Stereocontrolled total synthesis of antimalarial (+)-axisonitrile-3

Article abstract of DOI:10.1055/s-0029-1217826

Here we describe the total synthesis of the antimalarial sesquiterpene, (+)-axisonitrile-3. Three key features of this synthesis are: (i) non-Evans syn-aldol reaction of an isovaleric acid derivative bearing a chiral oxazolidinethione and crotonaldehyde w

Full text of DOI:10.1055/s-0029-1217826

LETTER
A
Stereocontrolled Total Synthesis of Antimalarial (+)-Axisonitrile-3
Total
S
ynthesis of
e
A
ntimalari
i
al (+)-A
j
xisoni
i
trile-3 Tamura, Atsuo Nakazaki, Susumu Kobayashi*
Faculty of Pharmaceutical Sciences, Tokyo University of Science (RIKADAI) 2641 Yamazaki, Noda-shi, Chiba 278-8510, Japan
Fax +81(4)71213671; E-mail: kobayash@rs.noda.tus.ac.jp
Received 8 May 2009
Abstract: Here we describe the total synthesis of the antimalarial
sesquiterpene, (+)-axisonitrile-3. Three key features of this synthe-
H
NC
N
sis are: (i) non-Evans syn-aldol reaction of an isovaleric acid deriv-
ative bearing a chiral oxazolidinethione and crotonaldehyde with
high diastereoselectivity, (ii) Claisen rearrangement of alkenyl di-
hydropyran affording spiro[4.5]decane with requisite functional-
ities, and (iii) highly stereoselective reduction in the sterically
congested O-methyl oxime system.
CHO
6
(+)-axisonitrile-3 (1)
(–)-axamide-3 (2)
Figure 1 Structures of axane sesquiterpenes (+)-1 and (–)-2
Key words: antimalarial activity, (+)-axisonitrile-3, Claisen rear-
rangement, O-methyl oxime, total synthesis
Imine derivative A can be derived from (+)-gleenol (3),
which is stereoselectively accessible using our established
strategy for its antipode (–)-3.6b Thus, the functionalized
spiro[4.5]decane B, a precursor of (+)-3, can be obtain-
able from enantioenriched 2-(propenyl)dihydropyran C
by means of a Claisen rearrangement as a crucial step. The
C7 and an allylic center is then introduced from the
(2S,3R)-aldol D. In the present study, we attempted a
preparation of D by a TiCl4-mediated non-Evans syn-
aldol reaction7 of an isovaleric acid derivative 5 bearing
an oxazolidinethione chiral auxiliary, because we encoun-
tered some difficulties in the previous protocol.6b,8
The axane sesquiterpene, (+)-axisonitrile-3 (1), was iso-
lated from the marine sponge Axinella cannabina in 1973.
X-ray crystallographic analysis of 1 showed it to possess
an isocyano group at the C6 position in the spiro[4.5]de-
cane motif as well as four contiguous stereogenic carbon
atoms involving a quaternary carbon center (Figure 1).1,2
While it has a simple scaffold, (+)-1 is found to exhibit po-
tent antimalarial activity.3 Related biologically active spi-
rocyclic sesquiterpene (–)-axamide-3 (2) is also produced
by marine organisms, and it possesses antifouling activity
against Barnacle larvae.4 Although nitrogen-containing
axane sesquiterpenes have attracted considerable atten-
tion, only one example of the synthesis has been pub-
lished. In 1978, Caine and co-workers achieved the first
synthesis of (–)-1, an antipode of the natural product, from
(+)-dihydrocarvone.5 The absolute stereochemistry of
natural compound was determined by comparison of the
specific rotation of the synthetic 1. Herein we wish to de-
scribe the first total synthesis of natural (+)-1. The synthe-
sis involves several key features, including a non-Evans
syn-aldol reaction of an isovaleric acid derivative bearing
a chiral oxazolidinethione and crotonaldehyde with high
diastereoselectivity. The spiro[4.5]decane containing all
the functionalities is afforded by Claisen rearrangement of
alkenyl dihydropyran. Finally, a highly stereoselective re-
duction in the sterically congested O-methyl oxime sys-
tem is achieved.
H
NC
N
CHO
6
(+)-1
(–)-2
N
OH
R
A
(+)-gleenol (3)
O
O
OP
O
7
Scheme 1 represents the synthetic strategy for (+)-1
through (+)-gleenol (3) as a versatile intermediate. Iso-
cyanide 1 can be obtained from formamide 2 through de-
hydration, which in turn can be synthesized via an imine
derivative A with an appropriate reductant for the stereo-
selective reaction of the sterically hindered imino group.
OP
Claisen
rearrangement
B
C
S
O
PO
CHO
+
N
O
H
non-Evans syn
aldol reaction
Ph
SYNLETT 2009, No. x, pp 000A–000D
x
x
.xx.
2
0
0
9
D
5
Advanced online publication: xx.xx.2009
DOI: 10.1055/s-0029-1217826; Art ID: U04809ST
Scheme 1 Synthetic strategy of (+)-1
© Georg Thieme Verlag Stuttgart · New York

