Highly Diastereoselective Synthesis of Manoyl Oxide Derivatives by TiCl4-Catalyzed Nucleophilic Cleavage of Ambracetal Derivatives

Article abstract of DOI:10.1055/s-2003-42124

The treatment of acetal 11 with KCN and AlCNEt₂ in the presence of TiCl₄ produces in high diastereoselectivity 2-cyanooxane 14, which can be easily converted into manoyl oxide derivatives. Using this strategy, 19-hydroxymanoyl oxide 20, diterpene from P. viscosum, was prepared from communic acids 7a-c after an 8-steps sequence in a 17% overall yield.

Full text of DOI:10.1055/s-2003-42124

LETTER
2313
Highly Diastereoselective Synthesis of Manoyl Oxide Derivatives by
TiCl4-Catalyzed Nucleophilic Cleavage of Ambracetal Derivatives
S
ynthesis of Mano
.
yl
O
xide
D
erFivatives by T 4
i
.
C
l
-Catalyze
B
dCleavage arrero,* E. J. Alvarez-Manzaneda Roldán,* J. L. Romera Santiago, R. Chahboun
Departamento de Química Orgánica, Facultad de Ciencias, Instituto de Biotecnología, Universidad de Granada, 18071 Granada, Spain
Fax +34(958)246387; E-mail: eamr@ugr.es
Received 24 July 2003
gain manoyl oxide derivatives. Acetal 11 is a suitable in-
Abstract: The treatment of acetal 11 with KCN and AlCNEt2 in the
termediate to elaborate terpenoids having ring A function-
presence of TiCl4 produces in high diastereoselectivity 2-cyanoox-
ane 14, which can be easily converted into manoyl oxide deriva-
alization.13
tives. Using this strategy, 19-hydroxymanoyl oxide 20, diterpene
from P. viscosum, was prepared from communic acids 7a–c after an
8-steps sequence in a 17% overall yield.
Lewis acid-catalyzed cleavage of the 6,8-dioxabicyc-
lo[3.2.1]octane derivatives 4 leads to oxane 5 and oxepane
type compounds 6 in variable proportions, depending
Key words: natural products, acetal cleavage, manoyl oxides,
upon the bicyclic acetal 4 framework and the nucleophile
Lewis acids, labdane diterpenes
structure (Scheme 1).
2
1
Nu:–
Path A
5
R2
Nu
R1
Manoyl oxides are a type of diterpene, which present
wide-reaching, interesting biological activities. A repre-
sentative example of such a diterpene is forskolin (1), the
synthesis of which has been the subject of many studies1
because of its potent activity.2
R2
R1
R2
R3
R1
8
O
+
R3
R3
Nu
O
O
O
L.A.
OH
OH
4
5a
5b
trans-oxane
cis-oxane
Recent studies have revealed that less functionalized
manoyl oxides, as well as their derivatives, exhibit a
considerable degree of biological activity: antimicrobial,3
antibacterial,4 adenylate-cyclase modifier,5 antitumor,6
cytotoxic,7 antilehmaniosis8 and antileucemic, causing
cell apoptosis.9 Compound 2 is a potent immuno-
suppressive10 and ent-manoyl oxide 3 presents anti-in-
flammatory activity (Figure 1).11
R2
HO
R3
R2
HO
2
1
Nu:–
+
Path B
5
R1
Nu
R2
R3
R1
8
Nu
R1
O
O
R3
O
O
L.A.
6a
6b
cis-oxepane
4
trans-oxepane
Scheme 1
HO
Significant amounts of oxepane derivatives, frequently
the main product, result when cyanide (TMSCN) is used
as the nucleophile.14 Oxanes are preferred when other nu-
cleophiles, such as DIBAH, Et3SiH, Ph3SiH or allyltrime-
thylsilane, are used.15 The selective formation of
oxepanes by reductive and allylative cleavage of bicyclic
acetals, such as 4, using chelation of TiCl4, has recently
been described; thus, oxepane 6 is the only product when
R2 is an alkoxymethyl group, the chelation of which
favours the coordination of the Lewis acid with O-8 (path
B in Scheme 1).
O
OH
O
O
O
OH
OH
OAc
COOH
2
1
3
Figure 1
During the last few years, some such compounds have
been prepared by chemical or microbiological
procedures3,5,7–9,12 in order to study structure-activity rela-
tionships and to prepare compounds that are more active
than those of natural origin.
