Biomimetic total syntheses of (-)-TAN1251A, (+)-TAN1251B, (+)-TAN1251C, and (+)-TAN1251D

Article abstract of DOI:10.1021/ol991401q

(equation presented) The muscarinic antagonists (-)-TAN1251A (1), (+)-TAN1251B (2), (+)-TAN1251C (3), and (+)-TAN1251D (4) have been synthesized biomimetically by enamine formation from an amino aldehyde to give TAN1251C ketal 18. Oxidation and reduction lead to TAN1251A (1), which has been hydroxylated to give TAN1251B (2). Stereospecific reduction of TAN1251C ketal 18 leads to TAN1251D (4).

Full text of DOI:10.1021/ol991401q

ORGANIC
LETTERS
2000
Vol. 2, No. 5
643-646
Biomimetic Total Syntheses of
(−)-TAN1251A, (+)-TAN1251B,
(+)-TAN1251C, and (+)-TAN1251D
Barry B. Snider* and Hong Lin
Department of Chemistry MS 015, Brandeis UniVersity,
Waltham, Massachusetts 02254-9110
snider@brandeis.edu
Received December 24, 1999
ABSTRACT
The muscarinic antagonists (−)-TAN1251A (1), (+)-TAN1251B (2), (+)-TAN1251C (3), and (+)-TAN1251D (4) have been synthesized biomimetically
by enamine formation from an amino aldehyde to give TAN1251C ketal 18. Oxidation and reduction lead to TAN1251A (1), which has been
hydroxylated to give TAN1251B (2). Stereospecific reduction of TAN1251C ketal 18 leads to TAN1251D (4).
TAN1251A (1), TAN1251B (2), TAN1251C (3), and
TAN1251D (4) were isolated from a Penicillium thomii RA-
89 fermentation broth at Takeda Industries.1 TAN1251A (1)
and TAN1251B (2) are muscarinic antagonists of value as
mydriatic or antispasmodic/antiulcer agents that inhibit the
acetylcholine-induced contraction of Guinea pig ileum with
ED50 values of 8.0 and 10.0 nM, respectively. The relative
stereochemistry of TAN1251B (2) was determined by X-ray
crystallographic analysis, and the absolute stereochemistry
was established by analysis of the CD of the dibenzoate of
the diol obtained by reduction of the R-hydroxy ketone
moiety.2 Since TAN1251A (1) is converted to 2 by Peni-
cillium thomii RA-89, it has the same absolute stereochem-
The TAN1251 series of compounds have a novel tricyclic
skeleton containing a 1,4-diazabicyclo[3.2.1]octane and a
spiro-fused cyclohexanone. We believe that they are bio-
synthetically related to the potent immunosuppressant
FR901483 (8),4 which is probably biosynthesized from
modified tyrosine dimer 6 by oxidative coupling to close
the pyrrolidine ring and further elaboration to provide keto
aldehyde 7 (see Scheme 1). An intramolecular aldol reaction
of the keto aldehyde will lead to the tricyclic skeleton of
istry. The absolute stereochemistry of TAN1251C (3) and
the absolute and relative stereochemistry of TAN1251D (4
or 5) were not known and have been assigned on the basis
of the syntheses reported herein. Kawahara and co-workers
recently reported the first total synthesis of racemic
TAN1251A (1).3
(1) Shirafuji, H.; Tsubotani, S.; Ishimaru, T.; Harada, S. PCT Int. Appl.
1991, WO 91 13,887; Chem Abstr. 1992, 116, 39780t.
(2) Personal communication from Dr. Tsuneaki Hida, Research Head,
Takeda Chemical Industries, Ltd., May 6, 1999.
(3) Nagumo, S.; Nishida, A.; Yamazaki, C.; Murashige, K.; Kawahara,
N. Tetrahedron Lett. 1998, 39, 4493-4496.
(4) Sakamoto, K.; Tsujii, E.; Abe, F.; Nakanishi, T.; Yamashita, M.;
Shigematsu, N.; Izumi, S.; Okuhara, M. J. Antibiot. 1996, 49, 37-44.
10.1021/ol991401q CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/16/2000

