Synthetic studies on haplophytine: Protective-group-controlled rearrangement

Article abstract of DOI:10.1055/s-2007-990911

The characteristic tetracyclic structure of haplophytine containing a bridged ketone, aminal, and γ-lactam was constructed by oxidative rearrangement of a tetrahydro-β-carboline derivative. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-990911

LETTER
3137
Synthetic Studies on Haplophytine: Protective-Group-Controlled
Rearrangement
Synthetic Studies
o
o
n Haplophy
j
tine i Matsumoto,a Hidetoshi Tokuyama,a,b Tohru Fukuyama*a
a
Graduate School of Pharmaceutical Science, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Fax +81(3)58028694; E-mail: fukuyama@mol.f.u-tokyo.ac.jp
b
Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba 6-3, Aramaki, Aoba-ku, Sendai 980-8578, Japan
Received 8 October 2007
Me
N
Abstract: The characteristic tetracyclic structure of haplophytine
containing a bridged ketone, aminal, and g-lactam was constructed
by oxidative rearrangement of a tetrahydro-b-carboline derivative.
O
N
O
N
O
N
O
HO
Key words: haplophytine, aspidophytine, alkaloids, oxidations, re-
arrangements
O
MeO
N
H
O
MeO
N
MeO
Me
H
MeO
Me
haplophytine (1)
Haplophytine (1, Figure 1) is the major alkaloid isolated
from the leaves of the Mexican ‘cockroach plant’, Haplo-
phyton cimicidum (Apocynaceae).1 After the pioneering
work of Snyder and co-workers,2 the structure of haplo-
phytine (1) was reported by Cava and Yates in 19733 and
was unambiguously confirmed by X-ray crystallography
in 1976.4 The compound is composed of two subunits,
which are connected by forming a quaternary carbon cen-
ter. The left-hand segment is a hitherto-unknown tetracy-
clic structure including bridged ketone and aminal
functionalities. The right-half constituent, aspidophytine
(2), is a member of the aspidosperma class of alkaloids,
which was obtained by acid-mediated chemical degrada-
tion of 1.3,5 Because of its structural complexity, com-
pound 1 has attracted considerable attention as a
challenging synthetic target. While no total synthesis of 1
has been reported to date,6,7 four groups have accom-
plished the total synthesis8–11 of the right-hand segment,
aspidophytine, including Corey’s first total synthesis8 and
one by our laboratory.9 After completion of the total syn-
thesis of the right-hand segment, we continued extensive
research toward the total synthesis of haplophytine (1) and
carried out model studies for the construction of the char-
acteristic left-hand segment. Recent publication of a sim-
ilar approach by Nicolaou and co-workers7 has prompted
us to disclose our own independent effort. We herein re-
port an efficient construction of the left-hand segment via
an oxidative skeletal rearrangement.12
aspidophytine (2)
Figure 1
Me
N
O
N
N
O
HO
O
O
MeO
N
H
MeO
Me
(+)-haplophytine (1)
aq NaHCO3
aq HBr
2 Br –
Me
N
+
+
N
OH
N
O
HO
MeO
N
CO2H
H
MeO
Me
3
Scheme 1 Skeletal rearrangement of haplophytine (1)
mer 3 was converted back into the natural form 1 under
basic conditions.
Based on these observations, we postulated that the char-
acteristic left-hand segment could be formed from a di-
amino epoxide, such as 5, through an epoxide opening by
electron-pushing from one of the nitrogens to give an imi-
nium ion species 4 and subsequent 1,2-shift of the C–N
bond (Scheme 2). The diamino epoxide 5 would be ob-
tained by oxidation of the 1,2-diaminoethene derivative 6.
The key intermediate 6 would be prepared via introduc-
tion of the aspidophytine segment to the tetrahydro-b-car-
boline derivative 8 and lactam formation.
