Total synthesis of (-)-FR901483

Article abstract of DOI:10.1021/ol301331t

A total synthesis of the immunosuppressive alkaloid (-)-FR901483 (1) has been described. The intriguingly azatricyclic structure of 1 was constructed by the semipinacol-type rearrangement and intramolecular Schmidt reaction of an azido cyclohexanone deriv

Full text of DOI:10.1021/ol301331t

ORGANIC
LETTERS
Total Synthesis of (ꢀ)-FR901483†
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Vol. XX, No. XX
000–000
Ai-Jun Ma, Yong-Qiang Tu,* Jin-Bao Peng, Qing-Yun Dou, Si-Hua Hou, Fu-Min Zhang,
and Shao-Hua Wang
State Key Laboratory of Applied Organic Chemistry and Department of Chemistry,
Lanzhou University, Lanzhou 730000, P. R. China
tuyq@lzu.edu.cn
Received May 14, 2012
ABSTRACT
A total synthesis of the immunosuppressive alkaloid (ꢀ)-FR901483 (1) has been described. The intriguingly azatricyclic structure of 1 was con-
structed by the semipinacol-type rearrangement and intramolecular Schmidt reaction of an azido cyclohexanone derivative. This strategy
provides a distinctive and competitive approach to the natural product 1.
FR901483 (1, Figure 1), a metabolite, was isolated from
the fermentation broth of the fungal stain Cladobotryum
sp. NO. 11231 by scientists at the Fujisawa Pharmaceutical
Co. in 1996.1 Its structure and relative configuration were
determined by X-ray crystallography, and the absolute
† Patent pending, Chinese Patent Application (No. 201210130574.1).
(1) Sakamoto, K.; Tsujii, E.; Abe, F.; Nakanishi, T.; Yamashita, M.;
Shigematsu, N.; Izumi, S.; Okuhara, M. J. Antibiot. 1996, 49, 37–44.
(2) For total syntheses of FR901483, see: (a) Snider, B. B.; Lin, H. J. Am.
Chem. Soc. 1999, 121, 7778–7786. (b) Scheffler, G.; Seike, H.; Sorensen, E. J.
Angew. Chem., Int. Ed. 2000, 39, 4593–4596. (c) Ousmer, M.; Braun, N. A.;
Ciufolini, M. A. Org. Lett. 2001, 3, 765–767. (d) Ousmer, M.; Braun, N. A.;
Bavoux, C.; Perrin, M.; Ciufolini, M. A. J. Am. Chem. Soc. 2001, 123, 7534–
7538. (e) Maeng, J.-H.; Funk, R. L. Org. Lett. 2001, 3, 1125–1128. (f) Kan,
T.; Fujimoto, T.; Ieda, S.; Asoh, Y.; Kitaoka, H.; Fukuyama, T. Org. Lett.
2004, 6, 2729–2731. (g) Brummond, K. M.; Hong, S.-P. J. Org. Chem. 2005,
survival time in the rat skin allograft model, which prob-
70, 907–916. (h) Ieda, S.; Asoh, Y.; Fujimoto, T.; Kitaoka, H.; Kan, T.;
Figure 1. Structure of (ꢀ)-FR901483 (1).
configuration was ascertained by total synthesis.2a It was
demonstrated that FR901483 exhibits potent immunosup-
pressive activity in vitro and significantly prolongs graft
ably resulted from the interference with de novo purine
nucleotide biosynthesis via inhibition of key enzymes
involved in the pathway.1 This alkaloid contains a unique
and highly strained 5-azatricyclo[6.3.1.01,5]dodecane ske-
leton, which was unprecedented in nature. Its potential
medicinal value and intriguingly azatricyclic structure are
very attractive to a number of synthetic chemists. Several
elegant total syntheses2 and numerous synthetic approaches3
toward 1 have been disclosed in the past few years. However,
developing an enantioselective total synthesis of 1 is still
necessary.
Fukuyama, T. Heterocycles 2009, 79, 721–738. (i) Carson, C. A.; Kerr,
M. A. Org. Lett. 2009, 11, 777–779.
(3) For approaches to FR901483, see: (a) Yamazaki, N.; Suzuki, H.;
Kibayashi, C. J. Org. Chem. 1997, 62, 8280–8281. (b) Snider, B. B.; Lin,
H.; Foxman, B. M. J. Org. Chem. 1998, 63, 6442–6443. (c) Bonjoch, J.;
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Diaba, F.; Puigbo, G.; Sole, D.; Segarra, V.; Santamarıa, L.; Beleta, J.;
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Ryder, H.; Palacios, J.-M. Bioorg. Med. Chem. 1999, 7, 2891–2897.
