 only); iii. 2.0 M NaOH, MeOH, 68%; iv. m-CPBA, NaHCO3,
CH2Cl2, 69%; v. 0.2 M H2SO4, 1,4-dioxane, 87%, vi. 2.0 M NaOH, MeOH,
98%.
Scheme 4 Reagents and conditions: i. N-iodosuccinimide, CHCl3, 85%;
ii. 2.0 M HCl, MeOH, 76%; iii. DBU, toluene, D; iv. 2.0 M HCl, MeOH,
60% from 7.
Fig. 2 Molecular structure of compound 17. Displacement ellipsoids are
Fig. 3 Molecular structure of compound 21. Displacement ellipsoids are
drawn at the 50% probability level.
drawn at the 50% probability level.
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dihydroxylation preferably takes place from the least hindered face
of the cyclohexene ring to give the trichloroacetamide derivative
of dihydroconduramine E-1 21 as the major product. To probe
whether the minor product of this reaction, triol 20 was actually
being formed by a directed dihydroxylation via the 2-hydroxyl
group or just as the minor product of a face selective non-
directed dihydroxylation, allylic alcohol 19 was also subjected
to standard Upjohn conditions (OsO4, NMO), a protocol where
dihydroxylation takes place by a non-directed mechanism.21,28 This
gel 60 (UV254) were used for thin layer chromatography and
were visualised by staining with potassium permanganate. 1H
NMR and 13C NMR spectra were recorded on a Bruker DPX
400 spectrometer with chemical shift values in ppm relative to
tetramethylsilane as the standard. Assignment of 1H and 13C
NMR signals are based on two-dimensional COSY and DEPT
experiments, respectively. Infrared spectra were recorded using
Golden Gate apparatus on a JASCO FTIR 410 spectrometer and
mass spectra were obtained using a JEOL JMS-700 spectrometer.
Melting points were determined on a Reichert platform melting
point apparatus. Optical rotations were determined as solutions
irradiating with the sodium D line (l = 589 nm) using an Autopol
V polarimeter. [a]D values are given in units 10-1 deg cm2 g-1. The
chiral HPLC methods were calibrated with their corresponding
1
gave triol 21 as a single stereoisomer (by H NMR spectroscopy
of the crude reaction material) and in 56% yield. The result
from this Upjohn dihydroxylation of 19 shows that formation of
triol 20 using the Donohoe conditions must occur by a directing
effect via the 2-hydroxyl group. To access dihydroconduramine 4,
the trichloroacetyl protecting group of 21 was removed under
base-mediated conditions. After purification by ion exchange
chromatography, dihydroconduramine E-1 4 was isolated in 68%
yield.
5
racemic mixtures. (S)-COP-Cl refers to di-m-chlorobis[h -(S)-(rR)-
4
2-(2¢-(4¢-methylethyl)oxazolinyl)cyclopentadienyl, 1-C, 3¢-N)(h -
tetraphenylcyclobutadiene)cobalt]dipalladium.
It was proposed that the synthesis of the enantiomer of
dihydroconduramine C-1, compound 5 could be achieved by a
directed epoxidation of allylic alcohol 19 followed by hydrolysis,
the same strategy used for the preparation of diol 15 (see Scheme
3). While dihydroxylation of 19 via a 2-hydroxyl directed reaction
was not particularly effective, there was significant literature
precedent for the directed epoxidation of cyclic allylic alcohols
according to Henbest’s rule using m-CPBA.29,30 Treatment of
19 with m-CPBA gave epoxide 22 in 90% diastereomeric excess
(Scheme 5). Purification by flash column chromatography gave the
major product, the all syn-diastereomer 22 in 69% yield. Difference
NOE experiments confirmed that the major diastereomer was
the 1,2-syn-2,3-syn-3,4-syn isomer.23 Hydrolysis of epoxide 22
under acidic conditions gave dihydroconduramine derivative 23
in 87% yield. Again, difference NOE experiments confirmed
that the product formed was the 1,2-syn-2,3-syn-3,4-anti isomer.23
Finally, hydrolysis of the trichloroacetamide group using sodium
hydroxide gave dihydroconduramine 5 in 98% yield.