For construction of the left-hand segment, we planned to
apply the inherent skeletal rearrangement of haplophytine
(1) that was observed during its structural determination
(Scheme 1). Yates and Cava found that treatment of
haplophytine (1) with HBr promoted a skeletal rearrange-
ment as depicted in Scheme 1 to provide a tetrahydro-b-
carboline derivative 3.5c,13 In addition, the rearranged iso-
SYNLETT 2007, No. 20, pp 3137–3140
x
x
.x
x
.2
0
0
7
Advanced online publication: 21.11.2007
DOI: 10.1055/s-2007-990911; Art ID: U09707ST
© Georg Thieme Verlag Stuttgart · New York
In order to examine the strategy for the construction of the
left-hand segment, we chose 2,3-dimethoxy-N,N-dimeth-

3138
K. Matsumoto et al.
LETTER
I
haplophytine (1)
Me
N +
O –
a–c
N
N
N
H
Bn
N
Ns
Ar
EtO2C
EtO2C
N
O
N
O
9
10
NMe2
N+
R1O
N
Me
OMe
OMe
N
O–
R1O
O
MeO
N
R4
~1:1
O
H
N
MeO
d
e–g
Me
4: Ar = aspidophytine
4
Ar
Ar
N
Ns
EtO2C
O–
N
R2
N
R2
Me
N
O
12
N +
O
NMe2
R1O
R1O
OMe
O
OMe
6
5
Ar
OMe
OMe
N
h
N
N
R2
N
H
R2
N
N
N
O
Ns
N
O
Ns
R1O
R1O
CO2R3
CO2R3
aspidophytine (2)
7
8
13
14
Me
Cbz
N
+
OMe
OMe
N
Scheme 2 Retrosynthetic analysis of haplophytine
i, j
ylaniline (11) as a model compound of the aspidophytine
unit and prepared the tetrahydro-b-carboline derivative 15
as a substrate for the oxidative rearrangement reaction
(Scheme 3).
N
Ns
O
15
Synthesis of compound 15 was started by esterification of
the known tetrahydro-b-carboline derivative 9, which was
readily prepared by modified Pictet–Spengler reaction.14
After switching the benzyl group to the 2-nitrobenzene-
sulfonyl (Ns) group,15 the resultant Ns-amide was treated
with N-iodosuccinimide to give the iodoindolenine deriv-
ative 10. At this stage, introduction of 2,3-dimethoxy-
N,N-dimethylaniline (11) was investigated. We found that
a Friedel–Crafts-type alkylation proceeds when iodoindo-
lenine 10 was activated with silver triflate in the presence
of aniline derivative 11 to furnish the desired coupling
product 12 as a ca. 1:1 mixture of diastereomers in mod-
erate yield. A lactam ring was then formed by saponifica-
tion, conversion of the resultant carboxylic acid into the
acid chloride, and cyclization with Hünig’s base. In an at-
tempt to oxidize the 1,2-diamino olefin moiety of com-
pound 13 with dimethyldioxirane, we instead observed
oxidation of the N,N-dimethylaniline moiety to form the
corresponding N-oxide 14. Thus, one of the methyl groups
was switched to a Cbz group by demethylation via a
Polonovsky-type elimination and protection of the result-
ant N-methylaniline derivative with a Cbz group.
Scheme 3 Reagents and conditions: (a) H2, Pd/C, AcOH–EtOH; (b)
NsCl, Et3N, CH2Cl2, 79% (2 steps); (c) NIS, CH2Cl2; (d) 2,3-dime-
thoxy-N,N-dimethylaniline (11), AgOTf, CH2Cl2, 0 °C to r.t., 38%;
(e) KOH, EtOH, 88%; (f) SOCl2, DMF (cat.); (g) i-Pr2NEt, CH2Cl2,
32% (2 steps); (h) dimethyldioxirane, CH2Cl2–acetone; (i) Ac2O, 2,6-
lutidine, DCE; (j) CbzCl, NaH, THF–DMF, 47% (3 steps).
