Stereoselective Synthesis of the C27-C48 Moiety of Aflastatin A by a Carbohydrate Strategy Using a Tin(II)-Mediated Aldol Reaction

Article abstract of DOI:10.1055/s-0035-1560572

The C27-C48 segment of aflastatin A was synthesized by using d-mannoside and l-erythrulose derivatives as chiral building blocks. The aldol reaction of undecan-2-one with mannolactone and a subsequent reduction gave the C37 and C39 stereogenic centers wit

Full text of DOI:10.1055/s-0035-1560572

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2015, 26, 2437–2441
letter
2437
S. Murakoshi, S. Hosokawa
Letter
Synlett
Stereoselective Synthesis of the C27–C48 Moiety of Aflastatin A
by a Carbohydrate Strategy Using a Tin(II)-Mediated Aldol Reac-
tion
Sawato Murakoshi
Seijiro Hosokawa*
OBn
30
Me
O
Me
O
PMBO
OPMB
OSn(II)
27
H
48
Me
Department of Applied Chemistry, Faculty of Science
and Engineering, Waseda University, 3-4-1 Ohkubo,
Shinjuku-ku, Tokyo 169-8555, Japan
31
OHC
O
8
e-mail_seijiro@waseda.jp
BnO
OBn
HO HO
OBn
H
OH
48
Me
O
39
31
27
38
30
33
37
8
HO HO HO
HO
OH
OH
OH
Received: 22.07.2015
Accepted after revision: 12.08.2015
Published online: 14.09.2015
preparation of contiguous polyol structures, such as the
C27–C39 moiety of aflastatin A, is a problem in organic syn-
thesis.
DOI: 10.1055/s-0035-1560572; Art ID: st-2015-u0570-l
Me
O
Abstract The C27–C48 segment of aflastatin A was synthesized by us-
ing D-mannoside and L-erythrulose derivatives as chiral building blocks.
The aldol reaction of undecan-2-one with mannolactone and a subse-
quent reduction gave the C37 and C39 stereogenic centers with high
selectivity. Another aldol reaction of a tin(II) enolate of a protected
erythrulose (C27–C30 segment) with a C31–C48 aldehyde segment
gave the C30,C31-syn adduct with the desired stereochemistry. Depro-
tection of the assembled product proceeded smoothly to give the C27–
C48 segment of aflastatin A containing a contiguous polyol moiety.
Me
Me
Me
OH Me
Me
Me
N
Me
1
HO
HO
HO
O
OH OH OH OH
OH OH
OH
Me
48
Me
Me
H
OH
39
31
27
O
33
37
OH OH OH OH OH
OH
OH
OH
Key words stereoselectivity, aflastatin A, aldol reactions, polyols, car-
OH
bohydrates
aflastatin A (1)
Figure 1 Structure of aflastatin A (1)
Aflastatin A (1; Figure 1), first isolated from Streptomy-
ces sp. MRI142 by Sakuda and co-workers,1 is an inhibitor of
aflatoxin produced by Aspergillus parasiticus. The structure
of aflastatin A features a variety of polyketide motifs includ-
ing polypropionate, polyacetate, and contiguous polyol
structures; consequently, it has become an attractive target
molecule for organic synthesis.2 In the course of our studies
on polyketide synthesis,3 aflastatin A became one of our
target molecules, as its preparation might lead to a general
and efficient strategy for the synthesis of complex
polyketides. Contiguous polyol moieties of various
polyketides, including aflastatin A, have been synthesized
by several groups. Evans and co-workers employed aldol re-
actions to construct the C9–C27 and C33–C36 moieties of
aflastatin A.2a,b McDonald and co-workers also reported a
synthesis of the C9–C27 segment by using alkyne–epoxide
cross coupling followed by intramolecular hydrosilation.2c
Ramana and co-workers synthesized the C31–C48 seg-
ment2d and the C27–C38 segment2e by palladium-catalyzed
dihydropyran formation. These studies indicate that the
Here, we present an alternative synthesis of the C27–
C48 segment of aflastatin A. To establish a straightforward
route, the starting materials should reflect the polyol align-
ment of the target compound. We therefore decided to syn-
thesize the polyol segment from carbohydrates. Our syn-
thetic plan is shown in Scheme 1. On the basis of the strate-
gy of using easily available polyols as starting materials, we
divided the C27–C48 moiety 2 into three segments: the
protected L-erythrulose 3 (C27–C30), the mannose deriva-
tive 4 (C31–C37), and undecan-2-one (5; C38–C48). We in-
tended to connect these segments by aldol reactions, which
needed to be stereoselective to establish an efficient route.
