Diastereoselective spiroannulation of phenolic substrates: Advances towards the asymmetric formation of the manumycin m-C7N core skeleton

Article abstract of DOI:10.3390/12092215

The asymmetric syntheses of two new spirolactones prepared in optically pure form from L-3-nitrotyrosine are described. The key step, an oxidative spiroannulation, was carried out on the optically active phenols 11a and 11b and afforded the new spirolacto

Full text of DOI:10.3390/12092215

Molecules 2007, 12, 2215-2222
molecules
ISSN 1420-3049
© 2007 by MDPI
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Full Paper
Diastereoselective Spiroannulation of Phenolic Substrates:
Advances Towards the Asymmetric Formation of the
Manumycin m-C7N Core Skeleton
Guy L. Plourde*, Randy R. Spaetzel, Jolene S. Kwasnitza and Thomas W. Scully
University of Northern British Columbia, Department of Chemistry, 3333 University Way, Prince
George, British Columbia, Canada, V2N 4Z9; Tel: +1-250-960-6694, Fax: +1-250-960-5845
* Author to whom correspondence should be addressed; E-mail: plourde@unbc.ca
Received: 7 September 2007; in revised form: 24 September 2007 / Accepted: 24 September 2007 /
Published: 25 September 2007
Abstract: The asymmetric syntheses of two new spirolactones prepared in optically pure
form from L-3-nitrotyrosine are described. The key step, an oxidative spiroannulation, was
carried out on the optically active phenols 11a and 11b and afforded the new spirolactones
5a and 5b in 85% and 83% yields, respectively, as mixtures (3:1 dr) of diastereomers. The
major diastereomers from these mixtures could be isolated in optically pure form by
trituration using acetone-hexanes as the solvent. Thus, the optically active spirolactones
(+)-5a (+ 92.8o, c=0.125 acetone) and (+)-5b (+112.0o, c= 0.125 acetone) were obtained
after four synthetic steps from L-3-nitrotyrosine in 41% and 43% yield, respectively.
Keywords: Spiroannulation, oxidation, phenol, diastereoselective, asymmetric,
Manumycins, Aranorosins, Gymnastatins.
Introduction
Our previous investigations of the diastereoselective spiroannulation of simple phenols have
shown that it is possible to obtain facial selectivity in these reactions [1-4]. While only modest
diastereoselectivities (~4:1 ratio) have been obtained to date, these results suggested that this method
could be used in the design of diastereoselective syntheses of natural products. More accurately, we

Molecules 2007, 12
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felt that spirocompounds of general structure 1 (Figure 1) could be used in the synthesis of the core
carbon skeleton of natural products (or analogs) from three families: Gymnastatins (2), Aranorosins
(3) and Manumycins (4). A representative example for each family is shown in Figure 1 (structures 2-
4).
Figure 1.
O
O
H
N
OH
O
Cl
R1
R4
O
O
O
O
O
O
OH
O
R3
N
OH
OH
HN
R3
O
R2
H
2 Gymnastatin E
1
3 Aranorosin
4 Nisamycin
HOOC
CH3 CH3
CH3
=
R3
=
R4
O
O
Assuming that the spirocompound 1 bears the proper functional groups at positions R1 and R2, it
appears to be a good starting point for the syntheses of these natural products. While there are already
numerous syntheses of members of the Manumycins [5-13], Aranorosins [14-16] and Gymnastatins
[17], this new approach could be advantageous since it may allow for the synthesis of more than one of
these structures from the same starting material. We have investigated the asymmetric synthesis of
spirolactones 5 (Figure 2) bearing substituents that would mimic the general functionality found in
most members of the Manumycin family (cf. structure 4). We now wish to report our preliminary
results toward the asymmetric synthesis of compound 5, which we hope will become a precursor for
the synthesis of analogs of the Manumycin family of compounds.
Results and Discussion
The diastereoselective formation of spirolactones 5a and 5b is described in Scheme 1.
Commercially available L-3-nitrotyrosine 8 was chosen as the starting material for two reasons: (1) it
provides the means to generate the amide function found in the Manumycins via its nitro function (see
Figure 1), and (2), it bears an optically pure chiral center on the side chain para to the hydroxyl, as
shown in phenols 11a/11b. Our previous studies of the diastereoselective spiroannulation of simple
phenols have shown that for side chains similar to the one found in 11, it was possible to induce face
selectivity and obtain a 4:1 diastereomeric ratio of spiroethers 6a-c and 7, which are analogous in
structure to 5/12, as shown in Figure 2 [1,2,4]. We hoped that in the formation of spirolactones 5/12, a

