Total synthesis of nothapodytine b and (-)-mappicine

Article abstract of DOI:10.1021/ja973007y

Concise total syntheses of naturally occurring nothapodytine B (1, mappicine ketone) and ( - )-mappicine (3) are detailed. The approach is based on the implememation of a room-temperature, inverse electron demand Diels-Alder reaction of the N-sulfonyl-1-aza-1.3-butadiene 11 for assemblage of a pyridone 1) ring precursor central to the structure. A Friedlander condensation is utilized for constructing the AB ring system of 1 and 3. An acid-catalyzed reaction sequence is used to accomplish a deprotection with subsequent ring-closure for introduction of the C ring in a single step.

Full text of DOI:10.1021/ja973007y

1218
J. Am. Chem. Soc. 1998, 120, 1218-1222
Total Synthesis of Nothapodytine B and (-)-Mappicine
Dale L. Boger* and Jiyong Hong
Contribution from the Department of Chemistry and The Skaggs Institute for Chemical Biology,
The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037
ReceiVed August 26, 1997
Abstract: Concise total syntheses of naturally occurring nothapodytine B (1, mappicine ketone) and (-)-
mappicine (3) are detailed. The approach is based on the implementation of a room-temperature, inverse
electron demand Diels-Alder reaction of the N-sulfonyl-1-aza-1,3-butadiene 11 for assemblage of a pyridone
D ring precursor central to the structure. A Friedlander condensation is utilized for constructing the AB ring
system of 1 and 3. An acid-catalyzed reaction sequence is used to accomplish a deprotection with subsequent
ring-closure for introduction of the C ring in a single step.
Nothapodytine B (1) along with nothapodytine A (2) have
recently been isolated from Nothapodytes foetida of which the
ethanol extract exhibits significant cytotoxity in the human KB
cell line (Figure 1).1 Nothapodytine B (1) is an oxidized
derivative of mappicine (3)2 and an E ring decarboxylated
analogue of camptothecin (4), the parent member of a clinically
useful class of DNA topoisomerase I inhibitors that exhibit
efficacious antitumor activity.3 Recently, nothapodytine B (1,
mappicine ketone) has been identified as an antiviral lead with
reported selective activities against HSV-1, HSV-2, and human
cytomegalovirus (HCMV) with PR50’s of 2.9, 0.5, and 13.2 µM,
respectively.4 Because the antiviral mechanism of nothapody-
tine B (1) is distinct from that of Acyclovir (ACV) as demon-
strated by the observation that ACV-resistant HSV-1 and HSV-2
are inhibited by nothapodytine B (1) and that nothapodytine
B-resistant mutants remain sensitive to ACV, potentially it may
be used with ACV cooperatively.5 While camptothecin (4) is
now available from natural sources in quantity, nothapodytine
B (1) has only been isolated from Nothapodytes foetida and in
low content which prohibits isolation of useful amounts for
further studies. Hence, recent efforts have described improve-
ments in the degradation of camptothecin6 as well as the
development of synthetic routes to nothapodytine B (1)6 and
related analogues.4,6
Figure 1.
In conjunction with synthetic efforts on this important class
of naturally occurring alkaloids, herein we detail concise total
syntheses of nothapodytine B (1) and (-)-mappicine (3). The
availability of the natural products has permitted their cytotox-
icity testing addressing ambiguities regarding their contribution
to the Nothapodytes foetida EtOH extract activity.1 Central to
our approach was the implementation of a room-temperature,
inverse electron demand Diels-Alder reaction7 of the N-sul-
fonyl-1-aza-1,3-butadiene 11 for the introduction of the pyridone
D ring8 with assemblage of the full carbon skeleton of 1 (Scheme
1). The incorporation of a strong C4 electron-withdrawing
substituent into the electron-deficient azadiene 11 accelerates
its rate of participation in the LUMOdiene-controlled Diels-Alder
reaction to the extent that cycloaddition could be confidently
expected to occur at 25 °C without altering the inherent
cycloaddition regioselectivity.9 That is, the substitution of the
diene with both a strong C4 and C2 electron-withdrawing group
(1) Wu, T. S.; Chan, Y. Y.; Leu, Y. L.; Chern, C. Y.; Chen, C. F.
Phytochemistry 1996, 42, 907.
(2) Govindachari, T. R.; Ravindranath, K. R.; Viswanathan, N. J. Chem.
Soc., Perkin Trans. 1 1974, 1215.
(3) Wall, M. E.; Wani, M. The Chemistry of Heterocyclic Compounds:
Monoterpenoid Alkaloids, Vol. 25; Saxton, J. E., Ed.; Wiley: Chichester,
U.K. 1994; p 689. Wall, M. E.; Wani, M.; Nocholas, A. W.; Manikuma,
G.; Tele, C.; Moore, L.; Truesdale, A.; Leitner, P.; Besterman, J. M. J.
Med. Chem. 1993, 36, 2689. Suffness, M.; Cordell, G. A. The Alkaloids,
Vol 25; Brossi, A., Ed.; Academic: Orlando, FL, 1985.