(d) Suzuki, H.; Yamazaki, N.; Kibayashi, C. Tetrahedron Lett. 2001, 42,
3013–3015. (e) Brummond, K. M.; Lu, J. Org. Lett. 2001, 3, 1347–1349.
(f) Wardrop, D. J.; Zhang, W. Org. Lett. 2001, 3, 2353–2356. (g) Puigbo,
G.; Diaba, F.; Bonjoch, J. Tetrahedron 2003, 59, 2657–2665. (h) Bonjoch, J.;
Diaba, F.; Puigbo, G.; Peidro, E.; Sole, D. Tetrahedron Lett. 2003, 44,
8387–8390. (i) Kropf, J. E.; Meigh, I. C.; Bebbington, M. W. P.; Weinreb,
S. M. J. Org. Chem. 2006, 71, 2046–2055. (j) Kaden, S.; Reissig, H.-U. Org.
Lett. 2006, 8, 4763–4766. (k) Gotchev, D. B.; Comins, D. L. J. Org. Chem.
2006, 71, 9393–9402. (l) Simila, S. T. M.; Reichelt, A.; Martin, S. F.
Tetrahedron Lett. 2006, 47, 2933–2936. (m) Diaba, F.; Ricou, E.; Sole,
D.; Teixido, E.; Valls, N.; Bonjoch, J. ARKIVOC 2007, 320–330. (n) Asari,
A.; Angelov, P.; Auty, J. M.; Hayes, C. J. Tetrahedron Lett. 2007, 48, 2631–
2634. (o) Simila, S. T. M.; Martin, S. F. J. Org. Chem. 2007, 72, 5342–5349.
(p) Seike, H.; Sorensen, E. J. Synlett 2008, 695–701. (q) Ieda, S.; Kan, T.;
Fukuyama, T. Tetrahedron Lett. 2010, 51, 4027–4029.
ꢀ
In light of Aube’s report of the improved intramolecular
Schmidt reaction,4 many important relevant reactions
have been designed and widely applied in the total synth-
eses of alkaloids.5 However, construction of the bridged
azapolycyclic system still remains an under-explored
r
10.1021/ol301331t
XXXX American Chemical Society

project by utilizing these reactions. As a result, only a
few examples were reported.4a,6 In connection with our
longstanding interest in the semipinacol rearrangement
reaction,7 the intramolecular Schmidt reaction8 and rela-
tive alkaloid syntheses,9 herein, we wish to present our
total synthesis of (ꢀ)-FR901483 (1) by these reactions of
an azido cyclohexanone derivative and subsequent ela-
boration of the resulting aza-tricyclic skeleton.
Our retrosynthetic analysis is outlined in Scheme 1.
FR901483 (1) could be easily obtained from the precursor
2 by means of transformation of functional groups. Com-
pound 2 might be accessed via introduction of an amino
group at C3 in 3. The aza-tricyclic structure of key inter-
mediate 3 was conceived via an intramolecular Schmidt
reaction of azido spirocyclobutanone 4, which will be
derived from carbonyl compound 5 through a semipina-
col-type rearrangement reaction. The azide 5 might be
synthesized by azido transfer reaction from amide 6, which
can be easily obtained from commercially available ketone
7 and Boc-protected chiral amino aldehyde 8.
With the above synthetic strategy in mind, we began
with construction of the key precursor 17 of the intra-
molecular Schmidt reaction (Scheme 2). The known diol
9 was prepared from 7 and 8 through an aldol reaction
and a reduction reaction according to the protocol of
Brummond.2g Under our modified conditions,10 benzyl pro-
tection of 9 afforded 71% yield of 10, whose configuration
was confirmed by X-ray crystallography analysis.11 After
removal of the Boc protecting group,2g treatment of the
amine with shelf-stable imidazole-1-sulfonyl azide hydro-
chloride (11)12 gave the azido compound 12 in 82% yield
over two steps. The ketal protecting group was removed from
12 using TsOH to produce the carbonyl compound 13 in
excellent yield. We synthesized 17 using a semipinacol-type
rearrangement reported by Trost,13 which utilized selenoxide
as a leaving group to promote the formation of stereoreversed
cyclobutanone (Scheme 2). Accordingly, ketone 13 was treat-
ed with cyclopropyldiphenyl-sulphonium tetrafluoroborate
(14) and KOH in DMSO at room temperature to produce 15.
