Synthesis of dysideaproline e using organocatalysis

Article abstract of DOI:10.1039/c0ob00617c

(S)-4,4-Dichloro-3-methylbutanoic acid was prepared in 51% overall yield from commercially available starting materials using an organocatalytic transfer hydrogenation to 4,4-dichloro-3-methylbut-2-enal in the key step. The (S)-dichloro acid was used as an intermediate in the first total synthesis of dysideaproline E and a diastereomer confirming the structure of the natural product.

Full text of DOI:10.1039/c0ob00617c

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PAPER
Synthesis of dysideaproline E using organocatalysis†
Ernest Owusu-Ansah,a Amanda C. Durow,a John R. Harding,b Angela C. Jordan,b Susan J. O’Connella and
Christine L. Willis*a
Received 23rd August 2010, Accepted 5th October 2010
DOI: 10.1039/c0ob00617c
(S)-4,4-Dichloro-3-methylbutanoic acid was prepared in 51% overall yield from commercially available
starting materials using an organocatalytic transfer hydrogenation to 4,4-dichloro-3-methylbut-2-enal
in the key step. The (S)-dichloro acid was used as an intermediate in the first total synthesis of
dysideaproline E and a diastereomer confirming the structure of the natural product.
Introduction
An intriguing feature of many biologically active natural products
is the presence of halogens. In the majority of cases these are
located at sites in accord with biohalogenation occurring via
electrophilic species, and haloperoxidases which catalyze such
reactions have been widely studied.1 However an interesting family
of chlorinated natural products exist in which the halogens are
located at aliphatic positions remote from activating groups.
The mechanism of biohalogenation via a remarkable direct
chlorination of the pro-R methyl group of leucine has been a
topic of much recent interest.2 Examples of such compounds
are six related chlorinated natural products, dysideaprolines A
Fig. 1 Examples of chlorinated natural products.
to F (1–6) isolated from extracts of Dysidea sp (NCI 1517)
collected in the Philippines (Fig. 1).3 The peptide structures
(1–6) were determined by extensive spectroscopic methods and
with the exception of dysideaproline D, 4, all contain the 4,4-
dichloro-3-methylbutanoic acid 8 moiety. This was assigned the S
configuration by analogy with other chlorinated natural products
isolated from Dysidea sp.4 Degradation studies on dysideaproline
A, 1, revealed the S-configuration for C-13 but C-5 was not
assigned. Further degradation studies on dysideproline E, 5, and
Marfey analysis indicted that it is assembled on an N-methyl-
D-leucine core i.e. C-5 has the R-configuration.3 Interestingly
X-ray studies have revealed that sintokamide A (Fig. 1), a
further polychlorinated natural product isolated from Dysidea sp.,
contains both D-trichloroleucine and L-dichloroleucine derived
fragments and is an inhibitor of the androgen receptor in prostate
cancer.5
to provide material for full biological assessment. Herein we
describe a practical and efficient synthesis of (S)-4,4-dichloro-3-
methylbutanoic acid 8 using organocatalysis and its use in the first
total synthesis of dysideaproline E 5 and the diastereomer 7
Results and discussion
Retrosynthetic analysis of dysideaproline E 5 gives three fragments
(8–10) which could be coupled via standard peptide chemistry. A
similar strategy was proposed for the synthesis of diastereomer 7
assembled on an N-methyl L-leucine core required for comparison
with the natural product 5 (Scheme 1).
The first goal was to develop an efficient synthetic approach
to (S)-dichloro acid 8. Previous syntheses of natural products
containing a dichloromethyl group have introduced the halogens
either by direct conversion of an aldehyde to a dichloride e.g. in
the synthesis of (2S,4S)-5,5-dichloroleucine,6 dysithiazolamide,7
sintokamide C8 and nakiteropiosin9 or via enolate chemistry to
prepare an a,a-dichloro acid followed by decarboxylation as in
the synthesis of dysamide B.10
Since these polychlorinated natural products are produced
in only small quantities the development of methods for their
synthesis is an important goal for structure confirmation and
aSchool of Chemistry, University of Bristol, Cantock’s Close, Bristol, UK,
BS8 1TS. E-mail: chris.willis@bristol.ac.uk; Tel: 0117 9287660
bAstraZeneca, Mereside Alderley Park, Macclesfield, Cheshire, UK, SK10
4TG
We proposed that an a,a-dichlorination/decarboxylation strat-
egy could be adopted for the synthesis of the target dichloro
acid 8 using a conjugate addition to chiral crotonate 11 to
create the required stereocentre (Scheme 2). Thus 11 was treated
† Electronic supplementary information (ESI) available: Determination of
the enantiopurity of acid 8; NMR spectra of 7, 8, 18, 20 and dysideaproline
E 5. See DOI: 10.1039/c0ob00617c
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formation of a vinyl chloride) or concomitant reduction of the
dichloride.
Inspired by biological processes which use enzyme mediated
reductions with dihydropyridine cofactors such as NADH to
perform highly stereoselective reductions, several research groups
have successfully replaced the enzymes and co-factors by small
molecule organocatalysts and dihydropyridine analogues. For
example List and MacMillan have shown that Hantzsch esters
can be used in the presence of chiral amine catalysts to reduce b,b-
disubstituted-a,b-unsaturated aldehydes in good yields and high
enantioselectivities.14 The method is versatile and a series of un-
saturated aldehydes with aromatic, heteroaromatic and aliphatic
groups at the b-position have been reduced successfully.14,15 Hence
we questioned whether the enantio- and chemoselective reduction
of a b-dichloromethyl-b-methyl-a,b-unsaturated aldehyde (X H,
Scheme 3) could be achieved using the biomimetic reaction with
an inexpensive hydride source and an air stable chiral catalyst.
The required substrate 18 was prepared in 2 steps and
62% overall yield using a Horner–Wadsworth–Emmons chain
extension of commercially available a,a-dichloroacetone with
triethyl phosphonoacetate followed by DIBALH reduction of the
resultant ester 17 (Scheme 4). From the 1H-NMR spectrum of 18
it was apparent that a 3 : 1 mixture of isomers had been formed,
Scheme 1 Retrosynthesis of dysideaproline E.
¨
with the minor isomer showing an nOe between the methyl group
and olefinic proton in accord with the Z-geometry.
Scheme 4 Synthesis of unsaturated aldehyde 18.
Scheme 2 Preparation of (S)-4,4-dichloro-3-methylbutanoic acid 8.
with allylmagnesium bromide, CuBr·SMe2, LiCl and TMSCl
under the conditions reported by Lipshutz and co-workers11 to
give the known12 alkene 12 in 94% yield. Oxidative cleavage of
alkene 12 to aldehyde 13 followed by a,a-dichlorination using
N-chlorosuccinimide and tert-butylamine13 gave, after hydrolysis,
dichloroaldehyde 14 in good yield. Oxidation of 14 gave acid 15
required for the key decarboxylation step in the presence of a
hydride source which would not reduce the dichloride moiety.
