Synthesis of the optically active key intermediate of FR901483

Article abstract of DOI:10.1016/j.tetlet.2010.05.089

Efficient synthesis of the tricyclic key intermediate 2 for (-)-FR901483 1 was accomplished. The precursor of the intramolecular aldol reaction 4b is constructed by the Ugi 4CC reaction and subsequent intramolecular Dieckmann condensation. This approach allows a fully stereocontrolled total synthesis of (-)-FR901483, which would provide various derivatives.

Full text of DOI:10.1016/j.tetlet.2010.05.089

Tetrahedron Letters 51 (2010) 4027–4029
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of the optically active key intermediate of FR901483
Shigeru Ieda a, , Toshiyuki Kan b,à, Tohru Fukuyama a,
*
a Graduate School of Pharmaceutical Science, University of Tokyo 7-3-1 Hongo, Bunkyo-ku 113-0033, Japan
b School of Pharmaceutical Sciences, University of Shizuoka and Global COE Program, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Efficient synthesis of the tricyclic key intermediate 2 for (À)-FR901483 1 was accomplished. The precur-
sor of the intramolecular aldol reaction 4b is constructed by the Ugi 4CC reaction and subsequent
intramolecular Dieckmann condensation. This approach allows a fully stereocontrolled total synthesis
of (À)-FR901483, which would provide various derivatives.
Received 24 March 2010
Revised 14 May 2010
Accepted 21 May 2010
Available online 2 June 2010
Ó 2010 Elsevier Ltd. All rights reserved.
OPO(OH)2
OH
OTBS
N
(À)-FR901483 1 is an immunosuppressant isolated from the
fermentation broth of Cladobotryum sp. No. 11231.1 Because its un-
ique tricyclic structure is an attractive target for the total synthesis,
several synthetic studies2 and total syntheses3 have been reported.
Since we reported a stereoselective total synthesis of racemic 1 in
2004,3e our next challenge has been to devise a synthetic route to
the optically active form of 1. Herein, we report a short-step and
stereocontrolled synthesis of optically active tricyclic 2, a key
intermediate of our racemic total synthesis of 1.
O
N
Ar
Ar
O
MeHN
1
2
Our retrosynthetic analysis of 1 is illustrated in Scheme 1. In
view of the fact that the crucial step in our racemic synthesis
was an intramolecular aldol reaction of the keto-aldehyde 4a to
provide the tricycle intermediate 3a, our first attempt was to per-
form an enantioselective intramolecular aldol reaction of 4a by
means of chiral catalysts. Since desymmetrical aldol reactions of
4a with several types of chiral catalysts did not give satisfactory re-
sults,4 we decided to examine a diastereoselective aldol reaction of
4b to construct the tricycle intermediate 3b, which could easily be
converted to intermediate 2 according to our racemic synthesis.
The crucial step of our synthesis, therefore, should be the facile
construction of the optically pure spiro intermediate 4b. While
(Ar = p-MeOC6H4)
O
O
OH
R
CHO
N
N
R
O
O
4a (R = H)
3a (R = H)
4b (R = p-MeOC6H4CH2) 3b (R = p-MeOC6H4CH2)
numerous procedures have been reported on the synthesis of a-tri-
substituted amines, we opted to employ the Ugi 4CC reaction5 to
construct 5 because of its powerfulness in assembling complex
molecules from simple components.6
O
O
MeO
OMe
As shown in Scheme 2, a mixture of commercially available
cyclohexanedione monoethyene acetal 6, optically active amine 7
(Scheme 4),7 p-methoxyphenyl isocyanide 8,8 and acetic acid 9 in
MeO
C
H2N
N
O
O
N
6
Ar
7
Ar
O
Ar
OH
* Corresponding author.
E-mail addresses: kant@u-shizuoka-ken.ac.jp (T. Kan), fukuyama@mol.f.u-to-
kyo.ac.jp (T. Fukuyama).
8
5
O
Present address: Process Chemistry Labs, Astellas Pharma Inc. 160-2, Akahama,
Takahagi, Ibaraki 318-0001, Japan.
9
à
Fax: +81 54 264 5745.