Then the epoxy moiety of 15 was opened with phenylselenide
in ethanol to give the hydroxysenide 16. After oxidation of 16
with m-CPBA at ꢀ30 °C inn-hexane and CH2Cl2, rearrange-
ment in the presence of pyridine from ꢀ30 °C to room
temperature afforded the azido spirocyclobutanone 17 in
57% yield over three steps and its diastereoisomer 170 in 14%
yield. The structures of two compounds were confirmed by
X-ray analysis, respectively11 (see Figure 2). It should be
noted that no purification was needed for compound 15 and
16 during this procedure.
Scheme 1. Retrosynthetic Analysis of (ꢀ)-FR901483 (1)
Scheme 2. Preparation of Azido Ketone 17
ꢀ
(4) (a) Aube, J.; Milligan, G. L. J. Am. Chem. Soc. 1991, 113, 8965–
ꢀ
8966. (b) Milligan, G. L.; Mossman, C. J.; Aube, J. J. Am. Chem. Soc.
1995, 117, 10449–10459. For a recent review of the intramolecular
ꢀ
Schmidt reaction, see: (c) Grecian, S.; Aube, J. In Organic Azides:
€
Syntheses and Applications; Brase, S., Banert, K., Eds.; John Wiley and
Sons: Chichester, UK, 2009; pp 191ꢀ237.
ꢀ
(5) For selected references, see: (a) Iyengar, R.; Schildknegt, K.; Aube,
J. Org. Lett. 2000, 2, 1625–1627. (b) Wrobleski, A.; Sahasrabudhe, K.;
ꢀ
Aube, J. J. Am. Chem. Soc. 2002, 124, 9974–9975. (c) Smith, B. T.; Wendt,
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J. A.; Aube, J. Org. Lett. 2002, 4, 2577–2579. (d) Golden, J. E.; Aube, J.
Angew. Chem., Int. Ed. 2002, 41, 4316–4318. (e) Gracias, V.; Zeng, Y.;
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Desai, P.; Aube, J. Org. Lett. 2003, 5, 4999–5001. (f) Wrobleski, A.;
Sahasrabudhe, K.; Aube, J. J. Am. Chem. Soc. 2004, 126, 5475–5481. (g)
Zeng, Y.; Reddy, D. S.; Hirt, E.; Aube, J. Org. Lett. 2004, 6, 4993–4995. (h)
Iyengar, R.; Schildknegt, K.; Morton, M.; Aube, J. J. Org. Chem. 2005, 70,
10645–10652. (i) Zeng, Y.; Aube, J. J. Am. Chem. Soc. 2005, 127, 15712–
15713. (j) Frankowski, K. J.; Golden, J. E.; Zeng, Y.; Lei, Y.; Aube, J.
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ꢀ
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J. Am. Chem. Soc. 2008, 130, 6018–6024. (k) Ghosh, P.; Judd, W. R.;
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Ribelin, T.; Aube, J. Org. Lett. 2009, 11, 4140–4142. (l) Kapat, A.;
Nyfeler, E.; Giuffredi, G. T.; Renaud, P. J. Am. Chem. Soc. 2009, 131,
17746–17747.
ꢀ
(6) (a) Meyer, A. M.; Katz, C. E.; Li, S.-W.; Velde, D. V.; Aube, J.
Org. Lett. 2010, 12, 1244–1247. (b) Puppala, M.; Murali, A.; Baskaran,
S. Chem. Commun. 2012, 48, 5778–5780.
(7) (a) Coveney, D. J. In Comprehensive Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; pp 777ꢀ801. (b) Wang,
B.; Tu, Y. Q. Acc. Chem. Res. 2011, 44, 1207–1222. (c) Song, Z.-L.; Fan,
C.-A.; Tu, Y.-Q. Chem. Rev. 2011, 111, 7523–7556.
(8) (a) Gu, P.; Zhao, Y.-M.; Tu, Y. Q.; Ma, Y.; Zhang, F. Org. Lett.