Treatment of 15 with Pb(OAc)4 and 1,4-cyclohexadiene generated
the required dichloride 16 and finally cleavage of the auxiliary gave
the target dichloro acid 8 in 7 steps and 18% overall yield from
crotonyl sultam 11.
The chemoselectivity of the key reduction step was investigated
by treating unsaturated aldehyde 18 with dihydropyridine 19 in
the presence of dibenzylamine TFA salt as the catalyst in THF
at room temperature (Method 1, Scheme 5). Dichloroaldehyde 20
was isolated as the sole product in a pleasing 80% yield confirming
that the required conjugate reduction had occurred selectively.
Aldehyde 20 was readily oxidized to acid 8 using Jones reagent.
Having established a short and efficient approach to dichloro acid
8, the reduction of 18 was repeated using dihydropyridine 19 and
Whilst the above method gave the target 8, a more concise
approach was required to prepare large quantities of the dichloro
acid for use in total synthesis. Hence a new strategy was proposed
involving the asymmetric reduction of an unsaturated carbonyl
compound already containing the requisite dichloromethyl group
(Scheme 3). However such a reduction would be challenging as
it would be necessary to effect a selective asymmetric conjugate
reduction without either competing SN2¢ attack (leading to
Scheme 3 Proposed new strategy to dichloro acid 8.
266 | Org. Biomol. Chem., 2011, 9, 265–272
Scheme 5 Reduction of unsaturated aldehyde 18.
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with L-proline TFA salt as a chiral catalyst (Method 2, Scheme 5)
and the resultant aldehyde oxidized to acid 8. The enantiopurity of
acid 8 was determined by coupling to a thiazolidinethione chiral
auxiliary (see ESI†) revealing a 34% ee. Hence a more effective
chiral catalyst was required. Imidazolines have been used to good
effect in the organotransfer hydrogenation of enals.15,16 In this
case reduction of unsaturated aldehyde 18 using imidazolidinone
21 as the catalyst gave significantly better enantioselectivity
(90% ee) than with L-proline TFA salt (Method 3, Scheme 5).
The absolute configuration was confirmed by comparison with
material prepared using the Oppolzer camphorsultam (Scheme
2). Thus a short and efficient synthetic route has been developed
giving (S)-dichloro acid 8 in 4 steps and 51% overall yield from
commercially available starting materials.
The second component common to both dysideaproline E 5
and its diastereomer 7 was the salt of thiazole 10 which was
prepared via a modified Hantzsch method (Scheme 6). First CBz
L-proline 22 was converted to amide 23 via a mixed anhydride and
reaction with aqueous ammonia,17 then treatment with Lawesson’s
reagent in CH2Cl2 at room temperature18 in dichloromethane
gave the required thioamide 24 in 61% overall yield from acid
22. Reaction of thioamide 24 with a-bromoacetaldehyde diethyl
acetal in THF at reflux gave thiazole 25 and finally removal of the
CBz protecting group with hydrobromic acid yielded the required
proline derivative 26.
Scheme 7 Completing the total synthesis of dysideaproline E 5 and the
diastereomer 7.
Reaction of the L-leucine derivative S-9 with 26 under the same
conditions gave 29 in 63% yield. Deprotection of dipeptides 27 and
29 using hydrobromic acid proceeded cleanly to give the salts 28
and 30 in quantitative yield which were coupled with (S)-dichloro
acid 8 giving the target compounds 5 and 7. There was an excellent
correlation of the 1H- and 13C- NMR data for synthetic 5 with that
of the natural product and the optical rotation, [a]D +43.8 (c 0.02,
MeOH) was in accord with the literature value3 of [a]D +45.5
(c 0.02, MeOH) for dysideaproline E. In contrast diastereomer 7
assembled on the N-methyl-L-leucine core had an optical rotation
[a]D -42.6 (c 1.0, MeOH).
Conclusions
In conclusion two different strategies for the synthesis of (S)-
4,4-dichloro-3-methylbutanoic acid 8 have been explored. An
operationally simple and efficient approach used an organocat-
alytic transfer hydrogenation to 4,4-dichloro-3-methylbut-2-enal
18 in the key step giving the target 8 in 51% overall yield from
commercially available starting materials. Dichloro acid 8 was used
as an intermediate in the first total synthesis of dysideaproline E 5
and its diastereomer 7 confirming the structure of the natural
product. This organocatalytic transfer methodology will be of
value in the total synthesis of further polychlorinated natural
products.
Scheme 6 Preparation of L-proline thiazoline 26.
To confirm that the stereochemical integrity at C-2 had been
maintained throughout the synthetic route the product 26 was
compared with racemic material by chiral HPLC. The final
compounds needed for the total synthesis of dysideaproline E
5 and diastereomer 7 were N-CBz-N-methyl D- and L- leucines
(R-9) and (S-9). We have previously prepared S-9 from L-leucine
in two steps and 74% yield via CBz protection followed by N-
methylation with NaH/MeI in MeCN10 and the same approach
was used herein to prepare both enantiomers.
With all the necessary building blocks in hand for the total
synthesis of dysideaproline E 5 and the diastereomer 7, the first
coupling to be investigated was N-CBz N-methyl D-leucine R-9
with salt 26. Several standard coupling conditions were explored
and EDCI, HOBt, NMM in DCM–DMF gave the best yield (54%)
of dipeptide 27 (Scheme 7).
Experimental
General details
All commercially available compounds were used without further
purification except where stated. All moisture or air sensitive
reactions were carried out in oven-dried glassware under a positive
pressure of nitrogen using standard syringe/septa techniques.
Anhydrous solvents were obtained by passing through a modified
Grubbs system of alumina columns, manufactured by Anhydrous
Engineering. When stated, DMF was dried sequentially over three
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˚
portions of 10% w/v 3 A MS beads for 24 h each, and then
(1S,2R)-N-[(3¢R)-Methylpent-5¢-al]-bornane-10,2-sultam 13
stored under nitrogen. Petroleum ether is of the 40–60 ◦C boiling
point range. Routine monitoring of reactions was performed
using precoated Merck–Kieselgel 60 F254 aluminium backed TLC
plates. The spots were visualised by UV254 light, or potassium
permanganate. Flash column chromatography was performed
using silica gel (obtained from Fluorochem Ltd.) as the adsorbent.
Melting points were determined on an electrothermal apparatus
and are uncorrected. Optical rotations were recorded using with
the sodium D line (l = 589 nm) on a Bellingham and Stanley
ADP220 polarimeter and the [a]D values are quoted in units 10-1
deg cm2 g-1. Infrared spectra were recorded on a Perkin Elmer
Spectrum One FT-IR spectrometer in the solid or liquid state.
