Concise total synthesis of vicenistatin

Article abstract of DOI:10.1055/s-0030-1258574

A highly convergent total synthesis of macrocyclic lactam glycoside vicenistatin is described. Key features of the synthesis include rapid assembly of the macrolactam part and macrocyclic ring closure via intramolecular Stille coupling. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1258574

LETTER
2589
Concise Total Synthesis of Vicenistatin
T
otal
S
ynthesis of
a
V
icenistati
y
n
ato Fukuda,a Shiina Nakamura,a Tadashi Eguchi,b Yoshiharu Iwabuchi,a Naoki Kanoh*a
a
Graduate School of Pharmaceutical Sciences, Tohoku University, Aobayama, Sendai 980-8578, Japan
Fax +81(22)7956847; E-mail: kanoh@mail.pharm.tohoku.ac.jp
Graduate School of Science and Engineering, Tokyo Institute of Technology, 2-12-1 O-okayama, Meguro-ku, Tokyo 152-8551, Japan
b
Received 21 July 2010
We were intrigued with vicenistatin (1) as a potential new
cancer therapeutic lead and with its unknown mode-of-
action. We report herein a concise total synthesis of vice-
nistatin (1) utilizing a highly convergent strategy.
Abstract: A highly convergent total synthesis of macrocyclic lac-
tam glycoside vicenistatin is described. Key features of the synthe-
sis include rapid assembly of the macrolactam part and macrocyclic
ring closure via intramolecular Stille coupling.
Key words: vicenistatin, macrolactam, vicenisamine, total synthe- Our retrosynthetic analysis is shown in Scheme 1. Our
sis
strategy to vicenistatin (1) involves coupling of glycosyl
fluoride 3 and macrolactam 4. To facilitate future struc-
ture–activity relationship (SAR) study, we adopted a con-
vergent synthetic strategy by dividing macrolactam 4 into
iodoaldehyde 5 and phosphonate 6. Thus, macrolactam 4
could be obtained through successive coupling reactions;
that is, the Horner–Wadsworth–Emmons (HWE) reaction
between fragments 5 and 6 followed by intramolecular
Stille coupling, or vice versa.
In 1993, Shindo et al. discovered a novel macrocyclic lac-
tam glycoside, designated as vicenistatin (1), from Strep-
tomyces halstedii HC-34.1 Structurally, vicenistatin (1)
consists of a 20-membered macrolactam and a unique
amino sugar vicenisamine (Figure 1). Its relative and ab-
solute stereochemistries were elucidated by NMR
analyses1 and degradation studies,2 and finally confirmed
by the total synthesis.3 Vicenistatin (1) is reported to ex-
hibit in vitro cytotoxicity against human leukemia HL-60
(IC50 0.24 mM) and human colon carcinoma COLO205
(IC50 0.38 mM), and to be effective in a mouse xenograft
model.1 In contrast, its natural congener, vicenistatin M
(2),4 which possesses D-mycarose instead of vice-
nisamine, shows essentially no growth-inhibitory activity
against human and mouse cancer cell lines (Figure 1).
Vicenisamine is therefore thought to play an important
role in the antitumor activity of vicenistatin (1). Vicenista-
tin (1) was recently re-discovered as a hit substance from
the National Cancer Institute (NCI) libraries using a high-
throughput yeast toxicity screen.5
H
O
F
2
TMSO
N
3
1
+
Me
O
N
O
14
O
13
3
4
H
2
3
N
TMSO
H
I
6
(EtO)2(O)P
Bu3Sn
7
18
O
O
+
14
13
5
6
Scheme 1 Retrosynthetic analysis
H
O
O
N
The synthesis of glycosyl fluoride 3 commenced with a
known allyl alcohol ( )-7 (Scheme 2).6 Sharpless kinetic
resolution of ( )-7 gave syn-epoxy alcohol (+)-8 in 33%
yield and 99% ee, along with the starting material (–)-7
(49%, 52% ee). After (+)-8 was converted into anti-epoxy
alcohol (+)-9 via the Mitsunobu reaction,7 transformation
of (+)-9 to cyclic carbamate (–)-10 was achieved utilizing
Roush’s protocol.8 Treatment of (+)-9 with benzoyl isocy-
anate in CH2Cl2 followed by 1,8-diazabicyclo[5.4.0]un-
dec-7-ene (DBU) gave (–)-10 in 89% yield through N→O
rearrangement of the benzoyl group. N-Methylation of
benzoate (–)-10 using MeI and subsequent methanolysis
gave the alcohol (+)-11. Pyran ring formation was accom-
plished by ozonolysis of (+)-11 in MeOH followed by a
reductive workup and acid treatment to give protected
amino sugars 12 in 89% yield. To activate the anomeric
position, a mixture of cyclic carbamates 12 was first con-
verted to the corresponding thioglycosides using phenyl
Me
O
N
H
OH
vicenisamine
vicenistatin (1)
H
N
O
O
O
HO
OH
D-mycarose
vicenistatin M (2)
Figure 1 Structure of vicenistains
SYNLETT 2010, No. 17, pp 2589–2592
Advanced online publication: 23.09.2010
DOI: 10.1055/s-0030-1258574; Art ID: U05710ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
1
0

