A formal enantioselective total synthesis of FR901483

Article abstract of DOI:10.1021/ol302165d

A formal enantioselective total synthesis of the potent immunosuppressant FR901483 (1) has been accomplished. Our approach features the use of chiron 6 as the starting material, the application of the one-pot amide reductive bisalkylation method to construct the chiral aza-quaternary center (dr = 9:1), regio- and diastereoselective intramolecular aldol reaction to build the bridged ring, and ring closing metathesis to form the 3-pyrrolin-2-one ring.

Full text of DOI:10.1021/ol302165d

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
A Formal Enantioselective Total Synthesis
of FR901483
Hao-Hua Huo,† Hong-Kui Zhang,† Xiao-Er Xia,† and Pei-Qiang Huang*,†,‡
Department of Chemistry, College of Chemistry and Chemical Engineering,
Xiamen University, Xiamen, Fujian 361005, P. R. China, and State Key Laboratory of
Bioorganic and Natural Products Chemistry, 354 Fenglin Lu, Shanghai 200032, P. R. China
pqhuang@xmu.edu.cn
Received August 3, 2012
ABSTRACT
A formal enantioselective total synthesis of the potent immunosuppressant FR901483 (1) has been accomplished. Our approach features the use
of chiron 6 as the starting material, the application of the one-pot amide reductive bisalkylation method to construct the chiral aza-quaternary
center (dr = 9:1), regio- and diastereoselective intramolecular aldol reaction to build the bridged ring, and ring closing metathesis to form the
3-pyrrolin-2-one ring.
FR901483 (1, Figure 1) is a potent immunosuppressant
isolated from the fermentation broth of the Cladobotryum
sp. No. 11231 by a research group at the Japan Fujisawa
Pharmaceutical Company in 1996.1 Due to its promising
biological activity and challenging structure, this mole-
cule has attracted the attention of many research groups.
To date, six enantioselective total syntheses/formal total
syntheses2,3 and numerous synthetic studies4,5 toward
FR901483 (1) have been reported. As a continuation
† Xiamen University.
‡ State Key Laboratory of Bioorganic and Natural Products Chemistry.
(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 enantioselective total syntheses, 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) Ma, A.-J.; Tu, Y.-Q.; Peng,
J.-B.; Dou, Q.-Y.; Hou, S.-H.; Zhang, F.-M.; Wang, S.-H. Org. Lett.
2012, 14, 3604–3607. For formal total syntheses, see: (f) Brummond,
K. M.; Hong, S. P. J. Org. Chem. 2005, 70, 907–916. (g) Carson, C. A.;
Kerr, M. A. Org. Lett. 2009, 11, 777–779.
(5) For racemic synthetic studies, see: (a) Yamazaki, N.; Suzuki, H.;
Kibayashi, C. J. Org. Chem. 1997, 62, 8280–8281. (b) Quirante, J.;
Escolano, C.; Massot, M.; Bonjoch, J. Tetrahedron 1997, 53, 1391–1402.
(c) Bonjoch, J.; Diaba, F.; Puigbo, G.; Sole, D.; Segarra, V.; Santamaria,
L.; Beleta, J.; Ryder, H.; Palacios, J.-M. Bioorg. Med. Chem. 1999, 7,
2891–2897. (d) Wardrop, D. J.; Zhang, W. Org. Lett. 2001, 3, 2353–2356.
(e) Brummond, K. M.; Lu, J.-L. Org. Lett. 2001, 3, 1347–1349. (f)
Suzuki, H.; Yamazaki, N.; Kibayashi, C. Tetrahedron Lett. 2001, 42,
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Bebbington, M. W. P.; Weinreb, S. M. J. Org. Chem. 2006, 71, 2046–
2055. (i) Simila, S. T. M.; Martin, S. F. J. Org. Chem. 2007, 72, 5342–
5349.