Ethyl (2E)-2,7-octadienoate (9)31
Dimethyl sulfoxide (7.10 mL, 0.10 mol) was added to a stirred
solution of oxalyl chloride (5.08 mL, 0.06 mol) in dichloromethane
(100 mL) at -78 ◦C under an argon atmosphere. The reaction
mixture was stirred for 0.3 h before 5-hexen-1-ol (8) (4.00 g, 0.04
mol) in dichloromethane (50 mL) was slowly added. The mixture
was stirred for a further 0.3 h before triethylamine (27.8 mL,
0.20 mol) was added. This reaction mixture was stirred for 0.5
h at -78 ◦C and then allowed to warm to room temperature
and stirred for a further 2 h. Meanwhile, a solution of lithium
chloride (2.97 g, 0.07 mol), triethyl phosphonoacetate (11.9 mL,
0.06 mol) and 1,8-diazabicyclo[5,4,0]undec-7-ene (8.97 mL, 0.06
mol) in acetonitrile (100 mL) was prepared and stirred for
1.0 h under an argon atmosphere. The Swern solution was
concentrated in vacuo, then the Horner Wadsworth Emmons
solution was added and the reaction mixture was stirred at room
temperature overnight. The reaction was quenched by the addition
of a saturated solution of ammonium chloride (50 mL) and
concentrated to give an orange residue, which was then extracted
with diethyl ether (4 ¥ 75 mL). The organic layers were combined,
dried (MgSO4) and concentrated to give an orange oil. Flash
column chromatography (petroleum ether/diethyl ether, 10 : 1)
yielded ethyl (2E)-2,7-octadienoate (9) (5.91 g, 88% yield) as
a colourless oil. Spectroscopic data consistent with literature.31
Conclusions
In summary, a one-pot tandem process involving an Overman rear-
rangement and RCM reaction has been used for the highly efficient
multi-gram synthesis of (1S)-N-(cyclohexenyl)trichloroacetamide
7. Oxidation of 7 has been studied leading to the preparation of
two diol derivatives in excellent diastereoselectivity. Conversion
of 7 to allylic alcohol 19 via 4,5-dihydro-1,3-oxazole 16 by a
three-step process was followed by further oxidation leading to
the preparation of two dihydroconduramines. These studies have
generated further insight into the stereoselective functionalisation
of substituted cyclohexenes and work is currently underway to
extend these processes for the preparation of more complex
biologically active compounds.
n
max/cm-1 (NaCl) 2933 (CH), 1721 (CO), 1655 (C C), 1367,
1267, 1198, 1044; dH (400 MHz, CDCl3) 1.28 (3H, t, J 7.1 Hz,
OCH2CH3), 1.52–1.58 (2H, m, 5-H2), 2.06–2.12 (2H, m, 6-H2),
2.18–2.25 (2H, m, 4-H2), 4.17 (2H, q, J 7.1 Hz, OCH2CH3), 4.96–
5.06 (2H, m, 8-H2), 5.73–5.96 (2H, m, 2-H and 7-H), 6.95 (1H, dt,
J 15.5, 6.9 Hz, 3-H); dC (100 MHz, CDCl3) 14.3 (CH3), 27.1 (CH2),
31.5 (CH2), 33.1 (CH2), 60.2 (CH2), 115.1 (CH2), 121.5 (CH), 138.0
(CH), 149.0 (CH), 166.7 (C); m/z (CI) 169.1232 (MH+. C10H17O2
requires 169.1229), 141 (90%), 123 (75), 95 (100), 81 (53), 55 (32).
Experimental
(2E)-Octa-2,7-dien-1-ol (6)31
All reagents and starting materials were obtained from commercial
sources and used as received. All dry solvents were purified using
a PureSolv 500 MD solvent purification system. Flash column
chromatography was carried out using Fisher matrix silica 60.
Macherey–Nagel aluminium-backed plates pre-coated with silica
Ethyl (2E)-2,7-octadienoate (9) (5.00 g, 27.5 mmol) was dissolved
in diethyl ether (100 mL) and cooled to -78 ◦C under argon.
DIBAL-H (1.0 M in hexane) (60.5 mL, 60.5 mmol) was added
dropwise and the reaction mixture was stirred at -78 ◦C for 3
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h, before warming to room temperature overnight. The solution
was cooled to 0 C and quenched by the addition of a saturated
(1S,2S,3R)-1-(2¢,2¢,2¢-Trichloromethylcarbonylamino)-2,3-
◦
dihydroxycyclohexane (13)21c
solution of ammonium chloride (100 mL) and warmed to room
temperature with vigorous stirring over 1 h producing a white
precipitate. The reaction mixture was filtered through a pad of
(1S)-1-(2¢,2¢,2¢-Trichloromethylcarbonylamino)cyclohexa-2-ene
(7) (0.10 g, 0.42 mmol) was dissolved in dichloromethane (10 mL)
at -78 ◦C under argon. Tetramethylethylenediamine (0.07 g,
0.45 mmol) was added and the reaction mixture stirred for 0.1
h before the addition of osmium tetroxide (0.10 g, 0.43 mmol).
R
Celiteꢀ and washed with diethyl ether (500 mL). The filtrate was
then dried (MgSO4) and concentrated in vacuo. Flash column
chromatography (petroleum ether/diethyl ether, 1 : 4) yielded
(2E)-octa-2,7-dien-1-ol (6) (3.56 g, 95% yield) as a colourless oil.
◦
The dark coloured solution was stirred for 1 h at -78 C before
warming to room temperature and stirred for a further 1 h. The
solvent was removed in vacuo and the dark coloured solid was
redissolved in methanol (10 mL). Concentrated hydrochloric acid
(5 drops) was added and the reaction mixture stirred for 2 h. The
solvent was removed in vacuo to afford a dark solid. Flash column
chromatography (elution with petroleum ether/diethyl ether, 1 : 4)
afforded (1S,2S,3R)-1-(2¢,2¢,2¢-trichloromethylcarbonylamino)-
2,3-dihydroxycyclohexane (13) (0.11 g, 93%) as a colourless oil.