B
K. Tamura et al.
LETTER
S
S
OH
O
O
OH
O
TESO
b
c–e
f
a
CHO
OMe
N
O
N
O
i-Pr
Ph
Ph
5
6
7
8
O
O
TESO
OH
TESO
O
O
O
g
h
i, j
O
OTES
9
10
11
12
O
O
r
l, m
k
n–q
OTES
OTES
OH
O
(+)-3
13
14
15
Scheme 2 Stereocontrolled syntheses of ketone 15 through (+)-gleenol (3). Reagents and conditions: (a) (i) TiCl4, i-Pr2NEt, CH2Cl2, 0 °C, 1
h; (ii) –78 °C, 40 min; (iii) crotonaldehyde, –78 °C, 25 h, 81% (non-Evans syn/anti = 94:6); (b) NaOMe, MeOH, r.t., 35 min, 58%; (c) TESOTf,
2,6-lutidine, CH2Cl2, –78 °C, 35 min, quant.; (d) DIBAL, CH2Cl2, –78 °C, 30 min, 80% (>95% dr); (e) Dess–Martin periodinane, CH2Cl2, 0 °C
to r.t., 2 h, quant.; (f) (i) LDA, cyclopentanone, THF, –78 °C, 2 h; (ii) aldehyde 8, –78 °C, 6 h, 91%; (g) (i) TFAA, DMSO, CH2Cl2, –78 °C, 50
min; (ii) Et3N, –60 °C, 12 h, 98%; (h) 0.01 N HCl in EtOH, r.t., 23 h 25 min, 96%; (i) LiAlH4, Et2O, 0 °C, 35 min; (j) TESCl, imidazole, DMAP,
CH2Cl2, 0 °C to r.t., 17 h, 73% (2 steps); (k) triglyme, 250 °C, 1 h, 84% (>95% dr); (l) H2 (1 atm), [Ir(cod)(PCy3)py]PF6, CH2Cl2, r.t., 14 h,
quant.; (m) LDA, MeI, THF, –78 °C, 12 h, 90%; (n) LiAlH4, THF, –78 °C, 5 h; (o) MsCl, pyridine, 0 °C, 22 h; (p) DBU, toluene, 150 °C, 16
h; (q) TBAF, THF, r.t., 17 h, 93% (4 steps); (r) Dess–Martin periodinane, CH2Cl2, r.t., 3 h, 92%.
In addition, this type of non-Evans syn-aldol reaction us- of 2-(propenyl)dihydropyran 12 was complete within 1
ing an acyl imide bearing a bulky group, such as an iso- hour, affording spiro[4.5]decane 13 in 84% yield. The
propyl group, is unprecedented. Thus, much attention is enantiomeric excess of (+)-gleenol (3) was confirmed by
centered on its stereochemical outcome.
chiral HPLC analysis to be 97.8%.
Stereocontrolled synthesis of ketone 15 through (+)- Having obtained the requisite ketone, we then examined
gleenol (3) was conducted based on our reported method the introduction of a nitrogen group at the C6 position by
with several modifications (Scheme 2). The synthesis means of stereoselective reduction of O-methyl oxime
commenced with the preparation of (2S,3R)-aldol adduct (Scheme 3).11,12 Exposure of ketone 15 with meth-
6 through the non-Evans syn-reaction, which was carried oxyamine hydrochloride in pyridine at 65 °C provided O-
out according to Crimmins’ protocol with slight modifica- methyl oxime 18 in 97% yield. The reaction resulted in
tions.7 Thus, treatment of an isovaleric acid derivative 5 the exclusive formation of an E-isomer, which was con-
bearing an oxazolidinethione chiral auxiliary9 derived firmed by NOE correlation between a methoxy group and
from D-phenylglycine with 1.1 equivalents of TiCl4 and an isopropyl group. Diastereoselective reduction of 18
1.1 equivalents of i-Pr2NEt in CH2Cl2 at –78 °C led to the with various reductants was then examined. However,
corresponding titanium enolate. The in situ generated eno- conventional reagents, such as L-Selectride, LiAlH4 and
late was then treated with 1.1 equivalents of crotonalde- AlH3·EtNMe2, were found to be ineffective in this system.
hyde at the same temperature affording the desired To our delight, the reaction of 18 with NaBH3CN in
(2S,3R)-aldol adduct 6 in 81% yield with high stereoselec- AcOH12 at room temperature resulted in the formation of
tivity (non-Evans syn/anti = 94:6).10 To achieve good lev- the corresponding methoxyamine 19 in 84% yield as a
els of conversion and diastereoselectivity, a prolonged single diastereomer. Gratifyingly, the stereochemistry of
mixing time of 5 with TiCl4 and base was required. Re- newly generated C6 atom was assigned as the desired S-
moval of the chiral auxiliary from the obtained aldol ad- configuration on the basis of a small coupling constant
duct 6 was achieved by using NaOMe in methanol to (2.6 Hz) of H6 and H7. This result indicates that the reduc-
provide the corresponding methyl ester 7 in 58% yield. tion might proceed from the less hindered face in more
The yield of the oxidation of the second aldol adduct 9 favorable conformer A. Although conformer A seems un-
was improved (98% yield) when the reaction was con- favorable due to 1,3-diaxial interaction, conformer B suf-
ducted at –60 °C. Furthermore, improved yield of the silyl fers from a severe allylic strain between the methoxy
ether 12 was achieved in CH2Cl2 rather than DMF (42% group and the C7 isopropyl group (Figure 2).13 It is worth
yield), which might be attributed to a decrease in the de- noting that the methoxy group plays an important role
composition of both allyl alcohol and the TES ether 12 us- throughout the reduction, although several extra steps are
ing the less polar solvent. The key Claisen rearrangement required to remove it.
Synlett 2009, No. x, A–D © Thieme Stuttgart · New York

