A synthesis of FR901464

Article abstract of DOI:10.1016/S0040-4039(01)01763-4

FR901464, a potent cell cycle inhibitor, was synthesized in a convergent manner using natural chiral pool, L-threonine, ethyl (S)-lactate and 2-deoxy-D-glucose as starting materials.

Full text of DOI:10.1016/S0040-4039(01)01763-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8207–8210
A synthesis of FR901464
Masato Horigome,a Hajime Motoyoshi,b Hidenori Watanabeb and Takeshi Kitaharab,*
aTechnical Support Section, Ueda Plant, Nisshin Pharma Inc., 751 Kamishiojiri, Ueda-City, Nagano 386-0042, Japan
bDepartment of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo,
1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
Received 20 August 2001; revised 10 September 2001; accepted 14 September 2001
Abstract—FR901464, a potent cell cycle inhibitor, was synthesized in a convergent manner using natural chiral pool,
ethyl (S)-lactate and 2-deoxy- -glucose as starting materials. © 2001 Elsevier Science Ltd. All rights reserved.
L-threonine,
D
FR901464 (1), which has two highly functionalized
tetrahydropyran rings linked by a diene chain (Fig. 1),
was isolated from the culture broth of the bacterium
Pseudomonas sp. No. 2663.1 This compound shows
transcriptional regulating activity and induces charac-
teristic G1 and G2/M phase arrest in the cell cycle.
Related to these activities, it also exhibits a potent
antitumor effect. The absolute configuration of 1,
which was initially ambiguous, was elucidated by spec-
troscopic and chemical analysis.2 Its unique structure as
well as the significant biological activities prompted us
to undertake the synthesis of this compound. Herein,
we describe a stereoselective synthesis of 1.
contrast, we decided to synthesize all of the segments
taking full advantage of materials from the chiral pool.4
Segments A and C would be prepared from commer-
cially available ethyl (S)-lactate and 2-deoxy-D-glucose,
respectively. Segment B, in which all the substituents on
the tetrahydropyran ring are cis-oriented, would be
synthesized by stepwise carbon chain elongation via D
and E starting from Garner’s aldehyde5 derived from
L
-threonine.
The synthesis of segment B is shown in Scheme 2.
Garner’s aldehyde5 was subjected to a Wittig reaction
followed by hydrogenation to give an inseparable 2:1
mixture of diastereoisomers. In this hydrogenation step,
high stereoselectivity as described in the literature6 was
not observed. This mixture was converted under stan-
dard conditions into lactone 3, which was then treated
with Lawesson’s reagent7 affording thiolactone 4.
Although the methyl group at C-2 epimerized com-
pletely to the undesired a-orientation during this reac-
tion, its stereochemistry was not important hereafter.
The carbon chain was elongated by another Wittig
reaction, and deconjugation was performed with DBU
to furnish 5. The double bond of 5 was stereoselectively
hydrogenated with platinum oxide to give the desired
all cis-isomer 6 exclusively. The ester moiety of 6 was
reduced to an aldehyde with DIBAL and a three-car-
bon chain was added by the Wittig reaction. The
resultant ethyl ester 7 was then reduced to an alcohol
and converted into the desired sulfone 8 in four steps.
Our synthetic strategy is illustrated in Scheme 1. From
a synthetic perspective, we sought an efficient and
convergent approach to our target, and decided upon
disconnections at the diene and amide bonds generating
segments A, B and C. Recently, Jacobsen et al. reported
a total synthesis of 1 in which every chiral building
block was prepared using asymmetric catalysts.3 In
19
17
16
5'
OAc
O
O
11
O
1
5
OH
1'
N
H
HO
20
O
18
FR901464 (1)
Figure 1.
The synthesis of segment A is displayed in Scheme 3.
Known aldehyde 9,8 derived from ethyl (S)-lactate, was
subjected to the (Z)-selective Horner–Emmons
reaction9 followed by hydrolysis with LiOH to furnish
a,b-unsaturated carboxylic acid 10 quantitatively.
Keywords: FR901464; cell cycle inhibitor; asymmetric synthesis; cou-
pling reactions.
* Corresponding author. Fax: 81-3-5841-8019; e-mail: atkita@
mail.ecc.u-tokyo.ac.jp
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01763-4

