Ring a functionalization of terpenoids by the unusual Baeyer-Villiger rearrangement of aliphatic aldehydes

Article abstract of DOI:10.1055/s-1999-2722

A new methodology is described for transforming resinic acids into nor- alcohols and nor-olefins, via the Baeyer-Villiger rearrangement of the derived aldehyde. Based on this methodology 4-hydroxy-18-nor-abieta-8,11,13- trien-7-one and 18-nor-abieta-8,11,13-triene-4,7α-diol, two new terpenoids recently described, have been synthesized from abietic acid.

Full text of DOI:10.1055/s-1999-2722

LETTER
713
Ring A Functionalization of Terpenoids by the Unusual Baeyer-Villiger
Rearrangement of Aliphatic Aldehydes
a
a
b
a
a
Alejandro F. Barrero,* E. J. Alvarez-Manzaneda, R. Alvarez-Manzaneda, Rachid Chahboun , R. Meneses ,
b
Marta Aparicio B.
a
Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Granada, 18071 Granada, Spain
bDepartamento de Química Orgánica, Facultad de Ciencias, Universidad de Almería, 04120 Almería, Spain
Fax +34 58 24 33 18; E-mail: afbarre@goliat.ugr.es
Received 31 March 1999
thesized by applying the Barton decarboxylation proto-
col.2
Abstract: A new methodology is described for transforming resinic
acids into nor-alcohols and nor-olefins, via the Baeyer-Villiger re-
arrangement of the derived aldehyde. Based on this methodology 4- Aldehydes undergo Baeyer-Villiger rearrangement to
hydroxy-18-nor-abieta-8,11,13-trien-7-one and 18-nor-abieta-
give carboxylic acids due to preferential migration of hy-
8
,11,13-triene-4,7a-diol, two new terpenoids recently described,
drogen. Alternative migration of the carbon group to yield
formates seldom occurs. Aryl aldehydes having electron-
releasing groups are the only exceptions and are converted
to aryl formates by the Baeyer-Villiger oxidation. At the
present time only a few examples of the preferred migra-
have been synthesized from abietic acid.
Key words: Baeyer-Villiger rearrangement, nor-Terpenes
Some interesting terpenoids, due to their biological activ- tion of a carbonmoiety in an aliphatic aldehyde have been
ity, have a functionalized A-ring structure. Representative reported.1 Recently we have found that aldehyde 7a is
2-14
1
compounds are quassinoids, such as bruceantin (1), and transformed with an excellent yield into the formate 7b
2
15
the antiherpes nor-diterpenes 2 and 3. Over the last few through peroxyacid treatment. In order to elucidate the
years the isolation of different natural nor-terpenes, e.g. 4- scope and synthetic applications of this reaction the be-
3
,4
6
, 12c and 20, has been reported .
haviour of aldehydes 8a-12a having a variety of carbon
skeletons, including mono-, di-, tri- and tetracyclic struc-
tures, and different additional functions have been stud-
ied. They were efficiently prepared with an 65-70%
overall yield from carboxylic acid in a two-step sequence
involving reduction with lithium aluminium hydride and
further oxidation with pyridinium chlorochromate. Treat-
ment of these aldehydes with peroxyacid afforded the cor-
responding formates 8b-12b as the only product in all
cases. These esters might easily be transformed into the
derived alcohols or olefins (Scheme 1). The complete se-
quence constitutes a simple and efficient way for trans-
forming terpenic acids into the corresponding nor-
alcohols and nor-olefins.
R4
OH
HO
COOMe
O
O
R1
O
O
R2 R3
HO
O
1
2
3
4
2
3
4
5
6
R : OH; R , R : =CH2; R : H
R : OH; R , R : =O; R : H
R : H; R : Me; R : OH; R : H
R : H; R : OH; R : Me; R : H
1
2
3
4
1
1
2
3
4
1
2
3
4
1
2
3
4
R : H; R : Me; R : OH; R : OH
Following the authors’research into the synthesis of valu-
able compounds from available natural diterpenes, 5 we
are now dealing with the synthesis of A-ring functional-
ized terpenes, such as quassinoids and other nor-terpenes,
from terpenic acids by removing the carboxylic group
through the corresponding aldehyde.
,6
OH
COOH
CHO
OCHO
The most common and widely studied reagent for oxida-
tive decarboxylation, lead tetraacetate, usually produces a
mixture of unsaturated hydrocarbons with small admix-
Scheme 1
7
tures of acetates and the corresponding alcohols. The ox-
idative decarboxylation by hydrogen peroxide and a
mercury (II) salt has also been used to transform carboxy-
lic acids into the corresponding nor-derivatives. The Bar-
Time reactions and yields of the steps leading from 7a-
2a to the derived nor-alcohols and nor-olefins are sum-
marized in Table 1.
