l - Whitesides Research Group - Harvard University
TetrahedronVol.43, No. 8, pp. l87l to 1879, l9g7 Printed in Great Britarn.
0040-4020187$1.00+.00 1987PergamonJournalsLtd.
A SHORTSYNTHESISOF AMBROX@ FROMSCLAREOLT
R E N ED E C O R Z A N TC,H R I S T I A NV I A L , a n d F E R D I N A N D NiF.' F i r m e n i c h S A , R e s e a r c hL a b o r a t o r i e s , C H - 1 2 1 1G e n e v a8
GEORCM E . hTIITESIDES H a r v a r d U n i v e r s i t y , D e p a r t m e n to f C h e m i s t r v , C a m b r i d g e ,M a s s a c h u s e t t s0 2 1 3 8
(Receiued in LlK 22 Dec'entber 1986\
AbsLract- - A th(,-step transformation of sclareol into Ambroy@(overall v'ra B-cleavage of an al,koxy radical intermediate II-l2Z) is described.
I n t r o d u c t i o n - A m b r o x o( 1 a ) I ) ,
one of
discovered by Hinder and Stoll
in 1950 f2a, bl.
p'ocess ( pr.cl'ci ug C.III
the most j-mportant ambergrr-s f ragrance It
is
sti11
, r . M n I l \ { a s te , m a x i m u mo v e r r l I L v i e l d
manufactured 522) of
yield
c h e nj c a l s
b1' a teciious
natural
I 1] ,
was
degradation
sclarer-,1
(D ,2)3)
Scheme i
IH t0
6
"l 2a
r\mbroxo la v)
Rc-asenLs: i ) CrO.,/AcOH; ii) v)
i 1) 2)
Dedicated
to
iso-i\mbrr-,x lb
150"/vactlrm;
Professor
K l 4 n O O ;i l j ) O r l A ; vi)
LiAlll//ether;
George Bijchi
on the
iv)
vil)
occasion
KoH. then HC1; B_naphrhtalenesul-fonic
of
his
65th
acid
birthdav.
Trade name of Firmenich SA for an ambergris fragrance chemlcal, whose Chem. lb.sfr. naphtho[2,r-b lfuran, dodecahydro-3a,6,6,9a-tetrarnethyl-, [ 3 a R - ( 3 a : r , 5 a B , 9 a o , 9 b B )] . L'hc:n,Abstr. narnes: 1-naphthalenepropanol , o,-ethenyldecahydro-2-hydroxy-o [ 1,t-(tolp*),2f3,4a8,8ao) ], and (l3R)-1abd-14-ene-g, i3-dto1.
3 ) The relative given
in
[3a,
is:
,2,5,5,8a-pentamethyl-,
and absolute configuration (2a) (and 13-epr-sc1are.1) of sclareol b], and has been confirmed by x-ray crysrallography i:.].
1871
name
is
drawn as
R. Dsconzevr et al.
t8'72 rhe
n rincinal ts_ - ".-rr-_
s" - o u- r c e
of
reactions
4,
and
which
acid,
produce
routes
to
conditlons
4
cyclizes
Ia
to
5 and 6 with
but
more stable,
the
vra
[2])
5
1s
diol
6
much weaker
olfactively
( la)
Ambrox
since
Ambrox (1a).
into
in
steps these
acid-catalyzed under
readlly
isomerizes (lU1
iso-Ambrox
[6]
two
Although
flnal
the
acid
Lhe acetoxy
transformed
flnally
sLereochemlstrv,
correct
the
care
special
needs
Lactone
t5].
cyclizatlon
ozone Lo yield
is
a sequence
using
indirectly
or
[4], (3),
oxide
sclareol
5
lactone
to
intermediates
6
give
(2a)
sclareol
AccordinSlY,
L.).
scfarea
chromium trloxide
using
directly
and acid-catalyzed
the
of
cyclization
sage (Salvia
clary
permanganate to
comprising
(LlA1H4 reduction
ls
5 either
lactone
degraded to
which
of
acid
wlth
together
other
compounds[7].
(rhpme
2
Ret
rncvnLheL
i c
s
anafVsi
OH
6o v
qs-+$,"-)$'-i-6$ 1a
2a
publication
This vra
presumably (cf.