Scheme 1. Structure and synthetic strategy of (À)-FR901483.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.089

4028
S. Ieda et al. / Tetrahedron Letters 51 (2010) 4027–4029
quatorial aldol product 3b. Following the route established for
Ar
N
C
racemic 3a, 3b was converted uneventfully to 2. Thus, stereoselec-
tive reduction of 3b was carried out by NaBH(OAc)3 via chelation
with the hydroxyl group to give 14 (Scheme 3).
Selective protection of the exo-oriented hydroxy group of 14 as
the TBS ether followed by Swern oxidation of the remaining alco-
hol provided the key intermediate 2. All spectral data (1H NMR,
13C NMR, IR, and HRMS) of 2 are in agreement with our intermedi-
ate in the racemic synthesis, except for an optical rotation. The
8
AcOH
9
O
O
N
O
O
+
H
MeOH, rt
81%
N
H2N
Ar
Ar
O
O
Ar
7
6
Me
10
O
(Ar = p-MeOC6H4)
MeO
OMe
CSA
HC(OMe)3
AcO-
Ar
O
LHMDS
THF
N
H+
O
AcOH
MeOH, rt
95%
MeO
CHO
cat. Pyrrolidine
-78 °C to rt
N
H
92%
AcOEt, rt,
60%
O
Ar
N
Me
O
Ar
N
5
O
O
4b: Ar = p-MeOC6H4
13
O
OR1
MeO
OMe
1) NaBH4, MeOH, rt
2) POCl3, Pyridine, 60 °C
R
O
3) Mg, MeOH
; H+, rt
OH
O
OH
Ar
N
O
N
O
NaBH(OAc)3
61%
(3 steps)
Ar
Ar
N
AcOH, MeCN, 0 °C
60%
N
11
Ar
12 (R = CH2)
4b (R = O)
O3, MeOH; Me2S, -78 °C
93%
O
O
3b
14 : R1 = H
15 : R1 = TBS
TBSOTf, Et3N,
CH2Cl2, -20 °C,
64%
Scheme 2. Synthesis of cyclization precursor 4b for an intramolecular aldol
reaction.
MeOH was allowed to stand at room temperature to afford 10,9 in
which all the carbon atoms necessary to construct the tricyclic key
OTBS
intermediate
2 were efficiently assembled in a single step.
Although hydrolysis of the C-terminal amide bond in the Ugi ad-
ducts is often troublesome,10 methanolysis of the p-methoxy-
phenyl amide in 10 proceeded (Scheme 5)11 unusually smoothly
with a concomitant acetal exchange to provide 5. Subsequent
intramolecular Dieckmann condensation proved to be quite effec-
tive in constructing the spiro-lactam ring. Thus, upon treatment
with LHMDS, 5 underwent a cyclization to give 11. The ensuing
deoxygenation of the carbonyl group in 11 was carried out in a
three-step sequence involving a reduction of the ketone with
NaBH4, dehydration with phosphoryl chloride, and a chemoselec-
tive one-electron reduction of the resultant unsaturated lactam,
giving the desired amide 12. In addition, simultaneous hydrolysis
of the dimethyl acetal occurred during the acidic work-up of the
last step.12 At this stage, oxidative cleavage of terminal olefin in
12 was performed by ozonolysis to afford 4b.
DMSO,
O
(COCl)2; Et3N
11 steps
ref. 3e
15
1
N
CH2Cl2, -78 °C
93%
Ar
O
2
Scheme 3. Synthesis of optically active key intermediate 2.
O
OMe
O
HO
Cl
Cl
ii
iii
BocHN
BocHN
BocHN
Ar
Ar
18
Ar
With the desired optically active keto-aldehyde 4b in hand, we
then focused on the diasteroselective intramolecular aldol reac-
tion. The similar intramolecular cyclization of 4b was reported
by Snider.13 Although we have tested the same reactions, the
reproducibility was not enough. Therefore we selected acidic con-
ditions at room temperature. After several attempts, upon treat-
16: Ar = p-HOC6H4
19
i
17: Ar = p-MeOC6H4
O
iv
v, vi
vii
ment of keto-aldehyde 4b with acetic acid and
a catalytic
7
amount of pyrrolidine,14 the desired cyclization proceeded
smoothly to afford 3b. The advantage of this transformation is that
the two chiral centers were distinctively generated in one step.