(4) Pendrak, I.; Barney, S.; Wittrock, R.; Lambert, D. M.; Kingsbury,
W. D. J. Org. Chem. 1994, 59, 2623. Pendrak, I.; Wittrock, R.; Kingsbury,
W. D. J. Org. Chem. 1995, 60, 2912.
(5) Barney, S.; Wittrock, R.; Petteway, S. R., Jr.; Kingsbury, W. D.;
Berges, D.; Gallagher, G.; Taggart, J.; Lambert, D. M. 17th International
Herpesvirus Workshop, Edinburgh, Scotland, U.K.; August 1-6, 1992.
(6) From camptothecin: (a) Fortunak, J. M. D.; Mastrocola, A. R.;
Mellinger, M.; Wood, J. L. Tetrahedron Lett. 1994, 35, 5763 and Kingsbury,
W. D. Tetrahedron Lett. 1988, 29, 6847. Total synthesis: (b) Kametani,
T.; Takeda, H.; Nemoto, H.; Fukumoto, K. Heterocycles 1975, 3, 167.
Kametani, T.; Takeda, H.; Nemoto, H.; Fukumoto, K. J. Chem. Soc., Perkin
Trans. 1 1975, 1825. (c) Comins, D. L.; Saha, J. K. J. Org. Chem. 1996,
61, 9623. (d) Josien, H.; Curran, D. P. Tetrahedron 1997, 53, 8881.
(7) Boger, D. L. Chemtracts: Org. Chem. 1996, 9, 149. Boger, D. L.;
Patel, M. In Progress in Heterocyclic Chem., Vol. 1; Suschitzky, H., Scriven,
E. F. V., Eds.; Pergamon: London, 1989; p 30. Boger, D. L. Chem. ReV.
(Washington, D.C.) 1986, 86, 781. Boger, D. L. Bull. Soc. Chim. Belg.
1990, 99, 599. Boger, D. L.; Weinreb, S. M. Hetero Diels-Alder
Methodology in Organic Synthesis; Academic: San Diego, CA, 1987. Boger,
D. L. Tetrahedron 1983, 39, 2869.
(8) Boger, D. L.; Cassidy, K. C.; Nakahara, S. J. Am. Chem. Soc. 1993,
115, 10733. Boger, D. L.; Nakahara, S. J. Org. Chem. 1991, 56, 880. Boger,
D. L.; Hu¨ter, O.; Mbiya, K.; Zhang, M. J. Am. Chem. Soc. 1995, 117, 11839.
Boger, D. L.; Zhang, M. J. Org. Chem. 1992, 57, 3974.
S0002-7863(97)03007-2 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/30/1998

Synthesis of Nothapodytine B and (-)-Mappicine
J. Am. Chem. Soc., Vol. 120, No. 6, 1998 1219
Scheme 1
Scheme 3
Scheme 2
Scheme 4
does not diminish or reverse the inherent regioselectivity of the
[4 + 2] cycloaddition reaction despite their potential to do so,
but both contribute to a reaction rate acceleration by lowering
the diene LUMO despite this noncomplementary substitution
on the diene.
Friedlander condensation of 2-aminobenzaldehyde with 2-ox-
obutyric acid (NaOMe, MeOH, 65 °C, 12 h) and subsequent
Fischer esterification (H2SO4, MeOH, 65 °C, 24 h) of the crude
carboxylic acid 5 provided methyl 3-methylquinoline-2-car-
boxylate (6) in 70% overall yield as described (Scheme 2).10
Analogous to a Danishefsky procedure employing NBS/CCl4,
benzylic bromination of 6 with 1,3-dibromo-5,5-dimethylhy-
dantoin (DBH, 0.5 equiv) provided 7 smoothly in high yield
(78%) accompanied by e10% of the dibromination product in
refluxing CCl4 containing a catalytic amount of benzoyl peroxide
(0.05 equiv).11 Conversion of 7 to the â-ketophosphonate 9
was accomplished following the procedure outlined by Ciufo-
lini.12 Thus, treatment of 7 with concentrated H2SO4 (10 equiv)
in MeOH (65 °C, 12 h) provided 8 in excellent yield (89%)
and subsequent treatment with R-lithio dimethyl methylphos-
phonate (2 equiv, -78 °C, 1 h) afforded 9 quantitatively.
Wadsworth-Horner-Emmons reaction of the â-keto phos-
phonate 9 to provide the R,â-unsaturated γ-keto ester 10
(Scheme 3) was carried out with ethyl glyoxylate and t-BuOK
in DME (-20 to 25 °C, 5 h), Scheme 3.13 Two approaches to
the conversion of 10 to the key N-sulfonyl-1-aza-1,3-butadiene
11 required for use in the LUMOdiene-controlled Diels-Alder
reaction were examined. The initial two-step procedure requir-
ing conversion of 10 to the corresponding oxime14 (NH2OH-
HCl, EtOH, 25 °C, 24 h, 84-92%) followed by oxime
O-methanesulfinate formation (CH3SOCl, Et3N, CH2Cl2, 0 °C,
20 min) and in situ homolytic rearrangement (Scheme 4)9,15
failed to provide 11 in yields competitive with a direct
condensation of 10 with methanesulfonamide. Similarly, treat-
ment of the oxime 10 with methanesulfonyl cyanide under
conditions (CCl4, Et3N, or DBU) that lead to rearrangement to
methylsulfinyl cyanate, subsequent oxime O-sulfinate formation,
and homolytic rearrangement to the methanesulfonylimine failed
to provide 11 cleanly (Scheme 4).16 By contrast, the direct
TiCl4-promoted (1.3 equiv) condensation of 10 with methane-
(9) Boger, D. L.; Corbett, W. L.; Curran, T. T.; Kasper, A. M. J. Am.