(la)
Lertiary
its
retrosynthetic
giving There
j-nto ketones
(S-cteavage)
radicals
alkoxy
i,
analysis).
ra<Jical
oxygen-centred
scheme 2t
in is
process
degradation
fragmentative
a
describes
two
radicals
and alkl'1
t9].
tBl
pure
Ambrox
tlre fragmenLation of
.n
I iterature
(2a),
sclareol
slereochemicalLy
steps
amplc
of
Wlth
non-identical
t')?
groups
aIkyI
being
of
the
f]
(scheme 3,
eqn.
such
(1)).
present
as
This
j-ons Lo g-Lve ulti-mately nucleophile
to
attached is
$-cleavage
favour
(scheme 3,
ether,
Q));
Schene
0.
most
R'
+
stable
I
R'),
alky1
under the
further
an alcohol
or
sonetimes also
ls
an olefin
atom the
of
be oxidized
needs to
, an a1kyl
ha1lde
eqn,
formatlon
the
a1ky1 radical
an alky1
carbon
ox)'gen-carryrng
the
to
(R'
etc. '
t-he selectivity radical reactlon
depending
[9g,
h,
conditon
the
obtained.
3
0
I
*
*t,t(*'
?. R"
+
nrAn2
(1)
R-
*hrl. [*r.l' LJ g
metal
Results
oxidants
red on
direct
slmplicity,
lithium
S.l".tively
oxidation
a series
of
i- were rried
radical
alcoholate
were isolated
4)
may be used instead
is
(2)
best
. ^ II out bv Cu" alrhough other
carried
[ 10].
and discussion
1, ALtenpted For
radical
a carbon-centred
of
The oxidation
R3-Nu
*
l4))
of
scTareol
firsr.
C"rV
gave
(2a)
oxidations
di-rect
no
[11], useful
of
sclareol
c,,rr /s2082results;
of
2a with
BuLi
[12],
starting
on1y.
formed by treatment
(2a)
[7].
likely Pb(oAc)o material
to
generaLe the
[13.], and air and/or
oxygen-cent(in
complicated
this
case
mixtures
A short synthesisof Ambroxh
l 873 0c1
0Li
\
2.
(Ia)
Anbrox
A second
fron
approach
chlorites
h].
[9g,
(9)
dihydrosclareoL to
However,
the
cal
bond. 0n the
intermediate =0.52
other
10,
hand,
followed
of
Ambrox (la)
A1ky1 nitrite
homolysis
to
deconposiLion by the
necessary
aBents, such as sodium hypochlorite double
via
j- was offered
radlcaf
and tert-butyl
together
of
the
saturaLed
10.
of
preferentially
alcohol
9 [4]
the
the
vinvl
hypotheti-
chloride
f1?)
led
(scheme 4).
products
Ambrox (la)
nor give
hypo-
chlorinating
give
to
(via
unknown decomposition did
t-ertiary
attacked
elther.
lt
oil
..i43
of
be inaccesslble:
and base treatment
A1k0-N=O,iheat l14l)
9, ltr'tnt
to
hypochlorite,
a multitude
(A1k0-N=0/Ir/hv,
hypochlorrte
its
proved
8
decomposition
wlth
of
documented decomposltion
hypochlorite
chlorination
by thermal
well
oc1 i)
.Lq} -----\o-
rr)
_+
iij)>
. 2a
l0
.ji'l
-f4,,,:l
,\o, J iii
Reagcnt-s: i)
.^tm
w
iv)
-{r>
lt
lr7,Pd-C/lrt0ll;
ii)
la
, r 1u1( i o u s
i v ) N ; r l l / ' f l l [ , 3 l r r c f I i r x.
r? .
sA^-; re y, , n- Lt n e s r s-
a^ ^n) a d e c o n p o s i t i o n
A major
difficulty
lack
selectivity
of
^ ^ ^ f a c e L ,y, l1 a^ +Li t o^ n- .
hand
the
oxide
^ C o L
in
for
sclareol
a11y1ic
when either
treated
rather
Reaction amount of
of
of
l2a
rnanoyl oxides 952 pure
and
1:l
114')
as
opposed
mixture
of
should
to
the
the
two
undergo
than
13.
peroxide metals (2a/b,
acld
at
(2:1)
[15].
and 9OZ pure
positional
alcohol
with
a
TiIII,
gave
1itt1e
Chromatography
so
(Scheme 5). seems to
a1coho1.
monoacetaLes t7l. displacement
and
therefore
readily
give
und vlrI
the
382 isolated
of
the
give
of
the
the
radicals
a catalytic two eprmerlc
hydroperoxide al-1owed the
were characterized
per-
pyrolyzed.
or
presence yield
other
hydrogen
oxygen-centred
undesired
and crysrallizarion
On the
with
k]
be the
Srmilarly,
selectively
[9i,
in
13. The new peroxides
(la) far
tertiary
7OZ aqueous HrO, in
room temperature
together
non-allv1ic
Hvdroperoxides
with
to Anbrox
dlscussed
nucleophilic
such as Furr, 9:l)
route
reactions
non-a1l-y1ic.