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Lett. 2001, 3, 1125–1128. (b) Kan, T.; Fujimoto, T.; Ieda, S.; Asoh, Y.;
Kitaoka, H.; Fukuyama, T. Org. Lett. 2004, 6, 2729–2731. (c) Ieda, S.;
Asoh, Y.; Fujimoto, T.; Kitaoka, H.; Kan, T.; Fukuyama, T. Hetero-
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(6) (a) Xu, C.-P.; Xiao, Z.-H.; Zhuo, B.-Q.; Wang, Y.-H.; Huang,
P.-Q. Chem. Commun. 2010, 46, 7834–7836. (b) Xiao, K.-J.; Luo, J.-M.;
Ye, K.-Y.; Wang, Y.; Huang, P.-Q. Angew. Chem., Int. Ed. 2010, 49,
3037–3040. (c) Xiao, K.-J.; Wang, Y.; Ye, K.-Y.; Huang, P.-Q. Chem.;
Eur. J. 2010, 16, 12792–12796. (d) Liu, X.-K.; Zheng, X.; Ruan, Y.-P.;
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10.1021/ol302165d
XXXX American Chemical Society

of our endeavor to develop step-economical6 and
3-benzyloxyglutarimide7-based synthetic methodologies
for the asymmetric synthesis of piperidine ring-containing
alkaloids,8 we have embarked on the enantioselective
total synthesis of FR901483. We report herein a formal
enantioselective total synthesis of FR901483 (1).
determined by 1H NMR of the crude sample). The stereo-
chemistry of the major diastereomer was deduced to be
trans on the basis of the mechanistic consideration that the
vinyl group approaches the iminium ion intermediate from
the R-side opposing the benzyloxy group, which was
confirmed at a latter stage. It is worth mentioning that,
among various synthetic approaches for the synthesis of
FR901483 (1), this is the first example utilizing the one-pot
amide reductive bisalkylation method to construct the
chiral aza-quaternary center.
The selective O-debenzylation of compound 4 was
achieved by treatment of piperidine 4 (diastereomeric
mixture) with lithium naphthalenide (LN)9 in THF
at À40 °C for 1 h, which gave, after chromatographic
separation, the piperidin-3-ol 7 as a pure diastereomer in
85% yield.
Figure 1. Potent immunosuppressant FR901483 (1).
Scheme 2. Stereoselective Synthesis of the Key Intermediate 7
As illustrated retrosynthetically in Scheme 1>, our
synthetic plan is based on two key synthetic methodologies
developed from our laboratory, namely, the use of chiron
68 as the starting point and the amide reductive bisalkyla-
tion method6b for a one-pot conversion of piperidin-2-one
5 to piperidine 4 with the formation of two CÀC bonds.
Scheme 1. Retrosynthetic Analysis of FR901483 (1)
Next, the piperidin-3-ol 7 needed to be oxidized to the
ketone 8 before the key intramolecular aldol ring closure
reaction could be commenced. After unsuccessful trials
with the Dess-Martin periodinane, and partial success with
the Ley oxidation (35% yield), the Swern oxidation was
attempted. It was found that by the use of an extreme
excess of triethylamine, the desired ketone could be ob-
tained in 90% yield [(COCl)2 6 equiv, DMSO 12 equiv,
CH2Cl2, À78 °C, 1 h; and then NEt3 25 equiv]. After
deacetalization of compound 8 with a 4 N HCl solution,
the resulting keto-aldehyde, in the form of its hydrochlo-
ride salt, was heated with ethylene glycol (4.0 equiv)10 and
CSA (0.3 equiv) in toluene at 90 °C. The desired regiose-
lective intramolecular aldol reaction took place smoothly
with concomitant acetalization of the ketone to give
compound 9 as the solely observable regio- and diaste-
reomer in 53% yield (Scheme 3). The relative stereochem-
istry of 9 was established on the basis of the observed
The synthesis commenced with the partial and regio-
selective reduction8b of (3R)-benzyloxyglutarimide 6 with
NaBH4 followed by reductive dehydroxylation (BF3•OEt2,
Et3SiH, CH2Cl2) via an iminium ion intermediate8a,c
(Scheme 2). The subsequent bisalkylation of lactam6b
5 (Tf2O, DTBMP, CH2Cl2; then successive addition of
two Grignard reagents) proceeded as planned to produce
the desired lactam 4 in 75% yield. Remarkably, the reac-
tion proceeded with high diastereoselectivity (dr = 9:1,
(7) Ruan, Y.-P.; Wei, B.-G.; Xu, X.-Q.; Liu, G.; Yu, D.-S.; Liu,
L.-X.; Huang, P.-Q. Chirality 2005, 17, 595–599.
