Total synthesis of largazole

Article abstract of DOI:10.1055/s-2008-1078270

The stereocontrolled total synthesis of largazole was accomplished, unambiguously confirming its structure. Key steps included the use of the Nagao thiazolidinethione auxiliary for a diastereoselective acetate aldol reaction, thiazoline-thiazole formation, and macrolactamization by use of the Mukaiyama reagent. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1078270

LETTER
2379
Total Synthesis of Largazole
zole Ren, Lu Dai, Hui Zhang, Wenfei Tan, Zhengshuang Xu,* Tao Ye*a,b
a
a
a
a
a,b
S
Q
ynthesis of Larga
i
a
Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, University Town of Shenzhen, Xili, Nanshan District,
Shenzhen 518055, P. R. of China
Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong
Fax +86(852)22641912; E-mail: bctaoye@inet.polyu.edu.hk
b
Received 16 May 2008
synthetic manipulation of the b-hydroxyl-g,d-unsaturated
ester while avoiding b-elimination, protecting group mi-
gration, and intramolecular cyclization.
Abstract: The stereocontrolled total synthesis of largazole was ac-
complished, unambiguously confirming its structure. Key steps in-
cluded the use of the Nagao thiazolidinethione auxiliary for a
diastereoselective acetate aldol reaction, thiazoline–thiazole forma-
tion, and macrolactamization by use of the Mukaiyama reagent.
Bearing this analysis in mind, we devised a retrosynthetic
strategy toward largazole (1) as illustrated in Scheme 1.
Due to the lability of the thioester moiety to nucleophilic
displacement, the octanoic acid will be incorporated into
Key words: largazole, cyclodepsipeptide, total synthesis, anti-
tumor, macrolactamization
9
the molecule at a later stage. Literature precedence sug-
gests that the reaction of carboxylic acid with the allylic
Marine cyanobacteria have produced a wide variety of secondary alcohol to afford the corresponding ester is
1
secondary metabolites, many of which have demonstrat- achievable. We envisioned that our synthetic approach in-
2
3
ed antiproliferative activity, acute cytotoxic activity, or volving the esterification–macrolactamization would ren-
4
have specific neurotoxic activity. Their diversity in both der the compounds impervious to b-elimination.
biological activity and in structural complexity has made Therefore, we proposed to prepare largazole in a conver-
these natural products the focus of much work in recent gent manner through the assembly and cyclization of lin-
years. The small quantities of compounds that are pro- ear precursor 2. Further disconnection of 2 at the amide
duced by many marine cyanobacteria have proven to be a linkage provides two intermediates (3 and 4) of similar
severe obstacle for the development of promising new structural complexity. The intermediate 3 should be easily
5
leads for the development of novel drugs. In order to ob- obtained from b-hydroxyl ester 5 which is readily acces-
tain significant amounts of these structurally interesting sible through the use of N-acetylthiazolidinethione-medi-
6
7
10
marine natural products, we and other groups have un- ated asymmetric aldol reaction. Furthermore, thi-
dertaken extensive programs towards their syntheses. In azoline–thiazole derivative 4 would be accessible by ap-
connection with our own proposed studies in the area of plying a similar approach developed by Pattenden and co-
synthesis of anticancer natural products and our continu- workers.11
ing interests in devising strategy toward analogue devel-
opment, we herein report the total synthesis of largazole
1) that is amenable to analogue construction.