Chem. Soc. 1991, 113, 1713. Boger, D. L.; Corbett, W. L. J. Org. Chem.
1993, 58, 2068. Boger, D. L.; Curran, T. T. J. Org. Chem. 1990, 55, 5439.
Boger, D. L.; Corbett, W. L.; Wiggins, J. M. J. Org. Chem. 1990, 55, 2999.
Boger, D. L.; Kasper, A. M. J. Am. Chem. Soc. 1989, 111, 1517.
(10) Danishefsky, S.; Bryson, T. A.; Puthenpurayil, J. J. Org. Chem.
1975, 40, 796.
(13) The ratio of trans:cis 10 obtained in the Wadsworth-Horner-
Emmons reaction was 4: 1, and this ratio was not altered employing
different reaction condition (K2CO3, DMF, -25 to 25 °C, 24 h).
(14) For the oxime: 1H NMR (CDCl3, 400 MHz) 1:1 mixture of syn:
anti isomers: δ 9.90 (br s, 1H), 8.32 (s, 1H), 8.19 and 7.62 (two d, 1H, J
) 16.3 and 16.1 Hz), 8.14 (t, 1H, J ) 9.2 Hz), 7.86 (t, 1H, J ) 7.8 Hz),
7.72 (t, 1H, J ) 7.7 Hz), 7.59 (t, 1H, J ) 7.5 Hz), 5.92 and 5.62 (two d,
1H, J ) 16.3 and 16.1 Hz), 4.59 and 4.50 (two s, 2H), 4.19 and 4.15 (two
q, 2H, J ) 7.1 and 7.2 Hz), 3.42 and 3.40 (two s, 3H), 1.24 and 1.21 (two
t, 3H, J ) 7.1 and 7.2 Hz); 13C NMR (CDCl3, 100 MHz) δ 166.0, 155.5,
146.9, 146.5, 139.9, 135.1, 130.4, 130.1, 129.9, 129.1, 127.7, 127.6, 125.5,
70.7, 60.7, 58.7, 14.1; IR (film) νmax 2925, 2854, 1714, 1622, 1494, 1448,
1367, 1301, 1260, 1183, 1107, 1035, 974, 760 cm-1; FABHRMS (NBA-
NaI) m/e 315.1351 (M + H+, C17H18N2O4 requires 315.1345).
(11) NBS (1.4 equiv) and AIBN (0.14-0.19 equiv), CCl4 (reflux)
provided 7 in lower conversion (45-49%) accompanied by the dibromi-
nation product (15-24%), and larger amounts of NBS (2.0 equiv, 0.2 equiv
AIBN) provided predominately the dibrominated product (75%). For methyl
3-(dibromomethyl)quinoline-2-carboxylate: 1H NMR (CDCl3, 400 MHz)
δ 8.91 (s, 1H), 8.18 (d, 1H, J ) 8.5 Hz), 7.92 (s, 1H), 7.90 (d, 1H, J ) 8.2
Hz), 7.77 (ddd, 1H, J ) 1.5, 6.9, 8.4 Hz), 7.64 (ddd, 1H, J ) 1.1, 6.9, 8.1
Hz), 4.06 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 165.7, 146.8, 142.7,
139.8, 135.0, 131.6, 129.9, 129.3, 128.6, 127.8, 53.6, 37.0; IR (film) νmax
3062, 2950, 1721, 1558, 1489, 1455, 1436, 1304, 1195, 1168, 1139, 1070,
853, 786, 753, 694, 618 cm-1; FABHRMS (NBA-NaI) m/e 359.9072 (M
+ H+, C12H9Br2NO2 requires 359.9058).
(15) Brown, C.; Hudson, R. F.; Record, K. A. F. J. Chem. Soc., Perkin
Trans. 2 1978, 822. Brown, C.; Hudson, R. F.; Record, K. A. F. J. Chem.
Soc., Chem. Commun. 1977, 540. Hudson, R. F.; Record, K. A. F. J. Chem.
Soc., Chem. Commun. 1976, 831.
(12) Ciufolini, M. A.; Roschangar, F. Angew. Chem., Int. Ed. Engl. 1996,
35, 1692; Tetrahedron 1997, 53, 11049.