14a and 14b (7:3)
12a (m.p.
a viable
corresponding
sclareot
12b
l2a/b:
and chlorination
sclareol
transition
p-toluenesulphonic
hydroperoxides the
in the
with
hydroperoxide
a11y1ic
gave a
than
l2a/b
of
oxidation
the
alcohol
much faster
hydroperoxides
the
bv a)
13 and
isolation
iodometric
R. Drconza.Nr et al.
t874
S c h e m e5
i) __l>
\
ooH
OH
OH
d$d"' 13 Reagents:
7OZ aquenus I{.()"/p- l sOil/Cl{rC1.r;
i)
to
and hydroxy
the
o and b-carbon
t'C-NMR
b)
function
(Table)
exhibits
of
(nr
match) thc
meric
at
diffcrence
could
all
I2a
back
of
by-product
fL rL -I E, a rL ,W' U^ -I I -I d- T^I "U r} A values
tlon
This
hydroperoxide
the
of
carbon
the
the two
atoms of
suggests
posiLion
that
atoms C-9,
the
C-l3 major
by
mixture
the
function
on the
hvdroperoxide
C-13,
hydroperoxj-des the
12b 13-epr-sclareol
(reduction
the
of
shift
The
hydroperoxide/terr-butanol.
Za/2b for
Ad-values other
of
hydroperoxv
valuable
C-14,
pal rs
hydroperoxlde
funcLion
exactly
and C-16 para11e1 are
and 2a/b
l2a/b
12a has sclareol Chemical
configuration.
opposed
differenr-es
shift
C-15,
12b which
12a and
epimeric
as
neighbouring
also
epi-
no shift configu-
transformation
th:-s assignrnent. Structure 1? 1 l3 (without stereochemical assignmenL) was evidenL Irom'-C and'H-NMR spectra rrrd 'l? ' ' C N M R ^-ides (I4a/b) were identif ied by compar-ison of therr values wilh the reporUA-
into
2a
triphenvlphosphine)
corroborated
I l) l. When the
f"II/CuII
the
be detected.
and the minor
ration of
ted
For
The
obtained.
and diagnostically
tert-buty1
C-13 epimers
corresponding
C-l3.
mixtures
localization
atoms allowing
between the
the
a typrcal
by using Lhe known reference pair A6 observed
ItZOIC\OH, 2hl50'
Cu(0Ac)r.21{rOll'eSO 4.7
ri)
titration
14tr
Ii7]
(250',
Ambrox (ta)
contact
of
two hydroperoxides
(=3OZ isolated
ti,me =l0s)
1ed onlv
yield) to
traces
l2a/b
was direcrly of
(2:l)
reacted
with
formed (scheme 5).
Ambrox (la)
and a multitude
the
redox couple
Thermal decomposiof
unknown prod-
ucts. Mechanistically, lined
gether
in
the
catalyLic
deconnposiLion of
l2a/b
mighr
be rationaljzed
as
out-
scheme 6 ln
with
analoCy known, related reactions [7a] [Bu] [9a, i] t10l t171. !g In step (1) Fett cleaves the hydroperoxide to give the radical intermediate i . III Fe^--. In step (2) the free radical fragments into the radical intermediate i
toii
I875
A short svnthesisof Ambrox* c'.l
c\ O
N
l--
\O
O\
$$\to'tnca
C\
c . ] N C \ N N
tn
trl
\a
Ln
\t
o-1
C\
C\
c\l
N
C{
(\l
\t
\t
ca
\t
\t
c'
'rl X c l. c,
ca ca
ca ca
ca ci
ca ca
./-r ca
ca ca
-o
'ou
o ii
E -J-Jta\OL^O
r-
ra)
r^
a
tn
La
tr\
\o
: {
r)
-o
I
O q)
Latnc!C!Gtca\O@ ca
r/) \O cr' --c\NNNNol
'-
\O
Lr iJ
C-.i
@
o
@@clcC@Nc!r Ln o@ci$oo\
C
O
o, ,c
\1
E
\OO,@NO'C1)
-t
\O \O -t $\acn-t\t$\Ts
.$$
a-'l
O
t'
I C)
CC
l\
c!
c-'l
ca l--
--l tt-
a^
\
CFJ
rn
O'\
c\l
O
tn
ca r--
ca '--
ca r-
-T @
$ @
-t t\
cl c-
: : .-
N N
l'-
cC
O'
tn
\O
C.l
r^\toa-ta-T -Jjc^\t:^3-
N
N
O,
@
Lr\
@
Cn
r-'
CO
a^
a^
I
$ N q*i
o
(-cao.'-1
O
':
CL^
O,C,@c..r_C. ol -
ac a-'
a-
u
\
!J a
r\o.'\Otij$@\C
A-)
\O
\O
NNC\!nLn@ \O \C \O
tr\
ul
Lr\
'1.
