Different modes of cyclization in zoanthamine alkaloid system, bisaminal versus spiroketal formation

Article abstract of DOI:10.1021/ol200486c

Bisaminal cyclization in the zoanthamine alkaloid system was strongly affected by the stereochemistry of the C4 methyl. While cyclization of the (4S)-methyl precursor gave only a bisaminal compound, cyclization of the (4R)-methyl isomer produced both spiroketal and bisaminal products.

Full text of DOI:10.1021/ol200486c

ORGANIC
LETTERS
2011
Vol. 13, No. 12
2980–2983
Different Modes of Cyclization in
Zoanthamine Alkaloid System, Bisaminal
versus Spiroketal Formation
Takahiro Nakajima, Daisuke Yamashita, Kaname Suzuki, Atsuo Nakazaki,
Takahiro Suzuki, and Susumu Kobayashi*
Faculty of Pharmaceutical Sciences, Tokyo University of Science (RIKADAI),
2641 Yamazaki, Noda-shi, Chiba 278-8510, Japan
kobayash@rs.noda.tus.ac.jp
Received February 22, 2011
ABSTRACT
Bisaminal cyclization in the zoanthamine alkaloid system was strongly affected by the stereochemistry of the C4 methyl. While cyclization of the
(4S)-methyl precursor gave only a bisaminal compound, cyclization of the (4R)-methyl isomer produced both spiroketal and bisaminal products.
Zoanthamine alkaloids are attractive target molecules
from a synthetic point of view because of their structural
complexity and potent biological activity (Figure 1).1
Indeed, extensive synthetic studies have been carried out
toward the synthesis of norzoanthamine (1), zoanthamine
(2), and zoanthenol (3) over the past few years.2 The total
synthesis of norzoanthamine was accomplished by Miya-
shita/Tanino and our group.3,4a,4b One of the most chal-
lenging problems in the synthesis of zoanthamine alkaloids
is the formation of the pentacyclic core (CDEFG ring),
which possesses eight chiral centers including three qua-
ternary carbons and two aminal moieties. In 1998, we
reported the first entry for the construction of the fully
functionalized pentacyclic bisaminal core (Scheme 1).5aÀc
Figure 1. Zoanthamine alkaloids.
Namely, treatment of aminohydroxy diketocarboxylic
acid 4a with 2 N HCl in THF produced monoaminal 5,
and subsequent hydrogenolysis of the Cbz group resulted in
simultaneous aminal formation to afford bisaminal 6.5a,b
We also developed a one-step transformation of Boc-pro-
tected precursor 4b to specifically generate pentacyclic
(1) (a) Fukuzawa, S.;Hayashi, Y.;Uemura, D.;Nagatsu, A.;Yamada,
K.; Ijuin, Y. Heterocycl. Commun. 1995, 1, 207–214. (b) Kuramoto, M.;
Hayashi, K.; Fujitani, Y.; Yamaguchi, K.; Tsuji, T.; Yamada, K.; Ijuin,
Y.; Uemura, D. Tetrahedron Lett. 1997, 38, 5683–5686. (c) Kuramoto,
M.; Hayashi, K.; Yamaguchi, K.; Yada, M.; Tsuji, T.; Uemura, D. Bull.
Chem. Soc. Jpn. 1998, 71, 771–779.
(2) For a review, see: Behenna, D. C.; Stockdill, J. L.; Stoltz, B. M.
Angew. Chem., Int. Ed. 2008, 47, 2365–2386.
(3) Miyashita, M.; Sasaki, M.; Hattori, I.; Sakai, M.; Tanino, K.
Science 2004, 305, 495–499.
(4) (a) Murata, Y.; Yamashita, D.; Kitahara, K.; Minasako, Y.;
Nakazaki, A.; Kobayashi, S. Angew. Chem., Int. Ed. 2009, 48, 1400–
1403. (b) Yamashita, D.; Murata, Y.; Hikage, N.; Takao, K.-i.; Naka-
zaki, A.; Kobayashi, S. Angew. Chem., Int. Ed. 2009, 48, 1404–1406.
(5) (a) Hikage, N.; Furukawa, H.; Takao, K.-i.; Kobayashi, S.
Tetrahedron Lett. 1998, 39, 6237–6240. (b) Hikage, N.; Furukawa, H.;
Takao, K.-i.; Kobayashi, S. Tetrahedron Lett. 1998, 39, 6241–6244. (c)
Hikage, N.; Furukawa, H.; Takao, K.-i.; Kobayashi, S. Chem. Pharm.
Bull. 2000, 48, 1370–1372.
r
10.1021/ol200486c
Published on Web 05/16/2011
2011 American Chemical Society

