Synthesis of (-)-lapatin B

Article abstract of DOI:10.1016/j.tetlet.2007.06.089

The synthesis of (-)-lapatin B (1) has been achieved from l-tryptophan. The key reactions involve oxidative cyclization of N,N-diacetylglyantrypine (8) using PhI(OH)(OTs), and an indole-to-oxindole transformation in the penultimate step.

Full text of DOI:10.1016/j.tetlet.2007.06.089

Tetrahedron Letters 48 (2007) 6214–6216
Synthesis of (À)-lapatin B
Steven J. Walker and David J. Hart*
Department of Chemistry, The Ohio State University, 100 W. 18th Avenue, Columbus, OH 43210, USA
Received 3 May 2007; accepted 18 June 2007
Available online 23 June 2007
Abstract—The synthesis of (À)-lapatin B (1) has been achieved from L-tryptophan. The key reactions involve oxidative cyclization
of N,N-diacetylglyantrypine (8) using PhI(OH)(OTs), and an indole-to-oxindole transformation in the penultimate step.
Ó 2007 Elsevier Ltd. All rights reserved.
16
(À)-Lapatin B (1) is a member of a growing family of
17
spirooxindole-containing quinazolinone alkaloids whose
structure was reported by the Larsen group in 2005 after
isolation from the fungus Penicillium lapatayae.1 Lapa-
tin B closely resembles (+)-alantrypinone (2) whose
structure was reported in 1998 after isolation from
Penicillium thymicola.2,3 One interesting relationship
between lapatin B and alantrypinone is their pseudo-
enantiomeric relationship. The absolute configuration
of alantrypinone was initially determined by X-ray crys-
tallography and has been confirmed by synthesis of its
enantiomer.2,4,5 The absolute configuration of lapatin
B has been suggested based on a comparison of its CD
spectrum with that of alantrypinone.1 This Letter
describes an enantioselective synthesis of (À)-lapatin B
(1) from L-tryptophan that confirms the aforementioned
assignment of absolute stereochemistry.6
15
H
H
18
N
N14
13
19
20
O
O
5
H3C
H
4
6
N
N
H
H
N
N
2
10
N
O
N
7
9
11
O
O
8
O
1 (-)-Lapatin B
2 (+)-Alantrypinone
H
O
N
O
N
2
11
N
N
H
H
N
H
N
N
H
N
The strategy used to prepare lapatin B (1), outlined in
Figure 1, mimics our previously reported approach to
alantrypinone. We planned to use (+)-glyantrypine (3)
as a point of departure.7 We hoped that C2 oxidation
of this alkaloid (lapatin B numbering), followed by an
N-acyliminium ion cyclization, would provide bridged
indole 4. An indole-to-oxindole rearrangement was then
to be used to provide lapatin-B (1).
O
O
3 (+)-glyantrypine
4
Figure 1. Structure of lapatin B and synthetic plan.
the syntheses of both enantiomers of glyantrypine that
rely on an Eguchi cyclization in the key step.9,10 The
Ganesan group has reported a four-step synthesis of
(À)-glyantrypine from anthranilic acid, D-tryptophan
methyl ester and N-Fmoc-glycine.11 We decided to pre-
pare 3 using a variation of the Ganesan synthesis
(Scheme 1). We began by preparing iminobenzoxazine
7 as described in the literature.11 Isatoic anhydride was
treated with the methyl ester of L-tryptophan to provide
amide 5 in 61% yield. Acylation of aniline with the acid
chloride of N-Fmoc-glycine provided 6 in 70% yield.
Treatment of 6 with triphenylphosphine and iodine in
Several syntheses of glyantrypine have been reported.
The most efficient synthesis of (À)-glyantrypine was
reported by the Liu group.8 This synthesis requires only
two steps from anthranilic acid, N-Boc-glycine and
D-tryptophan methyl ester and relies on microwave reac-
tion technology. The Avendano group has reported
*
Corresponding author. Tel.: +1 614 292 1677; fax: +1 614 292
1685; e-mail: hart@chemistry.ohio-state.edu
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.06.089

S. J. Walker, D. J. Hart / Tetrahedron Letters 48 (2007) 6214–6216
6215
R
O
N
O
N
N
H
11
R
O
N
2
R
N
N
PhI(OH)(OTs)
N
N
R
O
9 R = Ac
CH3ONa (cat), CH3OH
4 R = H
3 R = H
Ac2O (see text)
8 R = Ac
Scheme 1. Synthesis of (+)-glyantrypine.