Spectroscopic data consistent with literature.31 max/cm-1 (NaCl)
n
3346 (OH), 2928 (CH), 1640 (C C), 1439, 1090, 997, 970; dH
(400 MHz, CDCl3) 1.34 (1H, br s, OH), 1.46–1.51 (2H, m, 5-H2),
2.02–2.10 (4H, m, 4-H2 and 6-H2), 4.07 (2H, d, J 4.6 Hz, 1-H2),
4.94–4.97 (1H, m, 8-HH), 5.01 (1H, dq, J 17.0, 1.7 Hz, 8-HH),
5.60–5.73 (2H, m, 2-H and 3-H), 5.80 (1H, ddt, J 17.0, 10.2, 6.7
Hz, 7-H); dC (100 MHz, CDCl3) 28.3 (CH2), 31.6 (CH2), 33.2
(CH2), 63.7 (CH2), 114.6 (CH2), 129.2 (CH), 133.0 (CH), 138.6
(CH); m/z (CI) 109.1009 (MH+-H2O. C8H13 requires 109.1017),
95 (16%), 81 (12), 67 (47).
Spectroscopic data consistent with literature.21c max/cm-1 (NaCl)
n
3407 (NH/OH), 2942 (CH), 1700 (CO), 1512, 1042, 821; [a]D25
-3.8 (c 1.0, CHCl3); dH (400 MHz, CDCl3) 1.30–1.43 (1H, m,
5-HH), 1.59–1.80 (5H, m, 4-H2, 5-HH and 6-H2), 2.56 (1H, br
s, OH), 2.90 (1H, br s, OH), 3.83–3.93 (2H, m, 2-H and 3-H),
3.95–4.05 (1H, m, 1-H), 7.73 (1H, br s, NH); dC (100 MHz,
CDCl3) 18.3 (CH2), 26.1 (CH2), 28.4 (CH2), 52.1 (CH), 70.4
(CH), 70.9 (CH), 92.7 (C), 161.8 (C); m/z (CI) 275.9960 (MH+.
C8H1335Cl3NO3 requires 275.9961), 242 (35%), 179 (12), 123 (89),
109 (88), 73 (100).
(1S)-1-(2¢,2¢,2¢-Trichloromethylcarbonylamino)cyclohexa-2-ene
(7)32
(2E)-Octa-2,7-dien-1-ol (6) (3.00 g, 23.8 mmol) was dissolved
in dichloromethane (80 mL) and cooled to 0 ◦C under argon.
1,8-Diazabicyclo[5.4.0]undec-7-ene (0.90 mL, 5.94 mmol) was
then added to the solution followed by trichloroacetonitrile
(3.60 mL, 35.8 mmol). The reaction mixture was warmed to room
temperature and stirred for 2 h. The reaction mixture was then
filtered through a short pad of silica gel and washed with diethyl
ether (400 mL). The resulting filtrate was then concentrated to give
allylic trichloroacetimidate 10, which was used without further
purification. Allylic trichloroacetimidate 10 (6.60 g) was dissolved
in dichloromethane (200 mL) under an argon atmosphere. (S)-
COP-Cl catalyst 11 (1.77 g, 1.21 mmol) was then added to the
solution and the reaction mixture was stirred at 45 ◦C for 3
days. Grubb’s 1st generation catalyst (1.98 g, 2.40 mmol) was
2¢,2¢,2¢-Trichloro-N-[(1S,2S,3R)-oxabicyclo[4.1.0]hept-2-
yl]acetamide (14)22
(1S)-1-(2¢,2¢,2¢-Trichloromethylcarbonylamino)cyclohexa-2-ene
(7) (0.24 g, 0.97 mmol) was dissolved in dichloromethane (15 mL)
along with sodium hydrogencarbonate (0.16 g 1.95 mmol). To
the stirred suspension was added meta-chloroperoxybenzoic acid
(0.34 g 1.95 mmol) at room temperature. The resulting suspension
was stirred vigorously for 19 h. A 20% aqueous solution of sodium
sulphite (10 mL) was added and the resulting two-phase mixture
was stirred vigorously for 0.25 h. The two layers were separated
and the aqueous layer was extracted with dichloromethane (2 ¥
20 mL). The combined organic layers were washed with a 20%
aqueous solution of sodium sulphite (10 mL) and a 5% aqueous
solution of sodium hydrogencarbonate (2 ¥ 20 mL), dried
(Na2SO4) and evaporated under reduced pressure. Purification
by flash column chromatography (petroleum ether/diethyl ether,
2 : 5) gave 2¢,2¢,2¢-trichloro-N-[(1S,2S,3R)-oxabicyclo[4.1.0]hept-
2-yl]acetamide (14) (0.24 g, 95%) as white solid. Spectroscopic
data consistent with literature.22 Mp 75–77 ◦C; nmax/cm-1 (NaCl)
3421 (NH), 3020 (CH), 1712 (CO), 1363, 1217, 757; [a]2D5 -26.8
(c 1.0, CHCl3); dH (400 MHz, CDCl3) 1.20–1.59 (4H, m, 5-H2
and 6-H2), 1.82–1.20 (2H, m, 4-H2), 3.25 (1H, t, J 3.4 Hz, 2-H),
3.30 (1H, td, J 3.8, 3.4 Hz 3-H), 4.25–4.32 (1H, m, 1-H), 7.02
(1H, br s, NH); dC (100 MHz, CDCl3) 17.6 (CH2), 23.1 (CH2),
25.8 (CH2), 47.5 (CH), 53.0 (CH), 54.6 (CH), 92.7 (C), 161.8 (C);
m/z (CI) 257.9852 (MH+. C8H1135Cl3NO2 requires 257.9855), 224
(28%), 191 (6), 137 (21), 107 (45), 73 (100).