The structural determination of the two products by X-ray
crystallographic analysis revealed that the structure of the
minor product 16 was certainly the desired product, which
had the bridged ketone and the aminal functionalities. The
major product 17,16 however, was not the one we expect-
ed, but the tetracyclic compound possessing a pyrro-
lo[2,3-b]indole skeleton.
Plausible mechanistic details for the formation of com-
pounds 16 and 17 are depicted in Scheme 5. The desired
compound 16 (minor product) should be formed by epoxi-
dation of the 1,2-diaminoethene moiety and subsequent
ring opening of the epoxide due to electron-pushing from
nitrogen of the Ns-amide (path a) to form 19, followed by
a 1,2-shift of the C–N bond. On the other hand, opening
of the epoxide by the other nitrogen of the lactam ring
(path b) and subsequent 1,2-shift of the C–N bond would
lead to the undesired product 17 (major product). Thus,
the low selectivity of the expected rearrangement pathway
(path a) is attributed to competitive epoxide opening due
to electron-pushing from nitrogen of the lactam ring (path
b). Based on this observation, we speculated that the se-
lectivity of the mode of oxidative rearrangements should
Having synthesized the desired key intermediate 15, we
then subjected it to oxidation conditions to examine the
expected oxidation of the double bond followed by skele-
tal rearrangement (Scheme 4). Unexpectedly, treatment
of the 1,2-diaminoethene derivative 15 with MCPBA pro-
vided a mixture of two products in a ratio of 6:1, which
were separated after deprotection of Ns and Cbz groups.
Synlett 2007, No. 20, 3137–3140 © Thieme Stuttgart · New York

LETTER
Synthetic Studies on Haplophytine
3139
Me
Cbz
Me
Cbz
N
N
OMe
OMe
Me
Cbz
Ar =
N
OMe
OMe
OMe
N
a–c
Ar
OMe
N
O
Ns
b
MCPBA
N
a
N
N
Ns
N
Ns
15
O
O
NHMe
O
18
NHMe
15
OMe
OMe
OMe
path b
path a
OMe
NH
Ar
Ar
O
+
N+
N
N
N
N
H
+ N
Ns
N
Ns
O
O–
O
O
–
O
O
O
20
19
16 (desired)
16/17 = 1:6
17 (undesired)
H
N
Ar
N
Ar
O
N
N
O
O
Ns
N
N
Ns
O
Me
O
MeO
N
H
O
MeO
16' (desired)
17' (undesired)
Scheme 4 Reagents and conditions: a) MCPBA, NaHCO3, CH2Cl2,
r.t., 60 h, 64%; b) PhSH, Cs2CO3, MeCN, 79%; c) H2, Pd/C, EtOH,
94%.
Scheme 5 Two modes of the oxidative rearrangement
References and Notes
be controlled by tuning of electron density on the two ni-
trogens by switching the protective group.
(1) For a review of the earlier work on haplophytine, see:
Saxton, J. E. Alkaloids 1965, 8, 673.
(2) (a) Rogers, E. F.; Snyder, H. R.; Fischer, R. F. J. Am. Chem.
Soc. 1952, 74, 1987. (b) Snyder, H. R.; Fischer, R. F.;
Walker, J. F.; Els, H. E.; Nussberger, G. A. J. Am. Chem.
Soc. 1954, 76, 2819. (c) Snyder, H. R.; Fischer, R. F.;
Walker, J. F.; Els, H. E.; Nussberger, G. A. J. Am. Chem.
Soc. 1954, 76, 4601. (d) Synder, H. R.; Strohmayer, H. F.;
Mooney, R. A. J. Am. Chem. Soc. 1958, 80, 3708.
(3) Yates, P.; MacLachlan, F. N.; Rae, I. D.; Rosenberger, M.;
Szabo, A. G.; Willis, C. R.; Cava, M. P.; Behforouz, M.;
Lakshmikantham, M. V.; Zeigler, W. J. Am. Chem. Soc.
