Asymmetric synthesis of macrolactin analogue

Article abstract of DOI:10.1016/j.tetlet.2003.11.055

Total asymmetric synthesis of macrolactin A analogue was accomplished by the convergent strategy. Rapid access to advanced intermediate 16 through isomerization of ynone to (E,E)-conjugated dienone is a key step of this synthesis. Overall, control of all

Full text of DOI:10.1016/j.tetlet.2003.11.055

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 677–680
Asymmetric synthesis of macrolactin analogue
Yusuke Kobayashi,a Akihiro Fukuda,a Tetsutaro Kimachi,b Motoharu Ju-ichib
and Yoshiji Takemotoa,*
aGraduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
bFaculty of Pharmaceutical Sciences, Mukogawa Womenꢀs University, 11-68 Koshien Kyuban-cho, Nishinomiya 663-8179, Japan
Received 14 October 2003; revised 8 November 2003; accepted 14 November 2003
Abstract—Total asymmetric synthesis of macrolactin A analogue was accomplished by the convergent strategy. Rapid access to
advanced intermediate 16 through isomerization of ynone to (E,E)-conjugated dienone is a key step of this synthesis. Overall,
control of all of the four stereocenters was achieved by means of asymmetric and diastereoselective reactions without using any
chiral natural sources.
ꢀ 2003 Elsevier Ltd. All rights reserved.
Macrolactin A was isolated from a deep sea marine
bacterium in 1989 as a 24-membered polyene macrolide
antibiotic.1 This compound possesses three sets of con-
jugated dienes and four stereogenic centers in the mol-
ecule, and exhibits a broad spectrum of activity with
significant antiviral and cancer cell cytotoxic properties
including inhibition of B16-F10 murine melanoma cell
replication.2 Because of its unreliable supply from cell
culture as well as its structural uniqueness and broad
therapeutic potential, macrolactin A has been an
attractive target for asymmetric synthesis. Although,
thus far, three total syntheses3 and novel synthetic
studies4 have been developed, there are still problems to
be solved for therapeutic applications. With the expec-
tation of increasing the stability and activity of macro-
lactin A, we designed new structural analogues of
macrolactin A 1a–b, bearing a more rigid aromatic ring
instead of the (E,Z)-dienic moiety (C8–C12).5 We report
herein an asymmetric total synthesis of a macrolactin
analogue that utilized three types of asymmetric C–C
bond formation and phosphine-catalyzed isomerization
from ynone to (E,E)-conjugated dienone.
serving not only as an ideal nucleophile for joining with
the amide 4, but also as a latent functional group of the
(E,E)-conjugated dienone moiety of 2. We anticipated
that these compounds 4 and 5 could be prepared from 6
and 11 by asymmetric propargylation6 and subsequent
diastereoselective aldol condensation of Nagaoꢀs
OH
OH
7
2
10
8
O
O
O
O
13
HO
HO
HO
23
15
HO
Macrolactin A analogue
Macrolactin A
OTBS
1a: 2(Z), 1b: 2(E)
asymmetric
propargylation
OTBS
diastereoselective
aldol condensation
TBSO
OTBS
The synthetic plan involves assembly of three fragments
3–5 as shown in Scheme 1. Alkyne 5 bearing a stereo-
genic center (C23), plays a central role in our strategy,
O
NMe(OMe)
HO
fragment B 4
O
+
2
OTBS
+
asymmetric
methylation
I
Keywords: Macrolactin A; Antibiotics; Antivirus; Asymmetric synthe-
sis; Ynone; Isomerization; (E,E)-Conjugated dienone.
fragment A 3
CO2Et
fragment C 5
* Corresponding author. Tel.: +81-75-753-4528; fax: +81-75-753-
4569; e-mail: takemoto@pharm.kyoto-u.ac.jp
Scheme 1.
0040-4039/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.11.055