(9) Liu, H.-J.; Yip, J.; Shia, K.-S. Tetrahedron Lett. 1997, 38, 2253–
2256.
(10) If the hydrochloride salt was neutralized and the mixture was
heated in the absence of ethylene glycol, a regiomeric aldol product was
obtained in 65% yield as a single diastereomer.
(8) For recent examples, see: (a) Fu, R.; Ye, J.-L.; Dai, X.-J.; Ruan,
Y. -P.; Huang, P.-Q. J. Org. Chem. 2010, 75, 4230–4243. (b) Yang, R.-F.;
Huang, P.-Q. Chem.;Eur. J. 2010, 16, 10319–10322. (c) Tuo, S.-C.; Ye,
J.-L.; Wang, A.-E; Huang, S.-Y.; Huang, P.-Q. Org. Lett. 2011, 13,
5270–5273.
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strong correlation betweenthe methine proton (δ 3.83) and
the Heq (δ 2.12), and a smaller correlation between the
methine proton (δ 3.83) and the Hax (δ 1.78) in its NOESY
spectrum (Scheme 3).
We next investigated the RCM reaction of 12. Forma-
tion of R,β-unsaturated lactams by the RCM reaction of
acrylamides has been well documented using either
Grubbs’ first or second generation catalyst.12 The reaction
generally proceededin CH2Cl2.5f,12 However inour case all
attempts to perform the RCM reaction of 12 by the use of
the Grubbs first or second generation catalyst in CH2Cl2
were unsuccessful. Considering the steric hindrance of the
substrate, it was envisioned that a higher reaction tem-
perature would favor the reaction. Indeed, when a toluene
solution of acrylamide 12 and the Grubbs second genera-
tion catalyst (25%) was heated to 85 °C for 12 h, the
desired cyclized product 13 was obtained in 30% yield,
along with 60% of the recovered starting material. Re-
markably, when the reaction (Grubbs II 25%, toluene,
85 °C) was run in the presence of 30% molar equiv of
Ti(OiPr)4,13 the desired cyclic core 13 was obtained in
92% yield (Scheme 5).
Scheme 3. Synthesis and the Observed NOE Correlations of
Compound 9
Scheme 5. Construction of the Tricyclic Core 13 by the RCM
Reaction
After securing access to the bicyclic core 9, the con-
version of the latter to a precursor for the ring closing
metathesis (RCM) reaction was investigated. Thus, the
hydroxyl group was protected as its benzyl ether 10 (BnBr,
NaH, Bu4NI, DMF, 90% yield) (Scheme 4). Compound
10 was subjected to Pd-catalyzed N-deallylation [Pd(Ph3P)4
(0.01equiv), NDMBA(3equiv), CH2Cl2, rt, 1h],11 and acryl-
oylation (acryloyl chloride, NEt3, CH2Cl2, 0 °C, 30 min),
which gave acrylamide 12 in 81% yield over two steps.
Now we were in a position to undertake the functional
group exchange and the functionalization of the core
structure. Thus, acetal 13 was cleaved by treatment with
a solution of 4 N HCl in acetone at reflux for 3 h to give the
keto-lactam 3 in 85% yield (Scheme 6). Inversedaddition3a
of the enolate, generated from ketone 3 by deprotonation
with KHMDS (1 equiv) in THF at À50 °C, with
p-methoxybenzyl bromide (3.0 equiv) in DMF at 0 °C
for 20 min produced compound 14 as the only observable
regio- and diastereomer in 75% yield. Pd/C-catalyzed
selective hydrogenation of 14 (Pd/C 30 wt %, H2, 1 atm,
EtOAc) produced lactam 15 in 90% yield. Subjection of
ketone-lactam 15 to the SmI2-mediated reduction3b,14
(SmI2 5 equiv, HMPA 25 equiv, MeOH 10 equiv, THF,
À78 °C, 12 h) yielded the desired cis-diastereomer 16 as the
only observable diastereomer in 85% yield. The spectral
data of our synthetic 16 matched those reported for the
racemic 16,5d which confirmed the relative stereochemistry
of our synthetic product.