2590
H. Fukuda et al.
LETTER
trimethylsilyl sulfide (PhSTMS). Finally, a substitution group in (–)-19, followed by palladium-catalyzed hy-
reaction using N-bromosuccinimide (NBS) and (diethyl- drostannation of the resulting terminal alkyne (–)-20 gave
amino)sulfur trifluoride (DAST) gave glycosyl fluoride 3 vinylstannane (–)-21 in 74% yield with high regio- and
in 65% yield for two steps.9
stereoselectivity.15 The minor gem-isomer could be easily
removed after the intramolecular Stille coupling reaction
(vide infra).
b
a
O
OH
OH ( )-7
OH (+)-8
ref. 5 and 6
a
OBz
O
c
d
O
14
13
HN
(+)-9
O
O
(–)-10
OH
O
OH
HO
OH
OMe
b
c
e
f
3
I
I
Me
Me
N
O
N
O
O
(–)-16
15
(+)-11
12
O
Scheme 2 Synthesis of glycosyl fluoride 3. Reagents and conditi-
ons: (a) TBHP, (–)-DIPT, Ti(Oi-Pr)4, MS 3 Å, CH2Cl2, –20 °C, 32%,
99% ee; (b) (i) 4-O2NC6H4COOH, Ph3P, DIAD, THF, 0 °C, 100%;
(ii) MeONa, MeOH, r.t., 84%; (c) (i) O=C=NBz, CH2Cl2, r.t., 100%;
(ii) DBU, CH2Cl2, reflux, 90%; (d) (i) MeI, NaH, THF, r.t., 95%; (ii)
MeONa, MeOH, r.t., 90%; (e) O3, MeOH, –78 °C then DMS, PTSA,
reflux, 89%; (f) (i) PhSTMS, TMSOTf, CH2Cl2, r.t., 91%; (ii) DAST,
NBS, CH2Cl2, –15 °C, 71%.
HO
3
H
I
TMSO
H
5
O
O
d
I
(–)-5
(–)-17
Scheme 3 Synthesis of fragment 5. Reagents and conditions: (a)
Me3Al, Cp2ZrCl2, CH2Cl2 (wet), 0 °C to r.t., then I2, THF, 0 °C, 64%;
(b) (i) Dess–Martin periodinane, CH2Cl2, r.t.; (ii) cis-2-butene, KOt-
Bu, n-BuLi, (+)-Ipc2BOMe, BF3·OEt2, THF, –78 °C, then MeOH, sat.
aq NaHCO3, 30% H2O2, –78 °C to 0 °C, 47%, 100% de, 94% ee; (c)
acrolein, H–G II, CH2Cl2, r.t.; (d) TMSCl, Et3N, CH2Cl2, r.t., 29% for
2 steps.
Synthesis of iodoenal 5 began from the known homoallyl
alcohol 14, which was prepared in four steps from cyclo-
propylmethylketone (13) using the Julia and Kakinuma
procedure (Scheme 3).3 Carboalumination of 14 in wet
dichloromethane followed by iodination gave vinyliodide
15 in 64% yield. It should be noted that the carboalumina-
tion reaction did not give reproducible results in the ab-
sence of water.10 Dess–Martin oxidation11 of vinyliodide
15 followed by Brown asymmetric crotylboration12 gave
the homoallyl alcohol (–)-16 in 47% overall yield and
with high enantio- and diastereoselectivity (100% de,
94% ee).