8208
M. Horigome et al. / Tetrahedron Letters 42 (2001) 8207–8210
OHC
R'O
O
O
Ts
OR
CO2H
1
+
+
OMe
H2N
A
B
C
O
OH
OH
CO2Et
HO
HO
A
C
Ethyl (S)-lactate
OH
2-Deoxy-D-glucose
CHO
NBoc
Garner's aldehyde
O
O
O
CO2Me
O
B
L-Threonine
BocHN
BocHN
D
E
Scheme 1.
1) Ph3P=C(Me)CO2Et
benzene, reflux, 95%
1) CSA, MeOH
12 h, 92%
CHO
O
O
Lawesson's reagent
CO2Et
O
O
NBoc
NBoc
toluene, 80 °C
7 h, 65%
2) H2, Pd(OH)2/C
2-propanol, 6 h, quant.
2) CSA, benzene
88%
BocHN
3
2
Garner's aldehyde
(2:1 mixture)
1) Ph3P=CHCO2Me, toluene
80 °C, 24 h, E/Z = 19:81, 81%
O
S
O
O
H2, Pt2O, AcOH
4 atm, 24 h, 68%
CO2Me
CO2Me
2
BocHN
BocHN
BocHN
2) DBU, benzene, reflux
6 h, quant.
4
5
6
1) DIBAL, toluene, -78 °C to rt, 82%
2) CBr4, PPh3, CH2Cl2, 90%
1) DIBAL, toluene
-70 °C, 94%
O
O
Ts
CO2Et
3) p-tolSO2Na, DMF, 17 h, 87%
4) 4N HCl, EtOAc, quant.
2) Ph3P=C(Me)CO2Et
benzene, reflux, 6 h
E/Z = 23:1, 97%
BocHN
H2N
7
8
Scheme 2.
OTBDPS
OH
OTBDPS
1) (CF3CH2O)2P(O)CH2CO2Me
KH, THF, -78 °C, E/Z = 1:10, 77%
ref. 8
CHO
CO2Et
Ethyl (S)-lactate
CO2H
2) LiOH, MeOH, H2O, quant.
9
10
Scheme 3.
To synthesize segment C, the two hydroxyl groups of
2-deoxy- -glucose were first protected as a p-methoxy-
it had proved difficult to remove the PMB group at a
later stage of the synthesis in earlier work. Removal of
the pivaloyl group and Dess–Martin oxidation11 fur-
nished aldehyde 17.
D
benzylidene acetal and the anomeric hydroxyl group
was selectively oxidized with bromine to lactone 11
(Scheme 4). Protection of the remaining hydroxyl group
followed by olefination with the Tebbe reagent10 pro-
vided vinyl ether derivative 12. Treatment of 12 with
PPTS and MeOH afforded a separable mixture of 13
and 14. Removal of the TBS group of 13 and Dess–
Martin oxidation11 of the liberated hydroxyl group,
followed by Tebbe methylenation10 gave exo-olefin 15.
DIBAL reduction generated a primary alcohol, which
in turn was protected as its pivalate ester. At this stage,
the PMB group was replaced with a TBS group because
In the final assembly phase, amine 8 and carboxylic
acid 10 were first condensed using HBTU to provide 18
(Scheme 5). Sulfone 18 and previously prepared alde-
hyde 17 were successfully coupled by Julia olefination12
to afford diene 19. The TBS group and TBDPS group
of 19 were removed with TBAF, and the resultant diol
20a was acetylated to give 20b. Diacetate 20b was then
hydrolyzed to furnish the desired 20c (37%), and the
undesired compounds (20a, 20b and 20d, 60% for three