2006, 8, 5271–5273. (b) Gu, P. M.; Zhao, Y.-M.; Tu, Y.-Q.; Wang, M.;
Zhang, S. Y. Chin. Chem. Lett. 2007, 18, 917–919. (c) Yang, M.; Zhao,
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B
Org. Lett., Vol. XX, No. XX, XXXX

slightly increased to 41% (Table 1, entry 8). Futher low-
ering the temperature had no effect on the yield, but longer
reaction time. Nonafluoro-1-butanesulfonic acid gave
similar results as TfOH (Table 1, entry 9). To our delight,
treatment of 17 with chlorosulfonic acid (ClSO3H) in
CH2Cl2 at 0 °C for only 5 min led to 18 in 40% yield
(Table 1, entry 10). After a series of experiments, we found
that treatment of 17 with ClSO3H in CH2Cl2 at ꢀ30 °C for
6 h gave the best result (Table 1, entry 11). To the best of
our knowledge, it was the first time that ClSO3H was used
as a promotor of the Schmidt reaction. Additionally, the
use of more acidic fluorosulfonic acid (FSO3H) resulted
in lower yield (Table 1, entries 13, 14 and 15). ClSO3H,
therefore, was selected as the promoter of the intramole-
cular Schmidt reaction for 17 leading to 18. However,
diastereoisomer 170 had no corresponding product under
the optimized conditions and most of 170 was consumed.
As illustrated in Scheme 3, the X-ray crystal structures
of compound 17 and 170 unambiguously reveal that the
carbonyl group is distant from the azido group in both
stable conformations in which the side substituents are at
an equatorial position (Figure 2). For compound 17, a
conformational inversion facilitates the intramolecular
Schmidt reaction successfully since azido group is close
to carbonyl group (see conformation II). However, con-
formational inversion is ineffective to 170, because both
of two conformations have unsuitable distance between
the two reactive groups for the expected intramolecular
Schmidt reaction under the optimized conditions (Scheme 3).
This information explains well with our experimental results.
Furthermore, coordination of the Lewis acids to the two
ether oxygen atoms of 17 more or less prevents the con-
formational inversion, which probably explains the failed
results during the optimization of the reaction conditions
(Table 1, entries 2ꢀ4 and 6).
Table 1. Intramolecular Schmidt Reaction of Azido Ketone 17
entry
conditions
TFA (neat), 60 °C
yield (%)
1
2
0a
0a
0a
0a
0a
0b
36
41
40
40
67
60
0b
35
25
MeAlCl2 (2 or 10 equiv), CH2Cl2, ꢀ78 °Cfrt
3
BF3 Et2O (2 equiv), CH2Cl2, ꢀ78 °Cfrt
3
4
SnCl4 (2 equiv), CH2Cl2, ꢀ78 °Cfrt
5
HBF4 Et2O (2 equiv), Et2O, ꢀ78 °Cfrt
3
614
7
TiCl4 (2 equiv), CH2Cl2, ꢀ78 °Cfrt
TfOH (2 equiv), CH2Cl2, 0 °C, 2 h
8
TfOH (2 equiv), CH2Cl2, ꢀ10 °C, 24 h
NfOH (2 equiv), CH2Cl2, 0 °C, 24 h
ClSO3H (2 equiv), CH2Cl2, 0 °C, 5 min
ClSO3H (2 equiv), CH2Cl2, ꢀ30 °C, 6 h
ClSO3H (2 equiv), CH2Cl2, ꢀ40 °C, 24 h
FSO3H (2 equiv), CH2Cl2, 0 °C
9
10
11
12
13
14
15
FSO3H (2 equiv), CH2Cl2, ꢀ30 °C, 2 h
FSO3H (2 equiv), CH2Cl2, ꢀ40 °C, 24 h
a All of the azido ketone 17 was recovered. b 17 disappeared, but no
desired product was present.
With the key precursor 17 in hand, our effort was
focused on the construction of challenging complex lactam
18 by the intramolecular Schmidt reaction. As shown in
Table 1, treatment of 17 with neat trifluoroacetic acid
(TFA) at 60 °C did not afford the desired product 18
(Table 1, entry 1). Lewis acids used frequently in Schmidt
reaction also gave the same results (Table 1, entries 2ꢀ5).
In particular, using TiCl4 as the promotor, 18 was not ob-
tained but 17 disappeared (Table 1, entry 6).14 Encouragingly,
when applying trifluoromethanesulfonic acid (TfOH) in
CH2Cl2 at 0 °C (Table 1, entry 7), we obtained the desired
product 18 albeit a low yield of 36%. When the reaction
was carried out at ꢀ10 °C for about one day, the yield
With the main skeleton of FR901483 (1) constructed,
subsequent introduction of the amino group and transfor-
mation of functional groups would complete the total
synthesis of 1 (Scheme 4). Compound 18 was treated with
LDA in THF at ꢀ78 °C, followed by DPPA (22) and
Boc2O at the same temperature gave 19 and its epimer in
85% yield (dr = 2:1).15 Despite its modest dr value, this
methodology provides a good method for the synthesis of
R-amino lactam. Removal of the benzyl protecting group
of 2-Boc-aminolactam 19 was completed with catalytic
hydrogenolysis over Pd(OH)2/C to give 20 in 95% yield.