Concerning the C-5 stereochemistry, stereoselective re-
ductive cleavages, which enable the obtention of trans- or
cis-oxanes, by selecting the nucleophile and the reaction
Following our research into the synthesis of bioactive
compounds starting from enantiomerically pure synthons
obtained from natural sources, we have investigated the
nucleophilic cleavage of bicyclic acetal 11 as a method to
Table 1 Oxidation of 9, 10 with OsO4/NaIO4
Entry Tempera- Reaction 11:12:13
OsO4/NaIO4 Yield
(equiv)
ture
time
1
2
3
r.t.
8 d
1:43:10
1:20:10
45:0:10
0.1:2.0
0.1:2.0
0.2:2.5
85%
89%
95%
SYNLETT 2003, No. 15, pp 2313–2316
Advanced online publication: 07.11.2003
DOI: 10.1055/s-2003-42124; Art ID: D18603ST.pdf
© Georg Thieme Verlag Stuttgart · New York
0
1
.1
2
.2
0
0
3
60 ºC
reflux
14 h
16 h

2314
A. F. Barrero et al.
LETTER
sentative results of this are shown in Scheme 4 and
Table 2. Treatment of 11 with TiCl4, AlEt2CN and KCN,
in the presence of 18-crown-6 ether affords variable
amounts of epimeric 13-cyanooxanes 14 and 15, or the
lactone 16, depending upon the reaction conditions. Ox-
ane 14 is the main product at low temperatures. Lactone
16 is the only product under reflux; equimolar quantities
of 14 and 15 result at room temperature. At no time were
oxepane derivatives observed.
HO
HO
CHO
CN
O
O
O
COOMe
CH2OH
COOMe
17
20
14
O
O
HO
O
CN
+
O
O
O
O
COOMe
COOMe
O
(i)
8a–c
11
COOMe
COOMe
COOMe
14 13R
Scheme 2
16
11
15 13S
temperature, have been reported; nevertheless, trans-
oxanes are the main products during cyanoaddition pro-
cesses.14
Scheme 4 (i) TiCl4, AlEt2CN, KCN, 18-crown-6-ether.
Table 2 Nucleophilic Cleavage of 1119,20,
A possible route to manoyl oxide derivatives, such as 20,
based on the above results, is depicted in Scheme 2. Ni-
trile 14, which results from the stereoselective Lewis acid-
catalysed nucleophilic cleavage of the bicyclic acetal 11
with KCN, is a key intermediate. The methyl group on C-
8 of 20 is elaborated after reduction of the corresponding
sulphonic ester on C-17; whereas the C-13 vinyl group is
obtained by Wittig reaction of the aldehyde 17, which re-
sults from the reduction of 14.
Entry
Temp.
–78 ºC
r.t.
Reacion time 14:15:16
Yield
90%
90%
70%
1
2
3
1 h
14 h
22 h
6:1:0
1:1:0
0:0:1
reflux
L.A.
O
OH
CN
COOMe
COOMe
O
O
(ii)
11
14
COOR
COOMe
–CN–
+CN–
12
7a–c R:H
8a–c R:Me
9
∆
∆
1
"trans" attack
(i)
13
L.A.
O
10
4.5
O
(iii)
O
CHO
COOMe
COOMe
O
O
+
O
O
O
+
+
16
"cis" attack
+CN–
COOMe
COOMe
COOMe
13
–CN–
Hydrolysis
11
12
NH
OH
O
O
O
CN
Scheme 3 (i) CH2N2, Et2O, r.t., 5 min (100%). (ii) Na, t-BuOH,
80 ºC, 12 h (90%). (iii) OsO4: 0.2%, NaIO4, t-BuOH–H2O (7:3).
COOMe
COOMe
The synthesis of 11 from communic acids 7a–c, which has
been previously reported by our group,16 is considerably
improved. Acetal 11 is directly obtained from the diene
mixture 9 and 10, resulting from the reduction of methyl
esters 8a–c with Na in t-BuOH, by refluxing with OsO4/
NaIO4 in t-BuOH–H2O. In this way, the synthesis is short-
ened by one step and the yield increased by more than
10% (Scheme 3, Table 1).
15
Scheme 5
The observed acetal ring opening regioselectivity could
be attributed to the C17–O–C13 oxygen accessibility and
the high stability of the resulting tricyclic system. Further-
more, the above results reveal that 14, which results from
the nucleophilic attack by the less hindered a side of the
oxocarbenium ion, is the kinetic product.