While the stereochemistry of the hydroxy group in 3b is the
opposite of the natural product,15 it was needed in controlling
the endo-reduction of the ketone of 3b. Thermodynamic control
might presumably be operating for the stereochemistry of the die-
BocHN
BocHN
Ar
Ar
20
21
Scheme 4. Preparation of optically active amine 7. (i) MeI, K2CO3, DMF, rt, 99%; (ii)
sodium chloroacetate, Et3N, t-BuMgCl, THF, 0 °C to rt, 71%; (iii) NaBH4, MeOH, rt;
(iv) NaOH, THF–H2O, rt, 97% (two steps); (v) KSCN, THF–H2O, 60 °C; (vi) Ph3P,
toluene, 80 °C, 47% (two steps); (vii) 6 N HCl, MeOH, rt, 98%.

S. Ieda et al. / Tetrahedron Letters 51 (2010) 4027–4029
4029
(g) Kanden, S.; Lessig, H.-U. Org. Lett. 2006, 8, 4763; (h) Gotchev, D. B.; Comins,
D. L. J. Org. Chem. 2006, 71, 9393; (i) Diaba, F.; Ricou, E.; Sole, D.; Teixido, E.;
Valls, N.; Bonjoch, J. ARKIVOC 2007, 320; (j) Asari, A.; Angelov, P.; Auty, J. M.;
Hayes, C. J. Tetrahedron Lett. 2007, 48, 2631; (k) Simila, S. T.; Martin, S. F. J. Org.
Chem. 2007, 72, 5342; (l) Seike, H.; Sorensen, E. J. Synlett 2008, 695.
3. For total syntheses, see: (a) Snider, B. B.; Lin, H. J. Am. Chem. Soc. 1999, 121,
7778; (b) Scheffler, G.; Seike, H.; Solensen, E. J. Angew. Chem., Int. Ed. 2000, 39,
4593; (c) Ousmer, M.; Braun, M. A.; Bavoux, C.; Perrin, M.; Ciufolini, M. A. J. Am.
Chem. Soc. 2001, 123, 7543; (d) Maeng, J.; Funk, R. L. Org. Lett. 2001, 3, 1125; (e)
Kan, T.; Fujimoto, T.; Ieda, S.; Asoh, Y.; Kitaoka, H.; Fukuyama, T. Org. Lett. 2004,
6, 2729; (f) Brummond, K. H.; Hong, S. J. Org. Chem. 2005, 70, 907; (g) Carson, C.
A.; Kerr, M. A. Org. Lett. 2009, 11, 777.
10
5
H+, MeOH
OR2
R2O
OR2
R2O
H+
H
N
O
N+
Ar
N:
Ar
O
Ar
O
O
MeOH
4. For example:
L-proline, DMF, 24% yield, 0% ee and L-phenylalanine, DMF, 10%
yield, 18% ee; unpublished results.
(Ar = p-MeOC6H4)
(R2 = -CH2CH2- or Me)
22
5. For reviews of multicomponent reactions with isonitriles, see: (a) Hulme, C.;
Gore, V. Curr. Med. Chem. 2003, 10, 51; (b) Dömling, A.; Ugi, I. Angew. Chem., Int.
Ed. 2000, 39, 3168; (c) Gokel, G.; Lüdke, G.; Ugi, I. In Isonitrile Chemistry; Ugi, I.,
Ed.; Academic Press: New York, 1971; p 145; (d)Multicomponent Reactions; Zhu,
J., Bienaymé, H., Eds.; Wiley-VCH GmbH & Co. KGaA: Weinheim, 2005.
6. (a) Endo, A.; Yanagisawa, A.; Abe, M.; Tohma, S.; Kan, T.; Fukuyama, T. J. Am.
Chem. Soc. 2002, 124, 6552; (b) Mori, K.; Rikimaru, K.; Kan, T.; Fukuyama, T. Org.
Lett. 2004, 6, 3095; (c) Rikimaru, K.; Mori, K.; Kan, T.; Fukuyama, T. Chem.
