Catalytic and stoichiometric approaches to the desymmetrisation of centrosymmetric piperazines by enantioselective acylation: A total synthesis of Dragmacidin A

Article abstract of DOI:10.1039/b608910k

The enantioselective desymmetrisation of centrosymmetric piperazines was investigated using both catalytic and stoichiometric asymmetric acylation approaches. The catalytic approach involved the desymmetrisation of 2,5-trans-dimethylpiperazine under the c

Full text of DOI:10.1039/b608910k

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Catalytic and stoichiometric approaches to the desymmetrisation of
centrosymmetric piperazines by enantioselective acylation: a total synthesis of
Dragmacidin A†
Mark Anstiss and Adam Nelson*
Received 23rd June 2006, Accepted 12th September 2006
First published as an Advance Article on the web 4th October 2006
DOI: 10.1039/b608910k
The enantioselective desymmetrisation of centrosymmetric piperazines was investigated using both
catalytic and stoichiometric asymmetric acylation approaches. The catalytic approach involved the
desymmetrisation of 2,5-trans-dimethylpiperazine under the control of chiral DMAP analogues. With
one equivalent of piperazine, relative to the acylating agent, low yields of products were obtained in up
to 70% ee. It was shown that an inevitable ‘proof reading’ effect was occurring which increased the
enantiomeric excess of the desymmetrised product through its kinetic resolution. The desymmetrisation
of centrosymmetric piperazines with chiral acylating agents [(1R,2R)-N-formyl-1,2-bis(pentafluoro-
benzenesulfonamido)cyclohexane and (1R,2R)-N-acetyl-1,2-bis(trifluoromethanesulfonamido)-
cyclohexane] was also studied. The yield and enantioselectivity of the process was highly dependent on
the solvent used and the substitution of the piperazine. However, in some cases, good yields of
enantiomerically enriched products could be obtained (up to 87% based on the limiting chiral reagent)
in good enantiomeric excesses (up to 84% ee). The approach was exploited in the total synthesis of
Dragmacidin A.
reactions have now been exploited in the desymmetrisation of cen-
Introduction
trosymmetric molecules: asymmetric reduction,10 enantioselective
epoxide hydrolysis9 and enzymatic acylation.11
The trans-2,5-dimethyl piperazine ring system may be regarded
as a ‘privileged’1 fragment for ligand design. The ring system
is present in over 3000 reported compounds described in over
900 papers and patents, of which approximately 600 describe
studies of biological activity:‡ it is found in pharmaceutical
leads for the treatment of a wide range of conditions including
gastrointestinal2 and immune system disorders,3 inflammation3
and HIV.4 Examples of biologically active trans-2,5-dimethyl
piperazines include the pyruvate dehydrogenase kinase inhibitor5
1 and the d-opioid receptor agonist 2.6 In addition, many of the
Dragmacidin and Hamacanthin alkaloids, including Dragacidin
A (3) contain 2,5-disubstituted piperazine ring systems.
Despite the prevalence of the trans-2,5-dimethyl piperazine
ring system in biologically active molecules, asymmetric syntheses
of its N-substituted analogues are often highly unsatisfactory.5,6
For example, allylation of trans-2,5-dimethyl piperazine gives
a 50% yield of the inevitably racemic monoallylated product
which must be subsequently resolved.6 A six step procedure has,
however, been developed to convert the unwanted, monoallylated
enantiomer into its antipode in good yield.7 Furthermore, despite
the centrosymmetric fragments which embedded in the structures
of a range of natural products,8 this hidden symmetry has only
been exploited in the synthesis of an early intermediate in a total
synthesis of Hemibrevetoxin B.9 Nonetheless, a few asymmetric
An alternative approach to the synthesis of N-substituted trans-
2,5-disubstituted piperazines could involve the desymmetrisation
of the centrosymmetric ring system (Scheme 1): the nitrogen atoms
of 4 and 5 are enantiotopic, and are ‘coded’ by the absolute
configuration of their neighbouring stereogenic centres. Hence,
enantioselective functionalisation of either 4 or 5 would remove
the centre of symmetry, and could yield the corresponding N-
substituted piperazines in high yield and enantiomeric excess. In
this paper, we describe the desymmetrisation of centrosymmetric
piperazines using both catalytic and stoichiometric methods to
yield enantiomerically enriched N-acyl piperazines such as 6 and
7. The synthetic strategy was then applied in an enantioselective
total synthesis of the alkaloid, Dragmacidin A (3).