◦
then added and the reaction mixture was heated at 65 C under
reflux overnight. The mixture was cooled to room temperature,
R
filtered through a short pad of Celiteꢀ and washed with diethyl
ether (600 mL). The filtrate was then dried (MgSO4) and con-
centrated in vacuo. Purification by flash column chromatography
(elution with petroleum ether/diethyl ether, 97 : 3) gave (1S)-1-
(2¢,2¢,2¢-trichloromethylcarbonylamino)cyclohexa-2-ene (7) (5.21
g, 90% yield over 3 steps) as a white solid. 88% ee determined
by HPLC analysis using CHIRALPAK IB column (0.5% iso-
propanol/hexane at 0.75 mL min-1), retention time: tS = 8.2 min,
and tR = 9.2 min. Mp 85–86 ◦C, lit.32 86–87 ◦C; nmax/cm-1 (NaCl)
3421 (NH), 2941 (CH), 1676 (CO), 1519, 1073, 822; [a]2D3 -95.3
(c 2.1, CHCl3); dH (400 MHz, CDCl3) 1.62–1.79 (3H, m, 5-H2
and 6-HH), 1.94–2.03 (1H, m, 6-HH), 2.03–2.16 (2H, m, 4-H2),
4.42–4.54 (1H, m, 1-H), 5.65 (1H, ddt, J 10.0, 4.0, 2.2 Hz, 2-H),
5.98 (1H, dtd, J 10.0, 4.0, 1.9 Hz, 3-H), 6.60 (1H, br s, NH); dC
(100 MHz, CDCl3) 19.4 (CH2), 24.7 (CH2), 28.6 (CH2), 46.9 (CH),
92.7 (C), 125.7 (CH), 132.7 (CH), 161.1 (C); m/z (CI) 261.0144
+
(MNH4 . C8H1435Cl237ClN2O requires 261.0143), 259 (100%), 242
(23), 225 (9), 206 (21), 81 (10).
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(1S,2S,3S)-1-(2¢,2¢,2¢-Trichloromethylcarbonylamino)-2,3-
dihydroxycyclohexane (15)
(1S,2R)-1-(2¢,2¢,2¢-Trichloromethylcarbonylamino)-2-
hydroxycyclohexa-3-ene (19)
2¢,2¢,2¢-Trichloro-N-[(1S,2S,6R)-7-oxabicyclo[4.1.0]hept-2-yl]-
acetamide (14) (0.10 g, 0.35 mmol) was added to a 1 : 1
mixture of 0.2 M sulfuric acid/1,4-dioxane (15 mL) and the
reaction mixture was stirred at room temperature for 0.75
h. The reaction was then diluted with a saturated solution
of sodium hydrogencarbonate (10 mL) and extracted with
ethyl acetate (3 ¥ 30 mL). The organic layers were com-
bined, dried (MgSO4) and concentrated in vacuo. Purification
by flash column chromatography (petroleum ether/diethyl ether,
10 : 1) gave (1S,2S,3S)-1-(2¢,2¢,2¢-trichloromethylcarbonylamino)-
2,3-dihydroxycyclohexane (15) (0.08 g, 75%) as a colourless oil.
To a solution of (1S)-1-(2¢,2¢,2¢-trichloromethylcarbonylamino)-
cyclohexa-2-ene (7) (4.00 g, 16.5 mmol) in chloroform (100 mL),
N-iodosuccinimide (5.52 g, 25.0 mmol) was added and the
mixture stirred for 18 h under argon. The solvent was then
removed in vacuo. The resulting residue was dissolved in ethyl
acetate (120 mL) and the organic phase washed with water (3
¥ 50 mL), dried (MgSO4) and the solvent removed in vacuo.