1973, 95, 7842.
With these considerations in mind, we prepared a sub-
strate 2517 bearing a Cbz group instead of a Ns group on
the nitrogen by an improved synthetic sequence and sub-
jected it to the oxidation conditions with MCPBA
(Scheme 6).18 Interestingly, a dramatic rate acceleration
of the oxidative rearrangement was observed and the sub-
strate 25 gave the desired tetracyclic compound 26 exclu-
sively. Finally, deprotection of the Cbz group under
hydrogenation conditions and reductive methylation gave
the model compound 27 of haplophytine (1).
(4) Cheng, P.-T.; Nyburg, S. C.; MacLachlan, F. N.; Yates, P.
Can. J. Chem. 1976, 54, 726.
In summary, we have developed a protocol to construct
the left-half segment of haplophytine. The characteristic
tetracyclic structure containing bridged ketone and aminal
functionalities was selectively formed by the protective-
group-controlled oxidative skeletal rearrangement. Syn-
thetic studies toward haplophytine based on the strategy
described in this paper are currently under investigation.
(5) (a) Cava, M. P.; Talapatra, S. K.; Nomura, K.; Weisbach, J.
A.; Douglas, B.; Shoop, E. C. Chem. Ind. (London) 1963,
1242. (b) Cava, M. P.; Talapatra, S. K.; Yates, P.;
Rosenberger, M.; Szabo, A. G.; Douglas, B.; Raffauf, R. F.;
Shoop, E. C.; Weisbach, J. A. Chem. Ind. (London) 1963,
1875. (c) Rae, I. D.; Rosenberger, M.; Szabo, A. G.; Willis,
C. R.; Yates, P.; Zacharias, D. E.; Jeffrey, G. A.; Douglas,
B.; Kirkpatrick, J. L.; Weisbach, J. A. J. Am. Chem. Soc.
1967, 89, 3061.
(6) For synthetic studies, see: (a) Yates, P.; Schwartz, D. A.
Can. J. Chem. 1983, 61, 509. (b) Schwartz, D. A.; Yates, P.
Can. J. Chem. 1983, 61, 1126. (c) Rege, P. D.; Tian, Y.;
Corey, E. J. Org. Lett. 2006, 8, 3117.
Acknowledgment
The authors thank Grant-in-Aid from the Ministry of Education,
Culture, Sports, Science and Technology of Japan, PRESTO, the Ja-
pan Science and Technology Agency, and the Uehara memorial
foundation.
(7) For a similar approach of this work, see: Nicolaou, K. C.;
Majumder, U.; Roche, S. P.; Chen, D. Y. K. Angew. Chem.
Int. Ed. 2007, 46, 4715.
Synlett 2007, No. 20, 3137–3140 © Thieme Stuttgart · New York

3140
K. Matsumoto et al.
LETTER
(13) Yates, P.; MacLachlan, F. N.; Rae, I. D.; Rosenberger, M.;
Szabo, A. G.; Willis, C. R.; Cava, M. P.; Behforouz, M.;
Lakshmikantham, M. V.; Zeigler, W. J. Am. Chem. Soc.
1973, 95, 7842.
(14) Shimizu, M.; Ishikawa, M.; Komoda, Y.; Matsubara, Y.;
Nakajima, T. Chem. Pharm. Bull. 1982, 30, 4529.
(15) (a) Kan, T.; Fukuyama, T. J. Synth. Org. Chem., Jpn. 2001,
59, 779. (b) Kurosawa, W.; Kan, T.; Fukuyama, T. Org.
Synth. 2002, 79, 186. (c) Kan, T.; Fukuyama, T. Chem.
Commun. 2004, 353.