1220 J. Am. Chem. Soc., Vol. 120, No. 6, 1998
Boger and Hong
sulfonamide (1.5 equiv, 3 equiv of Et3N, CH2Cl2, -30 to 25
°C, 1 h) cleanly provided 11 (Scheme 3).8,9,17 This latter one-
step procedure afforded 1118 in high yield and of a sufficient
purity that it could be employed directly in the following Diels-
Alder reaction. Treatment of 11 with 1,1-dimethoxy-1-propene
1219 at room temperature (12 h, C6H6) led to the formation of
the sensitive [4 + 2] cycloadduct. Notably, the deliberate
incorporation of the noncomplementary C4 electron-withdrawing
substituent resulted in a Diels-Alder cycloaddition that pro-
ceeded at 25 °C presumably by lowering the diene LUMO
without altering the inherent [4 + 2] cycloaddition regioselec-
tivity. Due to the expected sensitivity of the Diels-Alder adduct
to hydrolysis, subsequent aromatization of the crude adduct (t-
BuOK, THF, -35 °C, 30 min) to provide 13 was conducted in
yields as high as 65% from 10 (3 steps) without intermediate
isolations. Presumably, aromatization proceeds by initial base-
catalyzed elimination of methanesulfinic acid which is facilitated
by the C4-CO2Me substitution followed by elimination of
methanol to provide 13.8
(S)-(-)-mappicine (73%, 99.9% ee) which exhibited a CD
spectrum identical with that described for naturally occurring
material confirming the original absolute configuration assign-
ment.2 The enantiomeric purity of the synthetic sample was
established by HPLC resolution of the enantiomers on a
ChiralCel OD column (R ) 1.19) enlisting racemic 3 for
comparison. The cytotoxic evaluation (L1210) of 1, 3, and
related synthetic intermediates revealed that 1 (40 µM), 13 (85
µM), and 14 (>280 µM) were essentially inactive and both (-)-
(S)-3, which to our knowledge has not been reported previously
as well as (+)-(R)-3 was also only weakly cytotoxic (IC50
13 and 23 µM, respectively).
)
Thus, concise and efficient total syntheses of nothapodytine
B (1, six steps from 9,12 35% overall; 11 steps from 2-ami-
nobenzaldehyde, 17% overall) and (S)-(-)-mappicine (3) based
on the implemenation of a room temperature [4 + 2] cycload-
dition of a N-sulfonyl-1-azadiene was accomplished and suggest
straightforward extensions to camptothecin and related ana-
logues. These and related efforts are in progress and will be
reported in due course.
Addition of EtMgBr to 13 in the presence of a tertiary amine20
(EtMgBr, Et3N, toluene, -10 °C, 4 h, 79%) proceeded cleanly
to give the corresponding ethyl ketone 14 without competitive
tertiary alcohol formation by virtue of tertiary amine-promoted
ketone enolization. The final conversion of 14 to 1 required
deprotection of both the benzylic and pyridone methyl ethers
and subsequent cyclization to form the C ring. This was
accomplished in one operation by treatment of 14 with a
saturated solution of HBr(g) in CF3CH2OH (80 °C, 24 h)8
followed by the addition of K2CO3 (25 °C, 1 h) to provide 1
directly without workup and isolation of the intermediate
benzylic bromide. This approach worked beautifully to give 1
in 88% overall yield, and the final product proved identical in
all respects with the properties reported for authentic material.1,6
Preliminary efforts involving treatment of 14 with BBr3 (CH2-
Cl2, -78 to 25 °C, 24 h) were less successful and gave a 1:1
mixture of 1 and benzyl alcohol 15 (eq 1).18 Prolonged reaction
times and elevated temperatures did not change this product
ratio suggesting that alcohol 15 was not an intermediate in route
to 1 but a competitive side product.
Experimental Section
Methyl 3-(Bromomethyl)quinoline-2-carboxylate (7). A solution
of 610 (2.8 g, 13.9 mmol) in CCl4 (200 mL) was treated with
1,3-dibromo-5,5-dimethylhydantoin (2.0 g, 6.9 mmol) and benzoyl
peroxide (166 mg, 0.7 mmol) and warmed at reflux under N2 for 5 h.
The reaction mixture was filtered through SiO2 (15% EtOAc-hexane),
and the filtrate was concentrated under reduced pressure. Chromatog-
raphy (SiO2, 10% EtOAc-hexane) afforded 7 (3.0 g, 78%) as a white
solid: Rf 0.4 (25% EtOAc-hexane, dibromide Rf 0.5); mp 85-86 °C;
1H NMR (CDCl3, 400 MHz) δ 8.24 (s, 1H), 8.19 (d, 1H, J ) 8.5 Hz),
7.80 (d, 1H, J ) 8.1 Hz), 7.75 (ddd, 1H, J ) 1.4, 6.9, 8.4 Hz), 7.61
(ddd, 1H, J ) 1.1, 7.0, 8.1 Hz), 4.95 (s, 2H), 4.00 (s, 3H); 13C NMR
(CDCl3, 100 MHz) δ 165.9, 147.4, 146.3, 138.6, 130.7, 130.4, 129.8,
128.8, 128.2, 127.2, 53.2, 30.1; IR (film) νmax 2916, 1712, 1454, 1300,
1218, 1199, 1137, 1077, 776, 752 cm-1; FABHRMS (NBA-NaI) m/e
279.9983 (M + H+, C12H10BrNO2 requires 279.9973).
Anal. Calcd for C12H10BrNO2: C, 51.45; H, 3.60; N, 5.00. Found:
C, 51.58; H, 3.48; N, 4.76.