The residue obtained was dissolved in toluene (100 mL) and
1,8-diazabicyclo[5,4,0]undec-7-ene (3.70 mL, 24.8 mmol) was
added. The reaction mixture was heated under reflux for 12
h under argon. The reaction mixture was then cooled and
solvent was removed in vacuo. The resulting dark coloured solid
was dissolved in methanol (80 mL). 2.0 M Hydrochloric acid
(30 mL) was added and reaction mixture was stirred at room
temperature for 1 h. The reaction mixture was then diluted with
a saturated solution of sodium hydrogencarbonate (80 mL) and
extracted with ethyl acetate (3 ¥ 70 mL). The organic layers were
combined, dried (MgSO4) and concentrated in vacuo. Purification
by flash column chromatography (petroleum ether/diethyl ether,
1 : 4) gave (1S,2R)-1-(2¢,2¢,2¢-trichloromethylcarbonylamino)-2-
hydroxycyclohexa-3-ene (19) (2.54 g, 60%) as white solid. Mp
105–109 ◦C; nmax/cm-1 (NaCl) 3404 (OH), 2940 (CH), 1699 (CO),
1506, 1096, 909, 822; [a]2D5 -71.9 (c 1.0, CHCl3); dH (400 MHz,
CDCl3) 1.50 (1H, br s, OH), 1.64–1.75 (1H, m, 6-HH), 1.86–1.94
(1H, m, 6-HH), 2.20–2.26 (2H, m, 5-H2), 3.97 (1H, ddd, J 11.9,
7.6, 3.6 Hz, 1-H), 4.14–4.21 (1H, m, 2-H), 5.85–5.91 (1H, m, 3-H),
6.00 (1H, dt, J 9.8, 3.6 Hz, 4-H), 7.36 (1H, br s, NH); dC (100
MHz, CDCl3) 22.4 (CH2), 24.8 (CH2), 51.4 (CH), 64.7 (CH), 92.5
(C), 127.2 (CH), 133.4 (CH), 162.5 (C); m/z (CI) 257.9857 (MH+.
C8H1135Cl3NO2 requires 257.9855), 224 (98%), 190 (36), 153 (48),
113 (59), 81 (100).
n
max/cm-1 (NaCl) 3408 (OH), 2942 (CH), 1700 (CO), 1512, 821;
[a]2D5 +9.9 (c 1.0, CHCl3); dH (400 MHz, CDCl3) 1.45–1.55 (2H,
m, 4-HH and 5-HH), 1.58–1.77 (2H, m, 5-HH and 6-HH), 1.84–
1.95 (2H, m, 4-HH and 6-HH), 3.01 (1H, br s, OH), 3.22 (1H,
br s, OH), 3.77 (1H, dd, J 6.0, 3.6 Hz, 2-H), 3.82–3.89 (1H, m,
3-H), 4.15–4.21 (1H, m, 1-H), 7.16 (1H, d, J 7.6 Hz, NH); dC (100
MHz, CDCl3) 18.6 (CH2), 26.3 (CH2), 28.5 (CH2), 51.0 (CH), 70.5
(CH), 72.1 (CH), 92.7 (C), 162.1 (C); m/z (CI) 275.9959 (MH+.
C8H1335Cl3NO3 requires 275.9961), 242 (59%), 208 (30), 158 (16),
113 (33), 69 (100).
(1S,2S,3S)-1-(2¢,2¢,2¢-Trichloromethylcarbonylamino)-2-hydroxy-
3-iodocyclohexane (17)
To a solution of (1S)-1-(2¢,2¢,2¢-trichloromethylcarbonylamino)-
cyclohexa-2-ene (7) (0.29 g, 1.20 mmol) in chloroform (15 mL),
N-iodosuccinimide (0.40 g, 1.81 mmol) was added and the mixture
stirred for 18 h under argon. The solvent was then removed in
vacuo. The resulting residue was dissolved in ethyl acetate (20 mL)
and the organic phase washed with water (4 ¥ 30 mL). The organic
layer was then dried (MgSO4) and the solvent removed in vacuo
to give (3aS,4S,7aS)-4-iodo-2-(trichloromethyl)benzoxazole (16)
(0.37 g, 85% yield) as a colourless oil which was used without
further purification. dH (400 MHz, CDCl3) 1.50–1.69 (2H, m,
5-H2), 1.90–2.23 (4H, m, 4-H2 and 6-H2), 4.17–4.30 (2H, m,
1-H and 3-H), 5.16 (1H, t, J 7.5 Hz, 2-H). To a solution of
(3aS,4S,7aS)-4-iodo-2-(trichloromethyl)benzoxazole (16) (0.37 g,
1.01 mmol) in methanol (20 mL) was added 2.0 M hydrochloric
acid (8 mL) and the reaction mixture was stirred at room
temperature for 0.75 h. The reaction mixture was then diluted with
a saturated solution of sodium hydrogencarbonate (10 mL) and
extracted with ethyl acetate (3 ¥ 30 mL). The organic layers were
combined, dried (MgSO4) and concentrated in vacuo. Purification
by flash column chromatography (petroleum ether/diethyl ether,
10 : 1) gave (1S,2S,3S)-1-(2¢,2¢,2¢-trichloromethylcarbonylamino)-
2-hydroxy-3-iodocyclohexane (17) (0.30 g, 76%) as a white solid.