1. NBS, THF-CF3CO2H-H2O (2:1:1)
2. Pt/C, CH3OH, AcOH, NaOAc
the presence of Hunig’s base gave 7 in 67% yield. This
rather unstable iminobenzoxazine was rearranged to 3
using two procedures. Ganesan accomplished this rear-
rangement in 87% yield by reacting 7 with piperidine fol-
lowed by chromatography over silica gel.11 We found
that this procedure proceeded in comparable yield
(57% from 7) in our hands. We also examined
[Me3AlSPh]Li as a reagent for promoting the imino-
benzoxazine-to-quinazoline rearrangement. This is a
reagent we used for a comparable transformation in
our synthesis of ent-(À)-alantrypinone.4,12 We found
that the use of this aluminum reagent, followed by a
brief treatment with piperidine to remove the Fmoc pro-
tecting group, mediated the transformation of 7 to (+)-
glyantrypine (3) in 47% yield.
H
N
H
N
H
19
O
13
13
2
19
O
H
N
H
N
2
N
H
N
N
N
O
O
O
O
10 13-epi-Lapatin B
Scheme 2. Synthesis of (À)-lapatin B.
1 (-)-Lapatin B
acetic anhydride (243 equiv) and pyridine (2 equiv) at
150 °C for 19 h provided 8 in 67% yield. Unfortunately,
complete racemization occurred at C11 during the course
of this reaction. With the hope of eliminating this prob-
lem, acylation was conducted using acetic anhydride
(225 equiv), pyridine (2 equiv) and 4-dimethylamino-
pyridine (0.15 equiv) at 80 °C for 1.5 h or at room tem-
perature for 24 h. This gave 8 in 81% yield, but nearly
complete racemization was still observed. We next
examined acidic acylation conditions and found that
treatment of (+)-3 with acetic anhydride (219 equiv)
and boron trifluoride etherate (2 equiv) at room temper-
ature for 72 h provided optically active 8 {[a]D +212 (c
0.10, CHCl3)} in 62% yield. Treatment of (+)-8 with
Koser’s reagent [PhI(OH)(OTs)]15 (1.1 equiv) in acetoni-
trile at 85 °C for 5 h gave bridged indole 9 {[a]D +150 (c
0.19, CHCl3)} in 35% yield after purification by column
A few comments about glyantrypine are warranted. The
(+)-glyantrypine (3) prepared as described in Scheme 1
was purified by crystallization from methanol. Crystals
of this material (regardless of the method of prepara-
tion) contained 1 equiv of methanol by both 1H and
13C NMR spectroscopies. The melting point of (+)-3
prepared by either rearrangement method (158–161 °C)
matched two reports in the literature (159–161 °C11
and 155–157 °C8), but did not match a third report
(mp 86–87 °C9). The specific rotations of the (+)-3 pre-
pared as described in Scheme 1 {[a]D +522 (c 0.12,
CHCl3) using piperidine11 and +512 (c 0.12, CHCl3)
using the aluminum reagent4} compared well with three
values reported for the enantiomer {[a]D À522 (c 0.24,
CHCl3),11 À535 (c, 0.028, CHCl3),8 À541 (c 0.24,
CHCl3)10}, but did not compare well with a fourth re-
port {[a]D +150 (c 0.105, DMSO),8 whereas the material
prepared as described in Scheme 2 exhibited [a]D +662 (c
0.13, DMSO)}. We note that the specific rotations for
our materials are corrected for the amount of methanol
known to be present in each sample. We are unable to
tell whether or not methanol was present in materials
for which data are reported in the literature.8,10,11 We
think the aforementioned data, in addition to compari-
son data in the literature, indicate that the (+)-3 used
in our subsequent studies was largely one enantiomer
(although we did not perform a chiral HPLC analysis).8
1
chromatography. We were surprised to find that the H
NMR signal for the C2 methine appeared as a singlet at
d 7.93. Support for this assignment, however, was read-
ily available from the HMQC spectrum, which revealed
a correlation between this signal and a methine at d 50.5
in the 13C NMR spectrum of 9. This extraordinary
downfield shift most likely results from sandwiching of
the C2 methine between the two oxygens of the acetyl