678
Y. Kobayashi et al. / Tetrahedron Letters 45 (2004) 677–680
OTBS
a, b
OH
HO
c
OH
PMBO
CHO
O
a
b-d
10
11
OBz
OH
CH2OBz
CHO
CH2OBz
d, e
HO
PMBO
6
8
7
13
12
OTBS
OTBS
OBz
OTBS
O
f, g
h, i
e
O
S
f, g
14
fragment C 5
N
HO
S
Scheme 3. Reagents and conditions: (a) PMBCl, NaH, THF, 0 ꢁC;
(b) IBX, DMSO, THF, 48% (two steps); (c) Me2Zn, (+)-TADDOL,
Ti(O-i-Pr)4, toluene, )25 ꢁC, 90%, 95% ee; (d) BzCl, Et3N, DMAP,
CH2Cl2, 0 ꢁC, quant; (e) DDQ, CH2Cl2, H2O, 80%; (f) IBX, DMSO,
THF, 95%; (g) (MeO)2P(O)CHN2, t-BuOK, THF, )78 ꢁC fi rt, 85%;
(h) 3 N KOH/MeOH (1:1), 87%; (i) TBSCl, imidazole, DMF, quant.
NMe(OMe)
fragment B 4
TESO
9
Scheme 2. Reagents and conditions: (a) CH2@C@CHB(OH)2, (+)-
diisopropyl tartrate, MS 4A, toluene, )78 ꢁC, 85%, 80% ee; (b) TBSCI,
imidazole, DMF, quant; (c) K2CO3, MeOH, 95%; (d) IBX, DMSO,
THF, 90%; (e) 3-acetyl-(4S)-IPTT, TiCl4, i-Pr2NEt, CH2Cl2, )78 ꢁC,
80%, 92% de; (f) MeONHMeÆHCl, Et3N, CH2Cl2 91%; (g) TESCl,
pyridine, quant.
which finally replaced the protecting group from benz-
oate to tert-butyldimethysilyl (TBS) ether to give the
desired product 5.
acetate7 [(S)-3-acetyl-4-isopropyl-1,3-thiazolidine-2-thi-
one], and asymmetric methylation with Me2Zn, respec-
tively. Construction of the fragment 4 commenced from
aldehyde 6. Propargylation of 6 with allenylboronic acid
With the two chiral building blocks now accessible, we
investigated the key steps of this strategy, that is, their
coupling reaction and stereoselective construction of the
(E,E)-conjugated dienone unit (Scheme 4). The coupling
reaction of 4 and 5 proceeded smoothly using ethyl-
magnesium bromide as a base11 to afford the desired
ynone 15 in good yield. Although the triphenylphos-
phine-catalyzed isomerization of ynone to conjugated
dienone has been reported,14 the desired product could
not be obtained in reasonable yield under the standard
conditions (toluene, 120 ꢁC). After many experiments,
use of bis(diphenylphosphino)butane (dppb) in a mix-
ture of toluene and THF (1:1) at room temperature led
to the best result to give 16 in 40% overall yield, after
removal of the TES protecting group. Subsequent con-
struction of the fourth stereogenic center was carried out
by hydroxyl-directed reduction.15 Reduction of 16 with
Me4NBH(OAc)3 provided the corresponding 1,3-anti-
diol in 89% yield and 93:7 diastereoselectivity.16 This
1,3-anti-diol was protected as acetonide 17 under the
standard conditions. We next examined the final cou-
pling of acetonide 17 and iodide 3 using Cu-catalyzed
reaction. Under carefully optimized conditions, bro-
mination/Pd-mediated hydrostannation17 of 17 was fol-
lowed by reaction with (Z)-3-iodopropenoate 3 in the
presence of copper(I) 2-thiophenecarboxylate18 (CuTC)
to afford the desired addition product 18 in 58% yield
and diisopropyl(L)-tartrate was carried out under
Yamamoto conditions6 and gave chiral alcohol 7 as the
single product, but with moderate enantioselectivity
(85% yield, 80% ee) (Scheme 2). Fortunately, the opti-
cally pure alcohol 7 (>95% ee) was easily obtained by
recrystallization of 7 (80% ee) from a mixture of AcOEt
and hexane. The enantioselectivity and absolute con-
figuration were determined by a modified method of the
Mosher protocol.8 After protection of the alcohol 7,
hydrolysis of the benzoate afforded the primary alcohol
(K2CO3, MeOH), which was oxidized with IBX9 (2-iod-
oxybenzoic acid) to provide the desired aldehyde 8.
Condensation of 8 with (S)-3-acetyl-4-isopropyl-1,3-
thiazolidine-2-thione in the presence of TiCl4 (1.1 equiv)
and i-Pr2NEt (1.1 equiv) afforded aldol product 910
along with a small amount of its diastereomer (80%
yield, 92% de). These were separated by column chro-
matography, and major product 10 was treated with
N-methoxymethylamine, followed by TESCl to yield
Weinreb amide 4 in good yield.11
Having established the synthesis of the C4–C15 frag-
ment, we next sought an efficient enantioselective
method for the preparation of alkynyl fragment C 5
(Scheme 3). Synthesis of 5 began with PMB aldehyde 11
derived from 1,7-heptanediol 10 in two steps. This
aldehyde 11 was first subjected to asymmetric methyl-
ation using Me2Zn and Ti(O-i-Pr)4 in the presence of
(+)-TADDOL12 (20 mol %) as a chiral ligand, and the
desired secondary alcohol 1210 was obtained in 90%
yield with high enantioselectivity (95% ee). The resulting
alcohol was protected as a benzoate before removal of
the terminal PMB ether to furnish primary alcohol 13.
Oxidation of 13 to an aldehyde, followed by exposure to
the Seyferth–Gilbert reagent,13 produced alkyne 14,
from 17. When this coupling reaction was performed
19
under Stille cross-coupling conditions
[Pd2(dba)2,
i-Pr2NEt, DMF], 18 was obtained in poor yield due to
serious production of a destannation adduct. At this
stage, it was revealed that regioselective deprotection of
two TBS groups (C7 and C23) was problematic. Al-
though the reaction of 18 under acidic conditions gave a
mixture of mono-TBS adducts, the C7 TBS group of 18
could be removed regioselectively with TBAF, which
was followed by protection/deprotection manipulation
to furnish the desired alcohol 19 as the single isomer.
After hydrolysis of 19, lactonization of the resulting