(1S,2S,3S,4S)-1-(2¢,2¢,2¢-Trichloromethylcarbonylamino)-2,3,4-
trihydroxycyclohexane (21)
(1S,2R)-1-(2¢,2¢,2¢-Trichloromethylcarbonylamino)-2-hydroxy-
cyclohexa-3-ene (19) (1.00 g, 3.89 mmol) was dissolved in
dichloromethane (50 mL) at -78 ◦C under argon. Tetram-
ethylethylenediamine (0.68 mL, 4.54 mmol) was added and
the reaction mixture stirred for 0.1 h before the addition of
osmium tetroxide (1.00 g 3.90 mmol). The dark coloured so-
lution was stirred for 1 h at -78 ◦C before warming to room
temperature and stirred for a further 1 h. The solvent was
removed in vacuo and the dark coloured solid was dissolved in
methanol (50 mL). Concentrated hydrochoric acid (1 mL) was
added and the reaction mixture stirred for 2 h. The solvent
was removed in vacuo to afford a dark solid. Column chro-
matography (elution with petroleum ether/diethyl ether, 1 : 4) af-
forded (1S,2S,3S,4S)-1-(2¢,2¢,2¢-trichloromethylcarbonylamino)-
2,3,4-trihydro◦xycyclohexane (21) (0.60 g, 53%) as a white solid.
Mp 151–153 C; nmax/cm-1 (NaCl) 3360 (OH), 2947 (CH), 1653
(CO), 1456, 1420, 1024; [a]2D5 -27.6 (c 0.9, MeOH); dH (400 MHz,
CD3OD) 1.63–1.83 (4H, m, 5-H2 and 6-H2), 3.83–3.92 (3H, m, 2-
H, 3-H and 4-H), 4.10 (1H, ddd, J 10.6, 4.4, 2.9 Hz, 1-H); dC (100
MHz, CDCl3) 24.7 (CH2), 27.4 (CH2), 50.6 (CH), 68.4 (CH), 72.3
(CH), 74.0 (CH), 93.8 (C), 163.0 (C); m/z (CI) 291.9908 (MH+.
◦
Mp 103–105 C; nmax/cm-1 (NaCl) 3402 (OH), 2941 (CH), 1695
(CO), 1509, 1155, 821; [a]2D5 +60.8 (c 1.0, CHCl3); dH (400 MHz,
CDCl3) 1.58–1.66 (1H, m, 6-HH), 1.68–1.98 (4H, m, 4-H2, 5-HH,
6-HH), 2.08–2.18 (1H, m, 5-HH), 2.32 (1H, br s, OH), 4.13 (1H,
t, J 4.1 Hz, 2-H), 4.41 (1H, q, J 4.2 Hz, 3-H), 4.46–4.54 (1H, m,
1-H), 7.02 (1H, br s, NH); dC (100 MHz, CDCl3) 21.4 (CH2), 26.2
(CH2), 29.0 (CH2), 32.9 (CH), 49.4 (CH), 72.8 (CH), 92.7 (C),
161.5 (C); m/z (CI) 387.8958 (MH+. C8H1235Cl237ClINO2 requires
387.8950), 352 (32%), 260 (100), 224 (64), 154 (42), 81 (21).
2806 | Org. Biomol. Chem., 2011, 9, 2801–2808
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C8H1335Cl3NO4 requires 291.9910), 258 (100%), 224 (50), 148 (22),
85 (12).
2951 (CH), 1705 (CO), 1510, 1223, 1078, 827, 756; [a]2D5 -125.3
(c 1.5, CHCl3); dH (400 MHz, CDCl3) 1.53–1.67 (2H, m, 6-H2),
1.96–2.06 (1H, m, 5-HH), 2.20 (1H, dt, J 15.7, 5.4 Hz, 5-HH), 2.40
(1H, d, J 9.0 Hz, OH), 3.44–3.48 (2H, m, 3-H and 4-H), 3.83–3.91
(1H, m, 1-H), 4.14–4.21 (1H, m, 2-H), 7.51 (1H, br d, J 5.3 Hz,
NH); dC (100 MHz, CDCl3) 20.2 (CH2), 22.1 (CH2), 50.6 (CH),
54.5 (CH), 55.2 (CH), 64.9 (CH), 92.6 (C), 161.8 (C); m/z (CI)
273.9804 (MH+. C8H1135Cl3NO3 requires 273.9805), 240 (100%),
206 (31), 172 (8), 156 (9), 137 (14), 121 (17), 71 (25).
