Synthetic studies toward the immunosuppressant FR901483. Facile construction of the azatricyclic skeleton

Article abstract of DOI:10.1016/j.tetlet.2006.02.116

A concise synthesis of the azatricyclic core structure of FR901483, a potent immunosuppressant, has been accomplished. The key elements of the approach involve a nucleophilic addition to an acyl iminium ion, a ring closing metathesis and a lactone-lactam

Full text of DOI:10.1016/j.tetlet.2006.02.116

Tetrahedron Letters 47 (2006) 2933–2936
Synthetic studies toward the immunosuppressant FR901483.
Facile construction of the azatricyclic skeleton
Suvi T. M. Simila, Andreas Reichelt and Stephen F. Martin*
Department of Chemistry and Biochemistry, The University of Texas, Austin, TX 78712, USA
Received 21 December 2005; revised 15 February 2006; accepted 17 February 2006
Available online 10 March 2006
Abstract—A concise synthesis of the azatricyclic core structure of FR901483, a potent immunosuppressant, has been accomplished.
The key elements of the approach involve a nucleophilic addition to an acyl iminium ion, a ring closing metathesis and a lactone–
lactam rearrangement to provide the tricyclic structure.
Ó 2006 Elsevier Ltd. All rights reserved.
A potent immunosuppressant, FR901483 (1), was
isolated in 1996 from the fermentation broth of the
fungal strain Cladobotryum sp. No. 11231 by Fujisawa
Pharmaceutical Company in Japan.1 The structure of
our strategy for the synthesis of 1, which differs from all
of the previously described approaches, and the success-
ful application of the underlying chemistry to the facile
construction of the tricyclic core.
1
1 was initially determined by H NMR and 13C NMR
spectroscopy, and the absolute configuration was
elucidated by Snider and Lin,2 who reported the first
total synthesis of 1. From a medicinal perspective,
FR901483 is of interest because it prolongs graft sur-
vival time in the rat skin allograft model by inhibiting
purine nucleotide synthesis, a mechanism of action that
differs from that of common immunosuppressants like
cyclosporin A and tacrolimus (FK-506).1 Five other
total syntheses of 1 have since been reported,3 most of
which were inspired by the postulated biosynthesis and
feature an intramolecular aldol reaction to provide the
azatricyclic core. We were attracted to the synthesis of
FR901483 (1) as a means of developing new chemistry
that may be of more general utility. Herein we describe
Our approach, which is outlined in Scheme 1, requires
the stereoselective elaboration of the advanced inter-
mediate 2 via a-hydroxylation of an amide enolate,
introduction of the p-methoxybenzyl group, and refunc-
tionalization of the protected hydroxyl group at C(3) to
give the requisite methylamino moiety. We envisioned
OMe
9
R1O
H2O3PO
O
7
N
N
HO
3
MeHN
R2O
1
2
MeO2C
7
O
R2O
R2O
OMe
H2O3PO
3
O
9
N
R3
N
R3
N
HO
MeHN
3
4
MeO2C
R2O
1
R2O
BrMg
3
3
7
+
O
N
R3
N
TMS
CO2Me
R3
Keywords: Additions to N-acyl iminium ions; Ring closing metathesis;
Lactone–lactam rearrangement.
5
6
8
*
Corresponding author. Tel.: +1 512 471 3915; fax: +1 512 471
4180; e-mail: sfmartin@mail.utexas.edu
Scheme 1.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.02.116