The fragment 3 (Scheme 2) was constructed in five steps
from 3-(tert-butyldimethylsilyloxy)-1-propanol (9):
Treatment of alcohol 9 with TEMPO-catalyzed oxidation
12
(
Largazole (1) was recently isolated from the Floridian ma- with trichloroisocyanuric acid to provide the requisite
1
3
rine cyanobacterium Symploca sp. by Luesch and co- propanal derivative, which was then reacted with (carb-
8
workers. Its structure was determined by a combination ethoxymethylene)triphenylphosphorane to afford the cor-
of chemical degradation, chiral chromatography, and responding (E)-a,d-unsaturated ester 10 in 84% yield over
spectroscopic analysis. Preliminary biological character- two steps. The conjugated ester 10 was subjected to suc-
ization indicated that largazole potently inhibited the cessive reduction with DIBAL-H and oxidation with
growth of highly invasive transformed human mammary Dess–Martin periodinane to afford enal 11. Reaction of 11
epithelial cells with nanomolar antiproliferative activity.8 with Nagao’s chiral N-acetylthiazolidine-2-thione un-
Furthermore, largazole has several interesting structural der Vilarrasa’s conditions1 proceeded in high diastereo-
features including a thioester that involves the novel 3-hy- selectivity to yield the readily separable allylic alcohol 13
10a
0j
1
4
droxy-7-mercaptohept-4-enoic acid unit and a substituted and its minor diastereomer (dr = 14:1). Displacement of
4
-methylthiazoline linearly fused to a thiazole.
the thiazolidinethione auxiliary with 2-(trimethylsilyl)
ethanol mediated by DMAP was carried out smoothly un-
der mild conditions to afford ester 5 in 94% yield. Finally,
esterification of the allyl alcohol 5 with N-Fmoc-valine
was promoted by DCC in the presence of catalytic quan-
tity of DMAP produced the key intermediate 3 in 91%
yield. As shown in Scheme 3, a modified Hantzsch
There are three principal challenges associated with the
synthesis of largazole: (1) the asymmetric construction of
3
-hydroxy-7-mercaptohept-4-enoic acid, (2) the forma-
tion of a 16-membered cyclic depsipeptide, and (3) the
SYNLETT 2008, No. 15, pp 2379–2383
Advanced online publication: 21.08.2008
DOI: 10.1055/s-2008-1078270; Art ID: W08008ST
©
1
5
.0
9
.2
0
0
8
15
reaction was employed for the synthesis of thiazole-4-
ester 15.16
Georg Thieme Verlag Stuttgart · New York

2
380
Q. Ren et al.
LETTER
esterification
O
O
S
N
S
N
N
NH
O
N
NH
O
O
S
TBSO
O
S
S
O
O
NHBoc
N
H
O
OTMSE
largazole (1)
2
macrolactamization
O
S
N
NHFmoc
N
+
O
TBSO
O
O
O
S
OTMSE
4
NHBoc
3
N
NHFmoc
S
N
TBSO
O
OH
6
8
NHBoc
+
+
O
SH
OTMSE
NH3Cl
O
OH
O
5
7
Scheme 1 Retrosynthetic analysis
TBSO
TBSO
O
S
EtO
O
TBSO
S
i
ii
i
ii
NHBoc
O
O
HO
2
H N
OH
N
NHBoc
SH
NHBoc
iii
O
H
1
1
14
15
1
0
9
iii
N
S
TBSO
iv
N
O
S
N
iv
TBSO
O
S
O
S
NH Cl
3
N
O
N
O
O
7
O
S
HO
S
NHBoc
4
8
NHBoc
HO
OTMSE
N
S
5
1
3
Scheme 3 Synthesis of fragment 4. Reagents and conditions: (i) (a)
i-BuOCOCl, Et N, THF, NH OH; (b) P S , Na CO , THF, 83% (over
v
3
4
2
5
2
3
2
steps); (ii) KHCO , –15 °C, BrCH COCO Et, TFAA, 2,6-lutidine,
3 2 2
1
2
–20 °C, 91%; (iii) (a) NH
–MeOH, MeOH, 51%; (b) POCl , pyridine,
3 3
CH Cl , 63%; (iv) 7, Et N, MeOH, 50 °C, 51%.