(1S,2S,3S,4S)-1-(2¢,2¢,2¢-Trichloromethylcarbonylamino)-2,3,4-
trihydroxycyclohexane (21)- Upjohn Reaction
A solution of (1S,2R)-1-(2¢,2¢,2¢-trichloromethylcarbonylamino)-
2-hydroxy-3-cyclohex-ene (19) (1.00 g, 3.89 mmol) in tetrahydro-
furan (25 mL), N-methylmorpholine-N-oxide (0.60 g, 5.10 mmol)
and osmium tetraoxide (0.06 g, 0.23 mmol) was added to a
stirred solution of sodium hydrogencarbonate (0.40 g, 4.76 mmol)
in tert-butyl alcohol (15 mL) and water (4 mL). The reaction
mixture was stirred at room temperature for 24 h and then a
10% sodium sulfite solution (20 mL) was added and the reaction
mixture was extracted with ethyl acetate (3 ¥ 30 mL). The
organic layers were combined, dried (MgSO4) and concentrated in
vacuo. Purification by flash column chromatography (elution with
petroleum ether/diethyl ether, 1 : 4) gave (1S,2S,3S,4S)-1-(2¢,2¢,2¢-
trichloromethylcarbonylamino)-2,3,4-trihydroxycyclohexane (21)
(0.63 g, 56%) as a white solid. Spectroscopic data as described
above.
(1S,2S,3R,4S)-1-(2¢,2¢,2¢-Trichloromethylcarbonylamino)-2,3,4-
trihydroxycyclohexane (23)
2¢,2¢,2¢-Trichloro-N-[(1S,2S,3R,4R)-2-hydroxyoxabicyclo[4.1.
0]hept-2-yl]acetamide (22) (0.70 g, 2.56 mmol) was added to a
1 : 1 mixture of 0.2 M sulfuric acid/1,4-dioxane (20 mL) and
the reaction mixture was stirred at room temperature for 8 h.
The reaction mixture was diluted with a saturated solution of
sodium hydrogencarbonate (30 mL) and extracted with ethyl
acetate (3 ¥ 40 mL). The organic layers were combined, dried
(MgSO4) and concentrated in vacuo. Purification by flash col-
umn chromatography (petroleum ether/diethyl ether, 1 : 10) gave
(1S,2S,3R,4S)-1-(2¢,2¢,2¢-trichloromethylcarbonylamino)-2,3,4-
trihydroxycyclohexane (23) (0.65 g, 87%) as a white solid. Mp
112–114 ◦C; nmax/cm-1 (NaCl) 3440 (OH), 2946 (CH), 1647 (CO),
1450, 1411, 1016; [a]2D4 +6.4 (c 2.2, MeOH); dH (400 MHz, CD3OD)
1.34–1.43 (1H, m, 5-HH), 1.73–1.80 (2H, m, 6-H2), 1.86–1.95 (1H,
m, 5-HH), 3.50–3.54 (1H, m, 3-H), 3.79 (1H, td, J 7.8, 4.1 Hz,
4-H), 3.88–3.94 (1H, m, 1-H), 3.95 (1H, t, J 3.0 Hz, 2-H); dC
(100 MHz, CD3OD) 24.5 (CH2), 30.9 (CH2), 54.1 (CH), 70.6 (2
¥ CH), 76.2 (CH), 94.0 (C), 163.3 (C); m/z (CI) 291.9904 (MH+.
C8H1335Cl3NO4 requires 291.9910), 258 (19%), 224 (5), 197 (5), 147
(14), 123 (12), 107 (100).
(1S,2S,3S,4S)-1-Aminocyclohexane-2,3,4-triol (4)8n
(1S,2S,3S,4S)-1-(2¢,2¢,2¢-Trichloromethylcarbonylamino)-2,3,4-
trihydroxycyclohexane (21) (0.15 g, 0.52 mmol) was dissolved
in methanol (15.0 mL) and 2.0 M sodium hydroxide (3.0 mL)
was added. The reaction mixture was stirred for 12 h at room
temperature and then concentrated in vacuo. Purification by ion
exchange column chromatography (Dowex 50 W), eluting with 0.5
M ammonia solution gave (1S,2S,3S,4S)-1-aminocyclohexane-
2,3,4-triol (4) as a white solid (0.052 g, 68%). Mp 96–97 ◦C, lit.8n
95–97 ◦C; nmax/cm-1 (NaCl) 3326 (NH/OH), 2945 (CH), 1653,
1451, 1411, 1118, 1022; [a]2D3 +10.8 (c 1.0, MeOH); dH (400 MHz,
CD3OD) 1.51–1.67 (4H, m, 5-H2 and 6-H2), 3.09–3.14 (1H, m,
1-H), 3.73–3.76 (1H, m, 3-H), 3.77–3.83 (2H, m, 2-H and 4-H);
dC (100 MHz, CD3OD) 25.8 (CH2), 27.1 (CH2), 49.9 (CH), 68.7
(CH), 72.5 (CH), 73.7 (CH); m/z (CI) 148.0971 (MH+. C6H14NO3
requires 148.0974), 128 (6%), 112 (7), 85 (13), 79(42).