1H and 13C NMR spectra were recorded at using either a Jeol
Delta/GX 400 MHz or a Jeol Eclipse 400 MHz spectrometer. The
chemical shifts (d) are reported in parts per million (ppm) and
the coupling constants (J) are in Hertz (Hz). Tetramethylsilane
was used as the internal reference for proton and carbon chemical
shifts. DEPT 135, COSY, HBQC and HMBC NMR spectra we
Ozone was bubbled through a solution of alkene 12 (21.6 g,
66.36 mmol) in DCM (200 ml) at -78 ◦C until a permanent blue
colour persisted. DMS (10 eq, 663.7 mmol, 50 ml) was added and
the reaction mixture warmed to room temperature before heating
under reflux overnight. The reaction mixture was allowed to cool
before adding water (50 ml). The layers were separated and the
aqueous layer extracted with DCM (3 ¥ 60 ml). The combined
organic layer was washed with water (35 ml), dried over anhydrous
magnesium sulfate, filtered and the solvent removed in vacuo.
Purification by column chromatography (20% EtOAc/petrol) gave
◦
aldehyde 13 as a white solid (15.03 g, 70%); m.p. 60–72 C; [a]D
-83.8 (c 2.1, CHCl3); dH (400 MHz) 0.96 and 1.15 (each 3H, s,
8-H3 and 9-H3), 1.05 (3H, d, J 6, CH3), 1.8–2.2 (7H, m, 3-H2, 4-H,
5-H2 and 6-H2), 2.34–2.4 (1H, m, 3-H¢), 2.5 (1H, ddd, J 16, 7, 2,
4¢-HH), 2.72 (3H, m 4¢-HH and 2¢-H2), 3.41 and 3.49 (each 1H,
d, J 14, 10-H2), 3.87 (1H, t, J 6, 2-H), 9.7 (1H, t, J 2, 5¢-H); dC
(100 MHz) 14.2 (CH3), 19.9 and 20.8 (C-8 and C-9), 25 (C-3¢),
26.5 (C-5), 32.9 (C-6), 38.6 (C-3), 41.9 (C-2¢), 44.7 (C-4), 47.8 (C-
7), 48.5 (C-1), 50.3 (C-4¢), 53 (C-10), 65.3 (C-2), 170.5 and 201.5
(CO); nmax/cm-1 2962, 1705, 1326 and 1166; m/z (CI) 328 (MH+,
53%), 257 (13), 135 (46) and 113 (100); Found C 58.38, H 7.57, N
3.93, S 9.7, C16H25NO4S requires C 58.69, H 7.7, N 4.28, S 9.79.
1
were routinely used to definitively assign the signals of H and
13C NMR spectra. Electron impact (EI) and chemical ionisation
(CI) mass spectra were recorded on a VG Analytical Autospec
mass spectrometer. Electrospray (ESI) mass spectra were recorded
on a Micromass LCT mass spectrometer or a VG Quattro mass
spectrometer. Methane was the ionisation gas used for chemical
ionisation.
(1S,2R)-N-[(3¢S)-Methylpent-4¢4¢-dichloro-5¢-al]-bornane-10,2-
sultam 14
tert-Butylamine (1eq, 29.95 mmol, 3.15 g) was added to a solution
of aldehyde 13 (9.81 g, 29.95 mmol) in CCl4 (100 ml) in the presence
of molecular sieves (4 A). The reaction mixture was stirred for 1.5
(1S,2R)-N-[(3¢R)-Methylhex-5¢-enyl]-bornane-10,2-sultam 12
˚
CuBr·Me2S (1.5 eq, 106 mmol, 21.79 g) and LiCl (1.5 eq,
106 mmol, 4.49 g) in THF (100 ml) were pre-stirred for 0.5 h
before adding to a solution of allyl magnesium bromide (1.4 eq,
98.84 mmol, 98.84 ml) in THF (300 ml) at -78 ◦C under N2.
TMSCl (1.5 eq, 106 mmol, 13.45 ml) was added to the reaction
mixture followed by the immediate addition of the crotonyl
auxiliary 11 (20 g, 70.6 mmol) in THF (140 ml). The reaction
mixture was stirred for 4 h before quenching with NH4Cl/NH4OH
(pH 8, 120 ml) and warming to room temperature overnight. Water
(50 ml) and Et2O (50 ml) were added and the layers separated.
The aqueous phase was extracted with Et2O (3 ¥ 150 ml) and
the combined organic layer was washed with water (2 ¥ 70 ml)
and brine (70 ml). The organic layer was dried over anhydrous
magnesium sulfate, filtered and the solvent removed in vacuo.
Purification by column chromatography (0–5% EtOAc/petrol)
gave alkene 12 as◦a white solid and single diastereomer (21.6 g,
94%); m.p. 74–76 C; [a]D -75.3 (c 3.4, CHCl3); lit.12b [a]D -88 (c
3.6, CHCl3), dH (400 MHz) 0.95 (3H, d, J 6, CH3), 0.96 and 1.18
(each 3H, s, 8-H3 and 9-H3), 1.2–2.2 (10H, m, 3-H2, 4-H, 5-H2,
6-H2, 3¢-H and 4¢-H2), 2.49 (1H, dd, J 16, 8, 2¢-HH), 2.76 (1H,
dd, J 16, 6, 2¢-HH), 3.41 and 3.49 (each 1H, d, J 14, 10-H2). 3.87
(1H, t, J 6, 2-H), 5.0 (2H, m, 6¢-H2), 5.75 (1H, ddt, J 18, 10, 7,
5¢-H); dC (100 MHz) 19.6 (CH3), 19.9 and 20. 9 (C-8 and C-9), 26.5
(C-5), 29.8 (C-3¢), 32.9 (C-6), 38.6 (C-2¢), 40.9 (C-3), 42.4 (C-4¢),
44.8 (C-4), 47.8 (C-1), 48.4 (C-7), 53.1 (C-10), 65.3 (C-2), 116.6
(C-6¢), 136.5 (C-5¢), 171.5 (CO); nmax/cm-1 3019, 2964, 1720, 1693,
1330 and 1166; m/z (CI) 326 (MH+, 100%), 284 (8), 218 (12), 135
(100); found C 62.4, H 8.72, N 3.45, S 9.91, C17H27NO3S requires
C 62.74, H 8.36, N 4.3, S 9.85.
h before adding additional CCl4 (20 ml) and magnesium sulfate.