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S. T. M. Simila et al. / Tetrahedron Letters 47 (2006) 2933–2936
that the azatricycle 2 would be obtained via a base pro-
moted lactone–lactam rearrangement of 3, which would
in turn be accessible from the b,c-unsaturated ester 4 via
a selective hydroboration–oxidation from the less hin-
dered face4 and a subsequent lactonization. The key step
in preparing the spirocycle 4 is a ring closing metathesis
(RCM) of the diene 5,5 which would be derived from the
geminal dialkylation of the carbonyl group in 6 with 7
and 8. The hydroxyl group in 6 would be expected to
direct the addition of the silane 8 to the intermediate
acyl iminium ion from the same face as the protected
hydroxyl group in analogy with the findings of Woerpel
and co-workers.6
At this stage, we were faced with the challenge of induc-
ing the stereoselective hydroboration of the azaspirane
13, a reaction for which there was no precedent in aza-
spirocyclic systems. There are scattered reports, however
that hydroboration of conformationally constrained
cyclohexenes do lead to equatorial alcohols as the major
products.14 We thus anticipated that the borane reagent
would approach the more stable conformer of 13 via a
transition state in which the boron atom would be deliv-
ered preferentially from an equatorial-like orientation as
shown in Figure 1 to establish the requisite stereochem-
istry at C(8) and C(9).
MeO2C
H–BR2
8
In order to establish the feasibility of our strategy for
fabricating the tricyclic skeleton of 1, we embarked on
a model study on a pyrrolidone substrate lacking the
hydroxyl function at C(3). In the event, addition of
the Grignard reagent 7 to the Boc-protected lactam 9
provided the linear ketone 10 in 98% yield (Scheme
2).7 Removal of the Boc protecting group using trifluoro-
acetic acid and cyclization of the intermediate amino
ketone gave the imine 118 in quantitative yield. The
imine 11 was then treated with CbzCl and the known
allylsilane 89 in the presence of trimethylsilyl triflate
(TMSOTf) to deliver the diene 12 in 42% yield.10 Silver
and scandium triflates could also be used instead of
TMSOTf to generate the intermediate N-acyl iminium
ion and to provide 12 in similar yields. However, the
addition did not proceed in the absence of a Lewis acid
promoter.11 The cyclization of 12 via RCM, a process
we have exploited as a key step in the syntheses of a
number of alkaloids and other natural products,12 was
performed using the Grubbs II catalyst,13 to give the
azaspirane 13 in 94% yield.
N
Cbz
9
13
Figure 1.
We had originally envisioned that it would be possible
to hydroborate the olefin without reducing the ester,
but all attempts to do so were unsuccessful. Various
reagents including BH3ÆTHF, BH3ÆDMS, 9-BBN, thexyl-
borane, and dicyclohexylborane were examined. Even
the salt of the corresponding carboxylic acid, which
should be unreactive, underwent reduction under condi-
tions for hydroboration using BH3ÆTHF. Ultimately, we
discovered that optimal conditions for the hydrobora-
tion and reduction of 13 involved initial reaction with
BH3ÆTHF (3 equiv) and subsequent oxidation with
NaBO3Æ4H2O15 to furnish a diastereomeric mixture
(6:1) of 14 and 15 in 99% combined yield. Oxidation
of the intermediate borane using the more conventional
method of H2O2/NaOH was lower yielding. Although
14 and 15 were easily separable by column chromato-
graphy, it was not possible to unequivocally determine
the relative stereochemistry of the major diastereomer
at this stage.
O
TFA, CH2Cl2
C→rt
7, THF, -78
C
˚
O
98%
N
0
˚
>99%
Boc
NHBoc
9
10
That the hydroboration of 13 was accompanied by
unavoidable reduction of the ester functionality was
only an inconvenience as we were able to selectively
oxidize 14 to the c-lactone 16 in 87% yield using
PhI(OAc)2 and catalytic TEMPO (Scheme 3).16,17 The
Cbz-group was removed by catalytic hydrogenation
giving amine 17 in virtually quantitative yield. The sub-
sequent NaOMe-promoted lactone–lactam rearrange-
ment in MeOH required heating in a microwave
reactor to deliver the azatricycle 18 in 90% yield;18 rear-
rangement using conventional heating was incomplete,
even after two days of heating under reflux. Formation
of a lactam from 17 verified our tentative assignment of
the relative stereochemistry of the major diol diastereo-
mer 14 in which the nitrogen atom and the two-carbon
side chain are cis. The alcohol moiety of 18 was then
acetylated to provide 19,19 which was more amenable
to full structural characterization by NMR. An
NOE interaction was observed between protons
C(3)–H and C(7)–Hax in 19 that was not observed in
the lactone 16.
CO2Me
CbzCl, 8, TMSOTf
Grubbs II
CH2Cl2, –78 C→rt
N
N
CH2Cl2, rt
94%
˚
Cbz
12
42%
11
MeO2C
BH3·THF, THF, 0 C
˚
OH
OH
OH
then
+
OH
NaBO3·4H2O, rt
99% (6:1)
N
N
N
Cbz
Cbz
Cbz
15
13
14
MesN
Cl
NMes
Ph
Ru
Cy3P
Grubbs II
Cl
Scheme 2.