LETTER
Total Synthesis of Antimalarial (+)-Axisonitrile-3
C
Completion of the total synthesis of (+)-1 through (–)-2
was achieved from methoxyamine 19. Exposure of 19 to
acetic formic anhydride and warming from room temper-
ature to 70 °C provided formamide 20 in excellent yield.
The SmI2-mediated N–O bond cleavage and dehydration
of the resulting (–)-axamide-3 (2) using TsCl in pyridine
at room temperature afforded (+)-axisonitrile-3 (1) in
good overall yield.14 Spectroscopic data of the synthe-
sized (+)-1 coincided with those of the natural product.1,15
see
text
OR
N3
(+)-axenol (4) R = H
16a R = Ts
16b R = Ms
17 trace
a
Scheme 4 Attempted introduction of a nitrogen atom at C6 via an
SN2 reaction. Reagents and conditions: (a) Ms2O, pyridine, 65 °C, 1
h, quant.
b
a
O
N
OMe
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
15
18
References and Notes
OMe
N
OMe
(1) Di Blasio, B.; Fattorusso, E.; Magno, S.; Mayol, L.; Pedone,
C.; Santacroce, C.; Sica, D. Tetrahedron 1976, 32, 473.
(2) For a review on marine isocyanides and related natural
products, see: Garson, M. J.; Simpson, J. S. Nat. Prod. Rep.
2004, 21, 164.
N
H
c
d
CHO
6
7
19
20
(3) (a) Angerhofer, C. K.; Pezzuto, J. M.; König, G. M.; Wright,
A. D.; Sticher, O. J. Nat. Prod. 1992, 55, 1787. (b) Wright,
A. D.; Wang, H.; Gurrath, M.; König, G. M.; Kocak, G.;
Neumann, G.; Loria, P.; Foley, M.; Tilley, L. J. Med. Chem.
2001, 44, 873. (c) Marrero-Ponce, Y.; Iyarreta-Veitía, M.;
Montero-Torres, A.; Romero-Zaldivar, C.; Brandt, C. A.;
Ávila, P. E.; Kirchgatter, K.; Machado, Y. J. Chem. Inf.
Model. 2005, 45, 1082.
H
N
e
NC
CHO
(–)-2
(+)-1
(4) Hirota, H.; Tomono, Y.; Fusetani, N. Tetrahedron 1996, 52,
2359.
(5) Caine, D.; Deutsch, H. J. Am. Chem. Soc. 1978, 100, 8030.
(6) (a) Nakazaki, A.; Era, T.; Kobayashi, S. Chem. Pharm. Bull.
2007, 55, 1606. (b) Nakazaki, A.; Era, T.; Kobayashi, S.
Chem. Lett. 2008, 37, 770.
Scheme 3 Completion of the total synthesis. Reagents and condi-
tions: (a) MeONH2·HCl, pyridine, 65 °C, 72 h, 97% (>95% E); (b)
NaBH3CN, AcOH, r.t., 2.5 h, 84% (>95% dr); (c) (i) AcOCHO, r.t.,
12 h; (ii) 70 °C, 96 h, 98%; (d) SmI2, THF, r.t., 2.5 h, 79%; (e) TsCl,
pyridine, r.t., 3 h, 87%.
(7) Crimmins, M. T.; King, B. W.; Tabet, E. A. J. Am. Chem.
Soc. 1997, 119, 7883.
OMe
N
(8) In the previous synthesis of (–)-gleenol, the use of
SuperQuat-type oxazolidine-2-one was necessary to
minimize the cleavage of the oxazolidin-2-one during the
removal of chiral auxiliary. Even employing SuperQuat,
substantial amount of undesired byproduct caused by the
ring opening of SuperQuat was formed.
N
OMe
Me
H–
conformer A
(9) Wu, Y.; Yang, Y.-Q.; Hu, Q. J. Org. Chem. 2004, 69, 3990.
(10) The absolute stereochemistry of (2S,3R)-aldol adduct 6 was
established by comparison of the specific rotation of the
primary alcohol derived from ester 7.
conformer B
Figure 2 Two possible conformations of O-methyl oxime 18
(11) An SN2 reaction of tosylate 16a prepared from axenol 4 with
potassium azide has been reported by Caine and co-workers
(Scheme 4).5 However, we were unable to observe the
formation of tosylate 16a using their protocol. Thus we
chose mesylate as an alternative leaving group.
Unfortunately, azidation of 16b under various reaction
conditions (i.e., NaN3, 15-crown-5, benzene, 80 °C; NaN3,
DMF, 100 °C; aq LiN3, DMF, 100 °C; n-Bu4NCl, NaN3,
NMP, 60 °C) was found to be unsuccessful. In each case,
only a trace amount of the desired azide 17 was detected.
Therefore we chose an alternative approach as shown in
Scheme 3.
In conclusion, we accomplished the total synthesis of
(+)-axisonitrile-3 via (–)-axamide-3 and (+)-gleenol. The
synthesis involves (i) non-Evans syn-aldol reaction of an
isovaleric acid derivative bearing oxazolidinethione and
crotonaldehyde in good yield with high diastereoselectiv-
ity, (ii) Claisen rearrangement of 2-(E-propenyl)dihydro-
pyran affording spiro[4.5]decane with the requisite
functionalities, and (iii) highly stereoselective reduction
in a sterically congested O-methyl oxime system.
Synlett 2009, No. x, A–D © Thieme Stuttgart · New York