The reaction mixture was filtered and NCS (2.2 eq, 65.89 mmol,
8.80 g) was added in one portion and the reaction mixture stirred
overnight. The succinimide was removed by filtration and the
filtrate concentrated in vacuo. The product was hydrolysed by
stirring in HCl (0.1 M, 260 ml) for 48 h. After this time, Et2O
(250 ml) was added and the layers separated. The aqueous layer
was extracted with Et2O (3 ¥ 150 ml), the combined organic layers
were washed with water (70 ml), dried over anhydrous magnesium
sulfate and the solvent removed in vacuo to give dichlorinated
◦
aldehyde 14 as a white solid (9.89 g, 84%); m.p. 98–101 C; [a]D
-72 (c 2, CHCl3); dH (400 MHz) 0.99 and 1.1 (each 3H, s, 8-H3
and 9-H3), 1.13 (3H, d, J 7, CH3), 1.2–2.1 (7H, m, 3-H2, 4-H, 5-H2
and 6-H2), 2.8 (1H, dd, J 17, 8, 2¢-HH), 3.13 (1H, dd, J 17, 4, 2¢-
HH), 3.20 (1H, m, 3¢-H), 3.45 and 3.53 (each 1H, d, J 14, 10-H2),
3.87 (1H, dd, J 8, 5, 2-H), 9.15 (1H, s, 5¢-H); dC (100 MHz) 16.0
(CH3), 19.9 and 20.8 (C-8 and C-9), 26.5 (C-5), 32.9 (C-6), 38.3
(C-3), 38.4 (C-2¢), 38.8 (C-3¢), 44.7 (C-4), 47.9 (C-7), 48.6 (C-1),
53 (C-10), 65.3 (C-2), 93.5 (C-4¢), 169 and 184 (CO); nmax/cm-1
2969, 1740, 1694, 1333 and 1135; m/z (CI) 396 (MH+, 92%), 362
(52), 216 (30), 135 (100); C16H24Cl2NO4 requires 396.0803, found
396.0800.
(1S,2R)-N-[(3¢S)-4¢,4¢-Dichloro-3¢-methylpentan-5¢-oic
acid]-bornane-10,2-sultam 15
Dichlorinated aldehyde 14 (7.79 g, 19.66 mmol) was dissolved in
acetone (130 ml) andJones reagent (20 ml) was added. Thereaction
was monitored by TLC and after 3 h had reached completion.
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The reaction mixture was quenched with MeOH (25 ml) and
the solvent removed in vacuo. Water (40 ml) was added and the
aqueous layer extracted with EtOAc (3 ¥ 70 ml). The combined
organic layer was washed with water (2 ¥ 30 ml), dried over
anhydrous magnesium sulfate and the solvent removed in vacuo.
Purification by column chromatography (20–50% EtOAc/petrol)
gave acid 15 as a white solid (7.03 g, 86%); m.p. 174–176 ◦C; [a]D
-80.4 (c 2.1, CHCl3), dH (400 MHz) 0.97 and 1.15 (each 3H, s,
8-H3 and 9-H3), 1.2 (3H, d, J 7, CH3), 1.3–2.1 (7H, m, 3-H2,4-H,
5-H2, 6-H2), 2.9 (1H, dd, J 17, 9, 2¢-HH), 3.13 (1H, dd, J 17, 2,
2¢-HH), 3.3 (1H, m, J 3, 3¢-H), 3.44 and 3.54 (each 1H, d, J 14,
10-H2), 3.9 (1H, dd, J 8, 5, 2-H), 9.4 (1H, br s, CO2H); dC (100
MHz) 16.2 (CH3), 19.3 and 20.9 (C-8 and C-9), 26.5 and 26.7 (C-3
and C-5), 32.9 (C-6), 38.4 (C-2¢), 41.8 (C-3¢), 44.7 (C-4), 47.9 (C-
7), 48.6 (C-1), 53.1 (C-10), 65.4 (C-2), 88.8 (C-4¢), 167.5 and 169.8
(CO); nmax/cm-1 2971, 1739, 1670, 1371 and 1136; m/z (CI) 412
(MH+, 10%), 376 (6), 339 (8), 295 (46), 135 (100), 216 (40); Found
C 46.9, H 5.69, N 3.41, S 7.52, Cl 17.01, C16H23Cl2NO5S requires
C 46.61, H 5.62, N 3.4, S 7.78, Cl 17.2.
over MgSO4, filtered and the solvent evaporated in vacuo to give
the crude product which was purified by column chromatography
using EtOAc/petroleum ether 1 : 9 as the eluent to give ester 17 as
a 3 : 1 mixture of E/Z isomer (0.67 g, 87%); vmax/cm-1 2979, 1745,
1320, 750; major isomer dH (400 MHz, CDCl3), 1.29 (3H, t, J 7.0,
OCH2CH3), 2.45 (3H, s, CH3), 4.21 (2H, q, J 7.0, OCH2CH3), 6.0
(1H, br. s), 6.18 (1H, s); dC (100 MHz, CDCl3) 14.2 (CH3), 77.1
(C-4), 118.3 (C-2), 151.9 (C-3), 165.4 (CO); minor isomer, dH (400
MHz, CDCl3), 1.29 (3H, t, J 7.0, OCH2CH3), 2.34 (3H, s, CH3),
4.21 (2H, q, J 7.0, OCH2CH3), 5.71 (1H, s), 7.99 (1H, s); dC (100
MHz, CDCl3) 13.2 (CH3), 67.3 (CHCl2), 118.0 (C-2), 151.7 (C-3),
164.7 (CO); m/z (CI) 201 (4%), 199 (25), 197 (MH+ 38), 196 (8),
161 (68), 133 (69), 85 (65), 83 (100); C7H11O2Cl2 requires 197.0129,
found 197.0136.
4,4-Dichloro-3-methylbut-2-enal 18
Diisobutylaluminium hydride (3.28 ml, 3.28 mmol, 1.1 eq) was
added to a stirring solution of ester 17 (0.588 g, 2.98 mmol) in dry
dichloromethane (10 ml) at -78 ◦C, under nitrogen over a period of
15 min. The reaction mixture was stirred at -78◦C for 0.5 h andwas
then quenched with Rochelle’s salt (5 ml). The mixture was allowed
to stir for 3 h at room temperature, the layers separated and the
aqueous layer extracted with ethyl acetate (3 ¥ 10 ml). The organic
layers were combined, washed with brine (50 ml) and dried over
magnesium sulfate. The solvent was removed in vacuo to give the
crude product which was purified using column chromatography
eluting with 5% ethyl acetate/petrol to give unsaturated aldehyde
18 as a 3 : 1 mixture of E/Z isomers as yellow oil (0.32 g, 71%);
vmax/cm-1 2789, 1738, 1645, 750; major isomer, dH (400 MHz,
CDCl3), 2.45 (3H, d, J 1.3, CH3), 6.08 (1H, br d, J 7.3, 2-H), 6.18
(1H, s, 4-H) 10.06 (1H, d, J 7.3, 1-H); dC (100 MHz, CDCl3) 14.2
(CH3), 79.6 (C-4), 128.7 (C-2), 156.3 (C-3), 193.3 (CO); minor
isomer, dH (400 MHz, CDCl3), 2.34 (3H, d, J 1.3, CH3), 5.94 (1H,
br. d, J 5.3, 2-H), 7.46 (1H, s, 4-H), 9.90 (1H, d, J 5.3, 1-H); dC
(100 MHz, CDCl3) 13.2 (CH3), 79.0 (CHCl2), 128.5 (C-2), 155.5
(C-3), 189.4 (CO); m/z (CI) 157 (8%),155 (22), 153 (MH+ 58), 117
(85), 113 (52), 97 (79), 89 (100); C5H7O35Cl2 requires 152.9870,
found 152.9874.