2
2
3
NHFmoc
Hence the thioamide 14 prepared in 83% yield from N-
O
O
O
Boc-glycine was reacted with ethyl bromopyruvate at –15
TBSO
OTMSE
°
C, followed by dehydration of the resulting hydroxylthi-
3
azoline with trifluoroacetic anhydride (TFAA) and 2,6-lu-
tidine to afford the thiazole-4-ester 15 in 91% yield. The
ester 15 was next converted to the corresponding amide
Scheme 2 Preparation of intermediate 3. Reagents and conditions:
i) (a) trichloroisocyanuric acid, TEMPO, CH Cl , 91%; (b)
(
2
2
17
and then to the nitrile 8. This then set to the stage for the
Ph PCHCO Me, CH Cl , 92%; (ii) (a) DIBAL-H, THF, 83%; (b)
3
2
2
2
DMP, CH Cl , 81%; (iii) 12, TiCl , DIPEA, CH Cl ; then 11, –78 °C, cyclocondensation. Thus, condensation reaction between
2
2
4
2
2
8
3% (dr = 14:1); (iv) TMSCH CH OH, DMAP, CH Cl , 94%; (v) L-
2 2 2 2
the nitrile 8 and the (R)-2-methylcysteine methyl ester hy-
drochloride (7) prepared according to Pattenden’s
Fmoc-Val-OH, DCC, DMAP, CH Cl , 91%.
2
2
Synlett 2008, No. 15, 2379–2383 © Thieme Stuttgart · New York

LETTER
Synthesis of Largazole
2381
O
S
N
NHFmoc
N
O
+
TBSO
O
O
O
S
OTMSE
4
NHBoc
3
i
ii
iii
O
S
N
O
S
N
NH
O
N
NH
O
iv
S
N
S
O
O
O
NHBoc
N
H
TBSO
O
OTMSE
HO
2
16
Scheme 4 Attempted marcrolactamization. Reagents and conditions: (i) i-Pr NH, CH Cl ; (ii) LiOH, H O–THF; (iii) Mukaiyama reagent,
2
2
2
2
DIPEA, CH Cl , 0 °C to r.t., 90% (two steps); (iv) (a) TFA, CH Cl ; (b) various coupling reagents.
2
2
2
2
NHFmoc
O
NHFmoc
O
NHFmoc
O
t-BuS
TBSO
O
i, ii
O
iii, iv
S
O
AcS
O
OTMSE
O
OTMSE
O
OTMSE
3
17
18
Scheme 5 Synthesis of disulfide 18. Reagents and conditions: (i) HF–py, py, THF, 82%; (ii) (a) TsCl, Et N, DMAP, CH Cl ; (b) KSAc, DMF,
3
2
2
8
3% in two steps; (iii) K CO , MeOH, 10 min, 66%; (iv) (a) DTNP, CH Cl , 2 h, (b) t-BuSH, Et N, MeOH, 10 min, 75% in two steps.
2
3
2
2
3
procedure11b led to the key intermediate 4 as viscous oil in sociated with the protecting group of the homoallylic al-
5
1% yield.
cohol in 3, we decided to convert 3 into the corresponding
disulfide 18 (Scheme 5). Thus, removal of the TBS pro-
tective group in 3 with HF–pyridine afforded the corre-
sponding alcohol in 82% yield. This was then subjected to
tosylation followed by displacement with potassium thio-
acetate in DMF to give 17 in good yield. Treatment of 17
with potassium carbonate in methanol regenerated the
corresponding free thiol which was then reacted succes-
sively with the thiol-specific reagent, 2,2¢-dithiobis(5-ni-
tropyridine) (DTNP)18 and t-BuSH in the presence of
triethylamine to afford disulfide 18 in 50% yield over
three steps.
