Total synthesis and stereochemical revision of burkholdac A

Article abstract of DOI:10.1055/s-0031-1290339

A stereocontrolled total synthesis of burkholdac A was completed, leading to a revision of the reported stereochemistry. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290339

LETTER
783
Total Synthesis and Stereochemical Revision of Burkholdac A
Synthesis
u
of Burkholda
n
c
A
yang Liu,a Xiao Ma,a Yuqing Liu,b Zhuo Wang,b Shuqin Kwong,b Qi Ren,a Shoubin Tang,a Yi Meng,a
Zhengshuang Xu,*a,b Tao Ye*a,b
a
Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, University Town of Shenzhen,
Xili, Nanshan District, Shenzhen, 5180505, P. R. of China
Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon,
b
Hong Kong, P. R. of China
Fax +85222641912; E-mail: bctaoye@inet.polyu.edu.hk; E-mail: xuzs@szpku.edu.cn
Received 13 December 2011
developments in isolation and analytical technologies
have made structural elucidation of natural product a rou-
tine operation. However, numerous natural products were
misassigned, including a substantial number of recently
elucidated marine natural products. Total synthesis plays
a critical role in natural product structure elucidation,
which accounts for the overwhelming majority of natural
product structural revisions.2,3 We have been interested
for some time in secondary metabolites and view their
syntheses as a key route to structural confirmation, struc-
tural modification, and subsequent activity control.4
While this manuscript was in preparation, Ganesan and
Abstract: A stereocontrolled total synthesis of burkholdac A was
completed, leading to a revision of the reported stereochemistry.
Key words: burkholdac A, total synthesis, antitumor, stereochemi-
cal assignment
Natural products represent validated starting points for
drug discovery. Their structural assignment and chemical
synthesis potentially provide the foundation for research
in the development of new therapeutic agents.1 Advanced
amide
MeS
formation
MeS
oxidative
coupling
O
O
H
N
H
N
TrtS
N
S
N
H
H
O
O
O
NH
O
NH
O
O
OTBS O
OH
O
STrt
S
macrolactonization
2
burkholdac A (1)
(proposed structure)
MeS
S
O
OH
H
N
TrtS
O
NHFmoc
S
N
MeS
O
NH
+
OTce
O
STrt
HO
4
NHFmoc
OH
O
3
5
+
S
O
O
NHBoc
NHBoc
+
TrtS
S
N
OMe
O
+
O
OH
OH
STrt
6
7
8
9
Scheme 1 Retrosynthetic analysis
SYNLETT 2012, 23, 783–787
x
x.
x
x.
2
0
1
1
Advanced online publication: 08.02.2012
DOI: 10.1055/s-0031-1290339; Art ID: W76811ST
© Georg Thieme Verlag Stuttgart · New York

784
J. Liu et al.
LETTER
co-workers reported the first total synthesis of burkholdac protective group of 7 was cleanly removed with trifluoro-
B and corrected the originally misassigned structure.5 The acetic acid, and the resulting free amine was immediately
stereochemical revision of burkholdac B is identical with exposed to a PyBOP-mediated coupling process with N-
that described in the current manuscript. Here we wish to Boc-D-cysteine to afford dipeptide 15 in 85% yield. Hy-
describe the total synthesis and revised stereochemical as- drolysis of ester 15 gave the corresponding acid, which
signment of burkholdac A.
was converted into 16 by Keck’s modification10 of
Steglich’s carbodiimide esterification. BF3·OEt2-promot-
ed removal of the Boc protective group of 16 followed by
coupling of the resulting amine with N-Fmoc-L-methion-
ine afforded 3 in 78% yield.