Synthesis of racemic samples
Racemic samples of potential desymmetrisation products were
prepared using the reactions described in Scheme 2. Hence, the
centrosymmetric piperazine 4 was reacted with one equivalent
of methyl chloroformate, and subsequently derivatised with b-
naphthoyl chloride: the chiral piperazine 10a, and the centrosym-
metric piperazines 9 and 11 were obtained in 31%, 32% and 26%
yield respectively. The unsymmetrical piperazine 10a could be
easily resolved by chiral analytical HPLC.
The corresponding N-acetyl derivative 10b was prepared in
a similar way. Hence, monoprotection of the centrosymmeric
piperazine 4 as its mono-Cbz derivative 12 was achieved in 36%
yield. Acetylation (→13), hydrogenolytic removal of the Cbz
School of Chemistry, University of Leeds, Leeds, LS2 9JT, UK
† Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/b608910k
‡ These figures are based on a survey of the Scifinder Scholar Database in
January 2006.
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Scheme 1
group, and b-naphthoylation gave the unsymmetrical piperazine
10b; 10b could also be easily resolved by chiral analytical HPLC.
An alternative approach was used in the preparation of the
racemic N-formyl piperazine 10c. Hence, treatment of the piper-
azine 4 with two equivalents of butyllithium, and one equivalent
of b-naphthoyl chloride, gave the monosubstituted piperazine 15
in 42% yield; formylation of 15 provided a racemic standard of the
N-formyl piperazine 10c which could also be resolved by analytical
chiral HPLC.
In order to assess the likely intervention of the uncatalysed
pathway, the direct reaction between the piperazine 4 and the
acylating agent 19 was studied. The reaction between 4 and
19 in dichloromethane was complete within 5 minutes at room
temperature, suggesting that the background reaction was likely
to be significant under these conditions. In contrast, no reaction
between 4 and 19 was detected after 4 hours at −42 ◦C in
chloroform,§ and attention was, therefore, focused on catalysed
reactions under these conditions.
With 5 mol% DMAP, the acylating agent 19 was completely
consumed within 2 hours at −42 ◦C in chloroform. After b-
naphthoylation, yields of the desymmetrised product 10a and
the acylated starting material (11), determined by analytical
HPLC, were 25% and 40% respectively (entry 1, Table 1). We
were surprised to isolate a worse than statistical yield of the
desymmetrised product.
Desymmetrisation of centrosymmetric piperazines by catalytic
asymmetric acylation
The catalytic asymmetric acylation of amines is challenging
because the reactivity of the acylating agent needs to be tuned
such that it reacts more rapidly with the nucleophilic catalyst than
(unselectively) with the amine reactant. The only example of a non-
enzymatic catalytic enantioselective acylation of amines has been
described by Fu:12a a range of racemic amines have been kinetically
resolved using a chiral DMAP derivative in conjunction with
the O-methoxycarbonylated azlactone 19. Fu’s optimised system
involved the use of 10 mol% of the chiral catalyst in chloroform
at −50 ◦C, and selectivity factors in the range of S = 12–27 were
observed in the kinetic resolution of a series of substituted a-
methyl benzylamines.12a
The catalytic asymmetric acylation of the centrosymmetric
piperazine 4 was investigated using the chiral DMAP analogues12
(R)-16,13 (S)-1714 and (R)-18.15 In each experiment, the piperazine
4 was treated with the acylating agent 19 in chloroform in the pres-
ence of a catalytic quantity of DMAP analogue (Scheme 3); the
initial products were acylated with b-naphthoyl chloride, and the
ratio of the desymmetrised product 10a and the centrosymmetric
bis-amide 11 (derived from acylation of any unreacted starting
material) was determined by analytical HPLC. The enantiomeric
excess of the desymmetrised product 10a was determined by chiral
analytical HPLC. The conditions screened, and our results, are
summarised in Table 1.
Our initial results with the chiral DMAP analogues (R)-16, (S)-
17 and (R)-18 are described in Table 1 (see entries 2a–b, 3a and 4a).