This strategy should form a straightforward method for
synthesizing contiguous polyol compounds.
The synthesis of the C31–C48 segment 11 is shown in
Scheme 2. The mannose derivative 64 was converted into
the cyanide 7,5 which was transformed into the lactone 4 by
sequential acetolysis, methanolysis, and oxidation reac-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2437–2441

2438
S. Murakoshi, S. Hosokawa
Letter
Synlett
Table 1 Reduction of the C-39 Keto Group of 8
HO HO
48
Me
H
OH
O
39
31
27
30
38
37
33
H
OH
O
Me
HO HO HO
OH
NC
BnO
HO
OH
7
O
OBn
OH
2
OBn
H
31
NC
O
O
8
BnO
OPMB
38
Me
48
Me
33
37
39
H
OH
H
OH
+
+
27
30
O
Me
39
O
Me
7
BnO
OBn
39
NC
BnO
NC
BnO
O
PMBO
O
OBn
7
7
OH
OH
OBn
OBn
3
4
5
OBn
OBn
Scheme 1 Synthetic plan toward the C27–C48 segment 2
(39R)-9 (desired)
(39S)-9
Entry Reductant
Solvent Temp
Time Yield dra
(h)
(%) (R/S)
tions. The nucleophilic addition of the lithium enolate of
undecan-2-one (5) to lactone 4 proceeded stereoselectively
to give adduct 8 as a single isomer. The ketone group in 8
was then reduced stereoselectively. Treatment of adduct 8
with sodium borohydride in ethanol gave (39S)-9 with high
stereoselectivity, whereas reduction of adduct 8 by using
tetramethylammonium triacetoxyborohydride6 in the pres-
ence of acetic acid gave (39R)-9 in excellent yield and high
stereoselectivity (Table 1).
1
2
NaBH4
Me4NBH(OAc)3–AcOH
EtOH
r.t.
0 °C to r.t.
1
2
95
97
1:18
13:1
MeCN
a Determined by 1H NMR.
The stereochemistry of diol 9 was determined through
conversion into the acetonide 10 (Figure 2). With (39R)-10,
an NOE was observed between H-39 and one of methyl
groups of the acetonide, which also showed an NOE with H-
33. On the other hand, with (39S)-10, an NOE was observed
between H-39 and H-36, as well as between H39 and the
methyl group of the acetonide opposite to the one correlat-
ing with H33. Because β-hydroxy lactol groups occur wide-
ly in natural products,7 the procedure involving an aldol re-
action between a lactone and a ketone followed by stereo-
selective reduction should be a powerful tool for the
synthesis of such natural products. Reduction of the cya-
nide group of 10 with diisobutylaluminum hydride gave al-
dehyde 11, the required C31–C48 segment.
H
H
O
OMe
OBn
O
OMe
OBn
NC
BnO
I
a
b–d
BnO
OBn
OBn
7
6
Me
Me
H
H
OH
O
Me
O
O
7
O
5
NC
NC
7
O
OBn
e
BnO
BnO
OBn
OBn
OBn
2.8%
CN
OBn
O
CN
OBn
O
5.8%
4
8 (dr > 20:1)
H
O
H
BnO
BnO
BnO
BnO
H
OH
Me
Me
39
O
Me
39
39
H
33
8
H
33
8
NC
see Table 1
f
H
H
O
36 O
7
O
OH
OBn
2.2%
BnO
Me
Me
Me
Me
6.8%
3.9%
OBn
(39R)-10 (desired)
(39S)-10
9
Figure 2 Structural determination of (39R)-10 and (39S)-10
H
O
O
H
O
O
48
Me
48
Me
31
O
O
NC
BnO
OHC
39
39
g
8
8
BnO
OBn
OBn
Next, we prepared the C27–C30 segment 3 from the
known tartrate derivative 12 (Scheme 3).8 Protection of the
primary alcohol groups of 12 as p-methoxybenzyl ethers
and subsequent reduction with diisobutylaluminum hy-
dride gave the secondary alcohol 13. Oxidation of alcohol
13 with 1-hydroxy-1λ5,2-benziodoxol-1,3-dione (IBX) gave
the ketone 3. The three-step sequence gave the C27–C30
segment 3 in high yield.