With the synthesis of the key subunits 3 and 4 completed,
the assembling of the macrocycle 16 was investigated
(
Scheme 4). Removal of the Fmoc protecting group in 3
by the action of diisopropylamine yielded the correspond-
ing amine, which was then condensed with the acid de-
rived from the saponification of methyl ester in compound
4
by the Mukaiyama reagent (2-chloro-1-methylpyridini-
um iodide) to furnish the linear depsipeptide 2 in excellent
yield. At this juncture, global deprotection of 2 with tri-
fluoroacetic acid followed by a marcrolactamization be-
came our next goal. Hence, treatment of depsipeptide 2
with TFA provided the fully deprotected acyclic precur- With disulfide 18 in hand, efforts were focused on the key
sor, which was then submitted to macrolactamization. Un- macrocyclization again (Scheme 6). Hydrolysis of the
fortunately, all attempts at this point to effect mac- methyl ester in 4 afforded the corresponding acid, which
rocyclization that employed a variety of coupling reagents was coupled to the free amine resulting from the dieth-
(
e.g., Mukaiyama reagent, DCC, HATU, BOPCl, PY- ylamine deprotection of compound 18, to provide the lin-
BOP) led only to the formation of uncharacterizable prod- ear depsipeptide 19 in 91% yield. Deprotection of both
ucts. The failure of the macrolactamization was not Boc and TMSE ester with TFA smoothly delivered the
readily explained, however, we assumed that the homoal- acyclic precursor which was then treated with a highly ef-
lylic alcohol might be involved in the protecting group fective activating reagent HATU in DMF to afford the
migration or intramolecular cyclization, presumably due corresponding cyclodepsipeptide 20 in 61% yield.19
to its nucleophilic nature. To circumvent the problem as- Tributylphosphine-promoted reductive cleavage of the di-
Synlett 2008, No. 15, 2379–2383 © Thieme Stuttgart · New York

2
382
Q. Ren et al.
LETTER
NHFmoc
O
O
S
N
N
t-BuS
O
S
i
O
S
4
18
O
OTMSE
NHBoc
ii
iii
O
S
N
O
S
N
N
NH
O
N
NH
O
iv
S
S
O
O
O
NHBoc
N
H
t-BuS
S
O
OTMSE
t-BuS
S
19
20
v
O
S
N
N
NH
O
O
S
S
O
O
N
H
largazole (1)
Scheme 6 Completion of the total synthesis. Reagents and conditions: (i) Et NH, MeCN; (ii) LiOH, H O–THF; (iii) Mukaiyama reagent,
2
2
DIPEA, CH Cl , 91%, two steps from 18; (iv) (a) TFA, CH Cl ; (b) HATU, HOAT, DIPEA, DMF, 61%, two steps; (v) (a) PBu , THF–H O;
2
2
2
2
3
2
(
b) n-C H COCl, DIPEA, DMAP, CH Cl , 78%, two steps.
7 15 2 2
sulfide bond in 20 gave the corresponding thiol which was Supporting Information for this article is available online at
then reacted with octanoyl chloride in the presence of http://www.thieme-connect.com/ejournals/toc/synlett.
2
0
DMAP to afford largazole in 78% yield. The optical ro-
2
0
tation of the synthetic product, [a]D 18.5 (c 0.2, MeOH),
Acknowledgment
was in close agreement with the value reported in the lit-
2
0
erature for natural largazole, [a]D 22 (c 0.1, MeOH). The We acknowledge the financial supports from Shenzhen Bureau of
1
13
Science, Technology and Information (Shenzhen Key Laboratory
Advancement Scheme), Shenzhen Graduate School of Peking Uni-
versity, and the Hong Kong Research Grants Council (Project:
PolyU 5015/03P). We would also like to thank Ms. Chunfeng Chen
and Mr. Yanchao Wang for their helpful technical assistance during
the initial stages of this work.
H NMR (500 MHz, CDCl ) and C NMR (125 MHz,
3
CDCl ) spectra for this compound exactly matched the
3
data reported for naturally derived largazole. Thus, the
original assignment of relative and absolute configuration
of largazole has been corroborated via unambiguous total
synthesis.
In summary, we have accomplished the total synthesis of
largazole from 3-[(tert-butyldimethylsilyl)oxy]propanol
in 5.8% overall yield with the longest linear sequence be-
ing 14 steps. This synthesis confirmed the structure of lar-
gazole and allowed for the preparation of significant
quantities of the desired material for biological, confor-
mational, and structure/conformation–activity studies.