With 20 mol% of Fu’s catalyst, (R)-16, no reaction was observed
after 7 hours at −42 ◦C in chloroform (data not shown).¶ It was
clear that the catalyst (R)-16 was considerably less active than
DMAP, presumably because 2-substituents reduce the catalyst’s
nucleophilicity.16 At −18 ◦C, with the reagent added in three equal
batches 48 hours apart, the acylating agent 19 was completely
consumed after 7 days; after b-naphthoylation, the desymmetrised
product 10a was obtained in 25% isolated yield and 44% ee (entry
2a). The sense of enantioselectivity observed is unknown, and
the absolute configuration of the desymmetrised product is drawn
◦
arbitrarily. At 0 C, the reaction was considerably faster, though
less enantioselective: after 16 hours, with the acylating agent 19
added in two portions eight hours apart, the piperazine 10a was
obtained, after b-naphthoylation, in 23% isolated yield and 33% ee
§ Under these conditions, all components of the reaction were completely
soluble at a reasonable (0.12 M) concentration of the reactants 4 and 19.
¶ In this experiment, the acylation agent 19 was added in two equal batches.
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Scheme 2
(entry 2b). Under these conditions, it is likely that the uncatalysed
pathway intervenes significantly.
Spivey’s catalyst (S)-17 and Vedejs’ catalyst (R)-18 were much
more active than Fu’s catalyst (R)-16. With both (S)-17 and (R)-
18, the acylating reagent 19 was consumed within a reasonable
timeframe at −42 ◦C. With 5 mol% (S)-17, the desymmetrised
product was obtained in rather low yield and 70% ee after 7 hours
and subsequent b-naphthoylation (entry 3a, Table 1); the sense
of enantioselectivity was the opposite to that observed with
(R)-16. The catalyst (R)-18 was rather less active than (S)-17 and,
Table 1 Desymmetrisation of the centrosymmetric piperazine 4 by catalytic enantioselective methoxycarbonylation (see Scheme 3)
10a
11
Entry
Catalyst (mol%a)
Eq. 4a
Temp./◦C
Time/h
Yieldb (%)
Eec
Yieldb (%)
1
DMAP
(R)-16 (20)
1
1
1
1
10
1
−42
−18
0
−42
−42
−42
−42
2
164d
16f
7
4
14
7
25
−
40
2a
2b
3a
3b
4a
4b
25e
23e
20
44
39e
33
−70
−26
64
37e
(S)-17 (5)
(R)-18 (5)
43
43g
22
h
34
h
10
49g
23
a Relative to the reagent 19. b Unless otherwise stated, determined by analytical HPLC by calibration against external standards. c Determined by chiral
analytical HPLC; negative values indicate that the sense of asymmetric induction was reversed. d The reagent was added in three batches. e Yield of isolated
product obtained after flash column chromatography. f The reagent was added in two batches. g Yield based on the reagent 19. h Not detected.
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Scheme 3
under the same conditions, the reaction required 14 hours to reach
completion. After b-naphthoylation, the desymmetrised product
10a was obtained in similar enantiomeric excess (64% ee) though
the sense of asymmetric induction was reversed (entry 4a). The
yield (22%) of 10a was, however, disappointing.
that this process may have increased the enantiomeric excess of
the desymmetrised product by the selective destruction (kinetic
resolution) of its minor enantiomer. This type of ‘proof reading’
effect, described in Scheme 4, has been previously recognised, for
example in the desymmetrisation of divinyl carbinols by Sharpless
asymmetric epoxidation.17
To investgate the possibility of a ‘proof reading’ effect, the
reactions catalysed by (S)-17 and (R)-18 were repeated using
ten equivalents of the centrosymmetric piperazine 4 relative to
the acylating agent 19. Under these conditions, it was expected
that the second acylation would be suppressed, and the gen-
uine enantioselectivity of the desymmetrisation step could be
determined. In each case, the desymmetrisation product 10a was
‘Proof-reading’ in the catalytic asymmetric desymmetrisation
reaction
The low yields of the desymmetrised product 10a obtained with
the chiral catalysts 16–18 stemmed from further reaction of
the required product with the acylating agent (19) under the
conditions of the reaction (entries 2a–b, 3a and 4a). We reasoned
Scheme 4
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Table 2 Desymmetrisation of the centrosymmetric piperazine 4 by enantioselective acylation with the chiral reagents 21 and 22 (see Scheme 5)
4
Et3N
Eq.a
11
Monoacylated product
Entry
Reagent
Solvent
Eq.a
Yieldb (%)
Product
Yieldb (%)
Eec (%)
d
d
1
21
21
21
21
21
21
22
22
22
22
DMPU
DMF
DMF
DMF
DMF
1
1
2
10
1
2
1
1
1
1
—
—
—
—
3
10
—
—
—
—
10b
10b
10b
10b
10b
10b
10c
10c
10c
10c
57
75
84
73
84
81
28
28
35
2a
2b
2c
3a
3b
4
5
6
7
41
—
—
37
20
48e
87e
31
DMF
—
51e
66
df
CDCl3
DMSO-d6
DMF
d
d
d
<10g
d
Dioxane
48g
−10
a Relative to the reagent 21 or 22. b Unless otherwise stated, isolated yield of purified compound. c Determined by chiral analytical HPLC; negative values
indicate that the sense of asymmetric induction was reversed. d Not determined. e Yield based on the reagent 19. f The yield of the diacylated product
23c, determined by 300 Hz 1H NMR spectroscopic analysis of the crude reaction mixture, was <10%. g Determined by 300 Hz 1H NMR spectroscopic
analysis of the crude reaction mixture.