(1S,2S,3R,4S)-1-Aminocyclohexane-2,3,4-triol (5)
(1S,2S,3R,4S)-1-(2¢,2¢,2¢-Trichloromethylcarbonylamino)-2,3,4-
trihydroxycyclohexane (23) (0.15 g, 0.52 mmol) was dissolved in
methanol (15 mL) and 2.0 M sodium hydroxide (3.0 mL) was
added. The reaction mixture was stirred at room temperature for
12 h and then concentrated in vacuo. Purification by ion exchange
column chromatography (Dowex 50 W), eluting with 0.5 M
ammonia solution gave (1S,2S,3R,4S)-1-aminocyclohexane-
2,3,4-triol (5) (0.075 g, 98%) as a white solid. Mp 64–66 ◦C;
2¢,2¢,2¢-Trichloro-N-[(1S,2S,3R,4R)-2-hydroxyox-
abicyclo[4.1.0]hept-2-yl]acetamide (22)
(1S,2R)-1-(2¢,2¢,2¢-Trichloromethylcarbonylamino)-2-hydroxy-
cyclohexa-3-ene (19) (1.20 g, 4.67 mmol) was dissolved in
dichloromethane (40 mL) along with sodium hydrogencarbonate
(0.86 g, 10.2 mmol). To the stirred suspension was added meta-
chloroperoxybenzoic acid (1.76 g, 10.2 mmol) at room temper-
ature. The resulting suspension was stirred vigorously for 24 h.
A 20% solution of sodium sulfite (30 mL) was added and the
resulting two-phase mixture was stirred vigorously for 0.25 h. The
two layers were separated and the aqueous layer was extracted with
dichloromethane (2 ¥ 50 mL). The combined dichloromethane
layers were washed with a 20% solution of sodium sulfite (40 mL)
and a 5% solution of sodium hydrogencarbonate (2 ¥ 40 mL), dried
(Na2SO4) and evaporated under reduced pressure to give the crude
product. Purification by flash column chromatography (petroleum
ether/diethyl ether, 2 : 5) gave 2¢,2¢,2¢-trichloro-N-[(1S,2S,3R,4R)-
2-hydroxyoxabicyclo[4.1.0]hept-2-yl]acetamide (22) (0.88 g, 69%)
as a white solid. Mp 122–125 ◦C; nmax/cm-1 (NaCl) 3389 (OH),
n
max/cm-1 (NaCl) 3355 (OH), 3263 (NH), 2957 (CH), 1947, 1669,
1445, 1214, 1016; [a]D22 +23.1 (c 0.9, MeOH); dH (400 MHz,
CD3OD) 1.11–1.25 (1H, m, 5-HH), 1.46–1.58 (2H, m, 6-H2), 1.79
(1H, ddt, J 12.4, 8.4, 4.0 Hz, 5-HH), 2.71–2.79 (1H, m, 1-H), 3.18
(1H, dd, J 8.8, 2.5 Hz, 3-H), 3.53–3.61 (1H, m, 4-H), 3.7 (1H, t,
J 2.5 Hz, 2-H); dC (100 MHz, CD3OD) 27.2 (CH2), 30.6 (CH2),
53.0 (CH), 70.4 (CH), 73.9 (CH), 77.2 (CH); m/z (CI) 148.0975
(MH+. C6H14NO3 requires 148.0974), 137 (5%), 97 (41), 81 (68),
71 (100).
Acknowledgements
Financial support from the HEC, Pakistan and the University of
Glasgow is gratefully acknowledged.
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13 The Masamune-Roush conditions for the HWE step were used. For
reference see: M. A. Blanchette, W. Choy, J. T. Davis, A. P. Essenfeld,
S. Masamune, W. R. Roush and T. Sakai, Tetrahedron Lett., 1984, 25,
2183.
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18 The
enantiomeric
excess
of
(1S)-1-(2¢,2¢,2¢-
was determined
trichloromethylcarbonylamino)cyclohexa-2-ene
by chiral HPLC. See experimental for full details.
7
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25 Crystallographic
data
for
(1S,2S,3S)-1-(2¢,2¢,2¢-
(17):
trichloromethylcarbonylamino)-2-hydroxy-3-iodocyclohexane
C8H11Cl3INO2, M = 386.43, monoclinic, a ◦= 8.06780(10), b =
3
˚
˚
16.6957(2), c = 9.65370(10) A, b = 99.4370(10) , U = 1282.73(3) A ,
T = 100 K, space group P21 (no.4), Z = 4, 11006 reflections measured,
5835 unique (Rint = 0.0335) which were used in all calculations. The
final R1(F2) = 0.0449, wR2(F2) = 0.0585 (all data). The absolute
configuration was not determined by this analysis.
26 Crystallographic
data
for
(1S,2S,3S,4S)-1-(2¢,2¢,2¢-
trichloromethylcarbonylamino)-2,3,4-trihydroxycyclohexane
(21):
C8H13Cl3NO4, M = 292.54, monoclinic, a = 39.705(2), b = 5.8312(3),
◦
3
˚
˚
c = 20.2162(14) A, b = 91.296(2) , U = 4679.4(5) A , T = 100 K, space
group C2 (no.5), Z = 16, 13482 reflections measured, 9273 unique
(Rint = 0.1025) which were used in all calculations. The final R1(F2) =
0.0752, wR2(F2) = 0.1434 (all data). The absolute configuration was
not determined by this analysis.
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2808 | Org. Biomol. Chem., 2011, 9, 2801–2808
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