Molecules 2007, 12
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similar or greater ratio of diastereomers could be generated since the chiral center in the side chain of
11 is located at a position similar to that of the chiral center used in our previous studies.
Figure 2.
O
O
O
NH
R
OCH3
O
OCH3
O
O
O
TsHN
O
C(CH3)3
R
6a R=methyl
6b R=isopropyl
6c R=tert-butyl
7
5a R=CH3
5b R=C6H5
Scheme 1.
OH
OH
OH
OH
OH
NH2
NO2
b
NO2
a
Ts-HN
H2N
Ts-HN
O
OH
10
O
O
9
8
c
OH
OH
H
N
O
H
N
O
H
N
R
R
R
d
O
O
O
+
O
O
Ts-HN
Ts-HN
O
O
NH-Ts
O
(+)-5a R= CH3
(+)-5b R= C6H5
12a R= CH3
12b R= C6H5
11a R= CH3
11b R= C6H5
(a) 1) TsCl, THF, 1M NaOH 2) 1M KOH, EtOH, 80-85 oC; (b) H2, 10% Pd/C, THF; (c) CH3COCl or PhCOCl, THF, rt;
(d) PIFA, acetone, 0oC

Molecules 2007, 12
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Treatment of 8 with p-toluenesulfonyl chloride in tetrahydrofuran afforded a mixture of products
1
consisting of the mono-N-protected phenol 9 and a product that we identified by H-NMR as a
diprotected product, ie. both the amino and hydroxyl functions in 8 had reacted with the sulfonyl
chloride. Hydrolysis of the resulting mixture with 1M KOH at 80oC afforded only 9 in 86% yield as a
yellow solid after recrystallization from benzene. Since the sulfonate ester is easier to hydrolyze than
the sulfonamide function, we were able to avoid the extra steps that protection/deprotection of the
phenolic hydroxyl would have necessitated. Hydrogenation of the nitro function in 9 afforded the
aniline derivative 10 as a white solid. The crude yield for 10 appeared to be quantitative (based on
mass recovery), however, every attempt to purify this compound by column chromatography or
recrystallization failed. In these cases, we obtained low yields (40-60%), but more importantly, these
1
purification attempts at 10 generated a product that was less pure (based on H-NMR) than the crude
reaction product itself. Consequently, compound 10 was used without purification in the subsequent
reaction and the identity of this compound was based primarily on its 1H-NMR spectrum.
Treatment of 10 with either acetyl chloride or benzoyl chloride afforded 11a and 11b in 84% and
87% yields, respectively, after purification by column chromatography. The spiroannulation of 11a
and 11b was carried out with phenyliodine(III) bistrifluoroacetate (PIFA) in acetone at 0oC. In the
reaction of 11a, a mixture of diastereomers 5a/12a was obtained in a 3:1 diastereomeric ratio. The
ratio of major/minor diastereomers formed in the spiroannulation was determined by integration for
1
the signals of H-9 (two doublets centered at 6.37 ppm) in the H-NMR spectrum of the crude
diastereomeric mixture. In the reaction of 11b, the two doublets for compounds 5b/12b (centered at
6.40 ppm) were overlapping slightly, making the determination of the diastereomeric ratio less
1
accurate. However, it was obvious from the H-NMR of the crude reaction mixture that one
stereoisomer was produced in a larger amount than the other one. We estimated that for 5b/12b this
ratio was between 3:1 and 4:1. Attempts to separate the major and minor stereoisomers from these
mixtures met with limited success. Our first attempt was carried out by column chromatography of the
5a/12a mixture using 50% ethyl acetate-hexanes as eluant. We were able to separate the major
diastereomer 5a from the mixture under these conditions but this fraction represented only 38% of the
total isolated mass (or 32% yield from 11a). We were not successful in isolating the minor
diastereomer from this mixture. We later found that both 5a and 5b could be isolated via trituration
using an acetone/hexanes mixture. In both cases, we were able to isolate the major diastereomers (+)-
5a and (+)-5b from the crude reaction mixtures. The isolated mass obtained for each compound
represents a 57% yield from the corresponding optically active phenols 11a/11b, or a 41% total yield
for (+)-5a and 43% for (+)-5b. Finally, while we were able to isolate the major diastereomer in these
reactions, we have not yet identified the configuration of the newly formed chiral spirocenter in 5a or
5b. As a result, in Scheme 1 we have not drawn the stereo bonds of the spirocenters in the structures of
5a/b or 12a/b. However, both major diastereomers gave a positive optical rotation and are labeled
accordingly in Scheme 1.
Conclusions
We have successfully prepared optically active spirocompounds (+)-5a and (+)-5b. While the
diastereomeric ratio observed in the reaction leading to these compounds is modest at best, it suggests
that the method could be useful in the asymmetric synthesis of natural products since we were able to