groups in 9. Upon treatment with a catalytic amount
of sodium methoxide in methanol, the N-acetyl groups
of 9 were removed to provide (+)-4 in 60% yield {[a]D
+119 (c 0.10, EtOAc)}. In accord with expectations,
the C2 methine appeared at a more normal chemical
shift of d 5.34 in 4. The synthesis of (+)-lapatin B was
completed upon treatment of 4 with N-bromosuccini-
mide (4 equiv) in THF–TFA–H2O (2:1:1) for 5 h, fol-
lowed by hydrogenolysis of the resulting brominated
oxindoles over Pt–C in methanol and acetic acid con-
The conversion of (+)-glyantrypine (3) to lapatin-B (1)
is outlined in Scheme 2. The key step, an oxidative cycli-
zation of N,N-diacetylglyantrypine (8) to bridged indole
9, was modeled after reports from the Avendano
group.13,14 Thus, heating (+)-3 with a large excess of

6216
S. J. Walker, D. J. Hart / Tetrahedron Letters 48 (2007) 6214–6216
taining a small amount of sodium acetate.16,17 Separa-
tion of the resulting mixture of products by preparative
thin layer chromatography over silica gel (eluted with
ethyl acetate) gave (À)-lapatin B (1) and 13-epi-(+)-lap-
atin B (10), both in 11% yield. Spectral data (1H NMR,
13C NMR, HRMS, CD) and the specific rotation {[a]D
À22.1 (c 0.375, EtOH), lit.1{[a]D À20 (c 1.6, EtOH)}
of synthetic 1 were in agreement with those reported
for the natural product. The 13-epi-(+)-lapatin B (10)
exhibited spectral data consistent with the assigned
structure.18 In particular H19 appeared as a doublet
(J = 7.5 Hz) at d 6.05, an upfield chemical shift consis-
tent with this proton being disposed over the p-system
of quinazolinone.19,20
7. For the insolation and structure determination of glyan-
trypine see: Penn, J.; Mantle, P. G.; Bilton, J. N.;
Sheppard, R. N. J. Chem. Soc., Perkin Trans. 1 1992,
1495–1496. This paper provides spectral data for the
natural product, but no melting point or specific rotation
measurements were reported. Thus, whereas both enanti-
omers of glyantrypine have been prepared by total
synthesis,8–11 the absolute configuration of the natural
product remains unknown.
8. Liu, J.-F.; Ye, P.; Zhang, B.; Bi, G.; Sargent, K.; Yu, L.;
Yohannes, D.; Baldino, C. M. J. Org. Chem. 2005, 70,
6339–6345.
´
9. Cledera, P.; Avendano, C.; Menendez, J. C. J. Org. Chem.
˜
2000, 65, 1743–1749.
´
10. Hernandez, F.; Lumetzberger, A.; Avendano, C.; So¨llhu-
˜
ber, M. Synlett 2001, 1387–1390.
11. Wang, H.; Ganesan, A. J. Org. Chem. 2000, 65, 1022–
1030.
12. For other work describing this type of rearrangement see:
He, F.; Snider, B. B. J. Org. Chem. 1999, 64, 1397–1399;
Mazurkiewicz, R. Monatsh. Chem. 1989, 120, 973–980.
In summary, the first enantioselective synthesis of lapa-
tin B (1) has been accomplished. Although the penulti-
mate step of the synthesis suffers from a low yield, the
work confirms the absolute configuration of the natural
product and clearly establishes its pseudo-enantiomeric
relationship with alantrypinone (2).
´
13. Sanchez, J. D.; Ramos, M. T.; Avendano, C. J. Org.
˜
Chem. 2001, 66, 5731–5735.
´
´
14. Martın-Santamarıa, S.; Espada, M.; Avendano, C. Tetra-
˜
hedron 1999, 55, 1755–1762.
Acknowledgments
15. Koser, G. F.; Relenyi, A. G.; Kalos, A. N.; Rebrovic, L.;
Wettach, R. H. J. Org. Chem. 1982, 47, 2487–2489.
16. A number of oxindole-to-indole reaction sequences have
been reported. We followed the protocols described by
Pellegrini [Pellegrini, C.; Stra¨ssler, C.; Weber, M.;
Borschberg, H.-J. Tetrahedron: Asymmetry 1994, 5,
1979–1992; Stahl, R.; Borschberg, H.-J.; Acklin, P. Helv.
Chim. Acta 1996, 79, 1361–1378] and did not examine
other protocols.
We thank Dr. Olivier Loiseleur and his coworkers for dis-
closure of their work on lapatin B and for copies of NMR
spectra of (rac)-1 and (rac)-10, and Mr. Eric King and Dr.
Thomas Magliery for assistance with the CD spectrum.