(1S,2R)-N-[(3¢S)-4¢,4¢-Dichloro-3¢methylbutane]-bornane-10,2-
sultam 16
Dichlorinated acid 15 (0.54 g, 1.3 mmol) was dissolved in MeCN
(15 ml) under N2 and stirred for 5 mins. Pb(OAc)4 (1eq, 1.3 mmol,
0.581 g) and 1,4-cyclohexadiene (1.2 eq, 1.6 mol, 0.15 ml) were
then added and the reaction mixture heated at reflux for 2 h. After
this time the reaction mixture was cooled before adding further
Pb(OAc)4 (1 eq) and 1,4-cyclohexadiene (1.2 eq) and heating at
reflux for an additional 1 h. The reaction mixture was diluted
with Et2O (20 ml) and washed with perchloric acid (7%, 2 ¥
15 ml). The aqueous layer was extracted with Et2O (2 ¥ 15 ml)
and the combined organic layer was washed with NaHCO3 (2 ¥
20 ml). The aqueous layer was extracted with Et2O (1 ¥ 20 ml)
and the combined organic layers were washed with water (10 ml).
The combined organic layer was dried over anhydrous magnesium
sulfate, filtered and the solvent removed in vacuo. Purification by
column chromatography (5–10% EtOAc/petrol) gave dichloride
16 as a white solid (0.32 g, 48%); m.p. 132–135 ◦C; [a]D -82.9
(c 2.2, CHCl3); dH (400 MHz) 0.97 and 1.15 (each 3H, s, 8 and
9-CH3), 1.2 (3H, d, J 6, CH3), 1.3–2.1 (7H, m, 3-H2, 4-H, 5-H2
and 6-H2), 2.79–2.85 (2H, m, 3-H¢ and 2¢-HH), 3.0 (1H, dd, J 19,
8, 2¢-HH), 3.44 and 3.51 (each 1H, d, J 14, 10-H2), 3.87 (1H, dd,
J 8, 5, 2-H), 5.97 (1H, d, J 3, 4¢-H); dC (100 MHz) 15.1 (CH3),
19.9 and 20.8 (C-8 and C-9), 26.5, 26.7 and 32.9 (C-3, C-5 and
C-6), 38.6 (C-2¢), 40.3 (C-3¢), 44.7 (C-2), 47.9 (C-4), 48.6 (C-7), 53
(C-10), 65.3 (C-1), 76.7 (C-4¢), 169.8 (CO); nmax/cm-1 2963, 1691,
1328 and 1133; m/z (CI) 368 (MH+, 94%), 332 (80), 151 (42) and
135 (100); C15H24Cl2NO3S requires 368.0849, found 368.0853.
(S)-4,4-Dichloro-3-methylbutanal 20
A solution of unsaturated aldehyde 18 (0.814 g, 5.32 mmol)
dissolved in chloroform (5 ml) was cooled to -20 ◦C in a dry
ice/acetone bath. To this solution was added the trichloroacetic
acid salt of (R)-2-tert-butyl-3-methylimidazolidin-4-one 21 (0.287
g, 1.06 mmol) and Hantzsch ester 19 (1.98 g, 6.33 mmol).
The resulting yellow suspension was stirred at -20 ◦C for 4 h
and allowed to warm room temperature overnight. The reaction
mixture was poured into HCl solution (10%, 30 ml) and diluted
with ether (30 ml). The organic layer was washed 4 times with HCl
solution (10%, 30 ml) and once with a saturated aqueous solution
of NaHCO3 (30 ml). The resulting organic solution was dried
with magnesium sulfate and concentrated in vacuo. The residue
was purified by flash chromatography using 5% ether in pentane
to give aldehyde 20 as a yellow oil (0.694 g, 85%); [a]2D3 -6.0 (c 1,
CHCl3). vmax/cm-1 2789, 1730, 750; dH (270 MHz, CDCl3), 1.25
(3H, d, J 6.8, CH3), 2.45 (1H, dd, J 10.5, 7.3, 2-HH), 2.84–2.95
(2H, m, 2-HH, 3-H), 5.89 (1H, d, J 3.3, 4-H), 9.81 (1H, br. s, 1-H),
Ethyl 4,4-dichloro-3-methylbut-2-enoate 17
Triethyl phosphonoacetate (0.78 ml, 3.9 mmol) in THF (10 ml) was
cooled to 0 ◦C under nitrogen and n-butyllithium in hexane (2.5 M,
1.58 ml, 3.9 mmol) was added dropwise. The solution was stirred
for 20 min and dichloroacetone (0.5 g, 3.9 mmol) in THF (10 ml)
was added dropwise. The solution was stirred at room temperature
and monitored by TLC. After 2 h it was quenched with water (15
ml). The mixture was extracted with EtOAc (3 ¥ 30 ml), dried
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dC (67.5 MHz, CDCl3), 15.8 (CH3), 38.4 (C-3), 46.4 (C-2), 76.6
(CHCl2), 199.8 (C-1), m/z (CI) 157 (5%), 155 (MH+ 10), 117 (55),
89 (55), 83 (100); C5H9OCl2 requires 155.0025, found 155.0030
temperature overnight under nitrogen. LCMS showed starting
material remaining and the mixture was therefore stirred for a
further 6 h at room temperature. Again starting material was
still remaining, so further KHCO3 (1.14 g, 11.36 mmol) and
ClCH2CHO (0.084 g, 1.14 mmol) were added. The reaction
mixture was left to stir at room temperature for a further 48
h. LCMS analysis showed no starting material remaining. The
reaction mixture was then passed through a pad of celite and
rinsed with diethyl ether (15 ml). The solution was concentrated
to give a yellow oil which was dissolved in DME (5 ml) and cooled
to 0 ◦C. Trifluoroacetic anhydride (2.36 ml, 17.04 mmol) was added
followed by pyridine (2.021 ml, 24.99 mmol). The reaction mixture
turned a dark red and was concentrated in vacuo after 10 min. The
residue was taken up in chloroform (10 ml) and washed with water
(2 ¥ 10 ml), and dried over magnesium and evaporated to give
the crude product which was purified by column chromatography
using 20% acetone:petrol to give thiazole 25 as a brown liquid (1.19
g, 69%); [a]2D3 -76.8 (c 1, CHCl3); nmax/cm-1 3404, 2976, 2883, 1705,
1499 and 1110; dH (400 MHz, both rotamers) 1.99 (2H, m, 4-H2),
2.33 (2H, m, 3-H2), 3.57–3.72 (2H, m, 5-H2), 5.1–5.18 (2H, m, O-
CH2), 5.31 (1H, m, 2-H), 7.15–7.38 (6H, m, PhH and 7-H), 7.71
(1H, m, 6-H); dC (100 MHz, both rotamers) 22.9 and 23.9 (C-4),
32.7 and 34.1 (C-3), 46.7 and 47.1 (C-5), 59.2 (C-2), 67.0 (OCH2),
118.4 and 118.6 (C-7), 127.7–128.4 (10 ¥ C-Ph), 136.4 and 136.7
(C-ipso), 142.0 (C-6), 155.1 and 155.1 (CO), 174.5 and 173.4 (C-
1); LCMS-m/z (ESI) 289 (MH+), C15H17O2 requires 289.099 found
289.1011.