obtained, after b-naphthoylation, in higher yield (based on the
reagent 19) but with reduced enantiomeric excess (compare entry
3b with entry 3a, and entry 4b with entry 4a). With both (S)-
17 and (R)-18, and one equivalent of the acylating agent 19,
enhancement of the enantiomeric excess of the desymmetrised
product did occur at the expense of yield. Unfortunately, the
‘proof reading’ effect was an inevitable consequence of the relative
rates of the two acylation steps: the experimenter is not, therefore,
able to choose an appropriate compromise between the yield and
enantiomeric excess of the product. However, with a cheap and
available centrosymmetric piperazine, such as 4, low (20–25%)
yields of desymmetrised products may be obtained with reasonable
enantiomeric excess.
We focused on the acetylation reagent18 21, and the formylating
reagent 22, prepared by formylation of the corresponding bis-
sulfonamide. Our results are summarised in Scheme 5 and Table 2.
Dipolar aprotic solvents, such as DMPU, DMF and HMPA,
have been previously shown to be most effective in the kinetic
resolution of chiral primary amines by acetylation with the reagent
21. We therefore studied the reaction of the centrosymmetric
piperazine 4 with one equivalent of the chiral acetylating agent 21
(entries 1 and 2a, Table 2). In DMPU, the desymmetrised product
10b was obtained, after b-naphthoylation, in extremely low yield
and 57% ee (entry 1). In DMF, the results were also disappointing,
and a 20% yield of 10b was obtained, albeit with 75% ee (entry 2a).
A comparison of the estimated19 pKa value of the deacetylated
bis-sulfonamide (pKa: 5.6 0.4) with the estimated19 pKaH values
of the piperazine 4 (pKaH: 10.0
lated product (pKaH: 8.1 0.7) suggested that, as the reaction
proceeded, the concentration of the piperazine 4 was being
unnecessarily depleted by its selective protonation. Such an effect
would selectively reduce the rate of the first acetylation and, hence,
0.6) and the monoacety-
Desymmetrisation of centrosymmetric piperazines with chiral
acylating reagents
We turned our attention to the use of chiral acylating reagents
for the desymmetrisation of the centrosymmetric piperazine 4.
Scheme 5
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the yield of the required product. Addition of three equivalents
of triethylamine (pKaH: 10.65,20 10.6 0.319) to the acetylation
reaction increased the yield of desymmetrised product to 31%,
suggesting that this effect was significant (compare entry 3a with
entry 2a, Table 1).
(entry 7). Previously, the sense and magnitude of asymmetric
induction in the kinetic resolution of chiral primary amines with
the reagent 21 has been shown to be highly dependent on the
nature of the solvent used.18
Nevertheless, the yield of the required product was still rather
low, and it was possible that the enantiomeric excess of the
products was being enhanced once more through an inevitable
‘proof reading’ mechanism. The desymmetrisation reaction was,
therefore, repeated with both two and ten equivalents of the
piperazine: in each case, the second acetylation reaction was
suppressed, and the yield of the desymmetrised product (relative to
the limiting reagent 21) increased dramatically (compare entries
2b and 2c with entry 2a, Table 2). However, in each case, the
enantiomeric excess of the desymmetrised product was similar to
that obtained with one equivalent of reagent. This observation
indicated that, although the yield of the product was less dimin-
ished by a competing, second acetylation, it is the first acetylation
that is enantioselective. ‘Proof reading’ does not, therefore, occur.