SMe
O
H
N
S
S
N
H
With fragment 3 in hand, we next turned our attention to
the synthesis of the b-hydroxyl acid fragment 4
(Scheme 3). Thus, conjugate addition of triphenyl-
methanethiol to acrolein gave rise to aldehyde 17 in 93%
yield. Subsequent Wittig olefination of 17 produced the
trans-a,b-unsaturated ethyl ester 18 in 85% yield (E/Z
>21:1). This conjugated ester was converted into the cor-
responding aldehyde 9 in 87% yield via a two-step se-
quence involving DIBAL reduction of ester followed by
Dess–Martin oxidation of the resulting primary alcohol to
give the corresponding aldehyde 9. Treatment of aldehyde
9 with N-acetylthiazolidinethione (8) in the presence of
TiCl4 and Hünig’s base in dichloromethane at –78 °C fur-
nished the acetate aldol adduct in 84% yield (dr = ca. 9:1),
O
O
R
NH
O
OH
O
burkholdac A R = Me
burkholdac B R = Et
Figure 1 Structure of burkholdacs A and B
Through the systematic overexpression of transcription
factors associated with natural product gene clusters en-
coded within Burkholderia thailandensis E264, Brady
and co-workers6 isolated burkholdacs A and B (Figure 1)
as two new members of a small class of bicyclic depsipep-
tides that includes spiruchostatins, FK228, and
FR901375.7 The constitution of burkholdacs A and B was
elucidated by extensive NMR spectroscopy studies, while
their absolute stereochemistry, as illustrated in Figure 1,
was proposed on the basis of the biosynthesis gene cluster
contains only one epimerase domain.
NHBoc
NHBoc
NHBoc
OH
ii
i
OMe
OMe
78%
60%
O
O
OH
O
O
10
N-Boc-L-Val-OH
7
iii
NHFmoc
NH
NHBoc
As outlined in our retrosynthetic analysis, burkholdac A
could be obtained from the advanced precursor 2 via di-
sulfide formation. It was envisaged that the 15-membered
macrolactone 2 could be constructed by macrolactoniza-
tion of the corresponding precursor which was planned to
be assembled from fragments 3 and 4. Further disconnec-
tion of fragments 3 and 4 led to smaller subunits 5–9
(Scheme 1).
TrtS
iv
OTce
85% v, vi
O
OH
O
OTce
11
TrtS
iv
NHBoc
12
OH
O
O
O
NH
NHFmoc
OTce
OMe
HN
TrtS
+
OH
O
15
The synthesis of L-valine-derived statine methyl ester 7
commenced with the condensation of N-Boc-valine with
methyl magnesium malonate,8 to afford b-keto ester 10 in
60% yield (Scheme 2). Diastereoselective reduction of 10
with KBH4 produced the desired alcohol 7 as the major
isomer (dr >11:1) that was easily separated by column
chromatography. Transesterification of a methyl ester to
the trichloroethyl ester 11 was achieved according to the
procedure of Ganesan.9 However, in our hands, we were
unable to reproduce dipeptide 12 by condensation of the
amine derived from 11 and activated D-cysteine that
Ganesan observed in his total synthetic of spiruchostatin
A.9 The major products isolated from our reaction were
ester 13 and g-lactam 14, which could arise from an in-
tramolecular cyclization of the amine derived from 11,
and nucleophilic attack of the activated D-cysteine by
trichloroethanol. At this stage, we decided to slightly
modify the synthetic sequence by formation of dipeptide
15 prior to a transesterification process. Thus, the Boc
O
OH
14
13
96%
vii, viii
MeS
NHBoc
NH
H
N
TrtS
TrtS
NHFmoc
ix, x
78%
O
O
O
NH
OTce
OTce
O
OH
O
OH
16
3
Scheme 2 Synthesis of fragment 3. Reagents and conditions: (i)
CDI, THF, then potassium methyl malonate, MgCl2, 60%; (ii) KBH4,
MeOH, –78 °C to r.t., 78 °C; (iii) (a) LiOH, THF–H2O (4:1), 0 °C; (b)
TCEOH, DCC, DMAP, CH2Cl2; (iv) (a) TFA, CH2Cl2; (b) Fmoc-
STrt-D-Cys, PyAOP, DIPEA, CH2Cl2, 74%; v, TFA, CH2Cl2; (vi) 6,
PyAOP, DIPEA, CH2Cl2, 85% (2 steps); (vii) NaOH, THF; (viii)
TceOH, EDCI, DMAP, CH2Cl2, 96% (2 steps); (ix) BF3⋅OEt2,
CH2Cl2; (x) 5, PyAOP, DIPEA, CH2Cl2, 78% (2 steps).