4,4-Dichloro-3-methylbutanoic acid 8
Jones reagent was prepared by dissolving chromium trioxide (25
g, 250 mmol) in a solution of concentrated sulfuric acid (20 ml)
and distilled water (70 ml). Aldehyde 20 (0.077 g, 0.49 mmol) was
dissolved in acetone (10 ml) and Jones reagent was added dropwise
until an orange colour persisted. The reaction was stirred for 15
min, after which time methanol (5 ml) was added dropwise to
quench the reaction followed by water (5 ml). The solvent was
removed in vacuo and the green-black residue diluted with water
(5 ml) and extracted with ethyl acetate (3 ¥ 10 ml). The combined
organic extract was dried over anhydrous MgSO4, filtered and the
solvent removed in vacuo. Purification by column chromatography
(20% EtOAc/petrol + 1% AcOH) gave dichlorinated acid 8 as a
clear liquid (0.083 g, 98%); [a]2D3 -8.2 (c 1, CHCl3), [a]D23 -7.8 (c
1, Et2O) vmax/cm-1 3400–3200, 2979, 1705, 750; dH (270 MHz,
CDCl3), 1.25 (3H, d, J 6.9, CH3), 2.45 (1H, dd, J 10.5, 7.3,2-HH),
2.61–2.80 (2H, m, 2-HH, 3-H), 5.89 (1H, d, J 3.3, 4-H), 10.5 (1H,
br s, OH), dC (100 MHz, CDCl3), 15.4 (CH3), 36.7 (C-3), 40.5
(C-2), 76.6 (CHCl2), 178.1 (C-1), m/z (CI) 175 (2%) 173 (10),
171 (MH+ 15),135 (35), 99 (100), 83 (65); C5H9O235Cl2 requires
170.9972, found 170.9980
N-Methyl-N-(benzyloxycarbonyl)-D-leucine (R)-9
Method 2. A solution of thioamide 24 (0.75 g, 2.8 mmol) and
diethyl bromoacetaldehyde acetal (0.43 ml, 2.8 mmol) in THF
was heated to reflux for 7 h. After the solvent had then been
evaporated, the residual oil was washed with petroleum ether (30
ml) to remove the excess acetal. The mixture was diluted with
aqueous sodium bicarbonate (10 ml) and extracted with ethyl
acetate (3 ¥ 20 ml). The combined organic extract was washed
with water, dried over MgSO4 and the solvent was evaporated.
The product was purified by column chromatography using 20%
acetone:petrol to give thiazole 25 (621 mg, 77%).
Cbz-D-Leucine (5 g, 18 mmol) was dissolved in acetonitrile (60 ml)
and cooled to 0 ◦C. Sodium hydride (2.17 g, 56.5 mmol) was added
followed by dropwise addition of methyl iodide (8 ml, 128 mmol)
to form a thick liquid. The reaction mixture was stirred overnight.
EtOAc (70 ml) and water (25 ml) were added and the solvent
evaporated off. The crude mixture was dissolved in ether (30 ml)
and water (30 ml), the layers were separated and the aqueous
layer was washed with ether (2 ¥ 20 ml). The organic layers were
combined and washed with saturated NaHCO3 (2 ¥ 15 ml). All the
aqueous layers were combined and acidified to pH 2 using HCl (1
M), extracted with EtOAc (3 ¥ 35 ml) and all organic layers were
combined and washed with water (15 ml), dried over magnesium
sulfate and the solvent evaporated to give a dark orange viscous
oil. This was purified by column chromatography (loaded on in
DCM) using eluent 20% EtOAc:petrol to give (R)-9 as a white
solid (4.7 g, 90% yield); mp 64–69 ◦C (no lit. mp reported); [a]2D3
+ 25.4 (c 1, EtOH) [lit.10 +23 (c 1, EtOH)]; dH (400 MHz), major
rotamer) 0.95 and 0.98 (each 3H, d, J 6, 2 ¥ CH3), 1.58 (1H, m,
4-H), 1.63–1.80 (2H, m, 3-H2), 2.89 (3H, s, N-CH3), 4.93 (1H, t,
J 7.9 (minor rotamer, dd, J 10,5 and 4.5), 2-H), 5.1–5.2 (2H, m,
OCH2), 7.3–7.4 (5H, m, PhH); dC (100 MHz both rotamers) 21.0
and 21.3 (CH3), 23.1 (CH3), 24.7 and 24.9 (C-4), 30.4 and 30.7
(NCH3), 37.3 and 37.7 (C-3), 56.6 and 56.8 (C-2), 67.6 (OCH2)
127.7–128.4 (PhH), 136.5 (ipso), 157.2 and 177.3 (CO).
2-((S)-2-Pyrrolidinyl)-1,3-thiazole hydrobromic salt 2619
Thiazole 25 (222 mg, 0.77 mmol) was dissolved in HBr (3 ml, 33%
in acetic acid) and stirred for 4 h at room temperature. The reaction
mixture was concentrated in vacuo and dried in the vacuum oven
at 60 ◦C overnight to give salt 26 as an orange solid (179 mg, 98%);
[a]2D3 +28.5 (c 1, H2O); vmax/cm-1 2860, 2440, 1564, 1368 and 1286
d
H (400 MHz, D2O) 2.21–2.48 (3H, m, 3HH and 4-H2), 2.65–2.77
(1H, m, 3HH), 3.54–3.63 (2H, m, 5-H2), 5.23 (1H, t, J 7.8, 2-H),
7.77 (1H, d, J 3.4, 7-H), 7.93 (1H, d, J 3.4, 6-H); dC (100 MHz)
23.5 (C-4), 30.9 (C-3), 45.9 (C-5), 59 (C-2), 122.3 (C-7), 142.8 (C-
6), and 164.4 (C-1); m/z (ESI) 289 (MH+); C15H17O2NS requires
289.0999 found 289.1011.