1
8
ton decarboxylation method has become a suitable
procedure for preparing olefins, nor-hydroperoxides or
9
,11
nor-alcohols from carboxylic acids. 2 and 3 were syn-
Synlett 1999, No. 6, 713–716 ISSN 0936-5214 © Thieme Stuttgart · New York

7
14
A. F. Barrero et al.
LETTER
Table1 Synthesis of nor-alcohols and nor-olefins from aldehydes
O
H
R
O
(i)
(iii)
O
H
R'
O
R
R
R
R
R
7
8
9
1
3 R: COOH
4 R: CH2OH
15 R: COOH, R': OAc
16 R: CH2OH, R': OH
12a R: CHO
12b R: OCHO
12c R: OH
(iv)
(v)
(vi)
(ii)
1
O
(vii)
O
(xi)
R
R
R
1
0
11
12
(x)
a R: CHO ; b R: OCHO ; c R: OH
R'
OH
OH
OH
R
OH
The treatment of the aldehyde with m-chloroperbenzoic
acid in methylene chloride at 50°C afforded the corre-
sponding formate with retention of the configuration,
which was converted into a mixture of the exo- and endo-
olefins by refluxing in collidine. Alternatively, the for-
mate was quantitatively saponified to the nor-alcohol, that
gave the olefins by treating with mesyl chloride and pyri-
dine at room temperature. As was to be expected, the
Baeyer-Villiger rearrangement of equatorial aldehyde
17 R: CH2OH, R': OAc
(viii)
(ix)
20
21
1
8 R: CHO, R': OAc
9 R: OCHO, R': OAc
1
(i) Hg (OAc)2 (2.2 eq), toluene, reflux, 1h (85 %). (ii) LiAlH4, THF, reflux,
15h (96 %). (iii) PCC (4 eq) , CH2Cl2, rt, 45 min (75 %). (iv) MCPBA (2.5 eq),
anh. CH2Cl2, Na2HPO4 ( 2.75 eq), reflux, 5h, (95%). (v) 2 N KOH-MeOH,
reflux, 1h (94%). (vi) LiAlH4, THF, reflux,10h (81 %). (vii) Hg (OAc)2 (2.2 eq),
toluene, reflux, 1h (80%). (viii) PCC (2 eq) , CH2Cl2, rt, 45 min (71 %).
(
(
ix) MCPBA (2.5 eq), anh. CH2Cl2, Na2HPO4 ( 2.75 eq), reflux,3h (89 %).
x) 2 N KOH-MeOH, reflux, 1h (95 %). (xi) NaBH4, EtOH, 0 °C,1h (93%).
Scheme 2
(12a) was faster than that of the axial ones. Moreover, in
most cases elimination took place in high regioselectivity
affording the exo isomer as the main compound.
Alternatively, reduction of 13 with LiAlH gave 14, which
This procedure may be more advantageous for preparing
4
after treating with mercuric acetate yielded 17, which was
oxydized with PCC to the aldehyde 18. This underwent
Baeyer-Villiger rearrangement to afford the diester 19
which was saponified to give 20, whose physical and
spectroscopic properties were identical to those reported
nor-alcohols than the above mentioned radical decarbox-
8
ylations, since epimerization is avoided. Based on this
methodology we have synthesized 12c and 20, two new
3
4
terpenoids isolated from J. chinensis and L. kaempferi
respectively, from abietic acid (13) (Scheme 2).
4
for the natural compound. Treatment of 12c with NaBH4
Treatment of 13 with mercuric acetate afforded the 7a-ac-
gave the 7b-isomer 21, which had the expected spectro-
scopic properties.
1
6
etoxyderivative 15, which was reduced to give the diol
1
1
6. Treatment of 16 with PCC afforded the ketoaldehyde
2a which, when treated with m-chloroperbenzoic acid,
Acknowledgement
gave the ketoester 12b, which after saponification with re-
fluxing 2N KOH-MeOH yielded 12c, whose physical and
spectroscopic properties were identical to those reported
We should like to thank the CICYT (Project PB-95 1182) for finan-
cial support.
3
in the literature. 12c is an immediate precursor of actives
2
terpenoids 2 and 3.
Synlett 1999, No. 6, 713–716 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Ring A Functionalization of Terpenoids
715
References and Notes
Saponification of formates 8b-12b: Preparation of nor-
alcohols 8c-12c.
(
(
1) Polonsky J. Forts. Chem. Org. Naturst. 1985, 47, 221.