Synlett 2012, 23, 783–787
© Thieme Stuttgart · New York

LETTER
Synthesis of Burkholdac A
785
and the desired diastereomer 4 was readily separated by Thus, the secondary alcohol in fragment 3 was protected
chromatography.11
as its TBS ether 18 in 98% yield. By taking advantage of
the good leaving-group ability of the thiazolidine-2-
thione moiety of fragment 4, transamidification with suit-
able amine should be a spontaneous process. Thus, re-
moval of the Fmoc group of 19 afforded the
corresponding free amine, which reacted with fragment 4,
in the presence of DMAP, to produce 20 in 85% yield over
the two steps. Reductive removal of the trichloroethyl es-
ter by treating 20 with zinc and ammonium acetate afford-
ed the corresponding sec-acid, which was subjected to
Shiina’s lactonization12 protocol employing 2-methyl-6-
nitrobenzoic anhydride (MNBA) and DMAP to provide
macrolactone 2 in 31% yield over two steps. Oxidative
deprotection of the bis(S-triphenylmethyl)lactone with io-
dine, followed by removal of the TBS protecting group
with HF–pyridine complex to give rise to the proposed
burkholdac A (1) in 63% yield.13
At this juncture, the time had arrived to explore the assem-
bly of two key fragments leading to linear peptide precur-
sor 20 for the final macrocyclization reaction (Scheme 4).
i
ii
TrtS
TrtS
CHO
CHO
CO2Et
93%
85%
18
17
S
O
N
iii, iv
87%
S
TrtS
8
iv
OH
O
S
O
TrtS
N
84%
S
9
4
Unfortunately, on comparison of our spectra and the pub-
lished data for natural burkholdac A, neither 1H NMR nor
13C NMR spectra for 1 were identical with those of the
natural product. These data suggested that structure 1,
proposed by Brady and co-workers, must be incorrect for
the true structure of burkholdac A. On the basis of the hy-
pothesis that FK228, FR901228, FR901375, spiruchosta-
tin, and burkholdacs are biosynthetically related, we
hypothesized that all three amino acids of natural burkhol-
dac are of D stereochemistry. We therefore elected to syn-
thesize the diastereomer epi-1 of the proposed structure 1.
As shown in Scheme 5, we prepared ent-7 following the
same synthesis as for 7, but with N-Boc-D-valine as the
starting material. Further elaboration of ent-7 to the re-
vised burkholdac A includes the incorporating of N-
Fmoc-D-methionine into epi-3 as the key intermediate.
This was readily achieved, and epi-114 was obtained in
3.9% overall yield as previously performed. To our de-
light, the spectral data (1H and 13C NMR) of the synthetic
burkholdac A (epi-1) are identical to those of the natural
burkholdac A.
Scheme 3 Synthesis of fragment 4. Reagents and conditions:
(i) TrtSH, CH2Cl2, 93%; (ii) Ph3P=CHCO2Et, CH2Cl2, 85%; (iii)
DIBAL, CH2Cl2; (iv) Dess–Martin periodinane, CH2Cl2, NaHCO3,
87% (2 steps); (v) 8, TiCl4, DIPEA, CH2Cl2, –78 °C, 84%.
MeS
MeS
H
H
N
N
TrtS
NHFmoc
TrtS
NHFmoc
i
98%
O
O
NH
O
NH
OTce
O
OTce
O
OH
3
TBSO
19
ii, iii
85%
MeS
MeS
O
H
N
O
TrtS
H
N
TrtS
N
H
N
H
O
iv, v
O
NH
O
O
NH
HO
OTce
31%
O
TBSO
O
NHBoc
TrtS
OMe
NHBoc
OH
STrt
TBSO
O
NHBoc
2
STrt
20
vi, vii
63%
O
NH
OTce
O
OH
O
MeS
N-Boc-D-Val-OH
ent-7
OH
O
O
H
N
epi-16
S
S
N
H
OH
O
S
MeS
O
O
NH
TrtS
N
S
MeS
O
O
O
H
N
4
S
N
H
HO
burkholdac A (1)
O
H
N
O
TrtS
NHFmoc
O
NH
(proposed structure)
O
O
NH
Scheme 4 Synthesis of the proposed burkholdac A (1). Reagents
and conditions: (i) TBSOTf, 2,6-lutidine, CH2Cl2, –78 °C, 98%; (ii)
diethyl amine, MeCN; (iii) 4, DMAP, CH2Cl2, 0 °C to r.t., 85% (2
steps); (iv) Zn dust, NH4OAc (aq), 40 °C; (v) MNBA, DMAP,
CH2Cl2, 31% (2 steps); (vi) I2, MeOH–CH2Cl2 (1:9); (vii) HF·py, 63%
(2 steps).