ketophosphonates 10aÀc (prepared from lactones
11aÀc).7,8 Aldehyde 8 could be prepared from the bicyclic
enone (À)-99 by introducing a methyl group followed by
the regioselective cleavage of the cyclopentanone ring
(Scheme 3).
Scheme 1. Construction of Pentacyclic Bisaminal Core
Treatment of enone (À)-9 with Gilman reagent and
subsequent in situ trapping of the enolate by addition of
TESCl and HMPA provided the silyl enol ether as a single
diastereomer. Reduction of the remaining carbonylgroup
withLiAlH4, followed by desilylation withTBAF afforded
ketone 12in92% overall yield from (À)-9. After protection
of the resulting hydroxyl group as BOM ether, a regiose-
lective silyl enol etherification of cyclopentanone 13 was
examined. Selective deprotonation using a strong base,
such as LDA, proved unsuccessful.
However, we were delighted to find that treatment of 13
with TBSOTf and NEt3 in CH2Cl2 at À78 °C led to the
isolation of desiredsilyl enol ether14in 96% yield. Wenext
attempted an oxidative cleavage of silyl enol ether 14.
Direct cleavage (ozone) or Rubottom-type oxidation of
14 (m-CPBA, DMDO, PIDA, Davis oxaziridine, or
MoOPH) was unsuccessful because of the low yields.10À12
Treatment of 14 with OsO4 and NMO in acetone gave
R-hydroxy ketone 15, albeit in moderate yield.13 Hydroxy
ketone 15 was then successfully converted to β-keto alde-
hyde 8, which can serve as a common intermediate for the
preparation of cyclization precursors 7aÀc.
bisaminal 6 by heating in aqueous acetic acid.5c This
methodology proved to be applicable to the final step in
the total synthesis of zoanthamine alkaloids.3,4a,5,6
Although the formation of pentacyclic bisaminal 6 is the
result of a thermodynamically favored process, we became
interested in the factors that lead to selective bisaminal
formation from among the many other possible cyclization
products. All naturally occurring zoanthamine alkaloids
possess a (4S)-methyl group. We reasoned that the stereo-
chemistry of the C4-methyl might affect the mode of
cyclization.
We next attempted HWE reaction of 8 with ketopho-
sphonate 10c (Scheme 4). Under normal conditions,14
the yield of 17c was very low because of the predominant
deformylation affording 19 through intermediate 18.
After extensive experiments, we found that the addition
of HMPA15 or DMPU dramatically improved the yield
of 17c. This remarkable effect might be attributed to a
facile elimination of diethyl phosphate from intermedi-
ate 18 in aprotic polar solvents. Other enones, 17a and
17b, were also prepared in good yield. Enones (17aÀc)
were subjected to a catalytic hydrogenation followed
by alkaline hydrolysis to obtain cyclization precursors
7aÀc.
Herein, we report the effect of the stereochemistry of the
C4 methyl group in terms of the cyclization with three
precursors; (4S)- and (4R)-methyl isomers and a demethyl
derivative.
Scheme 2. Synthetic Strategy for Cyclization Precursors 7aÀc
With three cyclization precursors in hand, we next
examined a tandem cyclization under different acidic con-
ditions. The conditions we examined were as follows:
(Conditions A) AcOHÀH2O at 60 °C for 6 h, then
(7) 11a and 11b can be prepared from lactones 11c, by methylation
and epimerization.
(8) Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863–927.
(9) Wei, Z.-L.; Li, Z.-Y.; Lin, G.-Q. Synthesis 2000, 1673–1676.
(10) Rubottom, G. M.; Vazquez, M. A.; Pelegrina, D. R. Tetrahedron
Lett. 1974, 15, 4319–4322.
(11) Davis, F. A.; Chen, B.-C. Chem. Rev. 1992, 92, 919–934.
(12) (a) Vedejs, E. J. Am. Chem. Soc. 1974, 96, 5944–5946. (b) Vedejs,
E.; Larsen, E. S. Org. Synth. 1986, 64, 127–136.
(13) McCormick, J. P.; Witold, T.; Johnson, M. W. Tetrahedron Lett.
1981, 22, 607–610.
(14) KHMDS/THF (trace), n-BuLi/THF (trace), LiCl, i-Pr2NEt/
CH3CN (13%), and NaH/THF (18%).
(15) (a) Paterson, I.; Gardner, N. M.; Guzman, E.; Wright, A. E.
Bioorg. Med. Chem. Lett. 2008, 18, 6268–6272. (b) Nagumo, Y.; Kakeya,
H.; Yamaguchi, J.; Uno, T.; Shoji, M.; Hayashi, Y.; Osada, H. Bioorg.
Med. Chem. Lett. 2004, 14, 4425–4429. (c) Zhang, Q.; Rivkin, A.;
Curran, D. P. J. Am. Chem. Soc. 2002, 124, 5774–5781.
Our strategy for the preparation of three precursors
7aÀc is outlined in Scheme 2. The cyclization precursors
could be obtained by HornerÀWadsworthÀEmmons
(HWE) reaction of aldehyde 8 and corresponding
(6) Takahashi, Y.; Yoshimura, F.; Tanino, K.; Miyashita, M. Angew.
Chem., Int. Ed. 2009, 48, 8905–8908.
Org. Lett., Vol. 13, No. 12, 2011
2981