Subsequently, the behaviour of acetal 11 towards cyanide,
in the presence of TiCl4, was studied, and the most repre-
Synlett 2003, No. 15, 2313–2316 © Thieme Stuttgart · New York

LETTER
Synthesis of Manoyl Oxide Derivatives by TiCl4-Catalyzed Cleavage
2315
(2) (a) Arew, S. V. B. Prog. Chem. Org. Nat. Prod. 1993, 1.
(b) Kopras, E.; Greeley, T.; Babcock, G. F.
The lactone 16, the isolation of which in related processes
has not been reported,14,17 is formed under thermodynam-
ic conditions. Lactone 16 is irreversibly formed from 15,
which is equilibrated with its epimer 14 (Scheme 5). In
support of this supposition is the fact that the treatment of
14 with KCN/ AlEt2CN and TiCl4 at room temperature af-
fords in high yield a 1:1 mixture of acetal 11 and lactone
16.
Gastroenterology 2002, 122, W1096. (c) Yool, A. J.;
Stamer, W. D.; Regan, J. W. Science 1996, 273, 1216.
(d) Robbins, J. D.; Boring, D. L.; Tang, W. J.; Shank, R.;
Seamon, K. B. J. Med. Chem. 1996, 39, 2745. (e) Tang, W.
J.; Gilman, A. G. Science 1995, 268, 1769.
(3) Kalpoutzakis, E.; Aligiannis, N.; Mitaku, S.; Chinou, L.;
Charvala, C.; Skaltsounis, A. L. Chem. Pharm. Bull. 2001,
49, 814.
The manoyl oxide framework of 14 was elaborated in ac-
cordance with the retrosynthetic Scheme 2. Treatment of
14 with DIBAH in THF at room temperature gives in high
yield aldehyde 17, which is converted into the vinyl deriv-
ative 18 after reaction with the methylenphosphorane. Re-
duction of tosyl derivative 19 by refluxing with LiAlH4 in
THF affords 19-hydroxymanoyl oxide 20, diterpene iso-
lated from P. viscosum.18 Spectroscopic properties of 20
are identical to those of the natural compound (Scheme 6).
(4) (a) Skaltsa, H. D.; Lazari, D. M.; Chinou, I. B.; Loukis, A. E.
Planta Med. 1999, 65, 255. (b) Roussis, V.; Tsoukatou, M.;
Chinou, I. B.; Ortiz, A. Planta Med. 1998, 64, 675.
(c) Kalpoutzakis, E.; Chinou, L.; Mitaku, S.; Skaltsounis, A.
L.; Charvala, C. Nat. Prod. Lett. 1998, 11, 173.
(5) García-Granados, A.; Liñán, E.; Martínez, A.; Onorato, M.
E.; Parra, A.; Arias, J. M. Phytochemistry 1995, 38, 287.
(6) Konishi, T.; Takasaki, M.; Tokuda, H.; Kiyosawa, S.;
Konoshima, T. Biol. Pharm. Bull. 2001, 24, 1440.
(7) (a) Dimas, K.; Demetzos, C.; Mitaku, S.; Vaos, B.;
Marselos, M.; Tzavaras, T.; Kokkinopoulos, D. Anticancer
Res. 1999, 19, 4065. (b) Angelopoulou, D.; Demetzos, C.;
Dimas, C.; Perdetzoglou, D.; Loukis, A. Planta Med. 2001,
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Harvala, C.; Kokkinopoulos, D. Planta Med. 1994, 60, 590.
(8) Garcia Granados, A.; Liñan, E.; Martinez, A.; Rivas, F.;
Mesa Valle, C. M.; Castilla Calvente, J. J.; Osuna, A. J. Nat.
Prod. 1997, 60, 13.
HO
HO
CHO
CN
O
O
(i)
COOMe
COOMe
17
14
(9) Dimas, K.; Demetzos, C.; Vaos, V.; Ioannidis, P.; Trangas,
T. Leukemia Res. 2001, 25, 449.
(ii)
(10) Duan, H.; Takaishi, Y.; Momota, H.; Ohmoto, Y.; Taki, T.;
Jia, Y.; Li, D. J. Nat. Prod. 1999, 62, 1522.
HO
(11) (a) De las Heras, B.; Hoult, J. R. Planta Med. 1994, 60, 501.
(b) De las Heras, B.; Villar, A.; Vivas, J. M.; Hoult, J. R.