OTce
O
O
OH
S
burkholdac A (epi-1)
(revised structure)
OH
epi-3
Scheme 5 Synthesis of the revised burkholdac A (epi-1)
© Thieme Stuttgart · New York
Synlett 2012, 23, 783–787

786
J. Liu et al.
LETTER
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The HDAC inhibitory evaluation of 1 and epi-1 with the
Biomol Fluor-de-Lys HDAC assay gave results of great
interest (Figure 2). Both 1 and epi-1 inhibited HDAC ac-
tivity from a HeLa cell nuclear protein extract. Important-
ly, epi-1 has a superior potency (IC50 = 31 pM) compared
to 1 (IC50 = 720 nM). This indicated that the stereochem-
istry of burkholdac A and its diastereoisomer appears to
be an important factor for its bioactivities. With an IC50 at
picomolar level, burkholdac A (epi-1) is an exciting lead
for further investigation.
(5) Benelkebir, H.; Donlevy, A. M.; Packham, G.; Ganesan, A.
Org. Lett. 2011, 13, 6334.
(6) Biggins, J. B.; Gleber, C. D.; Brady, S. F. Org. Lett. 2011,
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(9) Yurek-George, A.; Habens, F.; Brimmell, M.; Packham, G.;
Ganesan, A. J. Am. Chem. Soc. 2004, 130, 1026.
Figure 2 Effect of 1 and epi-1 in HDAC activity assay
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In summary, the first total synthesis of burkholdac A was
completed, leading to a revision of the reported stereo-
chemistry from structure 1 to epi-1.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
We acknowledge financial support from Innovation and Technolo-
gy Commisson, HKSAR (Project: ITS/215/09); the Hong Kong Re-
search Grants Council (Projects: PolyU 5638/07M; PolyU 5040/
10P); Fong Shu Fook Tong Foundation, and Joyce M. Kuok Foun-
dation; The Hong Kong Polytechnic University (PolyU 5636/08M;
PolyU 5634/09M); The Shenzhen Bureau of Science, Technology
and Information (SY200806300179A, ZD200806180051A,
JC200903160367A); JC201005260220A, NSFC (21072007), and
GDSFC (10151805704000005). We thank Dr Feng Hong for tech-
nical assistance.
(12) (a) Shiina, I.; Kubota, M.; Oshiumi, H.; Hashizume, M.
J. Org. Chem. 2004, 69, 1822. (b) Shiina, I.; Fukui, S.;
Sasaki, A. Nat. Protoc. 2007, 2, 2312.
(13) Synthesis of the Proposed Burkholdac A (1)
Compound 2 (46 mg, 0.04 mmol) was dissolved in MeOH–
CH2Cl2 (50 mL, 1:9) and added to a vigorously stirred
solution of I2 (126 mg, 0.50 mmol) in MeOH–CH2Cl2 (200
mL, 1:9) at r.t. over 0.5 h. After 10 min, the reaction was
quenched by addition of sat. aq solution of Na2S2O3 (20 mL)
and concentrated in vacuo. The residue was extracted with
EtOAc (3 × 30 mL). The combined organic layers were
washed with sat. aq solution of Na2S2O3 (20 mL) and brine
(30 mL), dried over anhyd Na2SO4 and concentrated in
vacuo. The residue was dissolved in pyridine (1 mL), after
HF·py (0.8 mL) was added at 0 °C, the reaction mixture was
stirred at r.t. for 12 h. All volatiles were removed in vacuo;
the residue was diluted with EtOAc (100 mL) and washed
References and Notes
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Med. Chem. 2011, 19, 6675.
(3) Maier, M. E. Nat. Prod. Rep. 2009, 26, 1105.
(4) (a) Wang, L.; Xu, Z. S.; Ye, T. Org. Lett. 2011, 13, 2506.