I
Me
N
a–c
d
+
OMe
OMe
N
9
N
Cbz
EtO2C
22
21
Me
Me
N
N
OMe
OMe
N
OMe
(16) Major product 17: mp 220–222 °C (dec.); IR (film): 3419,
3332, 2937, 1732, 1666, 1610, 1516, 1481, 1400, 912, 758
cm–1. 1H NMR (400 MHz, CDCl3): d = 8.28 (d, J = 8.4 Hz,
1 H), 7.20 (t, J = 8.4 Hz, 1 H), 7.14 (d, J = 8.4 Hz, 1 H), 6.98
(t, J = 8.4 Hz, 1 H), 6.87 (d, J = 7.6 Hz, 1 H), 6.38 (d, J = 8.0
Hz, 1 H), 3.59 (s, 3 H), 3.18–3.04 (m, 3 H), 2.84 (s, 6 H),
2.82–2.77 (m, 1 H), 2.69–2.60 (m, 2 H), 2.52–2.44 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 204.8, 169.1, 149.3, 143.0,
141.9, 139.9, 135.2, 127.9, 125.7, 124.4, 123.8, 121.3,
115.7, 104.7, 93.5, 64.0, 59.1, 58.4, 45.6, 42.1, 33.7, 31.3,
30.2. HRMS–FAB: m/z calcd for C23H25N3O4 [M + H]+:
408.1923; found: 408.1918.
(17) Compound 25: IR (film): 2944, 1706, 1681, 1601, 1390,
1336, 1158, 912, 756 cm–1. 1H NMR (400 MHz, CDCl3):
d = 8.20 (d, J = 7.2 Hz, 1 H), 7.35–7.24 (m, 13 H), 7.08 (d,
J = 8.4 Hz, 1 H), 7.03 (t, J = 8.4 Hz, 1 H), 5.11 (br s, 4 H),
3.65–3.55 (m, 2 H), 3.62 (br s, 3 H), 3.59 (br s, 3 H), 3.44–
3.35 (m, 1 H), 3.27–3.20 (m, 1 H), 3.20 (s, 3 H), 2.99 (dt,
J = 7.2, 15.6 Hz, 1 H), 2.76 (dd, J = 3.6, 15.6 Hz, 1 H), 2.46
(dt, J = 5.2, 15.6 Hz, 1 H), 1.82 (dt, J = 7.2, 14.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 166.2, 155.9, 152.6, 150.2,
140.2, 137.1, 136.9, 136.4, 135.9, 133.2, 128.8, 128.7,
128.6, 128.5, 128.1, 124.6, 124.5, 123.2, 122.0, 115.9, 67.7,
67.4, 60.5, 60.1, 49.3, 41.9, 37.9, 33.4, 21.3, 14.5. HRMS–
FAB: m/z calcd for C39H37N3O7: 659.2632; found: 659.2630.
(18) Oxidative Rearrangement
~1:1
OMe
N
e, f
g, h
N
Cbz
N
Cbz
EtO2C
24
23
O
Me
Cbz
Me
Cbz
N
N
OMe
OMe
OMe
OMe
i
N
N
O
Cbz
N
O
Cbz
N
25
26
O
Me
N
Cbz
N
O
O
N
O
N
j, k
O
Me
Me
MeO
N
MeO
N
To a solution of 25 (100 mg, 0.152 mmol) in CH2Cl2 (1.5
mL) was added NaHCO3 (38.2 mg, 0.455 mmol) and
MCPBA (40.2 mg, 65% purity, 0.152 mmol) at 0 °C under
an argon atmosphere. After stirring for 2 h at the same
temperature, the reaction mixture was quenched with sat.