Increasing the number of equivalents of the piperazine 4, relative
to the acetylation reagent 21, does not, therefore, reduce the
enantiomeric excess of the required, desymmetrised product.
Indeed, with 10 equivalents of triethylamine and two equivalents of
the piperazine 4, relative to the acetylation reagent 21, a reasonable
yield (51% based on the limiting reagent) of the desymmetrised
product was obtained in 81% ee (entry 3b).
Total synthesis of Dragmacidin A
The desymmetrisation of a centrosymmetric piperazine was ex-
ploited in a total synthesis of Dragmacidin A (3). The protected 6-
bromo tryptamine derivative21 24 was oxidized to yield the amino
ketone derivative 25, which was deprotected and condensed to
yield the pyrazine 26 (Scheme 6).6 SEM-protection (→27) and
diastereoselective reduction6 (90 : 10 trans–cis) gave the required
centrosymmetric piperazine 29.
A range of solvents were screened for the key desymmetrisation
step (see Scheme 7 and Table 3). Treatment of the centrosymmetric
piperzine 29 with the reagent 22 in chloroform gave the desym-
metrised product 30 in 61% yield (entry 1, Table 3); however,
although these conditions give good yield of the desymmetrised
product (compare entry 1, Table 3 with entry 4, Table 2), its
enantiomeric excess was very low. Of the other solvents screened
(entries 2–8, Table 3), the best result was obtained in dioxane:
Table 3 Desymmetrisation of the centrosymmetric piperazine 29 by
enantioselective formylation with the reagent 22 (see Scheme 7)
With the chiral formylating reagent 22, the nature of the solvent
had a profound effect on the distribution of products (entries 4–
7, Table 2). In deuterated chloroform, the major product was,
after b-naphthoylation, the required desymmetrised product 10c,
and only a trace of the disubstituted piperazine 23c was detected
(entry 4). In contrast, in the dipolar aprotic solvents DMSO-
d6 (entry 5) and DMF (entry 6), only small amounts of the
desymmetrised product were obtained, together with substantial
amounts of the diformylated product 23c. Under these conditions,
the second formylation step was much faster than the first. In
each case, the enantiomeric excess of the desymmetrised product
10c was determined by chiral analytical HPLC. Unfortunately,
disappointing enantiomeric excesses were observed, with a very
low, though reversed, sense of asymmetric induction in dioxane
Product 30
Entry
Solvent
Yielda (%)
Eeb (%)
1
2
3
4
5
6
7
8
CDCl3
DMF
THF
Toluene
Acetoned
EtOAcd
Cl3CCH2OH
Dioxane
61
46
70
50c
24c
31c
62
66
−12
0
19
−13
1
6
−3
48
a Isolated yield of purified compound. b Determined by chiral analytical
HPLC; negative values indicate that the sense of asymmetric induction
was reversed. c The reaction did not reach completion. d The piperazine 29
was only sparingly soluble under the reaction conditions.
Scheme 6
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Scheme 7
under these conditions, the required desymmetrised product, 30,
was obtained in 66% yield and 48% ee (entry 8).
under reduced pressure, a mixture of the piperazines 10a and 11
were separated from the residue by flash chromatography (gradient
elution 9 : 1 → 1 : 1 petrol–EtOAc). The yields of 10a and 11,
relative to an external standard, and the enantiomeric excess of 10a
The enantiomerically enriched formamide30 was converted into
Dragmacidin A (Scheme 7). Removal of the SEM groups with
TBAF, and reduction with borane, gave the N-methyl piperazine,
R
were determined by chiral analytical HPLC (Chiralcelꢀ OD) mon-
which was spectroscopically identical to the natural product.22
A
itoring at k = 250 nm; eluting with 9 : 1 hexane–IPA, 1 mL min−1
over 60 min, then 3 : 2 hexane–IPA, 1 mL min−1 over 30 min; re-
tention times: 10a, 24.1 min and 32.5 min; 11, 68.4 min (see ESI†).
sample of Dragmacidin A, prepared by Jiang et al.,23 was reported
to have 96% ee and an optical rotation of +4.0 in chloroform.
The sample which we prepared had 48% ee and a rotation of
+5.9 (in chloroform) or +5.8 (in acetone). The piperazine 3 is
believed to have the same absolute configuration as that previously
prepared by Jiang,23 although the reasons for the discrepancy in
the magnitude of the optical rotation measurement are unclear.