D
K. Tamura et al.
LETTER
(12) (a) Reisman, S. E.; Ready, J. M.; Hasuoka, A.; Smith, C. J.;
Wood, J. L. J. Am. Chem. Soc. 2006, 128, 1448.
(b) Reisman, S. E.; Ready, J. M.; Weiss, M. M.; Hasuoka,
A.; Hirata, M.; Tamaki, K.; Ovaska, T. V.; Smith, C. J.;
Wood, J. L. J. Am. Chem. Soc. 2008, 130, 2087.
(13) NOESY analysis of O-methyl oxime 18 indicated that 18
exists predominantly as the chair conformer A at r.t. in a
CDCl3 solution, see Supporting Information. Further,
molecular mechanics calculations (SPARTAN) also
supported the above observation.
MHz, CDCl3): d = 5.14 (q, J = 1.4 Hz, 1 H), 3.59 (br s, 1 H),
2.31–2.17 (m, 2 H), 2.01–1.90 (m, 2 H), 1.85–1.76 (m, 2 H),
1.74 (d, J = 1.4 Hz, 3 H), 1.59 (dqq, J = 9.4, 6.7, 6.7 Hz, 1
H), 1.51 (ddt, J = 13.4, 4.0, 3.5 Hz, 1 H), 1.33 (ddt, J = 12.8,
4.0, 13.4 Hz, 1 H), 1.20–1.11 (m, 1 H), 1.06 (ddt, J = 12.8,
4.0, 13.4 Hz, 1 H), 0.94 (d, J = 6.7 Hz, 3 H), 0.91 (d, J = 6.7
Hz, 3 H), 0.77 (d, J = 6.7 Hz, 3 H). 13C NMR (100 MHz,
CDCl3): d = 155.7, 144.8, 123.6, 64.5, 57.1, 43.8, 35.8, 34.9,
34.3, 31.2, 29.7, 24.9, 20.7, 20.3, 16.9, 16.1. IR (neat): 2925,
2131, 1541, 1456 cm–1. ESI-HRMS: m/z calcd for C16H26N:
232.2055; found: 232.2059.
(14) Spectral Data for (+)-1
White solid; mp 94–95 °C; [a]D24 +54.4 (c 0.107, CHCl3);
lit.1 [a]D +68.4 (c 1.0, CHCl3); lit.15 [a]D +43.4 (c 0.006,
CHCl3); Rf = 0.45 (hexane–i-Pr2O = 20:1). 1H NMR (400
(15) Jumaryatno, P.; Stapleton, B. L.; Hooper, J. N. A.;
Brecknell, D. J.; Blanchfield, J. T.; Garson, M. J. J. Nat.
Prod. 2007, 70, 1725.
Synlett 2009, No. x, A–D © Thieme Stuttgart · New York

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