Commun. 2005, 394.
7. Optically active amine 7 was prepared in seven steps from commercially
available N-Boc-tyrosine methyl ester 16. Epoxide 20 was prepared in
accordance with US Patent 59,29,284, 1997.
8. Synthesis of isocyanide 8: Gokel, G. W.; Widera, R. P.; Weber, W. P. Org. Synth.
Coll. Vol. VI 1988, 232.
Scheme 5. Neighboring group participation in the methanolysis of 10.
enantiomeric excess of 2 (96% ee) was determined by a chiral
HPLC.
In conclusion, we have achieved an efficient synthesis of the key
intermediate 2 for the total synthesis of (À)-FR901483 1, utilizing
the Ugi 4CC reaction and a diastereoselective intramolecular aldol
reaction. We are currently improving our racemic route16 for the
total synthesis of (À)-FR901483 and its analogs, and the results
will be published in due course.
9. In this Ugi 4CC reaction, the reaction rate depends on the structure of the
amine moiety 7. The vinyl group facilitated the reaction considerably as
compared with the other aldehyde equivalents.
10. (a) Rikimaru, K.; Yanagisawa, A.; Kan, T.; Fukuyama, T. Heterocycles 2007, 73,
403; (b) Rikimaru, K.; Yanagisawa, A.; Kan, T.; Fukuyama, T. Synlett 2004, 44.
11. Presumably, this reaction proceeds via oxazolonium intermediate 22 through
neighboring group participation. As shown in Scheme 5, the acetamide moiety
plays a key role in this transformation. This speculation is supported by the fact
that the amide of the Passerini compound, which has an acetate instead of the
acetamide moiety, was unaffected under the same methanolysis conditions.
Trimethyl orthoformate played an important role for dehydration as well as
trapping p-anisidine.
Acknowledgment
This work was financially supported by a Grant-in-Aid from the
Ministry of Education, Culture, Sports, Science and Technology,
Japan.
12. During the dehydration reaction with phophoryl chloride, concomitant
formation of methyl enol ethers was observed. After the mixture was
reduced with magnesium in methanol without purification, both enol ether
and dimethyl ketal were subjected to acidic hydrolysis to give ketone 12.
13. Snider, B. B.; Lin, H.; Foxman, B. H. J. Org. Chem. 1998, 63, 6442. Their reaction
conditions could not be applied in our study because we have found that the
cyclization reaction proceeded with significant racemization under the basic
conditions.
14. Spencer, T. A.; Schmiegel, K. K.; Williamson, K. L. J. Am. Chem. Soc. 1963, 85,
3785. This well-known classic condition was rediscovered in the Solensen’s
work3b although it exclusively gave the ‘undesired’ stereoisomer for their
synthetic studies.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.05.089.
References and notes
1. For isolation and structure elucidation, see: Sakamoto, K.; Tsujii, E.; Abe, F.;
Nakanishi, T.; Yamashita, M.; Shigematsu, N.; Izumi, S.; Okuhara, M. J. Antibiot.
1996, 49, 37.
2. For the synthetic studies, see: (a) Suzuki, H.; Yamazaki, N.; Kibayashi, C.
Tetrahedron Lett. 2001, 42, 3013; (b) Brummond, K. M.; Lu, J. L. Org. Lett. 2001, 3,
1347; (c) Wardrop, D. J.; Zhang, W. M. Org. Lett. 2001, 3, 2001; (d) Puigbo, G.;
Diaba, F.; Bonjoch, J. Tetrahedron 2003, 59, 2657; (e) Bonjoch, J.; Diaba, F.;
Puigbo, G.; Peidro, E.; Sole, D. Tetrahedron Lett. 2003, 44, 8387; (f) Kropf, J. E.;
Meigh, I. C.; Bebbington, M. W. P.; Weinreb, S. M. J. Org. Chem. 2006, 71, 2046;
15. Similar stereochemistry of the aldol product was observed with 4a. Both
hydroxy groups of 3a and 3b are equatorially oriented and syn to the carbonyl
groups.
16. In our racemic synthesis, conversion of 2 to 1 was accomplished in 11 steps
and 12% overall yield.3e