General procedure for desymmetrisation of
trans-2,5-dimethylpiperazine with the acetylating agent 21
A solution of the acetylating agent18 21 (120 mg, 0.286 mmol)
in dimethylformamide (0.75 mL) was added to a solution of the
trans-2,5-dimethylpiperazine (32 mg, 0.284 mmol) in dimethyl-
formamide (2.0 mL). After 40 hours, triethylamine (180 lL,
1.29 mmol) was added, followed by a solution of 2-naphthoyl
chloride (180 mg, 0.94 mmol) in dichloromethane (1.0 mL). The
mixture was stirred for 30 min, concentrated under reduced pres-
sure and the residue subjected to flash chromatography (gradient
elution 9 : 1 → 0 : 1 petrol–EtOAc to give the disubstituted
piperazine 11.
Summary
The enantioselective desymmetrisation of centrosymmetric piper-
azines was investigated using both catalytic and stoichiometric
asymmetric approaches. The catalysts (S)-17 and (R)-18, devel-
oped by Spivey and Vedejs respectively, were used for the first
time in the enantioselective acylation of amines. In the catalytic
approach investigated, an inevitable ‘proof reading’ effect was
found to increase to enantiomeric excesses of the desymmetrised
products at the expense of yield.
The reaction of centrosymmetric piperazines with chiral acylat-
ing agents yielded the corresponding desymmetrised products. The
yield and enantioselectivity of the process was highly dependent on
the solvent used and the substitution of the piperazine. However,
in some cases, good yields of enantiomerically enriched products
could be obtained, particularly if the acylating agent was used
as the limiting reagent. The approach was applied in the total
synthesis of Dragmacidin A.
Also obtained was the substituted piperazine 10b, whose
enantiomeric excess was determined by chiral analytical HPLC
R
(Chiralcelꢀ OD) monitoring at k = 225 nm; eluting with 7 : 3
hexane–IPA, 1 mL min−1 over 40 min; retention times: 12.0 min
and 16.3 min (see ESI†).
General procedure for desymmetrisation of
trans-2,5-dimethylpiperazine with the formylating agent 22
The formylating agent 22 (75 mg, 0.125 mmol) was added to a
solution of the trans-2,5-dimethylpiperazine (13 mg, 0.114 mmol)
in a an appropriate solvent (2.0 mL). After 72 hours, sodium
hydrogen carbonate (30 mg, 0.35 mmol) was added, followed
by a solution of 2-naphthoyl chloride (48 mg, 0.25 mmol) in
dichloromethane (1.0 mL). The mixture was stirred for 30 min,
concentrated under reduced pressure and the residue subjected to
flash chromatography (gradient elution 9 : 1 → 0 : 1 petrol–EtOAc
to give the substituted piperazine 10c, whose enantiomeric excess
Experimental
General procedure for desymmetrisation of trans-2,5-dimethyl-
piperazine with chiral DMAP analogues and the reagent 19
A solution of the reagent12 19 (97 mg, 0.298 mmol) in chloroform
(0.5 mL) was added to a solution of trans-2,5-dimethylpiperazine
(32 mg, 0.284) an◦d the chiral catalyst (0.014 mmol) in chloroform
(2.0 mL) at −42 C. After complete consumption of the reagent
R
was determined by chiral analytical HPLC (Chiralcelꢀ OD–RH)
monitoring at k = 225 nm (gradient elution: 7 : 3 → 1 : 1 water–
MeCN), 1 mL min−1 over 40 min; retention times: 10.6 min and
12.6 min (see ESI†).