FR901483 (8), while dienamine formation from the second-
ary amine and aldehyde will provide TAN1251C (3), which
can be isomerized to TAN1251A (1) or reduced to TAN1251D
(4).
6 h, followed by acid-catalyzed lactam formation with a
catalytic amount of HOAc in CH2Cl2 for 12 h, provided 68%
of an inseparable 6:1 mixture of 14 and the diastereomer
and 17% of the phenol corresponding to 13, which was
recycled.
Scheme 1. Possible Biosynthesis of TAN1251A-D and
FR901483
Scheme 2
We have recently completed the first synthesis of (-)-
FR901483 (8), which proceeds along biomimetic lines
through an intermediate that is a protected analogue of keto
aldehyde 7, R ) OMe, which was prepared efficiently in
optically active form by a 1,3-dipolar cycloaddition product
of a nitrone and ethyl acrylate.5
Alkylation of 14 and the diastereomer with 1-bromo-3-
methyl-2-butene and cesium carbonate in acetone at 50 °C
provided 86% of a 6:1 mixture of 15 and the diastereomer,
which was tosylated with TsCl, Et3N, and DMAP (see
Scheme 3). Reaction of the crude tosylates with sodium azide
in DMF at 25 °C for 6 h provided 79% of pure azide 16 and
12% of the diastereomer, which were easily separated.
Adaptation of this route to the synthesis of the TAN1251
series will require the preparation of the protected amino
aldehyde with a prenyl rather than a methyl aryl ether and
condensation to form the dienamine. Since the prenyl group
is not compatible with the conditions required for the
preparation of the hydroxylamine or hydrogenation of the
isoxazolidine, tyrosine was protected as the benzyl ether.
N-BOC-tyrosine methyl ester was treated with benzyl
bromide and cesium carbonate in acetone at 50 °C to provide
the benzyl aryl ether, which was deprotected with 25% TFA
in CH2Cl2 to give O-benzyltyrosine methyl ester (9) in
quantitative yield. Hydroxylamine 10 was made by Grund-
ke’s procedure in 53% overall yield.6 Condensation of 9 with
anisaldehyde in MeOH at 25 °C for 6 h afforded the imine,
which was oxidized to the oxaziridine with m-CPBA.
Reaction of the oxaziridine with hydroxylamine hydrochlo-
ride afforded 10 (see Scheme 2).
Scheme 3. Synthesis of TAN1251C (3)
Condensation of hydroxylamine 10 with monoketal 117-9
in EtOH for 48 h gave nitrone 12, which was treated with
ethyl acrylate in toluene at reflux to afford 68% of a 6:1
mixture of diastereomers rich in desired isomer 13. Hydro-
genolysis of the N-O bond under 45 psi of H2 in HOAc for
(5) (a) Snider, B. B.; Lin, H.; Foxman, B. M. J. Org. Chem. 1998, 63,
6442-6443. (b) Snider, B. B.; Lin, H. J. Am. Chem. Soc. 1999, 121, 7778-
7786.
(6) Grundke, G.; Keese, W.; Rimpler, M. Synthesis 1987, 1115-1116.
(7) Hyatt, J. A. J. Org. Chem. 1983, 48, 129-131.
(8) This sequence was originally carried out with the mono dioxolane
ketal used in the FR901483 synthesis. This ketal can be cleaved from the
TAN1251A precursor 20, X ) O(CH2)2O, but not from the TAN1251C
and TAN1251D precursors 18, X ) O(CH2)2O, and 23, X ) O(CH2)2O.
644
Org. Lett., Vol. 2, No. 5, 2000