OBn
OBn
10
11
Scheme 2 Synthesis of the C31–C48 segment 11. Reagents and condi-
tions: (a) NaCN, DMSO, 60 °C, 17 h, 98%; (b) Ac2O, TFA, r.t., 2 d;
(c) K2CO3, MeOH, r.t., 30 min, 78% (2 steps); (d) IBX, DMSO, toluene,
70 °C, 1 h, 82%; (e) LiHMDS, THF, –70 °C, 1.5 h, 72%; (f) Me2C(OMe)2,
TsOH·H2O, 0 °C to r.t., 15 min, 97%; (g) DIBAL-H, CH2Cl2, –70 °C,
15 min, 97%.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2437–2441

2439
S. Murakoshi, S. Hosokawa
Letter
Synlett
dition of zinc chloride gave the adducts in high yields, but
the selectivity was not good (entries 2 and 6). In the case of
triisopropoxytitanium chloride,13 an anti-adduct (stereo-
chemistry not determined)14 was obtained with good selec-
tivity (entries 3 and 7). The desired stereoisomer was, how-
ever, obtained by addition of tin(II) chloride (entries 4 and
8).15 In the tin(II)-mediated aldol reaction (entries 4 and 8),
the p-methoxybenzyl-protected ketone 3 gave better re-
sults than did the tert-butyl(dimethyl)silyl-protected 3′. To
avoid the equilibrium between the lithium enolate and the
tin(II) enolate, we added 12-crown-4 to trap the lithium ion
(entry 9). The transformation gave the adducts in excellent
yield, which included the desired isomers in high selectivi-
ty. These results indicate that the aldol reaction with a
tin(II) enolate is useful for the synthesis of the contiguous
polyoxygenated compounds. We therefore used ketone 3
and the conditions shown in entry 9 of Table 2 to synthesize
the C27–C48 moiety of aflastatin A.
To investigate the origin of the stereoselectivity, we
trapped the enolate derived from 3 (Scheme 4). Treatment
of the lithium enolate with Meerwein reagent gave methyl
ether 16, which showed an NOE between the vinylic proton
at the C1 position and C3 proton, indicating it to be the (Z)-
vinyl ether. These results suggest that the reaction under
the conditions of Table 2, entry 9 proceeds via the transi-
tion state 17, in which tin(II) is not chelated with the near-
by ether oxygen atoms.
O
OBn
Ph
OH
HO
PMBO
a,b
OPMB
O
OH
12
13
OBn
30
c
PMBO
OPMB
27
O
3
Scheme 3 Synthesis of the C27–C30 segment 3. Reagents and condi-
tions: (a) NaH, PMBCl, DMF, 0 °C, 1 h, 91%; (b) DIBAL-H, toluene, 0 °C to
r.t., 30 min, 97%; (c) IBX, DMSO, toluene, 40 °C, 1 h, 97%.
Attachment of the polyol aldehyde to the polyol ketone
by an aldol reaction was examined by using the aldehyde
14, derived from cyanide 7, and the protected ketones 3 (Ta-
ble 2). We also prepared the tert-butyl(dimethyl)silyl ether
3′9 for comparison with the p-methoxybenzyl ether 3. Be-
cause the aldol reaction of the dicyclohexylborane enolate
of 3′ with the polyol aldehyde 1410 under Marco’s condi-
tions11 did not work well, we examined aldol reactions of
other enolates (Table 2). The aldol reaction between these
polyoxygenated compounds was markedly influenced by
the nature of the countercation, whereas the protecting
group of the primary alcohols had only a slight effect. In the
lithium-mediated aldol reaction (entries 1 and 5), the unde-
sired syn-adduct was obtained as the major product.12 Ad-
Table 2 The Aldol Reaction of Aldehyde 14 with the Enolates of Ketone 3
OBn
RO
OR
O
OBn OR
H
H
3' R = TBS
3 R = PMB
O
OMe
OBn
RO
O
OMe
OBn
7
6
8
R
1
O
OH
BnO
LiHMDS
additive
THF
BnO
OBn
OBn
7 R = CN
15a 7S, 8R desired syn
DIBAL-H
15b 7R, 8S undesired syn
15c anti
14 R = CHO
15d anti
Entry
R
Additive (1.6 equiv)
Temp (°C)
–30
Time (h)
Yield (%)
dra 15a/15b/15c/15d
1
2
3
4
5
6
7
8
9
TBS
–
3
5
62
85
70
59
70
95
90
78b
96
11:73:16:0
38:49:14:0
13:26:61:0
61:27:13:0
21:43:28:7
33:42:23:2
4:8:72:16
75:17:6:2
82:14:4:0
TBS
ZnCl2
–30 to –10
–30
TBS
(i-PrO)3TiCl
SnCl2
5
TBS
–30 to –10
–30
12
2
PMB
PMB
PMB
PMB
PMB
–
ZnCl2
–30
2
(i-PrO)3TiCl
SnCl2
–30
1
–30 to –10
–30 to –10
24
20
SnCl2, 12-crown-4
a Ratios of diastereomers were determined by 400 MHz 1H NMR.