The route is highlighted by the efficient generation of the
enantiomeric pure 5 employing Nagao thiazolidinethione
auxiliary for a diastereoselective acetate aldol reaction.
The application of this chemistry to the preparation of
novel largazole analogues for biological evaluation is un-
der way and will be reported in due course.
References and Notes
(
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(
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5
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(
2
Synlett 2008, No. 15, 2379–2383 © Thieme Stuttgart · New York

LETTER
Synthesis of Largazole
2383
(
(
(
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CH Cl (3 mL) was added dropwise. Saturated NH Cl (20
2
2
4
(
mL) was added to the reaction mixture and CH Cl (3 × 30
2
2
mL) was used for extraction. The combined organic phases
1
were dried over anhyd MgSO and concentrated in vacuo to
4
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(
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(
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2
0
1
Ther. Pat. 2004, 14, 17. (c) Proksch, P.; Edrada, R. A.; Ebel,
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3
7.75 (s, 1 H), 7.18 (d, 1 H, J = 9.3 Hz), 6.50 (dd, 1 H, J = 2.7,
9.0 Hz), 5.88 (dd, 1 H, J = 6.9, 14.6 Hz), 5.65–5.71 (m, 1 H),
5.54 (dd, 1 H, J = 6.7, 15.5 Hz), 5.26 (dd, 1 H, J = 9.4, 17.6
Hz), 4.60 (dd, 1 H, J = 3.6, 9.4 Hz), 4.27 (dd, 1 H, J = 3.1,
17.6 Hz), 4.03 (d, 1 H, J = 11.3 Hz), 3.28 (t, 1 H, J = 10.5
Hz), 2.85 (dd, 1 H, J = 9.9, 16.3 Hz), 2.67–2.75 (m, 3 H),
2.37–2.46 (m, 2 H), 2.06–2.14 (m, 1 H), 1.86 (s, 3 H), 1.32
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1
3
C NMR (125 MHz, CDCl ): d = 173.5, 169.3, 168.8, 167.9,
3
(
164.5, 147.4, 132.8, 128.1, 124.1, 84.3, 71.9, 57.7, 47.8,
43.2, 41.0, 40.4, 39.4, 34.0, 31.8, 29.9, 24.1, 18.8, 16.6. ESI-
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+
(
c) Pettit, G. R.; Singh, S. B.; Hogan, F.; Lloyd-Williams, P.;
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[M + H] : 585.1689.
2
5
37
4
4 4
+
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Compound 20 (9.9 mg, 0.02 mmol) was dissolved in
(
130, 1806.
degassed THF–H O (v/v = 4:1, 2 mL) and treated with n-
2
(
9) (a) Demel, P.; Keller, M.; Breit, B. Chem. Eur. J. 2006, 12,
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3
6
669. (b) Eberle, M. K.; Weber, H. P. J. Org. Chem. 1988,
solution was made up to 50 mL with EtOAc and dried over
anhyd Na SO . The free thiol intermediate was obtained
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2
4
R.; Toupet, L.; Carrie, R. Tetrahedron Lett. 1987, 28, 1761.
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after removal of solvent in vacuo. The thiol intermediate was
then dissolved in CH Cl (5 mL), DIPEA (21.9 mg, 0.17
(
2
2
Inoue, T.; Hashimoto, K.; Fujita, E. J. Org. Chem. 1986, 51,
mmol), and octanoyl chloride (22 mg, 0.136 mmol) was
added at 0 °C followed by a catalytic quantity of DMAP. The
reaction mixture was stirred at r.t. for 10 min and then
quenched by sat. NaHCO (5 mL). CH Cl (3 × 30 mL) was
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2
2
used for extraction. The combined organic phases were dried
over anhyd Na SO and concentrated in vacuo to give the
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2
4
3
315. (f) Paterson, I.; Steven, A.; Luckhurst, C. A. Org.
crude product. Purification with chromatography on SiO2,
using EtOAc–hexane (2:1), provided the target molecule 1
(8.2 mg, 0.0132 mmol, 78%).