S. T. M. Simila et al. / Tetrahedron Letters 47 (2006) 2933–2936
2935
O
Ciufolini, M. A.; Peters, K.; Peters, E.-M. Tetrahedron
Lett. 1998, 39, 4667–4670; (k) Wardrop, D. J.; Zhang, W.
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OH
PhI(OAc)2, TEMPO
O
CH2Cl2, rt
87%
N
N
Cbz
Cbz
´
´
´
F.; Puigbo, G.; Peidro, E.; Sole, D. Tetrahedron Lett.
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14
16
O
O
Pd/C, H2
NaOMe, MeOH
4. Houk, K. N.; Rondan, N. G.; Wu, Y.-D.; Metz, J. T.;
Paddon-Row, M. N. Tetrahedron 1984, 40, 2257–2274.
5. For a review, see: Deiters, A.; Martin, S. F. Chem. Rev.
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70 C, MW (200W)
MeOH, rt
>99%
˚
N
H
45 min (3 cycles)
17
90%
9
AcO
HO
O
7
O
Ac2O, DMAP
N
N
Et3N, CH2Cl2, rt
90%
3
19
18
7. (a) Giovannini, A.; Savoia, D.; Umani-Ronchi, A. J. Org.
Chem. 1989, 54, 228–234; (b) Rudolph, A.; Machauer, R.;
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2003, 59, 3099–3108.
9. The methyl ester was prepared by methylating (K2CO3,
MeI, DMF 82% yield) the corresponding acid that was
prepared according to a literature procedure: Armstrong,
R. J.; Weiler, L. Can. J. Chem. 1983, 61, 2530–2539.
10. The structure assigned to each compound was in accord
with its spectral (1H and 13C NMR, IR, MS) characteris-
tics. All yields are based on isolated, purified materials.
11. Yamaguchi, R.; Hatano, B.; Nakayasu, T.; Kozima, S.
Tetrahedron Lett. 1997, 38, 403–406.
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Scheme 3.
In summary, we have developed a novel strategy to con-
struct the azatricyclic skeleton of the potent immuno-
suppressant FR901483 (1). The approach features an
addition of a functionalized allylsilane to an acyl imin-
ium ion to provide an intermediate that undergoes a
RCM to generate a spirocycle. Stereoselective hydro-
boration of the resultant olefin and a lactone–lactam
rearrangement then delivers the tricyclic core of 1.
Application of this strategy to an enantioselective syn-
thesis of 1 is in progress, and the results will be reported
in due course.
Acknowledgments
We thank the National Institutes of Health (GM 25439),
Pfizer, Inc., Merck Research Laboratories, and the Rob-
ert A. Welch Foundation for their generous support of
this research. We are also grateful to Dr. Richard Fisher
(Materia, Inc.) for catalyst support and to Dr. Scott Bur
for helpful discussions.
13. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett.
1999, 1, 953–956.
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4593–4596; (b) Ousmer, M.; Braun, N. A.; Bavoux, C.;
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17. Spectral data for 16: 1H NMR (CDCl3) d 7.36–7.27
(comp, 5H), 5.11 (d, J = 12.5 Hz, 1H), 5.06 (d,
J = 12.5 Hz, 1H), 3.91 (dt, J = 6.5, 11.0 Hz, 1H), 3.55–
3.47 (m, 2H), 2.77–2.72 (m, 1H), 2.51–2.44 (comp, 3H),
2.31–2.26 (m, 1H), 2.11–2.01 (m, 2H), 1.92–1.87 (m, 1H),
1.82–1.72 (comp, 3H), 1.62–1.58 (m, 1H), 1.39–1.33 (m,
1H); 13C NMR (CDCl3) d 176.7, 154.4, 136.7, 128.5,
128.0, 127.9, 82.9, 66.6, 62.5, 47.8, 43.9, 40.1, 38.2, 36.1,
31.2, 25.4, 21.6; IR (neat) m 2922, 1781, 1701, 1454, 1402,
1354, 1203, 1104, 1027 cmÀ1
.

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S. T. M. Simila et al. / Tetrahedron Letters 47 (2006) 2933–2936
18. For related applications of lactone–lactam rearrangements
in alkaloid synthesis, see: (a) Martin, S. F.; Bur, S. K.
Tetrahedron 1999, 55, 8905–8914; (b) Reichelt, A.; Bur, S.
K.; Martin, S. F. Tetrahedron 2002, 58, 6323–6328.
(dd, J = 14.0, 6.2 Hz, 1H), 2.77 (dt, J = 12.8, 3.8 Hz, 1H),
2.67 (m, 1H), 2.07 (s, 3H), 1.99–1.95 (m, 1H), 1.89–1.78
(comp, 3H), 1.75–1.61 (comp, 4H), 1.23–1.16 (comp, 2H);
13C (CDCl3) NMR d 172.6, 170.8, 71.8, 64.1, 49.1, 39.6,
34.8, 33.8, 26.9, 25.2, 24.9, 22.7, 21.4; IR (neat) m 2926,
19. Spectral data for 19: 1H NMR (CDCl3) d 4.70 (dt, J = 4.0,
8.0 Hz, 1H), 3.48–3.44 (m, 1H), 3.40–3.35 (m, 1H), 3.10
1732, 1644, 1407, 1246, 1088, 1027 cmÀ1
.