Scheme 4. Synthesis of the Acrylamide Derivative 12
We next turned our attention to the stereoselective
R-amination of lactam 16. Thus, the hydroxyl group in 16
was first protected (TBSOTf, NEt3, CH2Cl2, 93%) as TBS
ꢀ
(11) (a) Garro-Helion, F.; Merzouk, A.; Guibe, F. J. Org. Chem.
1993, 58, 6109–6113. (b) Davies, S. G.; Fenwick, D. R. Chem. Commun.
1997, 565–566.
(13) Ghosh, A. K.; Cappiello, J.; Shin, D. Tetrahedron Lett. 1998, 39,
4651–4654.
(12) For reviews on the applications of the RCM reaction in the
synthesis of lactams, see: (a) Hassan, H. M. A. Chem. Commun. 2010, 46,
9100–9106. (b) Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104, 2199–
2238. (c) Felpin, F. X.; Lebreton, J. Eur. J. Org. Chem. 2003, 3693–3712.
For a recent example, see: (d) Zhang, H.-K.; Li, X.; Huang, H.; Huang,
P.-Q. Sci. Sinica Chim. 2011, 41, 732–740. Sci. China Chem. 2011, 54,
737–744 (in Chinese).
(14) For recent reviews on SmI2, see: (a) Procter, D. J., Flowers, R. A.,
Skrydstrup, T., Eds. Organic Synthesis Using Samarium Diiodide: A
Practical Guide; Royal Society of Chemistry Publishing: 2010. (b) Nicolaou,
K. C.; Ellery, S. P.; Chen, J. S. Angew. Chem., Int. Ed. 2009, 48, 7140–7165.
(c) Gopalaiah, K.; Kagan, H. B. New J. Chem. 2008, 32, 607–637.
Org. Lett., Vol. XX, No. XX, XXXX
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the concomitantly protected compound 18 in 90% yield
(Scheme 8). Treatment of compound 18 with a large excess
of LiAlH4 (30 equiv) in THF at 60 °C for 16 h afforded the
amino-diol 19 in 92% yield. It is worth noting that, in this
senario, N-Boc reduction to give N-Me group, lactam
reduction to give pyrrolidine, and O-desilylation occurred
sequentially. The 1H and 13C NMR spectral data of
compound 19 are in agreement with those reported by
Ciufolini.2d Since compound 19 has been converted into
FR901483 (1) in three steps,2d our synthetic approach thus
constitutes a formal total synthesis of (À)-FR901483 (1).
Scheme 6. Diastereoselective Synthesis of Compound 16
Scheme 8. Synthesis of the Known Precursor (19) of FR901483
Scheme 7. Synthesis of Compound 17
In summary, starting from the known chiron 6, we have
achieved the synthesis of the advanced intermediate 19 in
18 steps with an overall yield of 4.1%, which constitutes a
formal enantioselective total synthesis of FR901483 (1).
Acknowledgment. The authors are grateful to the NSF
of China (20832005, 21072160), the National Basic Re-
search Program (973 Program) of China (Grant No.
2010CB833200), and the Fundamental Research Funds
for the Central Universities of China (Grant No.
201112G001) for financial support. We are grateful to
Prof. Dr. L.-F. Xie (Xiamen University) for valuable
discussions.
ether 2 (Scheme 7). Successive treatment of lactam 2 with
LDA (3.0 equiv) and TrisN3 (3 equiv) at À78 °C for 5 min,
followed by addition of HOAc, led to the formation of the
desired azide 17 as a separable diastereomeric mixture in a
3:1 ratio with a combined yield of 90%. The stereochem-
istry of the major diastereomer 17, which was assumed to
be formed by approaching the electrophile from the less
hindered β-face, was determined by NOESY experiments.
To convert the azido group to the N-methylamino
group, azide 17 was hydrogenated (10%Pd/C 30 wt %,
H2 1 atm) in the presence of Boc2O (1.2 equiv), which gave
Supporting Information Available. Full experimental
1
procedures; H and 13C NMR spectra of all new com-
pounds; NOESY spectra of compounds 9 and 17. This
material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
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