Y. Kobayashi et al. / Tetrahedron Letters 45 (2004) 677–680
679
ever, these methods would be a versatile synthetic tool
for other macrolactin analogues. The synthetic deriva-
tives in these studies will be used in order to establish
structure–activity relationship, in particular the effects
of the (2Z,4E)- and (8E,10Z)-moieties of macrolactin A,
and to design compounds with better biological prop-
erties.
OTBS
a
b, c
5 (fragment C)
TESO
OTBS
O
15
OTBS
OTBS
Acknowledgements
d, e
f-h
OTBS
This research was supported by grants from 21st Cen-
tury COE Program ꢁKnowledge Information Infra-
structure for Genome Scienceꢀ and the Japan Health
Sciences.
OTBS
O
O
HO
O
17
16
OTBS
O
OMe
References and notes
i-k
OTBS
CO2Et
CO2Et
OH
1. Gustafson, K.; Roman, M.; Fenical, W. J. Am. Chem. Soc.
1989, 111, 7519.
2. Rychonovskyk, S. D.; Skalitzky, D. J.; Pathirana, C.;
Jensen, P. R.; Fenical, W. J. Am. Chem. Soc. 1992, 114,
671.
3. (a) Smith, A. B., III; Ott, G. R. J. Am. Chem. Soc. 1996,
118, 13095; (b) Kim, Y.; Singer, R. A.; Carreira, E. M.
Angew. Chem., Int. Ed. 1998, 37, 1261; (c) Marino, J. P.;
McClure, M. S.; Holub, D. P.; Comasseto, J. V.; Tucc, F.
C. J. Am. Chem. Soc. 2002, 124, 1664.
O
O
O
O
19
1b
18
O
OMe
Hb
O
O
n
l, m
Hc
Ha
O
4. (a) Boyce, R. J.; Pattenden, G. Tetrahedron Lett. 1996, 37,
3501; (b) Donaldson, W. A.; Bell, P. T.; Wang, Z.;
Bennett, D. W. Tetrahedron Lett. 1994, 35, 5829; (c)
O
20
€
Barmann, H.; Prahlad, V.; Tao, C.; Yun, Y. K.; Wang, Z.;
Scheme 4. Reagents and conditions: (a) EtMgBr, 4 (fragment B),
THF, 70%; (b) dppb, toluene, THF; (c) AcOH/THF/H2O (8:8:1), 40%
(two steps); (d) Me4NBH(OAc)3, AcOH, MeCN, 89%; (e) 2,2-
dimethoxypropane, PPTS, CH2Cl2, 83%; (f) BrCN, n-BuLi, THF,
)78 ꢁC fi )40 ꢁC, 90%; (g) PdCl2(PPh3)2, Bu3SnH, benzene; (h) CuTC,
ethyl (Z)-3-iodopropenoate 3, NMP, 64% (two steps); (i) TBAF, THF,
0 ꢁC, 92%; (j) CH2@CMe(OMe), PPTS, CH2Cl2, )40 ꢁC, 82%; (k)
TBAF, AcOH (1:1), THF, 89%; (l) 3 N KOH, THF, EtOH, 60 ꢁC; (m)
2,4,6-trichlorobenzoyl chloride, Et3N, THF, then DMAP, toluene,
40% (three steps); (n) PPTS, MeOH, 61%.
Donaldson, W. A. Tetrahedron 2000, 56, 2283; (d)
Tanimori, S.; Morita, Y.; Tsubota, M.; Nakayama, M.
Synth. Commun. 1996, 26, 559.
ꢀ
5. (a) Hachem, A.; Flocꢀh, Y. L.; Gree, R.; Rolland, Y.;
Simonet, S.; Verbeuren, T. Tetrahedron Lett. 2002, 43,
ꢀ
5217; (b) Benvegnu, T. J.; Gree, R. Tetrahedron 1996, 52,
11821.
6. Ikeda, N.; Arai, I.; Yamamoto, H. J. Am. Chem. Soc.
1986, 108, 483.
7. Nagao, Y.; Hagiwara, Y.; Kumagai, T.; Ochiai, M.;
Inoue, T.; Hashimoto, K.; Fujita, E. J. Org. Chem. 1986,
51, 2391.
8. (a) Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem.
1969, 34, 2543; (b) Ohtani, I.; Kusumi, T.; Kashman, Y.;
Kakisawa, H. J. Am. Chem. Soc. 1991, 113, 4092.
9. First preparation of IBX: Hartman, C.; Meyer, V. Chem.
Ber. 1893, 26, 1727; For a superior route to IBX, see:
Frigerio, M.; Santagostino, M.; Sputore, S. J. Org. Chem.
1999, 64, 4537.
10. The absolute configuration of 9 and 12 was determined by
a modified method of the Mosher protocol.8
11. Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22,
3815.
(2Z,4E)-carboxylic acid (JHa–Hb ¼ 11:3 Hz) by a modi-
fied Yamaguchiꢀs method20 did not provide the desired
(2Z,4E)-lactone at all, and gave unexpected (2E,4E)-
lactone 20 as the single isomer (JHa–Hb ¼ 15:3 Hz).21
From the fact that McClure and co-workers3c succeeded
in a total synthesis of macrolactin A by the same pro-
cedure, the replacement of the (8E,10Z)-dienic moiety to
the aromatic ring seems to prohibit the macrocyclization
into the (2Z,4E)-lactone. Finally, global deprotection of
the methoxyisopropylidene acetal and acetonide of 20
afforded the macrolactin A analogue 1b in 61% yield.
12. Schmidt, B.; Seebach, D. Angew. Chem., Int. Ed. Engl.
1991, 30, 99.
13. Hartman, C.; Seyferth, D.; Marmor, R. S.; Hilbert, P.
J. Org. Chem. 1971, 36, 1379; Brown, D. G.; Velthuisen,
E. J.; Commerford, J. R.; Brisbois, R. G.; Hoye, T. R.
J. Org. Chem. 1996, 61, 2540.
14. Trost, B. M.; Kazmaier, U. J. Am. Chem. Soc. 1992, 114,
7933; Guo, C.; Lu, X. J. Chem. Soc., Perkin Trans. 2 1993,
1921.
The synthesis of 1b was thus completed in 23 steps in the
longest linear sequence. The use of 5 allowed rapid
access to advanced intermediate 16 through isomeriza-
tion of ynone to (E,E)-conjugated dienone. Overall,
control of all of the four stereocenters was achieved by
means of asymmetric and diastereoselective reactions
without using any chiral natural sources. Unfortunately,
the desired product 1a could not be synthesized. How-
15. Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am.
Chem. Soc. 1998, 110, 3560.