Methyl 3-(Methoxymethyl)quinoline-2-carboxylate (8).12 A solu-
tion of 7 (194 mg, 0.69 mmol) in MeOH (25 mL) was treated cautiously
with concentrated H2SO4 (682 mg, 6.9 mmol) and warmed at reflux
under N2 for 16 h. After cooling, the reaction mixture was neutralized
with the addition of saturated aqueous NaHCO3 (pH ) 8) extracted
with EtOAc (3 × 50 mL), and the organic layer was dried (MgSO4)
and concentrated under reduced pressure. Chromatography (SiO2, 40%
EtOAc-hexane) afforded 8 (142 mg, 89%) as a white solid: mp 68-
69 °C (lit.12 mp 63-64 °C); H NMR (CDCl3, 250 MHz) δ 8.43 (s,
1
Reduction of 1 with NaBH4 as first described by Kametani
and later by Kingsbury and Comins provided (()-mappicine
(3).6 Additionally, reduction of 1 with (S)-BINAL-H21 provided
1H), 8.19 (d, 1H, J ) 8.5 Hz), 7.82 (d, 1H, J ) 8.1 Hz), 7.71 (ddd,
1H, J ) 1.4, 6.9, 8.4 Hz), 7.61 (ddd, 1H, J ) 1.0, 8.1, 8.6 Hz), 4.90
(s, 2H), 4.03 (s, 3H), 3.49 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ
166.3, 146.5, 146.0, 135.3, 131.8, 129.8 (2C), 128.7, 128.4, 127.3, 71.1,
58.7, 52.9; IR (film) νmax 2950, 1725, 1565, 1456, 1299, 1207, 1138,
1111, 1070, 785, 754 cm-1; FABHRMS (NBA-NaI) m/e 232.0981 (M
+ H+, C13H13NO3 requires 232.0974).
(16) Boger, D. L.; Corbett, W. L. J. Org. Chem. 1992, 57, 4777.
(17) Jennings, W. B.; Lovely, C. J. Tetrahedron Lett. 1988, 29, 3725.
(18) For 11: 1H NMR (CDCl3, 250 MHz) 1:1 mixture of syn:anti
isomers: δ 8.31 and 7.48 (two d, 1H, J ) 16 and 16 Hz), 8.26 and 8.17
(two s, 1H), 8.09 and 7.85 (two d, 1H, J ) 8.3 and 8.1 Hz), 6.19 and 6.07
(two d, 1H, J ) 16 and 16 Hz), 4.65 and 4.60 (two s, 2H), 4.21 (q, 2H, J
) 7.1 Hz), 3.43 and 3.39 (two s, 3H), 3.22 and 3.13 (two s, 3H), 1.27 (t,
3H, J ) 7.1 Hz); FABMS (NBA-NaI) m/e 377 (M + H+, C18H20N2O5S
requires 377). For alcohol 15: 1H NMR (CDCl3, 400 MHz) δ 8.25 (bs,
1H), 8.15 (bs, 1H), 7.93 (s, 1H), 7.86 (d, 1H, J ) 8.0 Hz), 7.74 (t, 1H, J
) 7.7 Hz), 7.58 (t, 1H, J ) 7.4 Hz), 5.30 (bs, 1H), 4.83 (d, 2H, J ) 5.2
Hz), 4.06 (s, 3H), 2.97 (q, 2H, J ) 7.1 Hz), 2.28 (s, 3H), 1.23 (t, 3H, J )
7.1 Hz); FABHRMS (NBA-NaI) m/e 337.1564 (M + H+, C20H20N2O3
requires 337.1552).
Anal. Calcd for C13H13NO3: C, 67.52; H, 5.67; N, 6.06. Found:
C, 67.21; H, 5.47; N, 6.09.
Dimethyl [2-[3-(Methoxymethyl)quinolin-2-yl]-2-oxoethyl]phos-
phonate (9).12 A solution of dimethyl methylphosphonate (1.93 mL,
17.3 mmol) in anhydrous THF (20 mL) under N2 at -78 °C was treated
with n-BuLi (1.6 M in hexane, 10.81 mL), and the solution was allowed
to stir at -78 °C for 30 min before a solution of 8 (1.0 g, 4.32 mmol)
in anhydrous THF (10 mL) was added. The resulting yellow solution
was stirred at -78 °C for 1 h and quenched with the addition of
saturated aqueous NH4Cl (10 mL). The reaction mixture was extracted
with EtOAc (3 × 30 mL), and the organic layer was dried (Na2SO4)
and concentrated under reduced pressure. Chromatography (SiO2, 90%
(19) Mueller, F. J.; Eichen, K. German Patent 2331675; Chem. Abstr.
1974, 81, 63153v.
(20) Kikkawa, I.; Yorifuji, T. Synthesis 1980, 877.
(21) Noyori, R.; Tomino, I.; Tanimoto, Y.; Nishizawa, M. J. Am. Chem.
Soc. 1984, 106, 6709.

Synthesis of Nothapodytine B and (-)-Mappicine
J. Am. Chem. Soc., Vol. 120, No. 6, 1998 1221
EtOAc-hexane) afforded 9 (1.37 g, 98%) as a white solid: mp 46-
(200 mg, 1.8 mmol). After stirring at -35 °C for 30 min, the reaction
mixture was diluted and extracted with EtOAc (2 × 20 mL), and the
organic layer was dried (Na2SO4) and concentrated under reduced
pressure. Chromatography (SiO2, 7% EtOAc-hexane) afforded 13 (55
mg, 64%; typically 40-65%) as a white solid: mp 80-81 °C; 1H NMR
(CDCl3, 250 MHz) δ 8.42 (s, 1H), 8.14 (d, 1H, J ) 8.4 Hz), 8.10 (s,
1H), 7.84 (d, 1H, J ) 8.1 Hz), 7.68 (ddd, 1H, J ) 1.3, 6.9, 8.3 Hz),
7.52 (ddd, 1H, J ) 1.0, 8.0, 8.9 Hz), 5.05 (s, 2H), 4.39 (q, 2H, J ) 7.1
Hz), 4.02 (s, 3H), 3.46 (s, 3H), 3.46 (s, 3H), 1.39 (t, 3H, J ) 7.1 Hz);
13C NMR (CDCl3, 100 MHz) δ 166.7, 161.8, 154.4, 152.8, 146.6, 140.5,
134.5, 131.1, 129.3, 129.3, 127.7, 127.4, 126.9, 121.3, 117.0, 72.4,
61.5, 58.6, 54.3, 14.2, 12.7; IR (film) νmax 2978, 1722, 1599, 1567,
1451, 1359, 1236, 1105, 1065, 927 cm-1; FABHRMS (NBA-NaI) m/e
367.1650 (M + H+, C21H22N2O4 requires 367.1658).