Both of Boc and the lactam group were reduced in one step
through LiAlH4 in refluxing THF, and then the resulting
secondary amine was protected with a Cbz group to afford
diol 21.2c Compound 21 was converted to 1 under mild
conditions in two steps.2e Selective phosphitylation of
the C-9 hydroxy gave the corresponding phosphite ester
intermediate, which was then oxidized with m-CPBA in
the presence of Et3N to give the dibenzyl phosphate 22.
(9) (a) Fan, C.-A.; Tu, Y.-Q.; Song, Z.-L.; Zhang, E.; Shi, L.; Wang,
M.; Wang, B; Zhang, S.-Y. Org. Lett. 2004, 6, 4691–4694. (b) Hu, X.-D.;
Tu, Y. Q.; Zhang, E.; Gao, S.; Wang, S.; Wang, A.; Fan, C.-A.; Wang,
M. Org. Lett. 2006, 8, 1823–1825. (c) Zhao, Y.-M.; Gu, P.; Tu, Y.-Q.;
Fan, C.-A.; Zhang, Q. Org. Lett. 2008, 10, 1763–1766. (d) Zhao, Y.-M.;
Gu, P.; Zhang, H.-J.; Zhang, Q.-W.; Fan, C.-A.; Tu, Y.-Q.; Zhang,
F.-M. J. Org. Chem. 2009, 74, 3211–3213. (e) Chen, Z.-H.; Zhang, Y.-Q.;
Chen, Z.-M.; Tu, Y.-Q.; Zhang, F.-M. Chem. Commun. 2011, 47, 1836–
1838. (f) Chen, Z.-H.; Chen, Z.-M.; Zhang, Y.-Q.; Tu, Y.-Q.; Zhang,
F.-M. J. Org. Chem. 2011, 76, 10173–10186.
(10) For a modified preparation of the literature procedure, see the
Supporting Information.
(11) CCDC 877989 (10), CCDC 877990 (17), and CCDC 877991 (170)
contain the supplementary crystallographic data for this paper. These
data can be obtained free of charge from the Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
(12) Goddard-Borger, E. D.; Stick, R. V. Org. Lett. 2007, 9, 3797–
3800.
(13) Trost, B. M.; Scudder, P. H. J. Am. Chem. Soc. 1977, 99, 7601–
7610.
(14) When we were preparing this paper, it was reported that the
TiCl4 could promote the semipinacolꢀSchmidt reaction of the simple
substance in reference 6b. However, our previous experiment indicated
that this condition did not work for 17, which contains the necessary
functional groups for synthesis of FR901483.
(15) The relative stereochemistry of product 19 was confirmed by
later synthesis. For the reaction with DPPA for synthesis of R-amino
lactam, see: (a) Villalgordo, J. M.; Linden, A.; Heimgartner, H. Helv.
Chim. Acta 1996, 79, 213–219. (b) Bentz, E. L.; Goswami, R.; Moloney,
M. G.; Westway, S. M. Org. Biomol. Chem. 2005, 3, 2872–2882.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 4. Completion of the Total Synthesis of (ꢀ)-FR901483
Figure 2. X-ray crystal structure of 17 and 170.
Scheme 3. Probable Process of the Intramolecular Schmidt
Reaction
and intramolecular Schmidt reaction of an azido cyclohex-
anone derivative as the key steps.
Acknowledgment. We gratefully acknowledge finan-
cial support from the NSFC (Grant Nos. 21072085,
20921120404, 21102061, and 20972059), the National
Basic Research Program of China (“973” Program,
Grant No. 2010CB833203), “111” Program of MOE,
Key National S&T Program “Major New Drug Develop-
ment” of the Ministry of Science and Technology of China
(2012ZX09201101-003), and the fundamental research funds
for the central universities (Grant No. Lzujbky-2012-086).
Simultaneous hydrogenolysis of the dibenzyl phos-
phate ester and benzyl carbamate of 22 over Pd/C
proceeded smoothly to afford FR901483 (1), of which
the spectral data were identified with those of the natural
product.1,2f
In conclusion, we have completed a total synthesis of
the potent immunosuppressant (ꢀ)-FR901483 in 3.5%
overall yield and 16 steps from commercially available
ketone 7 by utilizing the semipinacol-type rearrangement
Supporting Information Available. Experimental pro-
cedures and compound characterization data for all new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
The authors declare the following competing financial interest(s):
A related patent is pending for the Chinese Patent Application
(No. 201210130574.1).
D
Org. Lett., Vol. XX, No. XX, XXXX