HO
HO
ref. 16
a
18
(–)-19
TMS
Next, introduction of the C3–C5 enal moiety using a
cross-metathesis reaction was examined. After consider-
able screening of cross-metathesis conditions (solvent,
temperature, substrate concentration, and catalyst) and the
metathesis partner (acrolein and methyl acrylate), we
found that the reaction with acrolein in CH2Cl2 in the pres-
ence of a Hoveyda–Grubbs second-generation catalyst
(H–G II catalyst)13 gave reproducible results. However,
the desired enal (–)-17 was obtained in moderate yield
along with byproducts, one of which was cyclopentenol
produced by ring-closing metathesis (RCM) between the
terminal and C9–C10 olefin. Silylation of (–)-17 accom-
plished the synthesis of fragment 5 in 29% yield from (–)-
16.
HO
HO
b
c
Bu3Sn
(–)-21
(–)-20
H
N
N3
(EtO)2(O)P
d, e
O
Bu3Sn
Bu3Sn
(–)-6
(+)-22
Scheme 4 Synthesis of fragment 6. Reagents and conditions: (a)
K2CO3, MeOH, r.t., 96%; (b) n-Bu3SnH, Pd2(dba)3·CHCl3,
Cy3P·HBF4, i-Pr2NEt, CH2Cl2, r.t., 74%, gem/trans = 1:20; (c) DPPA,
DIAD, Ph3P, THF, 0 °C to r.t., 82%; (d) (i) H2 (balloon), Lindlar ca-
talyst, quinoline, MeOH, r.t.; (ii) (EtO)2P(O)CH2COOH 23, EDCI,
HOBt, Et3N, CH2Cl2, r.t., 80%.
Preparation of phosphonate 6 commenced from the chiral
known alcohol (–)-1914 (prepared in five steps from 18),
as shown in Scheme 4. Removal of the trimethylsilyl
Synlett 2010, No. 17, 2589–2592 © Thieme Stuttgart · New York

LETTER
Total Synthesis of Vicenistatin
2591
Vinylstannane (–)-21 was converted into azide (+)-22 un- Pr2NEt, DMF] to give the desired macrolactam 4 in mod-
der Mitsunobu conditions.16 After the reduction of (+)-22 est yield.
using Lindlar catalyst, condensation of the resulting
amine with diethylphosphonoacetic acid (23) furnished
fragment (–)-6.
Glycosylation of macrolactam 4 with glycosyl fluoride 3
using TMSOTf18 as an activator proceeded to give an in-
separable mixture of protected vicenistatin and its a-ano-
mer. Although Kakinuma et al. have accomplished this
glycosylation using glycosyl acetate 25 under the
Mukaiyama conditions3b,19 (SnCl4, AgClO4, MS 4 Å,
CH2Cl2), the reaction could not be reproduced in our
hands. Finally, removal of cyclic carbamate under the ba-
sic conditions proceeded to give vicenistatin (1) and its a-
anomer in 10% and 18% yield for two steps, respectively.
The spectroscopic data for the synthetic product were in
good agreement with those for the natural product.1
H
N
TMSO
H
I
(EtO)2(O)P
Bu3Sn
O
O
+
(–)-5
TMSO
(–)-6
H
N
b
a
O
In conclusion, we have accomplished a highly convergent
total synthesis of vicenistatin (1). Glycosyl fluoride 3 was
efficiently synthesized from allyl alcohol 7 in ten steps
and 12% overall yield, and the synthesis of macrolactam
4 was achieved in a highly convergent manner (seven
steps, 1.4% yield from 14). Although several reactions, in-
cluding fragment-coupling reactions and macrolactam
formation, need to be optimized, synthetic efficiency and
overall yield of the present synthesis are amenable to fur-
ther SAR study and synthesis of the probe molecules for
dissecting the mode-of-action of vicenistatin (1).
I
(–)-24
Bu3Sn
O
F
2
H
TMSO
N
Me
N
O
3
O
3
O
14
c
13
(+)-4
H
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
O
O
N
Me
O
N
H
OH
References and Notes
(1) Shindo, K.; Kamishohara, M.; Odagawa, A.; Matsuoka, M.;
Kawai, H. J. Antibiot. 1993, 46, 1076.
vicenistatin (1)
O
OAc
(2) Arai, H.; Matsushima, Y.; Eguchi, T.; Shindo, K.;
Kakinuma, K. Tetrahedron Lett. 1998, 39, 3181.
(3) (a) Matsushima, Y.; Itoh, H.; Eguchi, T.; Kakinuma, K.