Supplementary data
17. The predominant products from this procedure were
brominated at C18 prior to hydrogenolysis. This behavior
was also reported in our work on alantrypinone.4
18. Some properties of 13-epi-lapatin B (10) follow: 1H NMR
(DMSO-d6) d 2.35 (dd, J = 11.2, 2.8 Hz, 1H, CH2), 4.40
(d, J = 4.4 Hz, 1H), 5.55 (d, J = 1.2 Hz, 1H), 6.05 (d,
J = 7.5 Hz, 1H, ArH), 6.67 (t, J = 6.0 Hz, 1H), 6.90 (d,
J = 6.4 Hz, 1H), 7.17 (t, J = 6.0 Hz, 1H), 7.32–7.66 (m,
2H), 7.88 (t, J = 6.0 Hz, 1H), 8.27 (d, J = 6.4 Hz, 1H),
9.24 (q, J = 1.2 Hz, 1H), 10.72 (br s, 1H); The geminal
partner to the C12 methylene signal at d 2.35 is obscured
by signals from the solvent (DMSO-d6), but its presence
was revealed in the COSY spectrum. Therefore the
chemical shift of the other C12 methylene is approximately
d 2.50, but we cannot report its multiplicity; 13C NMR
(DMSO-d6) d 34.3 (CH2), 49.7 (C), 53.1 (CH), 59.4 (CH),
110.2 (CH), 120.9 (C), 121.9 (CH), 124.3 (CH), 127.1
(CH), 128.0 (CH), 128.1 (CH), 129.4 (CH), 129.7 (C),
135.4 (CH), 142.3 (C), 147.1 (C), 151.3 (C), 158.6 (C),
169.1 (C), 177.9 (C); [a]D À4.9 (c 0.35, CH3CN); HRMS
(electrospray ionization) calcd for C20H14N4O3Na
381.0964, found 381.0964; Compound 10 (Rf = 0.21 on
silica gel eluted with ethyl acetate) was considerably more
polar than 1 (Rf = 0.40 on silica gel eluted with ethyl
acetate) as expected based on its structure. We have
reported similar observations for alantrypinone (2) and its
related epimer.4
1H and 13C NMR spectra. Supplementary data associ-
ated with this article can be found, in the online version,
at doi:10.1016/j.tetlet.2007.06.089.
References and notes
1. Larsen, T. O.; Petersen, B. O.; Duus, J. Ø.; Sørensen, D.;
Frisvad, J. C.; Hansen, M. E. J. Nat. Prod. 2005, 68, 871–
874.
2. Larsen, T. O.; Frydenvang, K.; Frisvad, J. C.; Christo-
phersen, C. J. Nat. Prod. 1998, 61, 1154–1157.
3. For other members of this family of alkaloids, see:
Barrow, C. J.; Sun, H. H. J. Nat. Prod. 1994, 57, 471–
476 (spiroquinazoline); Ariza, M. R.; Larsen, T. O.;
Petersen, B. O.; Duus, J. Ø.; Christophersen, C.; Barrero,
A. F. J. Nat. Prod. 2001, 64, 1590–1592 (serantrypinone);
Kuriyama, T.; Kakemoto, E.; Takahashi, N.; Imamura,
K.; Oyama, K.; Suzuki, E.; Harimaya, K.; Yaguchi, T.;
Ozoe, Y. J. Agric. Food Chem. 2004, 52, 3884–3887
(alantrypinone and serantrypinone); Proenc¸a Barros, F.
A.; Rodrigues-Filho, E. Biochem. Syst. Ecol. 2005, 33,
257–268 (alanditrypinone, alantryphenone and alantr-
yleunone); For a relevant review see: Mhaske, S. B.;
Argade, N. P. Tetrahedron 2006, 62, 9787–9826.
4. Hart, D. J.; Magomedov, N. A. Tetrahedron Lett. 1999,
40, 5429–5432; Hart, D. J.; Magomedov, N. A. J. Am.
Chem. Soc. 2001, 123, 5892–5899.
19. NMR spectra (1H and 13C) of the synthetic (À)-lapatin B
(1) and 13-epi-lapatin B (10) matched the spectra of
synthetic (rac)-1 and (rac)-10.6
5. For a synthesis of rac-alantrypinone see: Chen, Z.; Fan, J.;
Kende, A. S. J. Org. Chem. 2004, 69, 79–85.
6. A total synthesis of (rac)-lapatin B has recently been
described: Leca, D.; Gaggini, F.; Cassayre, J.; Loiseleur,
O.; Pieniazek, S. N.; Luft, J. A. R.; Houk, K. N. J. Org.
Chem. 2007, 72, 4284–4287.
20. Chiral HPLC analysis (Chiracel OJ column eluted with
hexane/i-PrOH, 4:1) of synthetic 1 indicated the presence
of only one enantiomer. (rac)-Lapatin, prepared from
(rac)-8 (see text) was used to develop a baseline separation
of 1 and (ent)-1.