M. Horigome et al. / Tetrahedron Letters 42 (2001) 8207–8210
8209
O
O
O
O
OH
1) p-MeOC6H4CH(OMe)2
TsOH, DMF, 40 °C, 68%
O
O
HO
HO
1) TBSCl, imid., DMF, 97%
PMP
O
PMP
O
2) Tebbe reagent, pyridine
THF, -20 °C, 80%
2) Br2, NaHCO3
dioxane, H2O, 71%
OH
OTBS
OH
12
2-Deoxy-D-glucose
11
1) TBAF, THF, 18 h, 90%
2) Dess-Martin periodinane
pyridine, CH2Cl2, 18 h, 80%
O
O
O
OMe
O
O
OMe
PPTS, MeOH, CH2Cl2
+
13
PMP
O
PMP
O
3) Tebbe reagent, pyridine
THF, -20 °C, 94%
OTBS
13 (66%)
OTBS
14 (15%)
1) DDQ, CH2Cl2, H2O, 0 °C, 74%
2) TBSOTf, 2,6-lutidine, CH2Cl2,
1) DIBAL, CH2Cl2
-20 °C, 95%
O
O
OHC
O
PivO
OMe
OMe
OMe
3) DIBAL, CH2Cl2, -20 °C
67% (2 steps)
4) Dess-Martin periodinane
pyridine, CH2Cl2, 19 h, 91%
PMP
O
2) PivCl, DMAP, NEt3
CH2Cl2, 88%
PMBO
TBSO
15
16
17
Scheme 4.
OTBDPS
O
1) n-BuLi (2.5 eq.), 17, THF, -78 °C
then BzCl, 82%
O
Ts
HBTU, N-ethylmorpholine
CH3CN, 12 h, 86%
8
10
+
2) Na(Hg), THF, MeOH
-20 °C, 40%
N
H
18
OTBDPS
O
1) TBAF, THF, 12 h, 95%
2) excess Ac2O, DMAP
NEt3, CH2Cl2
O
O
OR1
O
O
O
OMe
OMe
N
H
TBSO
N
H
R2O
3) LiOH, MeOH
75% (2 steps)
19
20c: R1 = Ac, R2 = H
20d: R1 = H, R2 = Ac
20a: R1 = H, R2 = H
20b: R1 = Ac, R2 = Ac
Amberlyst 15, THF, H2O
56% (based on consumed 21)
OAc
O
O
O
mCPBA, NaHCO3
1
OMe
20c
CH2Cl2, -20 °C, 23%
N
HO
H
Amberlyst 15, MeOH, -15 °C, 3 h, 43%
O
21
Scheme 5.
compounds). Compounds 20a and 20d were acetylated
to provide diacetate 20b again. This acetylation–hydrol-
ysis process was repeated twice to give the desired 20c
in 75% total yield. Epoxidation of 20c with mCPBA (1
equiv.) furnished 21 in 23% yield.13 1H NMR spectro-
scopic data of our synthetic 21 showed complete accor-
dance with those of material derived from natural 1 by
acid treatment in MeOH.14–16 The final deacetalization
was examined by using the sample prepared from natu-
ral 1. After many investigations, we found out that
Amberlyst 15 in wet THF gave the target molecule 117
as a single isomer in a moderate yield despite the
acid-sensitivity of the product.
gations are under way to refine each step of the synthe-
sis. Results will be reported in a full account in due
course.
Acknowledgements
The authors sincerely thank Dr. H. Nakajima,
Fujisawa Pharmaceutical Co., Ltd, for a kind gift of
natural FR901464 and its spectral charts. This work
was supported by
a Grant-in-Aid for Scientific
Research from the Japanese Ministry of Education,
Culture, Sports, Science and Technology. The authors
also thank Sankyo Foundation of Life Science, and
Suntory Institute for Bioorganic Research for financial
support.
In conclusion, we have accomplished the relay synthesis
of FR901464 using natural chiral pool. Further investi-

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M. Horigome et al. / Tetrahedron Letters 42 (2001) 8207–8210
J. Am. Chem. Soc. 1980, 102, 3270–3272; (b) Tebbe, F.
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