J. Antibiot. 1998, 51, 688. (b) Matsushima, Y.; Itoh, H.;
Nakayama, T.; Horiuchi, S.; Eguchi, T.; Kakinuma, K.
J. Chem. Soc., Perkin Trans. 1 2002, 949.
(4) Matsushima, Y.; Nakayama, T.; Fujita, M.; Bhandari, R.;
Eguchi, T.; Shindo, K.; Kakinuma, K. J. Antibiot. 2001, 54,
211.
(5) Gassner, N. C.; Tamble, C. M.; Bock, J. E.; Cotton, N.;
White, K. N.; Tenney, K.; St. Onge, R. P.; Proctor, M. J.;
Giaever, G.; Nislow, C.; Davis, R. W.; Crews, P.; Holman,
T. R.; Lokey, R. S. J. Nat. Prod. 2007, 70, 383.
(6) Roush, W. R.; Brown, R. J. J. Org. Chem. 1983, 48, 5093.
(7) Martin, S. F.; Dodge, J. A. Tetrahedron Lett. 1991, 32, 3017.
(8) Roush, W. R.; James, R. A. Aust. J. Chem. 2002, 55, 141.
(9) (a) Nicolaou, K. C.; Seitz, S. P.; Papahatjis, D. P. J. Am.
Chem. Soc. 1983, 105, 2430. (b) Nicolaou, K. C.; Dolle,
R. E.; Papahatjis, D. P.; Randall, J. L. J. Am. Chem. Soc.
1984, 106, 4189.
Fmoc
N
Me
OAc
25
Scheme 5 Total synthesis of vicenistatin (1). Reagents and conditi-
ons: (a) 6, KHMDS, THF, –78 °C, then 5, 0 °C, 71%; (b)
Pd2(dba)3·CHCl3, AsPh3, i-Pr2NEt, DMF, r.t., ca. 23%; (c) (i) 3,
TMSOTf, MS 4 Å, CH2Cl2, 0 °C; (ii) 5 M KOH, MeOH, r.t., 10% for
1, 18% for the a-isomer (2 steps).
Having all fragments in hand, we then focused on con-
struction of the macrocyclic lactam skeleton (Scheme 5).
After several experiments, it was quickly recognized that
intermolecular Stille coupling between iodide 5 and vinyl-
stanane 6 was problematic. The reaction resulted in deg-
radation of the starting material. In contrast, coupling of
the two fragments using the HWE reaction proceeded
without difficulty: phosphonate 6 was treated with KH-
MDS in THF at –78 °C, and the resultant phosphonate
carbanion was successfully coupled with aldehyde 5 to
give pentaene (–)-24 in 71% yield. The intramolecular
Stille coupling reaction of (–)-24 proceeded under the
Nicolaou conditions17 [Pd2(dba)3·CHCl3, AsPh3, i-
(10) Wipf, P.; Lim, S. Angew. Chem., Int. Ed. Engl. 1993, 32,
1068.
(11) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(12) Brown, H. C.; Bhat, K. S.; Randad, R. S. J. Org. Chem.
1989, 54, 1570.
(13) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H.
J. Am. Chem. Soc. 2000, 122, 8168.
Synlett 2010, No. 17, 2589–2592 © Thieme Stuttgart · New York

2592
H. Fukuda et al.
LETTER
(14) Paquette, L. A.; Duan, M. S.; Konetzki, I.; Kempmann, C.
J. Am. Chem. Soc. 2002, 124, 4257.
(15) Darwish, A.; Lang, A.; Kim, T.; Chong, J. M. Org. Lett.
2008, 10, 861.
(17) Nicolaou, K. C.; Murphy, F.; Barluenga, S.; Ohshima, T.;
Wei, H.; Xu, J.; Gray, D. L. F.; Baudoin, O. J. Am. Chem.
Soc. 2000, 122, 3830.
(18) Hashimoto, S.; Hayashi, M.; Noyori, R. Tetrahedron Lett.
(16) Schmidt, J. P.; Beltran-Rodil, S.; Cox, R. J.; McAllister, G.
D.; Reid, M.; Taylor, R. J. K. Org. Lett. 2007, 9, 4041.
1984, 25, 1379.
(19) Mukaiyama, T.; Takashima, T.; Katsurada, M.; Aizawa, H.
Chem. Lett. 1991, 533.
Synlett 2010, No. 17, 2589–2592 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.