Scheme 3. Synthesis of Cyclization Precursors 7aÀc
depending on the substrates. Thus, bisaminal 6a was
obtained in high yield from (4S)-methyl isomer 7a after
9 h (entry 7). In contrast, (4R)-methyl isomer 7b was
transformed to bisaminal 6b very slowly (entries 8 and
11), andspiroketal22bremainedevenafter 24h. Structures
Scheme 4. HWE Reaction of Ketoaldehyde 8
of these products were fully established by 1H NMR, 13
NMR, and HRMS spectra (Figure 2).
C
These results are best explained in a qualitative
manner as follows: Formation of monoaminal 20a,
rather than spiroketal 21a, can be understood by con-
sidering the axial orientation of C4-methyl in spiroke-
tal 21a. In a similar manner, monoaminal 20b seems to
be thermodynamically less favorable by the nonbond-
ing interaction caused by axial C4-Me. The C4-methyl
group occupies an equatorial position in spiroketal 21b,
and 21b does not undergo a facile recyclization to
bisaminal 6b through monoaminal. In the case of C4-
demethyl derivative, both monoaminal 20c and spiro-
ketal 21c do not suffer from nonbonding interactions.
Therefore, spiroketal 21c was readily transformed to
the thermodynamically favorable bisaminal 6c via
monoaminal 20c under conditions C.
Na2SO4, at rt for 20 h; (conditions B) 2 N HCl aq at rt for 4
h; (conditions C) AcOHÀH2O at 100 °C for 9 h, then
Na2SO4 at rt for 3 h; (conditions D) AcOHÀH2O at 100 °C
for 24 h, then Na2SO4 at rt for 12 h. The results are
summarized in Table 1. When cyclization precursors
(7aÀc) were subjected to conditions A and B, monoam-
inals (20aÀc) and spiroketals (21aÀc) were subsequently
isolated. It should be noted that the ratio of monoaminal/
spiroketal was highly dependent on the stereochemistry
of C4-methyl. In the case of (4S)-methyl derivative 7a,
monoaminal 20a was isolated as a major isomer. By
contrast, spiroketal 21b was a major product for (4R)-
methyl derivative 7b. The results of demethyl derivative
7c were intermediate between those of 7a and 7b.
Because the N-Boc group remain protected under these
conditions, monoaminals 20aÀc did not undergo bisaminal
formation.
Cyclization precursors (7aÀc) were next heated in aqu-
eous AcOH (conditions C and D). The N-Boc group was
cleaved in AcOHÀH2O at 100 °C as we already developed,
and initially formed monoaminals were transformed to the
corresponding bisaminals 6aÀc in moderate to high yields
Figure 2. Structure of bisaminal, monoaminal, and spiroketal.
Org. Lett., Vol. 13, No. 12, 2011
2982

Table 1. Cyclization of 7aÀc
yield (%)
entry
conditiona
precursor
bisaminal 6
monoaminal 20
spiroketal 21
spiroketal 22
1
2
A
A
A
B
B
B
C
C
C
D
D
D
7a
7b
7c
7a
7b
7c
7a
7b
7c
7a
7b
7c
58
10
48
77
32
33
14
51
19
3
4
5
44
35
6
7
90
31
65
95
62
74
8
47
27
9
10
11
12
a Conditions A: AcOHÀH2O at 60 °C for 6 h, then Na2SO4 at rt for 24 h. Conditions B: 2 N HCl aq at rt for 4 h. Conditions C: AcOHÀH2O at 100 °C
for 9 h, then Na2SO4 at rt for 3 h. Conditions D: AcOHÀH2O at 100 °C for 24 h, then Na2SO4 at rt for 12 h.
In conclusion, we reveal that the mode of cyclization is
dependent on the stereochemistry at the C4 methyl in
zoanthamine alkaloids.
In addition, we also developed a straightforward and
efficient route to cyclization precursor 7 from ketoal-
dehyde 8 by the HornerÀWadsworthÀEmmons reac-
tion in the presence of DMPU. A synthetic study of
zoanthamine using the present methodology is cur-
rently underway.
Acknowledgment. This research was supported in part
by a Grant-in-Aid for Scientific Research (B) (KAKENHI
No.22390004) fromtheJapanSocietyforthe Promotion of
Science.
Supporting Information Available. Detailed experimen-
tal procedures and characterization data for all new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 12, 2011
2983