N-Methyl-[(R)-3-methyl-1-((S)-thiazol-2-yl-pyrrolidine-1-
N-(Benzyloxycarbonyl)-L-proline thiazole 25
carbonyl)-butyl]-carbamic acid benzyl ester 27
Method 1. a-Chloroacetaldehyde (0.168 g, 2.27 mmol) and
potassium hydrogen carbonate (ground, 0.227 mg, 2.27 mmol)
were added to a solution of the crude thioamide 24 (0.15 g,
0.57 mmol) in dimethoxyethane (5 ml) and stirred at room
L-Proline thiazole hydrobromic salt 26 (170 mg, 0.72 mmol) and
N-Cbz-N-Me-D-leucine (R)-9 (180 mg, 0.72 mmol) formed a
suspension with DCM–DMF (5 : 1 ratio, 11 ml). The reaction
mixture was cooled to 0 ◦C and EDCI (2 eq, 277 mg, 1.45 mmol),
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HOBt (1.1 eq, 108 mg, 0.79 mmol) and NMM (1.5 eq, 0.12 ml,
1.08 mmol) were added and the reaction mixture was stirred at
0 ◦C for 1 h and then at room temperature overnight. The reaction
was quenched with HCl (1 M, 5 ml) and diluted with EtOAc (15
ml). The mixture was separated and the organic layer was then
washed with NaHCO3 (10 ml), brine (10 ml), water (10 ml), dried
over magnesium sulfate and the solvent evaporated in vacuo to give
the crude product which was purified with flash chromatography
eluting with 20% acetone/petrol to give 27 as viscous white oil
(156 mg, 54%); [a]D23 +18.8 (c 1, MeOH); vmax/cm-1 2955, 2875,
1697, 1654; dH (400 MHz, major rotamer) 0.95 and 0. 97 (6H, 2 ¥
d, J 6.6, 2 ¥ CH3), 1.3 and 1.73 (2H, m, 3-H2), 1.5 (1H, m, 2-H),
1.97 (2H, m, 10-H2), 2.05–2.39 (2H, m, 9-H2), 2.83 (3H, s, N-CH3),
3.45–3.78 (2H, m, 11-H2), 5.09 (1H, m, 4-H), 5.22 (2H, m, OCH2),
5.5 (1H, dd, J 7.9, 2.8, 8-H), 7.17 (1H, d, J 3.3, 14-H), 7.67 (1H, d,
J 3.3, 13-H); dC (100 MHz major rotamer) 22.3 (C-1), 23.0 (C-7),
24.4 (C-10), 24.5 (C-2), 29.3 (C-6), 31.5 (C-9), 37.3 (C-3), 46.7
(C-11), 54.6(C-4), 58.6 (C-8), 67.3 (OCH2), 118.7 (C-14), 127.6-
128.8 (PhH), 136.7 (ipso-C), 142.2 (C-13), 156.6 (CO2CH2), 170
(CO), 172.2 (C-12), m/z (ESI) 416 (MH+); C22H30O3N3S requires
416.2008 found 416.2005.
4-(S)-4-N-Methyl-2-methylamino-1-((S)-2-thiazol-2-yl-pyrrolidin-
1-yl)-pentan-1-one 30
The above method was repeated with 29 (151 mg, 0.376 mmol) to
give 30 as an orange sticky solid (130 mg, 100%); vmax/cm-1 3387,
2959, 1643, 1551, 1332 and 1111; [a]2D3 -57.9 (c 1, H2O); dH (400
MHz, D2O) 1.03 and 1.07 (6H, 2 ¥ d, J 6, 2 ¥ CH3), 1.83 (3H,
m, 2-H and 3-H2), 2.25 (3H, m, 9HH and 10-H2), 2.57 (1H, m,
9HH), 2.80 (3H, s, N-CH3), 3.96 (2H, m, 11-H2), 4.38 (1H, t, J
6.5, 4-H), 5.64 (1H, dd, J 8.5, 3.7, 8-H), 7.70 (1H, d, J 3.5, 14-H),
7.90 (1H, d, J 3.5,13-H); dC (100 MHz) 21.1 (C-1), 21.8 (C-7), 23.9
(C-2), 24.05 (C-10), 32.0 (C-6), 32.1 (C-9), 38.8 (C-3), 48.0 (C-11),
58.8 (C-4), 59.0 (C-8), 67.5 120.0 (C-14), 140.6 (C-13), 168.4 (CO),
173.2 (CN), m/z (ESI) 282 (MH+); C14H24ON3S requires 282.1640
found 282.1637.
Dysideaproline E 5
L-Proline thiazole hydrobromic salt 28 (157 mg, 0.45 mmol) and
(S)-4,4-dichloro-3-methylbutanoic acid 8 (116 mg, 0.676 mmol,
1.5 eq) formed a suspension with DCM–DMF (5 : 1 ratio, 11 ml).
The reaction mixture was cooled to 0 ◦C and EDCI (2 eq, 173
mg, 0.9 mmol), HOBt (1.1 eq, 67 mg, 0.49 mmol) and NMM (1.5
eq, 0.1 ml, 0◦.676 mmol) were added and the reaction mixture was
stirred at 0 C for 1 h and then at room temperature overnight.
The reaction was quenched with HCl (1 M, 5 ml) and diluted with
EtOAc (15 ml). The mixture was separated and the organic layer
was then washed with NaHCO3 (10 ml), brine (10 ml), water (10
ml), dried over MgSO4 and solvent evaporated to give crude 5
which was purified with flash chromatography eluting with 20%
acetone/petrol to give dysideaproline E 5 as viscous clear oil (66
mg, 32%); [a]2D3 +43.8 (c 0.02, MeOH), [lit.3 +45.5 (c 0.02, MeOH)];
vmax/cm-1 2955, 2871, 1695, 1650, 1453 and 1153; dH (400 MHz,
major rotamer) 0.87 (3H, d, J 7.0, CH3), 0. 88 (3H, d, J 7.0, CH3),
1.09 (3H, d, J 6.6, CH3), 1.35 (1H, m, 7-H), 1.51 (1H, m, 6HH),
1.51 (1H, m, 6HH), 1.89 (1H, m, 15HH), 1.96 (1H, m, 15HH),
2.06 (1H, m, 14HH), 2.23 (1H, m, 14HH), 2.46 (1H, dd, J 7.6,
16.3, 3HH), 2.57 (1H, dd, J 7.6, 16.3, 3HH), 2.69 (1H, m, 2H),
2.81 (3H, s, N-CH3), 3.40 (1H, m, 16HH), 3.55 (1H, m, 16HH),
5.30 (1H, dd, J 3.2, 8.2, 13-H), 5.37 (1H, dd, J 6.6, 8.3, 5-H),
6.41 (1H, d, J 3.2, 11-H), 7.57 (1H, d, J 3.3, 19-H), 7.70 (1H, d,
J 3.3, 18-H); dC (100 MHz, DMSO) 14.5 (C-1), 22.1 (C-9), 23.0
(C-8), 23.9 (C-15), 24.0 (C-7), 30.2 (C-10), 31.5 (C-14), 35.6 (C-3),
36.9 (C-6), 40.2 (C-2), 46.4 (C-16), 51.7 (C-5), 58.4 (C-13), 79.1
(C-11), 119.5 (C-19), 142.1 (C-18), 169.2 (C-4), 170.2 (C-12) and
172.6 (C-17); m/z 438 (2%),436 (6),434 (10), 362(45), 280 (100),
100 (65); C19H30N3O2S35Cl2 requires 434.1425 found 434.1436.