2) Tagat,.R.; Nazareno, D.V.; Puar, M.S.; McCombie, S.V.;
Ganguly,J A.K. Bioorganic & Medicinal Chemistry Letters
To a solution of formate in MeOH was added a 2N solution of
KOH in MeOH and the mixture was refluxed for 1 h. The
solvent was evaporated and the crude was diluted with ether
and washed with water. The organic layer was dried and
concentrated under reduced pressure to afford the nor-
alcohols 8c-12c.
1
994, 4:, 1101.
3) Lee, C.-K.; Fang, J.M.; Cheng, Y.S. Phytochemistry 1995, 39,
91.
4) Ohtsu, H; Tanaka, R; Matsunaga, S. J. Nat. Prod. 1998, 61,
06.
5) Barrero, A. F. ; Altarejos, J.; Manzaneda, E.A.; Ramos, J.M.;
Salido, S. Tetrahedron 1993, 49, 6251.
6) Barrero, A. F.; Altarejos, J.; Manzaneda, E. A.; Ramos, J.M.;
Salido, S. Tetrahedron 1993, 49, 9525.
(
(
(
(
(
3
Dehydration of alcohols 8c-12c: Preparation of nor-olefins.
To a solution of alcohol in pyridine was added at 0° C MsCl
4
(3 eq) and the mixture was stirred at room temperature. Then
the mixture was poured into ice and extracted with ether. The
organic layer was washed with 2 N HCl, saturated NaHCO3
and brine, and then it was dried and concentrated under
reduced pressure to give the nor-olefin.
7) Bennett, C.R.; Cambie, R.C.; Franich, R.A.; Fullerton, T.J..
Austr. J. Chem. 1969,22, 1711.
(
18) All new compounds were fully characterized
spectroscopically and had satisfactory high resolution mass
spectroscopy data.
(
(
8) Tkachev, A.V.; Denisov, A.Y. Tetrahedron 1994, 50, 2591.
9) Barton, D.H.R.; Crich, D.; Motherwell, W.B. J. Chem.
Soc.,Chem. Commun. 1984, 242.
Selected data:
(10) Barton, D.H.R.; Crich, D.; Hervè, Y.; Potier, P.; Thierry, J.
1
1
(
(
2a H NMR (400 MHz, CDCl ) d : 1.24 (s, 3H, Me-20), 1.25
3
Tetrahedron 1985, 41, 4347.
d, J= 6.9 Hz, 6H, Me-16, Me-17), 1.29 (s, 3H, Me-19), 1.48
m, 1H), 1.87 (m, 1H), 2.26 (dd, J= 17.9, 3.5 Hz, 1H, H-6),
(
(
(
11) Barton, D.H.R.; Crich, D. Tetrahedron 1985, 41, 4359.
12) De Boer, A.; Ellwanger, R.E. J. Org. Chem. 1974, 39:, 77.
13) Alcaide, B.; Aly, M.F.; Sierra, M.A. J.Org. Chem. 1996, 61,
2.40 (dt, J= 12.8, 3.2 Hz, 1H), 2.44 (dd, J= 14.2, 3.5 Hz, 1H,
H-5), 2.68 (dd, J= 17.9, 14.2 Hz, 1H, H-6), 2.91 (h, J= 6.9 Hz,
8
819.
14) Gottlich, R.; Yamakoshi, K.; Sasai, H.; Shibasaki, M. Synlett
997, 971.
15) Barrero, A. F.; Manzaneda, E.A.; Chahboun, R.; Páiz, M.C.
Tetrahedron Letters, 1998, 39, 9543.
16) Irismetov, M.P.; Tolstikov, G.A.; Irismetova, R.S.; Goryaev,
M.I. Izv. Akad. Nauk. Kaz. SSR, Ser. Khim. 1968, 18, 73.
17) For preparation of 7a see ref 15. The synthesis of 8a and 11a
is described in ref 6. 9a was obtained by catalytic (Pd/C)
hydrogenation of ent-kaur-16-en-18-ol and further oxidation
with PCC. 10a was obtained after hidrogenation over Pd/C of
a mixture of methyl cis-, trans- and mirceocommunate.