1
47 °C (lit.12 mp 51 °C); H NMR (CDCl3, 400 MHz) δ 8.30 (s, 1H),
7.96 (d, 1H, J ) 8.4 Hz), 7.68 (d, 1H, J ) 8.1 Hz), 7.58 (ddd, 1H, J
) 1.4, 6.9, 8.4 Hz), 7.46 (ddd, 1H, J ) 1.2, 7.0, 8.1 Hz), 4.79 (s, 2H),
4.07 (d, 2H, J ) 22.1 Hz), 3.61 (d, 6H, J ) 11.2 Hz), 3.40 (s, 3H); 13
C
NMR (CDCl3, 100 MHz) δ 195.0 (d, J ) 7 Hz), 148.7, 145.0, 134.3,
132.3, 129.51, 129.45, 128.9, 128.7, 127.1, 70.8, 58.5, 52.49, 52.45,
36.3 (d, J ) 130 Hz); IR (film) νmax 2954, 1696, 1453, 1258, 1191,
1115, 1031, 990, 880, 849, 792, 755 cm-1; FABHRMS (NBA-NaI)
m/e 324.1010 (M + H+, C15H18NO5P requires 324.1001).
Anal. Calcd for C15H18NO5P: C, 55.73; H, 5.61; N, 4.33. Found:
C, 55.68; H, 5.93; N, 4.05.
Ethyl 4-[3-(Methoxymethyl)quinolin-2-yl]-4-oxo-2(E)-butenoate
(10). Method A. A solution of t-BuOK (256 mg, 2.3 mmol) in
anhydrous DME (5 mL) at -20 °C was treated with 9 (618 mg, 1.9
mmol) in DME (10 mL) and ethyl glyoxylate (50% in toluene, 0.75
mL, 3.8 mmol) sequentially. The reaction mixture was warmed to 25
°C gradually and stirred at 25 °C for 5 h. The resulting solution was
diluted and extracted with EtOAc (2 × 25 mL), and the organic layer
was dried (Na2SO4) and concentrated under reduced pressure. Chro-
matography (SiO2, 10% EtOAc-hexane) afforded 10 (446 mg, 78%)
as a white solid (trans:cis ) 4:1). Careful chromatography was
employed to obtain samples of the pure trans and cis isomers.
Method B. A solution of K2CO3 (207 mg, 1.1 mmol) in anhydrous
DMF (2 mL) at -20 °C was treated with 9 (227 mg, 0.70 mmol) in
DMF (2 mL) and ethyl glyoxylate (50% in toluene, 0.28 mL, 1.4 mmol)
sequentially. The reaction mixture was warmed to 25 °C gradually
and stirred at 25 °C for 24 h. The resulting solution was diluted and
extracted with EtOAc (2 × 25 mL), and the organic layer was dried
(Na2SO4) and concentrated under reduced pressure. Chromatography
(SiO2, 10% EtOAc-hexane) afforded 10 (137 mg, 65%) as a white
solid (trans:cis ) 4:1).
Anal. Calcd for C21H22N2O4: C, 68.84; H, 6.05; N, 7.65. Found:
C, 68.77; H, 6.25; N, 7.27.
1-[2-[3-(Methoxymethyl)quinolin-2-yl]-6-methoxy-5-methylpyri-
din-4-yl]propan-1-one (14). A solution of 13 (27.4 mg, 0.08 mmol)
in anhydrous toluene (2.8 mL) under N2 was treated with Et3N (0.13
mL, 0.90 mmol) and EtMgBr (3.0 M in Et2O, 0.15 mL), and stirred at
-10 °C for 4 h. The reaction mixture was quenched with the addition
of saturated aqueous NH4Cl (0.3 mL) and extracted with EtOAc (2 ×
20 mL), and the organic layer was dried (Na2SO4) and concentrated
under reduced pressure. Chromatography (SiO2, 7% EtOAc-hexane)
1
afforded 14 (20.8 mg, 79%) as a white solid: mp 117-118 °C; H
NMR (CDCl3, 400 MHz) δ 8.44 (s, 1H), 8.11 (d, 1H, J ) 8.4 Hz),
7.86 (s, 1H), 7.85 (d, 1H, J ) 7.8 Hz), 7.69 (td, 1H, J ) 1.1, 8.2 Hz),
7.54 (t, 1H, J ) 7.3 Hz), 5.07 (s, 2H), 4.02 (s, 3H), 3.48 (s, 3H), 2.96
(q, 2H, J ) 7.2 Hz), 2.27 (s, 3H), 1.22 (t, 3H, J ) 7.2 Hz); 13C NMR
(CDCl3, 100 MHz) δ 205.6, 161.8, 154.3, 153.1, 149.1, 146.5, 134.6,
131.2, 129.3, 129.2, 127.8, 127.5, 126.9, 117.9, 114.5, 72.4, 58.7, 54.2,
35.9, 12.5, 7.8; IR (film) νmax 2942, 1697, 1597, 1562, 1453, 1358,
1220, 1105, 750 cm-1; FABHRMS (NBA-NaI) m/e 351.1719 (M +
H+, C21H22N2O3 requires 351.1709).