Na2SO3 and stirred for 10 min. Then to the two-phase
mixture was added CH2Cl2, and the organic layer was
separated. The organic layer was washed with sat. NaHCO3,
brine, and dried over Na2SO4. Filtration and concentration
on a rotary evaporator afforded a crude product. The crude
product was purified by flash column chromatography on
silica gel (neutral; 30–40% EtOAc in hexane, gradient
elution) to give 26 (84.1 mg, 82%). IR (film): 2944, 1709,
1458, 1394, 1316, 1159, 912, 756 cm–1. 1H NMR (400 MHz,
CDCl3, mixture of rotamers): d = 8.29 (d, J = 8.4 Hz, 0.5 H),
8.08 (d, J = 8.0 Hz, 0.5 H), 7.36–6.95 (m, 14 H), 6.80 (dd,
J = 7.2, 11.2 Hz, 1 H), 5.15 (br s, 2 H), 5.12 (s, 2 H), 3.83–
3.76 (m, 0.5 H), 3.68–3.52 (m, 1.5 H), 3.68 (br s, 1.5 H), 3.61
(br s, 1.5 H), 3.41–3.29 (m, 1 H), 3.25 (s, 3 H), 2.99 (br s, 1
H), 2.88–2.76 (m, 1 H), 2.80 (br s, 3 H), 2.66–2.43 (m, 1.5
H), 2.25–2.05 (m, 1 H), 1.95–1.86 (m, 0.5 H). 13C NMR (100
MHz, CDCl3, doubling due to rotamers): d = 195.2, 171.9,
168.0, 155.4, 154.6, 149.4, 149.2, 140.2, 136.3, 136.2,
135.3, 135.1, 134.8, 132.8, 130.5, 128.4, 128.3, 128.0,
127.8, 127.2, 125.3, 123.9, 122.9, 122.2, 121.8, 120.8,
120.5, 120.2, 115.7, 81.4, 67.7, 67.6, 66.9, 59.9, 58.1, 56.4,
52.3, 46.1, 40.4, 39.3, 37.4, 36.1, 30.6, 30.3, 30.1, 21.0.
HRMS–FAB: m/z calcd for C39H37N3O8: 675.2581; found:
675.2578.
MeO
Me
MeO
26
Cbz
27
Scheme 6 Reagents and conditions: a) H2, Pd/C, EtOH; b) CbzCl,
NaHCO3, dioxane–H2O, 90% (2 steps); c) NIS, CH2Cl2; d) AgOTf,
CH2Cl2, –10 °C, 32% (2 steps); e) KOH (1 M), EtOH; f) SOCl2, DMF
(cat.); i-Pr2NEt, CH2Cl2, 56% (2 steps); g) Pd(PPh3)4, 1,3-dimethyl-
barbituric acid, CH2Cl2, 93%; h) CbzCl, NaHCO3, dioxane, 93%; i)
MCPBA, NaHCO3, CH2Cl2, 0 °C, 2 h, 82%; j) H2, Pd/C, EtOH, 84%;
k) aq HCHO, NaBH3CN, AcOH, CH2Cl2–MeOH, 69%.
(8) He, F.; Bo, Y.; Altom, J. D.; Corey, E. J. J. Am. Chem. Soc.
1999, 121, 6771.
(9) (a) Sumi, S.; Matsumoto, K.; Tokuyama, H.; Fukuyama, T.
Org. Lett. 2003, 5, 1891. (b) Sumi, S.; Matsumoto, K.;
Tokuyama, H.; Fukuyama, T. Tetrahedron 2003, 59, 8571.
(10) Mejia-Oneto, J. M.; Padwa, A. Org. Lett. 2006, 8, 3275.
(11) Marino, J. P.; Cao, G. F. Tetrahedron Lett. 2006, 47, 7711.
(12) (a) Matsumoto, K. PhD Dissertation; University of Tokyo:
Japan, 2006. (b) The preliminary results of this work were
communicated in the Pharmaceutical Society of Japan, the
33th Symposium on Progress in Organic Reaction and
Syntheses – Applications in the Life Science on November
7-8, 2005 (Book of Abstracts, ISSN 0919-2123). The
approach described in this paper and a similar approach
reported by K. C. Nicolaou and co-workers (ref. 7) were
developed independently.
Synlett 2007, No. 20, 3137–3140 © Thieme Stuttgart · New York

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