Molecules 2007, 12
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obtain the major diastereomers in optically pure forms. We have now begun an investigation of the use
of these compounds in the synthesis of the core skeleton of the Manumycins. Furthermore, we are
attempting to identify the configuration of the new chiral spirocenters in (+)-5a and (+)-5b as well as
ways to enhance the diastereomeric ratios observed in these reactions.
Acknowledgements
We acknowledge the financial contribution of the University of Northern British Columbia in
support of this work.
Experimental
General
Melting points were determined on a hot stage instrument and are uncorrected. Infrared spectra
1
13
were recorded on a Perkin Elmer System 2000 FTIR either as KBr pellets or neat. H- and C-NMR
spectra were recorded on a Bruker AMX300 spectrometer operating at 300 MHz (1H) and 75.4 MHz
(13C). Chemical shifts are expressed in ppm using TMS (1H) or the residual solvent signal (13C) as
internal standards. Coupling constants (J) are expressed in Hz. Mass spectra were recorded on a
Hewlett Packard 5898B spectrometer. Optical rotations were recorded on a Rudolph Research Autopol
III Automatic Polarimeter.
(2S)-3-(4-Hydroxy-3-nitrophenyl)-2-{[(4-methylphenyl)sulfonyl]amino} propanoic acid [(-)-9]
A solution of p-toluenesulfonyl chloride (7.012 g, 36.9 mmol, 8.1 eq.) in tetrahydrofuran (150 mL)
was added in three portions (5-10 minutes apart) to a solution of 3-nitro-L-tyrosine (1.029 g, 4.55
mmol) in 1M NaOH (100 mL). The resulting orange solution was stirred vigorously at room
temperature. After 25-30 minutes the solution became yellow, indicating an acidic environment (pH ~
3), therefore more 1M NaOH (25 mL) was added. The resulting orange solution was stirred overnight
(14-16 hours). The reaction mixture was acidified with 10% HCl (pH 2) and extracted with
dichloromethane (3 x 50 mL). The organic fractions were combined, dried (MgSO4) and the solvent
evaporated to afford a yellow solid. The crude yellow product was dissolved in ethanol (100 mL) and
1M KOH (50 mL) was added. The solution was stirred at 80-85oC overnight (12-14 hours). The
resulting reaction mixture was cooled and acidified with 10% HCl (pH 2), concentrated and extracted
with dichloromethane (2 x 150 mL). The organic fractions were combined, dried (MgSO4), and the
solvent was evaporated leaving a yellow solid. Recrystallization from benzene afforded a yellow solid
(1.485 g, 86 %); mp: 137-138oC; [α]D: -10.4o (c: 0.125, acetone); IR (KBr, cm-1): 3291 (OH), 1734
(CO); 1H-NMR (CDCl3) δ: 2.40 (s, 3H, H-7'), 2.91 (m, 1H, H-3a), 3.15 (m, 1H, H-3b), 3.74 (broad s,
1H, OH), 4.16 (m, 1H, H-2), 5.42 (d, 1H, J=8.5, N-H), 7.01 (d, 1H, J=8.6, H-8), 7.20 (d, 2H, J=8.3, H-
2', H-6'), 7.38 (dd, 1H, J=2.2, 8.6, H-9), 7.56 (d, 2H, J=8.3, H-3', H-5'), 7.74 (d, 1H, J=2.2, H-5), 10.46
13
(broad s, 1H, CO2H); C-NMR (CDCl3) δ: 21.7, 37.7, 56.6, 120.4, 125.6, 127.2, 127.7, 129.9, 133.3,
136.4, 139.2, 144.4, 154.5, 174.7; MS m/z (rel. %): 380 (32, M+), 293 (22), 258 (25), 228 (43), 209
(31), 178 (26), 155 (98), 135 (92), 117 (32), 106 (52), 91 (100), 77 (42), 65 (83), 51 (49).