b 12% of the starting material 14 was recovered.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2437–2441

2440
S. Murakoshi, S. Hosokawa
Letter
Synlett
NOE
10.1%
OBn
30
PMBO
H
O
O
LiHMDS
Me3OBF4
OPMB
OBn
BnO
H
31
OHC
48
Me
27
O
H
1
O
3
PMBO
PMBO
3
OPMB
OPMB
THF
–78 to –20 °C, 6 h
60%
8
a
BnO
OBn
O
MeO
OBn
16 (E/Z = 10:1)
3
11
‡
OPMB
OBn OPMB
OBn OPMB
OBn
H
H
O
O
H
31
29
O
b
PMBO
O
OMe
OBn
7
8
30
6
Me
1
H
SnII
O
H
PMBO
O
OH
BnO
O
OH
8
OBn
OPMB
R
BnO
O
OBn
18 (dr = 15:1)
OBn
17
PMB-15a
Scheme 4 Trapping of the lithium enolate and the proposed transition
state
OBn OPMB
H
O
O
48
29
31
O
Me
c
PMBO
OH OH
BnO
8
OBn
The C31–C48 segment 11 was coupled with the C27–
C30 segment 3 to construct the C27–C48 segment (Scheme
5). Aldehyde 11 was treated with the tin(II)-enolate of ke-
tone 3 in the presence of 12-crown-4 to give the desired ad-
duct 18 in high yield and with high selectivity. Reduction of
the keto group of adduct 18 with sodium triacetoxyborohy-
dride16 gave the desired 29R-isomer 19, in which all stereo-
genic centers were identical with those of the natural prod-
uct.1e,17 This two-step sequence accomplished the connec-
tion of the segments and alignment of stereogenic centers
to construct the C27–C48 moiety of aflastatin A. With the
partially protected C27–C48 moiety 19 in hand, we com-
pleted the synthesis of the C27–C48 moiety 2 by two-step
deprotection. The acetonide group bridging the C37 and
C39 oxygen atoms was removed by hydrolysis with 1 M
aqueous hydrochloric acid at 50 °C to give tetraol 20 in good
yield. Hydrogenolysis of the six benzyl ethers then afforded
the C27–C48 moiety 2 in high yield.18
OBn
19 (dr = 8:1)
OBn OPMB
H
OH OH
O
27
30
Me
d
PMBO
OH OH
8
OBn
BnO
OBn
20
OH OH
48
H
OH
39
O
Me
31
27
30
OH OH OH
HO
OH
OH
OH
2
Scheme 5 Synthesis of the C27–C48 moiety of aflastatin A 2. Reagents
and conditions: (a) LiHMDS, THF, –30 °C, 1 h, then SnCl2, 12-crown-4,
–78 to –5 °C, 23 h, 84%; (b) NaBH(OAc)3, CHCl3, 0 °C to r.t., 1.5 h, 84%;
(c) 1 M HCl, THF, 50 °C, 1 h, 83%, then H2, Pd(OH)2/C, THF, r.t., 13 h, 90%.