Agents Actions 1994, 41, 114. (c) Alcaraz, M. J.; Jiménez,
M. J.; Valverde, S.; Sanz, J.; Rabanal, R. M.; Villar, A. J.
Nat. Prod. 1989, 52, 1088.
R
O
O
(iii)
R1
COOMe
(12) (a) Fraga, B. M.; Hernández, M. G.; González, P.; López,
M.; Suárez, S. Tetrahedron 2001, 57, 761. (b) Fraga, B. M.;
González, P.; Hernández, M. G.; López, M.; Suárez, S.
Tetrahedron 1999, 55, 1781. (c) Fraga, B. M.; González, P.;
Guillermo, R.; Hernández, M. G. J. Nat. Prod. 1998, 61,
1237. (d) Fraga, B. M.; González, P.; Guillermo, R.;
Hernández, M. G. Tetrahedron 1998, 54, 6159. (e) García-
Granados, A.; Liñán, E.; Martínez, A.; Onorato, M. E.;
Arias, J. M. J. Nat. Prod. 1995, 58, 1695. (f) Amate, Y.;
García-Granados, A.; López, F. A.; Sáenz Buruaga, A.
Synthesis 1991, 371.
(13) Barrero, A. F.; Alvarez-Manzaneda, E. J.; Alvarez-
Manzaneda, R.; Chahboun, R.; Meneses, R.; Aparicio, M.
Synlett 1999, 713.
(14) Rychnovsky, S. D.; Dahanukar, V. H. Tetrahedron Lett.
1996, 37, 339.
(15) (a) Kotsuki, H.; Ushio, Y.; Kadota, I.; Ochi, M. Chem. Lett.
1988, 927. (b) Kotsuki, H.; Ushio, Y.; Kadota, I.; Ochi, M.
J. Org. Chem. 1989, 54, 5153. (c) Kotsuki, H. Synlett 1992,
97. (d) Ishihara, K.; Mori, A.; Yamamoto, H. Tetrahedron
Lett. 1987, 28, 6613. (e) Ishihara, K.; Mori, A.; Yamamoto,
H. Tetrahedron 1990, 46, 4595. (f) Kim, Y.; Mundy, B. P. J.
Org. Chem. 1982, 47, 3556. (g) Masaki, Y.; Serizawa, Y.;
Nagata, K.; Kaji, K. Chem. Lett. 1983, 1601. (h) Lewis, M.
D.; Cha, J. K.; Kishi, Y. J. Am. Chem. Soc. 1982, 104, 4976.
(i) Fotsch, C. H.; Chamberlin, A. R. J. Org. Chem. 1991, 56,
4141.
18
19 R: CH2OTs; R1: COOMe
20 R: Me; R1: CH2OH
(iv)
Scheme 6 (i) DIBALH, THF, 0 ºC–r.t., 1 h (80%). (ii) MePPh3Br,
n-BuLi, THF, 0 ºC, 45 min (80–90%). (iii) TsCl, Pyridine, r.t., 24 h
(95%). (iv) LiAlH4, THF, reflux, 48 h (50%).
In summary, the highly diastereoselective Lewis acid cat-
alyzed cyanoaddition of 11 enables the synthesis of
manoyl oxide derivatives from communic acids 7a–c.
Acknowledgment
We thank DGESEIC for financial support (Project PB98-1365) and
Ministerio de Educación y Ciencia for a pre-doctoral fellowship
(J. L. Romera).
References
(1) (a) Leclaire, M.; Levet, R.; Ferreira, F.; Ducrate, P.-H.;
Ricard, J.-Y. L. L. Chem. Commun. 2000, 18, 1737.
(b) Hanna, I.; Wlodyka, P. J. Org. Chem. 1997, 62, 6985.
(c) Nicolau, K. C.; Kubota, S.; Li, W. S. Chem. Commun.
1989, 512. (d) Corey, E. J.; Da Silva Jardine, P.; Rohloff, J.
C. J. Am. Chem. Soc. 1988, 110, 3672.
(16) Barrero, A. F.; Altarejos, J.; Alvarez-Manzaneda, E. J.;
Ramos, J. M.; Salido, S. Tetrahedron 1993, 49, 9525.
Synlett 2003, No. 15, 2313–2316 © Thieme Stuttgart · New York

2316
A. F. Barrero et al.
LETTER
(17) Fotsch, C. H.; Chamberlin, A. R. J. Org. Chem. 1991, 56,
4141.