Molecules 2007, 12
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(2S)-3-(3-Amino-4-hydroxylphenyl)-2-{[(4-methylphenyl)sulfonyl]amino} propanoic acid [(+)-10]
To a solution of (-)-9 (925 mg, 2.43 mmol) in tetrahydrofuran (100 mL) was added 10% Pd/C (250
mg). The resulting mixture was placed in a hydrogenator, flushed (five times) with H2 and left to
agitate under pressure (32 psi) for 16 hrs. The reaction mixture was vented, filtered through Celite®
and solvent evaporated to afford a whitish solid. Initial attempts to purify by recrystallization or
column chromatography failed and characterization of this product was carried out using the crude
product; mp: 112-113oC; [α]D: +10.2o (c: 0.125, CH3CN); 1H-NMR (D2O + Na2CO3) δ: 2.35 (s, 3H, H-
7'), 2.45 (m, 1H, H-3a), 2.78 (m, 1H, H-3b), 3.59 (m, 1H, H-2), 6.33 (m, 3H, H-5, H-8, H-9), 7.22 (d,
2H, J=8.6, H-3', H-5'), 7.39 (d, 2H, J=8.3, H-2', H-6'); MS m/z (rel. %): 350 (5, M+), 179 (4), 155 (5),
122 (100), 91 (16), 77 (8), 65 (11).
(2S)-3-[3(Acetylamino)-4-hydroxyphenyl]-2-{[(4-methylphenyl)sulfonyl]amino} propanoic acid
[(-)-11a]
To a solution of (+)-10 (188 mg, 0.54 mmol) in tetrahydrofuran (10 mL) was added acetyl chloride
(79 mg, 1.02 mmol, 1.9 eq.) and the solution was stirred at room temperature overnight (19 hours).
The reaction mixture was diluted with CH2Cl2 (50 mL), washed with brine (15 mL), dried (MgSO4)
and evaporated. Chromatography on silica gel using 20% methanol-chloroform as eluant afforded a
beige solid (176 mg, 84%); mp: 153-154oC; [α]D: -7.3o (c: 0.137, acetone); IR (KBr, cm-1): 3416
(NH), 3257 (NH), 1777 (CO), 1721 (CO); 1H-NMR (acetone-d6) δ: 2.20 (s, 3H, H-2"), 2.38 (s, 3H, H-
7'), 2.83 (m, 1H, H-3a), 2.93 (m, 1H, H-3b), 4.04 (m, 1H, H-2), 6.64 (d, 1H, NH), 6.70 (d, 1H, J=8.2,
H-8), 6.83 (dd, 1H, J=2.1, 8.2, H-9), 7.15 (broad s, 1H, H-5), 7.25 (d, 2H, J=7.9, H-2', H-6'), 7.55 (d,
2H, J=8.3, H-3', H-5'), 9.25 (broad s, 1H, CO2H); 13C-NMR (acetone-d6) δ: 21.5, 23.5, 37.7, 58.3,
119.0, 123.0, 127.3, 127.7, 127.9, 128.7, 130.3, 139.1, 143.8, 148.3, 172.6; MS m/z (rel. %): 392 (1.2,
M+), 203 (17), 155 (11), 147 (74), 146 (100), 122 (18), 105 (17), 91 (60), 77 (35), 65 (22), 51 (17).
(2S)-3-[3(Benzoylamino)-4-hydroxyphenyl]-2-{[(4-methylphenyl)sulfonyl]amino}propanoic acid
[(-)-11b]
To a solution of (+)-10 (568 mg, 1.62 mmol) in tetrahydrofuran (40 mL) was added benzoyl
chloride (258 mg, 1.84 mmol, 1.2 eq.) and the solution was stirred at room temperature overnight (20
hours). The reaction mixture was diluted with CH2Cl2 (50 mL), washed with brine (15 mL), dried
(MgSO4) and evaporated. Chromatography on silica gel using 20% methanol-chloroform as eluant
afforded a grey solid (640 mg, 87%); mp: 183-186oC; [α]D: -18.3o (c: 0.09, CH3CN); IR (KBr, cm-1):
3417 (NH), 3279 (NH), 1719 (CO), 1652 (CO); 1H-NMR (acetone-d6) δ: 2.31 (s, 3H, CH3), 2.83 (dd,
1H, J=5.3, 8.3, H-3a), 3.01 (dd, 1H, J=5.3, 13.8, H-3b), 4.07 (m, 1H, H-2), 6.80 (m, 3H, Ar-H), 7.21
(d, 2H, J=7.9, H-2', H-6'), 7.54 (m, 4H, Ar-H), 8.04 (d, 2H, J=7.9, H-3', H-5'), 9.18 (broad s, 1H,
exchangeable with D2O, NH), 9.45 (broad s, 1H, exchangeable with D2O, OH); 13C-NMR (acetone-d6)
δ: 21.7, 39.0, 58.6, 118.6, 124.4, 127.5, 127.8, 128.1, 128.7, 129.1, 129.8, 130.4, 133.2, 134.0, 135.1,
139.3, 143.9, 148.6, 167.4, 172.9; MS m/z (rel. %): M+ not observed, 266 (2.3), 209 (22), 208 (37),
155 (9), 105 (100), 91 (74), 77 (92), 65 (27), 51 (40).