(b) Liu, H.; Liu, Y.; Xu, Z. S.; Ye, T. Chem. Commun. 2010,
46, 7486. (c) Li, S.; Chen, Z.; Xu, Z. S.; Ye, T. Chem.
Commun. 2010, 46, 4773. (d) Gao, X. G.; Liu, Y.; Kwong,
Synlett 2012, 23, 783–787
© Thieme Stuttgart · New York

LETTER
with HCl (20 mL, 1.0 M in H2O) and brine (20 mL), dried
Synthesis of Burkholdac A
787
20.8, 15.6, 15.0 ppm. ESI-HRMS m/z calcd for
over anhyd Na2SO4 and concentrated in vacuo. The residue
was purified by flash chromatography (eluted with EtOAc–
hexanes–MeOH = 3:1:0.3) to provide the desired compound
1 (13.4 mg, 63% yield over 2 steps) as a white amorphous
solid: [a]D20 –166.5 (c 0.35, MeOH). 1H NMR (400 MHz,
CD3CN): d = 7.71 (d, J = 5.4 Hz, 1 H), 7.09 (d, J = 9.8 Hz, 1
H), 7.02 (br s, 1 H), 5.90 (br s, 1 H), 5.77 (d, J = 15.5 Hz, 1
H), 5.58 (dd, J = 6.1, 2.3 Hz, 1 H), 4.74 (br s, 1 H), 3.97–3.92
(m, 1 H), 3.83 (ddd, J = 10.2, 6.5, 4.0 Hz, 1 H), 3.68 (td,
J = 10.3, 3.0 Hz, 1 H), 3.40–3.22 (m, 2 H), 2.73–2.67 (m, 2
H), 2.64–2.56 (m, 3 H), 2.51–2.43 (m, 3 H), 2.40–2.26 (m, 3
H), 2.18–2.08 (m, 2 H), 2.06 (s, 3 H), 0.83 (d, J = 0.8 Hz, 3
H), 0.81 (d, J = 1.0 Hz, 3 H) ppm. 13C NMR (100 MHz,
CD3CN): d = 172.4, 171.4, 171.2, 170.8, 131.9, 131.0, 70.0,
69.6, 60.1, 54.9, 54.8, 43.7, 41.2, 41.2, 41.1, 31.4, 29.1, 28.3,
C22H36N3O6S3+ [M + H]+: 534.1761; found: 534.1757.
(14) The Analytical Data of the Revised Burkholdac A (epi-1)
[a]D20 –54.0 (c 0.23, MeOH). 1H NMR (500 MHz, CD3CN):
d = 7.51 (s, 1 H), 7.41 (d, J = 6.9 Hz, 1 H), 6.90 (d, J = 8.9
Hz, 1 H), 6.12–6.06 (m, 1 H), 5.90 (d, J = 15.5 Hz, 1 H),
5.56–5.54 (m, 1 H), 4.70 (td, J = 9.2, 3.6 Hz, 1 H), 4.47–4.43
(m, 1 H), 4.18–4.13 (m, 1 H), 3.33–3.30 (m, 1 H), 3.21 (d,
J = 10.5 Hz, 1 H), 3.13 (d, J = 14.0 Hz, 1 H), 2.96 (dd,
J = 13.1, 7.2 Hz, 1 H), 2.86–2.57 (m, 8 H), 2.25 (dq,
J = 13.6, 6.8 Hz, 1 H), 2.10 (s, 3 H), 2.08–2.01 (m, 2 H), 0.96
(d, J = 6.8 Hz, 3 H), 0.87 (d, J = 6.8 Hz, 3 H) ppm. 13C NMR
(125 MHz, CD3CN): d = 173.0, 172.2, 171.7, 170.1, 132.4,
131.5, 71.7, 69.0, 63.2, 56.8, 56.4, 41.8, 41.1, 40.8, 33.3,
31.2, 30.6, 30.5, 21.1, 19.8, 15.2 ppm. ESI-HRMS: m/z calcd
for C22H36N3O6S3+ [M + H]+: 534.1761; found: 534.1760.
© Thieme Stuttgart · New York
Synlett 2012, 23, 783–787

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