◦
19 was observed by TLC, the reaction was warmed to 0 C and
triethylamine (125 lL, 0.90 mmol) was added. A solution of 2-
naphthoyl chloride (125 mg, 0.66 mmol) in chloroform (1.0 mL)
was added and the mixture stirred for 30 min. Water (25 mL)
and dichloromethane (25 mL) were added, and the aqueous layer
separated and extracted with dichoromethane (2 × 25 mL). The
combined organic extracts were dried (MgSO4) and concentrated
(2R,5S)-1-Formyl-2,5-bis[6-bromo-1ꢀ-(2ꢀꢀ-trimethyl-
silanylethoxymethyl) indol-3ꢀ-yl]piperazine 30
The formylating agent 22 (246 mg, 0.408 mmol) was added to a
solution of the piperazine 29 in dioxane (6.5 mL). After 16 days the
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mixture was concentrated under reduced pressure and subjected
to flash chromatography eluting with dichloromethane to remove
the disulfonamide (200 mg, 81%). The elution was continued
(gradient: 199 : 1 → 99 : 1 CH2Cl2–MeOH/NH3) to give the
formamide 30 (206 mg, 66%) as a pale yellow glass, Rf 0.60 (97 :
3 CH2Cl2–MeOH/NH3); [a]D +10.4 (c 1.0 in acetone); mmax/cm−1
(film) 2955, 2924, 2855, 1736 and 1658; dH (300 MHz; CDCl3)
7.97 (1H, s, CHO), 7.70 (1H, d, J 8.5, 4ꢀ-H), 7.69 (1H, d, J 1.5,
7ꢀ-H), 7.65 (1H, d, J 1.5, 7ꢀ-H), 7.50 (1H, d, J 8.5, 4ꢀ-H), 7.27 (4H,
m, 2ꢀ-H and 5ꢀ-H), 5.45 (2H, s, 1ꢀ-NCH2), 5.41 (2H, s, 1ꢀ-NCH2),
4.79 (1H, dd, J 9.5 and 3.2, 2-H), 4.59 (1H, dd, J 13.1 and 3.1,
6-HAHB), 4.24 (1H, dd, J 9.6 and 3.1, 5-H), 3.48 (5H, m, 2 × 1ꢀꢀ-H
and 3-HAHB), 3.32 (1H, dd, J 11.9 and 3.2, 3-HAHB), 3.18 (1H,
dd, J 13.1 and 9.6, 6-HAHB), 0.91 (2H, t, J 8.1, 2ꢀꢀ-H), 0.91 (2H,
t, J 8.1, 2ꢀꢀ-H) and −0.03 (18H, s, SiMe3); dC (75 MHz; CDCl3)
161.4, 137.7, 137.6, 127.6, 126.2, 126.1, 125.9, 124.2, 123.4, 121.0,
120.9, 116.9, 116.3, 115.8, 114.4, 113.4, 110.3, 75.8, 75.8, 66.3,
66.1, 53.9, 52.4, 51.3, 46.4, 17.7, 17.7, −1.42 and −1.42; m/z (CI)
765 (4%, MH+), 763 (5), 761 (3), 647 (57), 645 (100), 643 (53), 567
(60), 565 (53) and 487 (48); m/z (ES) (Found: (M–C5H13OSi)+,
643.0728; C28H33N4O2BrSi requires 643.0734). The sample was
(2R,5S)-1-formyl-2,5-bis[6-bromoindol-3ꢀ-yl]piperazine (40 mg,
0.0796 mmol) in tetrahydrofuran (4 mL). The reaction mixture
was heated at reflux for 2 hours, cooled, quenched with methanol
(10 mL), diluted with water (10 mL) and extracted with ethyl
acetate (3 × 20 mL). The combined organic extracts were dried
(MgSO4) and concentrated under reduced pressure to give a crude
product which was purified by flash chromatography (gradient
elution: 49 : 1 → 24 : 1 CH2Cl2–MeOH/NH3) to give Dragmacidin
A 3 (20 mg, 51%) as a pale yellow glass, Rf 0.56 (23 : 2 CH2Cl2–
MeOH/NH3); [a]D +5.8 (c 1.0 in acetone), +5.9 (c 0.20 in CHCl3)
[lit.23 +4.0 (c 0.20 in CHCl3)]; mmax/cm−1 (film) 3413, 2849, 1695,
1615, 1543 and 1454; dH (500 MHz; acetone-d6) 10.29 (2H, br s,
1ꢀ-NH), 7.91 (1H, d, J 8.5, 4ꢀ-H), 7.80 (1H, d, J 8.5, 4ꢀ-H), 7.60
(2H, s, 7ꢀ-H), 7.37 (1H, d, J 1.9 2ꢀ-H), 7.33 (1H, d, J 2.1 2ꢀ-H),
7.16 (2H, d, J 8.5, 5ꢀ-H), 4.40 (1H, dd, J 10.4 and 2.6, 5-H), 3.36
(1H, dd, J 10.4 and 3.0, 2-H), 3.27 (1H, dd, J 11.7 and 10.4, 3-
HAHB), 3.16 (1H, dd, J 11.0 and 2.6, 6-HAHB), 3.06 (1H, dd, J
11.7 and 3.0, 3-HAHB), 2.34 (1H, dd, J 11.0 and 10.4, 6-HAHB);
dC (75 MHz; acetone-d6) 139.1, 139.0, 126.9, 125.3, 125.1, 124.1,
123.9, 123.1, 122.8, 122.5, 119.1, 117.6, 115.7, 115.6, 115.5, 115.4,
64.9, 63.7, 55.1, 54.8 and 44.7; m/z (CI) 491 (50%, MH+), 489
(100), 477 (57), 411 (52) and 409 (60); m/z (ES) (Found: MH+,
487.0129; C21H20N4Br2 requires MH, 487.0127).