Reduction of the azide, lactam, and ester was accomplished
with LAH in THF at reflux. The resulting primary alcohol
and amine were formylated with formic acetic anhydride
generated in situ.10 Reduction of the crude formamide with
LAH provided 58% of N-methylamine 17 from azide 16.
Swern oxidation of amino alcohol 17 with trifluoroacetic
anhydride and Et3N in DMSO11 afforded the trifluoroaceta-
mido aldehyde. Hydrolysis of the trifluoroacetamide with
K2CO3 in aqueous MeOH provided 60% of 18, the ketal of
TAN1251C. Acidic hydrolysis of the ketal with 0.1 M HCl
in aqueous acetone proceeded smoothly in 3 h to give
TAN1251C (3) in 75% yield. The 1H and 13C NMR spectral
data of synthetic TAN1251C are identical to those of the
natural product.1 The optical rotation for our synthetic
material, [R]D +23°, corresponds well with the reported value
of +24°, confirming that TAN1251C has the S configuration
as do TAN1251A and TAN1251B.
Reduction of 18 with NaBH(OAc)3 in HOAc afforded 90%
of a 1:9 mixture of ketals of 23 and 24. Acidic hydrolysis
of the major ketal 24 with 0.1 M HCl in aqueous acetone
gave 83% of epi-TAN1251D (5) whose spectral data are
quite different than those of TAN1251D (4) (see Scheme
5).
Scheme 5. Synthesis of TAN1251D (4)
Oxidation of ketal 18 with DDQ (slow addition)12 in dry
CH2Cl2 provided eniminium salt 19 which was reduced with
NaCNBH3 in acidic MeOH to yield 79% of 20, the ketal of
TAN1251A (see Scheme 4). Hydrolysis with 0.1 M HCl in
Scheme 4. Synthesis of TAN1251A (1)
Reduction of 18 with NaCNBH3 in acidic MeOH (HOAc
was added dropwise to keep the reaction mixture at pH 4)
afforded a 2:1 mixture of ketals 23 and 24. We were pleased
to find that the a similar reduction of 18 with NaCNBH3 in
CF3CH2OH provided a 6:1 mixture of ketals 23 and 24, while
use of the even more polar solvent (CF3)2CHOH afforded
90% of a >25:1 mixture of 23 and 24. Acidic hydrolysis of
the major ketal 23 with 0.1 M HCl in aqueous acetone
afforded 79% of TAN1251D (4), whose H and 13C NMR
1
aqueous acetone gave TAN1251A (1) in 89% yield. The 1H
and 13C NMR of synthetic TAN1251A are identical to those
of the natural product.13
TAN1251D (4) is probably biosynthesized by reduction
of the iminium salt formed by protonation of TAN1251C
and should be available chemically by a similar protocol.
spectral data matched those of the natural product and whose
optical rotation, [R]D +22°, corresponds well with the
reported value, +24°, confirming that the absolute config-
uration of TAN1251D (4) is also S.
Since the relative stereochemistry of TAN1251D had not
been established, the stereochemistry of ketones 4 and 5 and
ketals 23 and 24 was established by NMR experiments. The
stereochemistry of 23 was established by NOE experiments
on the formate salt. H2 absorbs at δ 3.92 as a broad triplet,
J ) 12 Hz, indicating that H2 has a large axial-axial
coupling constant and a large coupling constant to one of
the benzylic methylene protons. The stereochemistry was
confirmed by a strong NOE between H2 and H6R at δ 3.56.
NOE experiments did not provide useful information about
the stereochemistry of 4, 5, or 24 due to overlapping peaks.
Fortunately, the stereochemical assignments of 4 and 5 could
be confirmed by analysis of the 13C NMR shifts, which were
assigned by HSQC experiments. The axial benzyl substituent
of epi-TAN1251D (5) shifts the benzylic carbon and the one-
carbon bridge upfield to δ 39.7 and 52.4, respectively, from
(9) The dioxepane ketal 11 was chosen since these ketals are known be
more easily cleaved than the analogous dioxolanes or dioxanes: (a) Oshima,
T.; Ueno, S.-Y.; Nagai, T. Heterocycles 1995, 40, 607-617. (b) Conan,
par J.-Y.; Natat, A.; Priolet, D. Bull. Soc. Chim. Fr. 1976, 1935-1940. (c)
Smith, S. W.; Newman, M. S. J. Am. Chem. Soc. 1968, 90, 1249-1253.
(d) Smith, S. W.; Newman, M. S. J. Am. Chem. Soc. 1968, 90, 1253-
1257.
(10) Krishnamurthy, S. Tetrahedron Lett. 1982, 23, 3315-3318.
(11) Chamberlin, A. R.; Chung, J. Y. L. J. Org. Chem. 1985, 50, 4425-
4431.
(12) An inseparable 7:1 mixture of 20 and the E-isomer was formed if
DDQ was added too fast. The alkene hydrogen of the E-iosmer at δ 6.46
is deshielded by the syn nitrogen as compared to that of 20 at δ 5.91. The
ortho aromatic protons of 20 at δ 7.76 are deshielded by the syn nitrogen
as compared to those of the E-isomer at δ 7.05. These assignments were
confirmed by NOE studies.
(13) Mp 112-114 °C (lit.1 mp 118.5-120 °C); [R]D -9.1° (c 0.40,
MeOH) (lit.1 -8.1° (c 0.42, MeOH)).
Org. Lett., Vol. 2, No. 5, 2000
645