N-Methyl-[(S)-3-methyl-1-((S)-thiazol-2-yl-pyrrolidine-1-
carbonyl)-butyl]-carbamic acid benzyl ester 29
The above method was repeated with N-Cbz-N-Me-L-leucine (S)-
9 to give 29 as a viscous yellow oil (182 mg, 63%); [a]2D3 -99.1 (c 1,
MeOH); vmax/cm-1 2955, 2875, 1697, 1654; dH (400 MHz, major
rotamer) 0.95 and 0. 97 (6H, 2 ¥ d, J 6.6, 2 ¥ CH3), 1.57 (1H, m,
2-H), and 1.56 and 1.72 (2H, m, 3-H2), 1.5–1.64 and 2.0–2.16 (2H,
m, 10-H2), 1.96–2.08 and 2.2–2.35 (2H, m, 9-H2), 2.05–2.39 (2H,
m, 9-H2), 2.97 (3H, s, N-CH3), 3.78 (2H, m, 11-H2), 5.12 (1H, dd,
J 9.7, 5.2, 4-H), 5.17 (2H, m, OCH2), 5.5 (1H, dd, J 7.9, 2.8, 8-H),
7.17 (1H, d, J 3.3, 14-H), 7.67 (1H, d, J 3.3, 13-H); dC (100 MHz
major rotamer) 22.3 (C-1), 23.0 (C-7), 24.4 (C-10), 24.5 (C-2),
29.3 (C-6), 31.5 (C-9), 37.3 (C-3), 46.7 (C-11), 54.6(C-4), 58.6 (C-
8), 67.3 (OCH2), 118.7 (C-14), 127.6–128.8 (PhH), 136.7 (ipso-C),
142.2 (C-13), 156.6 (CO2CH2), 170 (CO), 172.2 (C-12), m/z (ESI)
416 (MH+); C22H30O3N3S requires 416.2008 found 416.2005.
4-(R)-4-N-Methyl-2-methylamino-1-((S)-2-thiazol-2-yl-
pyrrolidin-1-yl)-pentan-1-one 28
Amide 27 (167 mg, 0.4 mmol) was dissolved in HBr (2.5 ml,
33%w/w in acetic acid) and stirred at room temperature for 4
h. The acetic acid was evaporated off and the residue dried in the
◦
vacuum oven at 60 C for 3 days to give 28 as an orange sticky
Diastereomer 7
solid in quantitative yield (139 mg, 100%); vmax/cm-1 3323, 2955,
1651, 1551, 1385 and 1102; dH (400 MHz, D2O) 1.06 and 1.09
(6H, 2 ¥ d, J 6, 2 ¥ CH3), 1.86 (3H, m, 2-H and 3-H2), 2.24 (3H,
m, 9HH and 10-H2), 2.55 (1H, m, 9HH), 2.74 (3H, s, N-CH3),
3.78 (1H, m, 11-HH), 4.16 (1H, m, 11-HH), 4.41 (1H, dd, J 7.6,
5, 4-H), 5.61 (1H, dd, J 8, 2.4, 8-H), 7.74 (1H, d, J 3.5, 14-H),
7.92 (1H, d, J 3.5,13-H); dC (100 MHz) 20.91 (C-1), 22.23 (C-7),
23.54 (C-10), 23.85 (C-2), 32.07 (C-6), 32.29 (C-9), 38.39 (C-3),
47.76 (C-11), 59.11(C-4), 59.65 (C-8), 67.5 120.9 (C-14), 139.6 (C-
13), 168.0 (CO), 173.67 (CN), m/z (ESI) 282 (MH+); C14H24ON3S
requires 282.1640 found 282.1637.
L-Proline thiazole hydrobromic salt 30 (157 mg, 0.45 mmol) and
(S)-4,4-dichloro-3-methylbutanoic acid 8 (116 mg, 0.676 mmol,
1.5 eq) formed a suspension with DCM–DMF (5 : 1 ratio, 11 ml).
The reaction mixture was cooled to 0 ◦C and EDCI (2 eq, 173
mg, 0.9 mmol), HOBt (1.1 eq, 67 mg, 0.49 mmol) and NMM (1.5
eq, 0.1 ml, 0◦.676 mmol) were added and the reaction mixture was
stirred at 0 C for 1 h and then at room temperature overnight.
The reaction was quenched with HCl (1 M, 5 ml) and diluted
with EtOAc (15 ml). The mixture was separated and the organic
layer was then washed with NaHCO3 (10 ml), brine (10 ml), water
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(10 ml), dried over MgSO4 and solvent evaporated to give crude
7 which was purified with flash chromatography eluting with 20%
acetone/petrol to give 7 as viscous clear oil (61 mg, 31%); [a]D23
-42.6 (c 1, MeOH); 2955, 2871, 1695, 1650, 1453 and 1153; dH
(400 MHz, major rotamer), 0.87 (3H, d, J 7.0, CH3), 0. 88 (3H,
d, J 7.0, CH3), 1.09 (3H, d, J 6.6, CH3), 1.35 (1H, m, 7-H), 1.51
(1H, m, 6HH), 1.51 (1H, m, 6HH), 1.89 (1H, m, 15HH), 1.96
(1H, m, 15HH), 2.06 (1H, m, 14HH), 2.23 (1H, m, 14HH), 2.46
(1H, dd, J 7.6, 16.3, 3HH), 2.57 (1H, dd, J 7.6, 16.3, 3HH), 2.69
(1H, m, 2H), 2.81 (3H, s, N-CH3), 3.40 (1H, m, 16HH), 3.55 (1H,
m, 16HH), 5.30 (1H, dd, J 3.2, 8.2, 13-H), 5.37 (1H, dd, J 6.6,
8.3, 5-H), 6.41 (1H, d, J 3.2, 11-H), 7.57 (1H, d, J 3.3, 19-H),
7.70 (1H, d, J 3.3, 18-H); dC 14.5 (C-1), 22.1 (C-9), 23.0 (C-8),
23.9 (C-15), 24.0 (C-7), 30.2 (C-10), 31.5 (C-14), 35.6 (C-3), 36.9
(C-6), 40.2 (C-2), 46.4 (C-16), 51.7 (C-5), 58.4 (C-13), 79.1 (C-11),
119.5 (C-19), 142.1 (C-18), 169.2 (C-4), 170.2 (C-12) and 172.6 (C-
17); m/z 438 (2%),436 (6),434 (10), 362(45), 280 (100), 100 (65);
C19H30N3O2S35Cl2 requires 434.1425 found 434.1436
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We are very grateful to Drs George G. Harrigan, Gilles H. Goetz
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of the natural product dysideaproline E and to the following for
funding: BBSRC (ACD), EPSRC (SJO), AstraZeneca (ACJ) and
to the Government of Ghana for a scholarship (EOA)
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272 | Org. Biomol. Chem., 2011, 9, 265–272
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