(18) Stierle, D. B.; Stierle, A. A.; Larsen, R. D. Phytochemistry
1988, 27, 517.
(m, 11 H), 3.40 (dd, J = 11.1, 1.5 Hz, 1 H, 4a-CH2OH-A),
3.60 (s, 3 H, 7-COOMe), 3.61 (d, J = 11.6 Hz, 1 H, 4a-
CH2OH-B).
13C NMR (100 MHz, CDCl3): d = 177.4 (7-COOCH3), 122.4
(3-CN), 79.3 (C-4a), 66.8 (C-3), 63.7 (4a-CH2OH), 56.3*
(C-10b), 51.3 (7-COOMe), 48.3* (C-6a), 43.7 (C-7), 38.8
(C-10), 37.9 (C-10a), 37.7 (C-8), 36.6 (C-6), 31.9 (C-2), 29.2
(Me-3), 28.5 (Me-7), 21.2 (C-5), 18.9 (C-9), 14.4 (C-1), 12.7
(Me-10a).
(19) Typical Procedure for the Nucleophilic Cleavage of 11;
Synthesis of Oxanes 14 and 15: To a stirred solution of 11
(0.25 g, 0.78 mmol), 18-crown-6-ether (0.57 g, 2.14 mmol)
and KCN (0.2 g, 3.10 mmol) in CH2Cl2 (15 mL), was added
AlCNEt2 (1.0 M in CH2Cl2, 6.2 mL) and TiCl4 (1.0 M in
CH2Cl2,1.9 mL) at –78 ºC, under Ar atmosphere. The
reaction mixture was then stirred at the indicated
temperature during the time showed in Table 2. Then an aq
1 M NaHCO3 solution (8 mL) was added and the resulting
mixture was stirred for 3 h, and extracted with t-BuOMe (2
× 30 mL). The organic phase was successively washed with
5% aq NaHCO3 (2 × 30 mL), water (2 × 30 mL), brine (2 ×
30 mL), dried over anhyd Na2SO4 and evaporated to give a
crude product which was chromatographed (hexane–
t-BuOMe, 3:2) to yield 14 and 15.
Compound 18: 1H NMR (400 MHz, CDCl3): d = 0.57 (s, 3
H, Me-20), 0.88 (dt, J = 13.3, 4.1 Hz, 1 H), 0.98 (dt, J = 12.9,
3.9 Hz, 1 H), 1.00–1.25 (m, 1 H), 1.17 (s, 3 H, Me-18), 1.28
(s, 3 H, Me-16), 1.65–1.95 (m, 7 H), 2.16 (d, J = 13.1 Hz, 1
H), 2.23 (dt, J = 12.7, 3.4 Hz, 1 H), 3.56 (dd, J = 10.5, 1.7
Hz, 1 H, 17-CH2OH-A), 3.62 (d, J = 10.5 Hz, 1 H, 17-
CH2OH-B), 3.62 (s, 3 H, 19-COOMe), 4.99 (dd, J = 10.8, 1.1
Hz, 1 H, =CH2), 5.20 (dd, J = 17.4, 1.1 Hz, 1 H, =CH2), 5.93
(dd, J = 17.4, 10.8 Hz, 1 H, -CH=).
13C NMR (100 MHz, CDCl3): d = 177.7 (19-COOCH3),
146.7 (C-14), 111.4 (C-15), 77.1 (C-8), 74.4 (C-13), 63.2 (C-
17), 56.9* (C-9), 51.4* (C-5), 51.3 (19-COOMe), 43.8 (C-
4), 40.0 (C-1), 38.1 (C-3), 37.8 (C-10), 37.7 (C-6), 33.0 (C-
12), 30.0 (C-14), 28.6 (C-18), 21.5 (C-7), 19.1 (C-2), 15.1
(C-11), 13.0 (C-20).
(20) All new compounds were fully characterized
spectroscopically and had satisfactory HRMS data.
Selected data:
Compound 14: 1H NMR (400 MHz, CDCl3): d = 0.58 (s, 3
H, Me-10a), 1.04 (dc, J = 13.7, 4.2 Hz, 2 H), 1.16 (s, 3 H,
Me-7), 1.20–1.54 (m, 2 H), 1.57 (s, 3 H, Me-3), 1.65–2.30
Synlett 2003, No. 15, 2313–2316 © Thieme Stuttgart · New York