δ 41.4 and 61.9 observed in TAN1251D (4) because of the
gauche butane effect.
which should have a dihedral angle of 30° with the
bridgehead hydrogen. Similarly, the structure of 26 was
tentatively assigned on the basis of the NOE between the
CHOH peak at δ 4.23 (dd, J ) 12.8, 6.0) and H7 at δ 2.05.
Since this H7 absorbs as a br d, J ) 14 Hz, it is the hydrogen
indicated in the structure which has a dihedral angle of almost
90° with the bridgehead. Hydroxylation of the enolate of 1
with (1R)-10-(camphorsulfonyl)oxaziridine gave about 40%
of a 2:1 mixture of 25 and 26. The successful hydroxylation
leading to 25 and 26 without oxidation of the double bonds
or amines was encouraging, but these oxaziridines hydroxy-
lated the wrong face of the enolates of TAN1251A (1).
We therefore investigated hydroxylation of the trimeth-
ylsilyl enol ethers of 1 with OsO4. Treatment of 1 with LDA
in THF at -78 to -40 °C gave a mixture of enolates, which
was quenched with TMSCl. Reaction of the crude silyl enol
ethers with 1 equiv of NMO and 20% OsO4 in aqueous
t-BuOH for 5 min at 0 °C gave 39% of a 2:1:8:4 mixture of
25, 26, TAN1251B (2), and 27, 23% of triols resulting from
hydroxylation of both the enol ether and the prenyl group,
and 9% of recovered 1. PTLC gave 25% of a 2:1 mixture of
the major products 2 and 27, which were inseparable even
by normal and reverse phase HPLC. Fortunately, the isomers
were readily separable on a Chiralpak AD column since the
R-hydroxy ketone moieties have the opposite absolute
The stereochemical control in the reduction of ketal
enamine 18 occurs in the protonation step, which gives a
mixture of iminium salts 21 and 22, rather than in the
reduction of the iminium salts to ketal amines 23 and 24.
Kinetic protonation should occur from the less hindered axial
face to give iminium salt 21 with an equatorial benzyl group.
However, MM2 calculations suggest that 21 is less stable
than 22 by 3 kcal/mol because the steric hindrance between
the equatorial benzyl group of 21 and the spiro cyclohexane
ring is much greater than the steric hindrance due to the axial
benzyl group of 22. Therefore, if reduction of the iminium
salt is slow and protonation is reversible, ketal amine 24
should be the major product as is observed with the weak
reducing agent NaBH(OAc)3. With the stronger reducing
agent NaBH3CN, reduction of kinetic iminium salt 21 to give
amine ketal 23 is the major process. As the polarity of the
solvent increases, the ionic iminium salt is stabilized relative
to the enamine so that equilibration of the iminium salts is
slower. Therefore, the ratio of diastereomers 23 to 24
increases from 2:1 in MeOH to 6:1 in CF3CH2OH and to
>25:1 in (CF3)2CHOH with increasing solvent polarity.14
The hydroxylation15 of TAN1251A (1) to give TAN1251B
(2) is a very challenging problem since four R-hydroxy
ketones can be formed from 1 and the choice of oxidants is
limited by the presence of readily oxidizable amines and
double bonds. For instance, m-CPBA in CH2Cl2 at 0 °C
oxidized the N-methylamine of the trimethylsilyl enol ether
prepared from 1 to the amine oxide. TAN1251A (1) was
treated with NaHMDS to form the enolate, which was
oxidized with (1S)-10-(camphorsulfonyl)oxaziridine16 to give
50% of an inseparable 2:3 mixture of 25 and 26 and 50% of
recovered 1.
1
stereochemistry. The H and 13C NMR spectral data of 2
are identical to those of natural TAN1251B. Hydroxylation
with OsO4 to give 2 and 27 is moderately selective for the
desired face of the enol ether opposite the nitrogen. Unfor-
tunately, initial attempts at improving enolization selectivity
with the lithium base prepared from either (R, R)- or (S, S)-
bis(R-methylbenzylamine) gave lower selectivity.
In summary, we have completed the first syntheses of
TAN1251B (2), TAN1251C (3), and TAN1251D (4) enan-
tiospecifically and the first synthesis of (-)-TAN1251A (1).
These results confirm the absolute stereochemical assign-
ments based on CD studies and establish the relative
stereochemistry of TAN1251D.
Acknowledgment. We thank the NIH (GM-50151) for
financial support and Dr. Tsuneaki Hida, Takeda Chemical
Industries, for the 1H and 13C NMR spectra of TAN1251A-
D.
Supporting Information Available: Full experimental
procedures and spectral data for 1-5. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL991401Q
(14) March, J. AdVanced Organic Chemistry. Reactions, Mechanisms and
Structure, 4th ed.; Wiley: New York, 1992; pp 357-362.
The structure of 25 was tentatively assigned on the basis
of the NOE between the CHOH peak at δ 4.07 (dd, J )
10.8, 5.2) and H7 at δ 1.74. Since this H7 absorbs as a br dd,
J ) 14, 5 Hz, it is the hydrogen indicated in the structure
(15) Jones, A. B. In ComprehensiVe Organic Synthesis, Vol. 7; Trost,
B. M., Ed.; Pergamon: Oxford, 1991; pp 151-191.
(16) (a) Davis, F. A.; Haque, M. S. J. Org. Chem. 1986, 51, 4083-
4085. (b) Davis, F. A.; Chen, B.-C. Chem. ReV. 1992, 92, 919-934.
646
Org. Lett., Vol. 2, No. 5, 2000