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0
1
126, 10582. (h) Velazquez, F.; Olivo, H. F. Curr. Org.
[a]D 18.5 (c 0.2, MeOH). H NMR (500 MHz, CDCl ): d =
3
Chem. 2002, 6, 303. (i) Sinz, C. J.; Rychnovsky, S. D.
Angew. Chem. Int. Ed. 2001, 40, 3224. (j) Aiguadé, J.;
González, A.; Urpí, F.; Vilarrasa, J. Tetrahedron Lett. 1996,
7.76 (s, 1 H), 7.15 (d, 1 H, J = 9.3 Hz), 6.46 (dd, 1 H, J = 2.6,
9.5 Hz), 5.80–5.84 (m, 1 H), 5.65–5.68 (m, 1 H), 5.51 (dd, 1
H, J = 7.1, 15.5 Hz), 5.29 (dd, 1 H, J = 9.4, 17.6 Hz), 4.61
(dd, 1 H, J = 3.3, 9.2 Hz), 4.27 (dd, 1 H, J = 2.8, 17.6 Hz),
4.05 (d, 1 H, J = 11.3Hz), 3.28 (d, 1 H, J = 11.3 Hz), 2.90 (t,
2 H, J = 7.2 Hz), 2.86 (dd, 1 H, J = 10.5, 16.5 Hz), 2.68 (dd,
1 H, J = 2.0, 16.3 Hz), 2.53 (t, 2 H, J = 7.4 Hz), 2.29–2.33
(m, 2 H), 2.07–2.13 (m, 1 H), 1.87 (s, 3 H), 1.62–1.66 (m, 2
H), 1.25–1.30 (m, 8 H), 0.87 (t, 3 H, J = 6.8 Hz), 0.69 (d, 3
37, 8949.
(
11) (a) Boyce, R. J.; Mulqueen, G. C.; Pattenden, G.
Tetrahedron 1995, 51, 7321. (b) Pattenden, G.; Thom,
S. M.; Jones, M. F. Tetrahedron 1993, 49, 2131.
12) McDougal, P. G.; Rico, J. G.; Oh, Y.-I.; Condon, B. D.
J. Org. Chem. 1986, 51, 3388.
(
(
(
1
3
13) Dhokte, U. P.; Khau, V. V.; Hutchison, D. R.; Martinelli,
H, J = 7.0 Hz), 0.51 (d, 3 H, J = 7.1 Hz). C NMR (75 MHz,
M. J. Tetrahedron Lett. 1998, 39, 8771.
14) Procedure for the Preparation of Intermediate 13
CDCl ): d = 199.4, 173.5, 169.4, 168.9, 167.9, 164.6, 147.4,
3
132.7, 128.4, 124.2, 84.4, 72.1, 57.7, 44.1, 43.3, 41.1, 40.4,
34.2, 32.2, 31.6, 29.0, 28.9, 27.9, 25.6, 24.2, 22.6, 18.9, 16.6,
(
R)-3-Acetyl-4-isopropyl-1,3-thiazolidine-2-thione (12, 821
+
mg, 4.0 mmol) was dissolved in CH Cl (10 mL), TiCl (751
14.0. ESI-MS: m/z (%) = 623.23 (44.5) [M + H] , 645.21
2
2
4
+
mg, 4.0 mol) was added at 0 °C. After 5 min, the reaction
was brought to –78 °C, DIPEA (516 mg, 4.0 mmol) was
added via a syringe over 10 min. The reaction was kept at
(100.0) [M + Na] . ESI-HRMS: m/z calcd for C H N O S
2
+
9
43
4
5
3
+
[M + H] : 623.2396; found: 623.2371 [M + H] .
Synlett 2008, No. 15, 2379–2383 © Thieme Stuttgart · New York

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