Molecules 2007, 12
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N-((3S)-3-{[(4-Methylphenyl)sulfonyl]amino}-1-oxaspiro[4.5]deca-6,9-dion-2,8-dien-7-yl) acetamide
[(+)-5a]
To a cold (0oC) solution of (-)-11a (602 mg, 1.54 mmol) in acetone (100 mL) was added PIFA
(727 mg, 1.69 mmol, 1.1 eq.) in one portion. The orange solution was stirred at 0oC for 45 minutes,
diluted with EtOAc (200 mL) and washed with cold water (2 x 100 mL). The aqueous portion was
extracted with EtOAc (2 x 50 mL), the organic fractions combined, dried (MgSO4) and evaporated to
afford a brown solid (508 mg, 85%). The crude product was purified by trituration (acetone-hexanes)
providing the major diastereomer as a beige solid (340 mg, 57%); mp: 173-174oC; [α]D: +92.8o (c:
0.125, acetone); IR (KBr, cm-1): 3327 (NH), 1778 (CO), 1654 (CO), 1645 (CO); 1H-NMR (CD3CN) δ:
2.16 (s, 3H, H-7'), 2.28 (m, 1H, H-4a), 2.45(s, 3H, H-2"), 2.46 (m, 1H, H-4b), 3.54 (m, 1H, H-3), 6.12
(d, 1H, J=8.0, NH), 6.25 (d, 1H, J=10.0, H-9), 7.06 (dd, 1H, J=3.1, 10.0, H-10), 7.38 (d, 2H, J=8.0, H-
13
2', H-6'), 7.52 (d, 1H, J=3.1, H-6), 7.78 (d, 2H, J=8.3, H-3', H-5'), 8.18 (broad s, 1H, NH); C-NMR
(CD3CN) δ: 21.6, 24.7, 40.0, 53.0, 78.4, 124.8, 127.5, 128.0, 130.8, 133.5, 138.8, 145.2, 147.4, 170.9,
173.6; MS m/z (rel. %): 390 (0.4, M+), 203 (5), 155 (11), 147 (52), 146 (78), 139 (9), 122 (9), 105 (8),
91 (100), 77 (20), 65 (57), 51 (6).
N-((3S)-3-{[(4-Methylphenyl)sulfonyl]amino}-1-oxaspiro[4.5]deca-6,9-dion-2,8-dien-7-yl) benzamide
[(+)-5b]
To a cold (0oC) solution of (-)-11b (710 mg, 1.56 mmol) in acetone (100 mL) was added PIFA
(677 mg, 1.57 mmol, 1.0 eq.) in one portion. The orange solution was stirred at 0oC for 45 minutes,
diluted with EtOAc (200 mL) and washed with cold water (2 x 100 mL). The aqueous portion was
extracted with EtOAc (2 x 50 mL), the organic fractions combined, dried (MgSO4) and evaporated to
afford a brown solid (586 mg, 83%). The crude product was purified by trituration (acetone-hexanes)
providing the major diastereomer as an off-white solid (404 mg, 57%); mp: 174-175oC; [α]D= +112.0o
1
(c: 0.125, acetone); IR (KBr, cm-1): 3397 (NH), 3290 (NH), 1775 (CO), 1665 (CO), 1626 (CO); H-
NMR (CDCl3) δ: 2.43 (s, 3H, H-7'), 2.54 (dd, 1H, J=11.7, 13.6, H-4a), 2.76 (dd, 1H, J=8.7, 13.6,
H4b), 4.40 (m, 1H, H-3), 5.66 (d, 1H, J=5.1, NH), 6.39 (d, 1H, J=10.1, H-9), 6.92 (dd, 1H, J=3.1,
10.1, H-10), 7.33 (d, 2H, J=8.0, H-2', H-6'), 7.54 (m, 3H, H-6, H-3’, H-5’), 7.83 (m, 5H, aromatic Hs),
8.79 (broad s, 1H, NH); 13C-NMR (CDCl3) δ: 21.8, 40.8, 52.2, 77.4, 78.4, 124.4, 127.4, 129.2, 129.9,
130.3, 132.5, 132.8, 133.6, 136.5, 144.6, 145.9, 166.3, 172.6, 179.3; MS m/z (rel. %): 452 (0.2, M+),
208 (12), 155 (5), 139 (10), 123 (9), 122 (9), 105 (33), 92 (38), 91 (100), 77 (37), 65 (42), 51 (10).
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