Trans isomer: mp 63-64 °C; Rf ) 0.50 (SiO2, 17% EtOAc-
1
hexane); H NMR (CDCl3, 400 MHz) δ 8.60 (d, 1H, J ) 15.9 Hz),
Anal. Calcd for C21H22N2O3: C, 71.98; H, 6.33; N, 7.99. Found:
C, 72.30; H, 5.96; N, 7.59.
8.45 (s, 1H), 8.17 (d, 1H, J ) 8.4 Hz), 7.84 (d, 1H, J ) 8.0 Hz), 7.74
(ddd, 1H, J ) 1.4, 6.8, 8.4 Hz), 7.62 (ddd, 1H, J ) 1.2, 6.8, 8.1 Hz),
6.92 (d, 1H, J ) 15.9 Hz), 4.96 (s, 2H), 4.23 (q, 2H, J ) 7.1 Hz), 3.54
(s, 3H), 1.33 (t, J ) 7.1 Hz); 13C NMR (CDCl3, 100 MHz) δ 191.0,
165.8, 150.0, 145.7, 137.6, 134.8, 132.7, 132.0, 130.1, 129.8, 129.14,
129.10, 127.5, 71.2, 61.2, 58.9, 14.2; IR (film) νmax 2981, 2923, 2817,
1719,1676, 1447, 1336, 1300, 1266, 1228, 1176, 1111, 1100, 990, 909,
776, 747 cm-1; FABHRMS (NBA-NaI) m/e 300.1242 (M + H+, C17H17-
NO4 requires 300.1236).
Nothapodytine B (1). A solution of 14 (8.8 mg, 0.03 mmol) and
2 mL of CF3CH2OH saturated with HBr(g) in a sealed vessel was
warmed in an 80 °C oil bath for 24 h. The brown reaction solution
was treated with K2CO3 (40 mg) and stirred 1 h at 25 °C. The reaction
mixture was filtered through SiO2, and the filtrate was concentrated
under reduced pressure. Chromatography (SiO2, 2% MeOH-CH2Cl2)
afforded 1 (6.7 mg, 88%) as a pale yellow solid identical with authentic
material: mp 230-231 °C, lit. mp 210-215 °C (CHCl3),1 237-238
°C (MeOH);6b 1H NMR (CDCl3, 400 MHz) δ 8.34 (s, 1H), 8.17 (d,
1H, J ) 8.6 Hz), 7.90 (d, 1H, J ) 8.2 Hz), 7.79 (ddd, 1H, J ) 1.4,
6.9, 8.4 Hz), 7.62 (ddd, 1H, J ) 1.2, 6.9, 8.1 Hz), 7.23 (s, 1H), 5.27
(s, 2H), 2.89 (q, 2H, J ) 7.2 Hz), 2.27 (s, 3H), 1.22 (t, 3H, J ) 7.2
Hz); 13C NMR (CDCl3, 100 MHz) δ 205.5, 161.7, 152.7, 148.4, 148.1,
143.3, 131.3, 130.6, 129.3, 128.6, 128.2, 128.0, 127.8, 127.3, 98.2,
50.2, 36.0, 13.7, 7.8; IR (film) νmax 1705, 1651, 1600, 1445, 1413,
1377, 1226, 1181, 1141, 761 cm-1; FABHRMS (NBA-NaI) m/e
305.1299 (M + H+, C19H16N2O2 requires 305.1290).
(()-Mappicine ((()-3). A solution of 1 (2.5 mg, 0.008 mmol) in
2 mL of 50% MeOH-CH2Cl2 under N2 was treated with NaBH4 (1.6
mg, 0.04 mmol) and stirred at 25 °C for 1 h. The reaction mixture
was quenched with the addition of 0.02 mL of H2O and concentrated
under reduced pressure. The residue was dissolved in 50% EtOAc-
CH2Cl2 and filtered through SiO2. After removal of solvent under
reduced pressure, chromatography (SiO2, 2% MeOH-CH2Cl2) afforded
(()-3 (2.0 mg, 80%) as a yellow solid.
Resolution of (()-3. A solution of (()-3 in i-PrOH was subjected
to chromatography on an analytical HPLC CHIRACEL OD column
(250 mm × 4.6 mm, 10% i-PrOH-hexane, 1 mL/min flow rate). The
effluent was monitored at 254 nm, and the enantiomers eluted with
retention time of 31.4 min ((-)-3) and 37.5 min (ent-(+)-3), respectively
(R ) 1.19).
(S)-(-)-Mappacine ((-)-3). A solution of 1 (1.5 mg, 0.005 mmol)
in anhydrous THF (3 mL) under N2 was treated dropwise with (S)-
BINAL-H (0.37 M in THF, 0.07 mL)21 at -95 °C and stirred at -95
°C for 1 h. The reaction mixture was quickly warmed to -78 °C and
Anal. Calcd for C17H17NO4: C, 68.21; H, 5.72; N, 4.68. Found:
C, 68.09; H, 6.10; N, 4.39.