680
Y. Kobayashi et al. / Tetrahedron Letters 45 (2004) 677–680
16. The relative configuration of the 1,3-anti-diol was deter-
mined by the inspection of the 13C chemical shifts of the
acetonide methyl groups of 17.2 Both signals of two
methyl groups appeared at 25 ppm (d: 25.1 and 25.5).
17. Boden, C. D. J.; Pattenden, G.; Ye, T. J. Chem. Soc.,
Perkin Trans. 1 1996, 2417; Zhang, H. X.; Guibue, F.;
Balavoine, G. J. Org. Chem. 1990, 55, 1857.
19. Ma, S.; Lu, X. J. Chem. Soc., Chem. Commun. 1990, 1643;
Stille, J. K.; Groh, B. L. J. Am. Chem. Soc. 1987, 109, 813.
20. Hioka, M.; Tone, H.; Horita, K.; Yonemitsu, O. Tetra-
hedron 1990, 46, 4613; Inagawa, J.; Hirata, K.; Saeki, H.;
Katsuki, T.; Yamagutchi, M. Bull. Chem. Soc. Jpn. 1979,
52, 1989.
21. Ghosh, A. K.; Wang, Y.; Kim, J. T. J. Org. Chem. 2001,
66, 8973; Roush, W. R.; Blizzard, T. A. J. Org. Chem.
1984, 49, 4332.
18. Allred, G. D.; Liebeskind, L. S. J. Am. Chem. Soc. 1996,
118, 2748.