Typical Experimental Procedures
1H, H-15), 7.32 (d, J= 8.1 Hz, 1H, H-11), 7.42 (dd, J= 8.14,
(
(
(
(
2
.1 Hz, 1H, H-12), 7.88 (d, J= 2.12 Hz, 1H, H-14), 9.25 (s, 1H,
1
13
H-18). C NMR and DEPT (100 MHz, CDCl ) d : 37.5* (C-
3
1
1
1
2
2
1
), 17.3 (C-2), 37.0* (C-3), 49.2 (C-4), 41.7 (C-5), 32.2 (C-6),
97.8 (C-7), 130.6 (C-8), 152.4 (C-9), 36.7 (C-10), 123.6 (C-
1), 132.7 (C-12), 147.1 (C-13), 125.2 (C-14), 33.6 (C-15),
3.7 (C-16), 23.7 (C-17), 204.6 (C-18), 14.1 (C-19), 23.7 (C-
0) (*: interchangeable signals)
1
2b H NMR (400 MHz, CDCl ) d : 1.25 (s, 3H, Me-20), 1.25
3
(d, J= 6.9 Hz, 6H, Me-16, Me-17), 1.65 (s, 3H, Me-19), 1.88
m, 1H), 2.32 (m, 1H), 2.51 (dd, J= 14.1, 3.4 Hz, 1H, H-5),
(
2
.67 (dd, J= 17.7, 14.1 Hz, 1H, H-6), 2.74 (m, 1H), 2.91 (dd,
J= 17.7, 3.4 Hz, 1H, H-6), 2.93 (h, J= 6.9 Hz, 1H, H-15), 7.29
d, J= 8.2 Hz, 1H, H-14), 7.42 (dd, J= 8.2, 2.1 Hz, 1H, H-12),
Preparation of aldehydes 8a-12a
To a stirred solution of carboxylic acid (1 eq) in dry THF was
(
13
7.89 (d, J= 2.1 Hz, 1H, H-11), 7.96 (s, 1H, H-18). C NMR
added LiAlH and the mixture was stirred under reflux for 15
4
and DEPT (100 MHz, CDCl ) d : 36.7 (C-1), 19.7 (C-2), 37.5
3
h. The reaction mixture was poured into ice, then ether was
added and filtered under vacuum. The layers were separed and
the aqueous phase extracted with ether. After washing the
organic layer with brine, it was dried and evaporated to yield
the corresponding alcohol which was oxydized without
further purification.
(
(
C-3), 85.3 (C-4), 48.1 (C-5), 35.2 (C-6), 198.2 (C-7), 130.5
C-8), 152.1 (C-9), 38.6 (C-10), 123.8 (C-11), 132.7 (C-12),
1
1
1
47.1 (C-13), 125.0 (C-14), 33.6 (C-15), 23.1 (C-16), 23.8 (C-
7), 159.9 (C-18), 26.9 (C-19), 19.9 (C-20).
1
5 H NMR (300 MHz, CDCl ) d : 1.20 (s, 3H, Me-20), 1.23
3
(
d, J=6.9 Hz, 6H, Me-16, Me-17), 1.28 (s, 3H, Me-19), 2.02
To a stirred solution of alcohol (1 eq) in CH Cl was added
2
2
(s, 3H, AcO), 2.32 (bd, J=12.4 Hz), 2.64 (dd, J= 12.7, 1.5 Hz),
.86 (h, J= 6.9 Hz, 1H, H-15), 5.89 (bs, 1H, H-7), 7.04 (d,
PCC (1.5 eq) and the mixture was stirred at room temperature
for 45-60 min. Then it was filtered through a short silicagel
column under argon (eluted with ether) and the solvent was
evaporated under reduced pressure affording the aldehyde.
Treatment of aldehydes 8a-12a with MCPBA: Preparation of
formates 8b-12b.
2
J=1.8 Hz, 1H, H-14), 7.16 (dd, J= 8.2, 1.8 Hz, H-12), 7.25 (d,
J= 8.2 Hz, 1H, H-11).
13
C NMR and DEPT (75 MHz, CDCl ) d : 37.6 (C-1), 18.5 (C-
3
2), 36.5 (C-3), 47.0 (C-4), 40.0 (C-5), 28.2 (C-6), 71.0 (C-7),
31.9 (C-8), 147.6* (C-9), 37.3 (C-10), 124.5 (C-11), 128.5
1
To a stirred solution of aldehyde (1 eq) in CH Cl was added
a solution of MCPBA (2.5 eq) in CH Cl and Na HPO (2.75
2
2
(C-12), 146.6* (C-13), 127.3 (C-14), 33.5 (C-15), 23.8# (C-
16), 23.7# (C-17), 184.8 (C-18), 16.1 (C-19), 24.0# (C-20) (*
2
2
2
4
eq) and the mixture was stirred under reflux. The solvent was
evaporated under reduced pressure to give a crude which upon
silica gel chromatography (hexane-ether as eluent) afforded
the formate.
Treatment of formates 8b-12b with collidine: Preparation of
nor-olefins.
and #: interchangeable signals).