In conclusion, we have synthesized the C27–C48 moiety
of aflastatin A by a highly convergent route using aldol reac-
tions to connect the L-erythrulose derivative 3, the D-man-
nose derivative 4, and undecan-2-one (5). The aldol reac-
tion between mannolactone 4 and undecan-2-one (5) pro-
ceeded smoothly to give adduct 8 in a stereoselective
manner. Subsequent reduction gave the β-hydroxy lactols
(39R)-9 and (39S)-9 stereoselectively. In the next aldol reac-
tion between the contiguous polyol ketone 3 and the con-
tiguous polyol aldehyde 11, the tin(II) enolate method was
found to be useful in obtaining the desired stereoisomer 18.
Deprotection proceeded smoothly to afford the C27–C48
moiety of aflastatin A (2). This synthesis suggests an effi-
cient and straightforward methodology for the preparation
of compounds with contiguous polyoxygenated segments.
Studies toward a synthesis of aflastatin A are in progress in
our laboratory.
Acknowledgment
The authors are grateful for financial support from The Kurata Memo-
rial Hitachi Science, The Naito Foundation, and the Technology Foun-
dation, Scientific Research on Innovative Areas #24102531 of The
Ministry of Education, Culture, Sports, Science and Technology
(MEXT), Japan.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560572.
S
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p
p
o
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References and Notes
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2437–2441

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S. Murakoshi, S. Hosokawa
Letter
Synlett
M.; Okamoto, S.; Ono, M.; Tsukigi, H.; Suzuki, A.; Nagasawa, H.;
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(18) C27–C48 Fragment 2
20% Pd(OH)2/C (1.0 mg) was added to a solution of compound
20 (4.2 mg, 3.9 μmol) in THF (1.0 mL), and the mixture was
stirred for 13 h under H2. The mixture was filtered through a
pad of Celite and the filtrate was concentrated in vacuo. The
residue was purified by column chromatography [silica gel,
CHCl3–MeOH (1:1)] to give a white solid; yield: 1.7 mg (3.5
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Chem. Int. Ed. 2000, 39, 4111.
25
μmol, 90%); mp 126–127 °C; Rf = 0.30 (CHCl3–MeOH, 1:1); [α]D
(6) (a) Evans, D. A.; Chapman, K. T. Tetrahedron Lett. 1986, 27, 5939.
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+13.8 (c 1.34, MeOH). IR (thin film, KBr): 3535, 3073, 2959,
2924, 1260, 1124, 796, 668 cm–1. 1H NMR (400 MHz, DMSO-d6):
δ = 6.16–6.12 (br s, 1 H), 5.26 (d, J = 3.9 Hz, 1 H), 4.59 (d, J = 5.2
Hz, 1 H), 4.54 (d, J = 5.2 Hz, 1 H), 4.49 (dd, J = 5.6, 5.6 Hz, 1 H),
4.48 (d, J = 4.1 Hz, 1 H), 4.37 (d, J = 5.2 Hz, 1 H), 4.17 (d, J = 5.0
Hz, 1 H), 4.16 (d, J = 5.0 Hz, 1 H), 4.11 (d, J = 6.1 Hz, 1 H), 3.94–
3.81 (m, 2 H), 3.63 (ddd, J = 9.8, 9.8, 3.8 Hz, 1 H), 3.61–3.53 (m, 3
H), 3.48–3.34 (m, 4 H), 3.19 (ddd, J = 9.2, 9.2, 5.6 Hz, 1 H), 2.09–
2.01 (m, 1 H), 1.86–1.79 (m, 1 H), 1.53–1.38 (m, 2 H), 1.37–1.15
(m, 16 H), 0.85 (t, J = 6.9 Hz, 3 H). 13C NMR (100 MHz, DMSO-
d6): δ = 98.4, 73.1, 71.9, 71.7, 71.3, 70.7, 70.2, 69.3, 67.4, 62.8,
41.6, 38.2, 35.8, 31.3, 29.2, 29.1, 29.0, 28.7, 24.8, 22.1, 14.0.
HRMS (ESI): m/z [M + Na]+calcd for C22H44NaO11: 507.2776;
found: 507.2778.
(11) (a) Murga, J.; Falomir, E.; González, F.; Carda, M.; Marco, J. A.
Tetrahedron 2002, 58, 9697. (b) Marco, J. A.; Murga, J.; Carda, M.;
Díaz-Oltra, S.; Murga, J.; Falomir, E.; Roeper, H. J. Org. Chem.
2003, 68, 8577.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2437–2441