R
shown to have 48% ee by chiral analytical HPLC (Chiralcelꢀ OD–
RH) monitoring at k = 225 nm (gradient elution: 23 : 77 → 1 : 4
water–MeCN), 1 mL min−1 over 30 min; retention times: 23.7 min
and 26.7 min (see ESI†).
Acknowledgements
(2R,5S)-1-Formyl-2,5-bis[6-bromoindol-3ꢀ-yl]piperazine
We thank the EPSRC for funding, the EPSRC Mass Spectrometry
Service Centre, Swansea, for mass spectrometry, Professor David
Horne for helpful discussions, Dr Alan Spivey for the generous
donation of a sample of the acylation catalyst S-17 and for fruitful
discussions, Stellios Arseniyadis for helpful discussions, and James
Titchmarsh (University of Leeds) and Mick Lee (University of
Leicester) for technical assistance.
Tetrabutylammonium fluoride (2.62 mL, 1 M solution in tetrahy-
drofuran, 2.62 mmol), was added to a stirred mixture of the
˚
formamide 30 (100 mg, 0.131 mmol) and ground 4 A molecular
sieves in tetrahydrofuran (2 mL). The reaction mixture was heated
at reflux for 6 hours, cooled, filtered, diluted with acetone (10 mL),
water (10 mL) and ethyl acetate (20 mL). The mixture was washed
with water (3 × 10 mL) and the combined aqueous washes were
washed with ethyl acetate (15 mL). The combined organics were
dried (MgSO4) and concentrated under reduced pressure to give
a crude product which was purified by flash chromatography
(gradient elution: 49 : 1 → 24 : 1 CH2Cl2–MeOH/NH3) to give the
title compound (46 mg, 70%) as a pale yellow glass, Rf 0.31 (23 :
2 CH2Cl2–MeOH/NH3); [a]D +12.8 (c 1.0 in acetone); mmax/cm−1
(film) 3273, 2916, 1696 and 1642; dH (500 MHz; acetone-d6) 10.57
(1H, br s, 1ꢀ-NH), 10.26 (1H, br s, 1ꢀ-NH), 7.78 (1H, s, COH),
7.65 (1H, d, J 8.5, 4ꢀ-H), 7.55 (1H, d, J 1.3, 7ꢀ-H), 7.51 (1H, d, J
8.5, 4ꢀ-H), 7.48 (1H, d, J 1.3, 7ꢀ-H), 7.45 (1H, s, 2ꢀ-H), 7.28 (1H, s,
2ꢀ-H), 7.09 (1H, dd, J 8.5 and 1.3, 5ꢀ-H), 7.03 (1H, dd, J 8.5 and
1.3, 5ꢀ-H), 4.74 (1H, dd, J 10.1 and 3.0, 2-H), 4.35 (1H, dd, J 12.7
and 3.0, 6-HAHB), 4.09 (1H, dd, J 9.6 and 3.0, 5-H), 3.33 (1H, dd,
J 11.7 and 10.1, 3-HAHB), 3.15 (1H, dd, J 11.7 and 3.0, 3-HAHB),
3.04 (1H, dd, J 12.7 and 9.6, 6-HAHB); dC (75 MHz; acetone-d6)
161.8, 139.2, 139.0, 126.9, 126.8, 124.6, 123.9, 123.0, 122.4, 122.1,
117.4, 117.4, 116.4, 116.0, 115.8, 115.6, 111.6, 55.1, 53.8, 52.6 and
47.6; m/z (ES) 505 (54%, MH+), 505 (100) and 503 (50); m/z (ES)
(Found: MH+, 502.9908; C21H19N4OBr2 requires MH, 502.9905).
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