1
1
(
(
8 H NMR (300 MHz, CDCl ) d : 1.15 (s, 3H, Me-20), 1.19
3
s, 3H, Me-19), 1.21 (d, J= 7.1 Hz, 6H, Me-16, Me-17), 2.06
s, 3H, AcO), 2.85 (h, J= 7.1 Hz, 1H, H-15), 5.95 (d, J=2.9 Hz,
1
H, H-7), 7.06 (d, J=1.8 Hz, 1H, H-14), 7.17 (dd, J=8.3, 1.8
13
Hz, 1H, H-11), 7.24 (d, J=8.3 Hz, 1H, H-12). C NMR and
A solution of formate in collidine was stirred under reflux.
The mixture was cooled to room temperature, diluted with
ether and washed with 2N HCl and brine. The organic layer
was dried and concentrated under reduced pressure to afford
the nor-olefins.
DEPT (75 MHz, CDCl ) d : 37.5* (C-1), 17.8 (C-2), 32.1 (C-
3
3
), 49.4 (C-4), 49.1 (C-5), 28.3 (C-6), 70.1 (C-7), 131.9 (C-8),
46.9 (C-9), 39.3 (C-10), 124.4 (C-11), 127.3 (C-12), 146.9
1
(
2
C-13), 128.5 (C-14), 33.5 (C-15), 23.9 (C-16), 24.3 (C-17),
05.8 (C-18), 23.8 (C-19), 14.1 (C-20).
Synlett 1999, No. 6, 713–716 ISSN 0936-5214 © Thieme Stuttgart · New York

7
16
A. F. Barrero et al.
LETTER
1
1
(
(
1
9 H NMR (300 MHz, CDCl ) d : 1.14 (s, 3H, Me-20), 1.21
(s, 3H, Me-19), 1.24 (d, J= 6.9 Hz, 6H, Me-16, Me-17), 2.03
(dt, J=12.6, 5.9 Hz, 1H), 2.22-2.39 (m, 3H), 2.89 (h, J= 6.9 Hz,
1H, H-15), 4.86 (dd, J=9.4, 7.9 Hz, 1H, H-7), 7.10 (dd, J=8.1,
1.9 Hz, 1H, H-11), 7.20 (d, J=8.1 Hz, 1H, H-12), 7.45 (d,
J=1.9 Hz, 1H, H-14). C NMR and DEPT (75 MHz, CDCl3)
d : 36.1* (C-1), 23.6 (C-2), 38.4* (C-3), 70.7 (C-4), 46.3 (C-
5), 32.3 (C-6), 70.4 (C-7), 137.9 (C-8), 144.5(C-9), 39.7 (C-
10), 124.9 (C-11), 125.3 (C-12), 146.6 (C-13), 125.7 (C-14),
33.8 (C-15), 23.9 (C-16), 24.1 (C-17), 23.6 (C-19), 22.9 (C-
20) (*: interchangeable signals).
3
d, J= 6.9 Hz, 3H, Me-16) 1.22 (d, J=6.9 Hz, 3H, Me-17), 1.54
s, 3H, Me-19), 2.06 (s, 3H, AcO), 2.40 (dd, J=12.8, 1.9 Hz,
H), 2.65 (dd, J=9.4, 3.5 Hz, 1H), 2.96 (h, J= 6.9 Hz, 1H, H-
5), 5.99 (dd, J=4.3, 1.7 Hz, 1H, H-7), 7.05 (d, J=1.8 Hz, 1H,
H-14), 7.17 (dd, J=8.3, 1.9 Hz, 1H, H-11), 7.22 (d, J=8.3 Hz,
H, H-12), 8.01 (s, 1H, OCHO). C NMR and DEPT (75
1
3
1
1
3
1
MHz, CDCl ) d : 37.1* (C-1), 20.0 (C-2), 37.6* (C-3), 86.3
3
(
1
(
1
C-4), 44.5 (C-5), 25.3 (C-6), 70.4 (C-7), 131.9 (C-8),
46.9(C-9), 38.6 (C-10), 124.7 (C-11), 127.4 (C-12), 146.9
C-13), 128.5 (C-14), 33.5 (C-15), 23.9 (C-16), 24.3 (C-17),
60.3 (C-18), 23.8 (C-19), 19.9 (C-20), 21.6 (CH CO) (*:
3
interchangeable signals).
Article Identifier:
1437-2096,E;1999,0,06,0713,0716,ftx,en;L04099ST.pdf
1
21 H NMR (300 MHz, CDCl ) d : 1.04 (s, 3H, Me-20), 1.18
3
Synlett 1999, No. 6, 713–716 ISSN 0936-5214 © Thieme Stuttgart · New York