Cis isomer: mp 74-75 °C; Rf ) 0.45 (SiO2, 17% EtOAc-hexane);
1H NMR (CDCl3, 400 MHz) δ 8.49 (s, 1H), 8.08 (d, 1H, J ) 8.1 Hz),
7.85 (d, 1H, J ) 8.1 Hz), 7.70 (ddd, 1H, J ) 1.5, 6.9, 8.4 Hz), 7.60
(ddd, 1H, J ) 1.2, 6.9, 8.1 Hz), 7.43 (d, 1H, J ) 12.1 Hz), 6.28 (d,
1H, J ) 12.0 Hz), 5.07 (s, 2H), 4.03 (q, 2H, J ) 7.2 Hz), 3.60 (s, 3H),
1.16 (t, 3H, J ) 7.2 Hz); 13C NMR (CDCl3, 100 MHz) δ 195.3, 165.7,
150.4, 145.4, 141.5, 134.1, 132.6, 129.8, 129.5, 129.1, 128.7, 127.4,
125.8, 70.7, 60.7, 58.8, 13.7; IR (film) νmax 2982, 2933, 2821, 1714,
1688, 1454, 1382, 1280, 1218, 1159, 1119, 1100, 1029, 949, 784, 755
cm-1; FABHRMS (NBA-NaI) m/e 300.1246 (M + H+, C17H17NO4
requires 300.1236).
Anal. Calcd for C17H17NO4: C, 68.21; H, 5.72; N, 4.68. Found:
C, 68.19; H, 5.79; N, 4.54.
Ethyl 2-[3-(Methoxymethyl)quinolin-2-yl]-6-methoxy-5-meth-
ylpyridine-4-carboxylate (13). A solution of 10 (70 mg, 0.23 mmol)
and CH3SO2NH2 (34 mg, 0.35 mmol) in anhydrous CH2Cl2 (8 mL) at
-30 °C under N2 was treated with TiCl4 (1.0 M in CH2Cl2, 0.3 mL)
and Et3N (0.11 mL, 0.70 mmol) sequentially and warmed to 25 °C
gradually (1 h). After stirring for an additional 1 h at 25 °C, the reaction
mixture was filtered through Celite (50% EtOAc-hexane, 1 drop of
Et3N), and the filtrate was concentrated under reduced pressure. A
solution of crude N-sulfonyl-1-aza-1,3-butadiene 1118 (0.23 mmol) and
1,1-dimethoxy-1-propene (12,19 0.3 mL) in 2 mL of anhydrous C6H6
was stirred at 25 °C for 12 h under N2, and the reaction mixture was
concentrated in vacuo. The residue was dissolved in 2.3 mL of
anhydrous THF, cooled to -35 °C under N2, and treated with t-BuOK

1222 J. Am. Chem. Soc., Vol. 120, No. 6, 1998
Boger and Hong
stirred at -78 °C for 16 h. The reaction was quenched with the addition
of MeOH (0.2 mL), and the reaction mixture was filtered through SiO2
(2% MeOH-CH2Cl2). The filtrate was concentrated under reduced
pressure, and chromatography (SiO2, 2% MeOH-CH2Cl2) afforded
(-)-3 (1.1 mg, 73%, 99.9% ee) as a yellow solid identical with authentic
material: [R]25 -11.0 (c 0.0005, CHCl3-MeOH 4:1) (lit.6d [R]25
-7.4° (c 0.1, CHCl3-MeOH 4:1, 60% ee)); CD [θ]375 -1583° (c
0.0022, dioxane) (lit2 [θ]375 -1524° (c 0.024, dioxane)); 1H NMR
(CDCl3-CD3OD 5:1, 400 MHz) δ 8.27 (s, 1H), 8.02 (d, 1H, J ) 8.6
Hz), 7.79 (d, 1H, J ) 8.2 Hz), 7.69 (ddd, 1H, J ) 1.4, 6.9, 8.4 Hz),
7.51 (m, 2H), 5.152 (d, 1H, J ) 1 Hz), 5.145 (d, 1H, J ) 1 Hz), 4.78
(dd, 1H, J ) 5.6, 7.4 Hz), 2.14 (s, 3H), 1.67 (m, 2H), 0.92 (t, 3H, J )
7.4 Hz); 13C NMR (CDCl3-CD3OD 5:1, 100 MHz) δ 161.7, 154.8,
148.1, 131.4, 130.5, 128.52, 128.45, 128.1, 127.8, 127.5, 125.0, 100.3,
71.0, 50.0, 30.0, 11.7, 9.8; FABHRMS (NBA-NaI) m/e 307.1438 (M
+ H+, C19H18N2O2 requires 307.1447).
Acknowledgment. We gratefully thank the National Insti-
tutes of Health for financial support (CA 42056), Dr. Q. Jin for
conducting the cytotoxicity testing, D. H. Lee for the CD
measurements, and Dr. K. Mbiya for preliminary efforts leading
to the preparation of 10.
D
D
Supporting Information Available: A detailed experimen-
tal procedure and full characterization for 6 is provided (1 page).
See any current masthead page for ordering and Internet access
instructions.
JA973007Y