L^
a tr A) !
r\
\C
cY-r
-'l
C
C
-1 n
\t F-
L/l r\
\C Cla
L^ l--
.C r\
c I
: a-? f,> a ri 'o
c\l
U 9
\t-t\t\O"c' +-3$o1\t$
=
{ Laultac..lOO
U) AJ
c.J
U C-'.1
N t
aJ
N
C'J
c'l
--z -4.
= i3
OJ i
t
CtcL^Lf \O ln
\O L^
\C ta1
ul !r'l
\O Lr)
\O Ltl
N€ aa
a
'i3 o.lNNc^$ ca ca
a
al (-)
ca c]
ci ca
cil cl
u
!r ::
ca o-l
>a
U
a CJU
O O O O N N
(-)
C..l
-$
aJ
c!
N
-r
-t
-t
C\i
C\
\i
\t
9! !i CJ
(n tn
tn
-f,
In
\O
Y !,
It-
C, (ts^ qc -O+
co@@ccco@
'- c' ?l l l ( - )
'E \O
\O
c,.\ O'. -caca-Jalca
O\
Ir-
0
tn O
O\
q
.C-
=E z.o z (a
C,
OLn ca c!
o'u dod,6co-ot!-0 <jo.NNo\c{Ncn$\t Eo C')
a^ u
!a-
1816
et al.
R. Dnconznvr
Schene 6
.'^l I
I
r)z\. | |
V|.'/
o'
ooH - l a ' a
.
t"
rl''
\ t' o H
-re -rr -
r |
\av .\H
.,\H
I |
I\ [" oH
+
F.IrI
+
oH
(r)
i
l2a ot
-^-fll \-. ( -l. J,^,,I I tuH
.
(
^1,.-
-+
-.\ H
.^l^l" I
|
+
["oH
i
.-\?
-.\H ii
i
(' llr
(* cuTI -.
-\r\..
ll["oH>ll["oH+
..
L
cur
(3a)
\d-'l
-.\H
,{H ii
iv
(
f
tu"-
f'FJ'*, .\H
currrLn
^trAIJ
IT
ll+
(
dry
t t
-
J,
I
-...-w
llr'oH4 -\u
(4a)
la
iv
.^currrLn
^A# I
I
I
___-.____-.>-
.'\H
-N
>o'
+ cul
1a
FeIrI
+
cuI -+
F.rI
+
cuTI
(s)
t877
A short synthesisof Ambrox!
ketone.
vinyl
and methyl
The (an electron the
tively, species cess.
v
could
and
catalytic
in
be isolated,
step
step of
in
(4b)). iron
radical
ii
which
then
(3a))
radical
Finatly, and
contrast
of
(step
copper.
to
might
ii
elimlnation
upon reductive
(3b)
steDs
sequence
process,
ring-closing
which
primary
carbon-centred
transfer
simllar
It
involve
p"II
the give
cyclic,
that
(step
ur" neither
(a
ligand
regenerated olefin
( a)).
iv
Alterna-
organocopper(III)
transient
Ambrox (Ia)
ion
carbonium
the
to
Ambrox (la)
to
und CuII
noteworthy
cases [9a]
Uy CuII
oxidized
cyclizes
Cu'would
(5)), is
is
pro-
transfer
maklng the
15 nor
whole
chloride
1l
i10].
#* t5
Acknowledgements. The authors are jndebted
to Dr.
B. Maurer for
helpful
Experinerttal
discusslons.
Part
Generalities expressed are Chernical shifts NMR spectra are measured in CDC13 orr B Eruker WH 360 instrument. 'in nnm (A seal.) downfield Irom tetramethylsilane d s singleL, standard; abbreviations: as internal the assignmenLs of methvl q quadruplet, couplj.ng consLant (Hz); J spin-spin douh1er., L rriplet, t'C-NMR/tH-t'tt'tR IH-NMR (GC) was Gas chromatography correlation. srouDS in specLra were based or, 530 mu x 5m. Column using Methvl Srlicone carrj-ed out on a HewLett-Packard series 5890A instrument A11 reactions 0.063-0.200mm). gel Merck (particle size chromatography was performed on silica were carrj-ed out under argon. Pure solvents and reagents were purchased from Fluka (CH 9470 Buchs) (CH 4800 - Zofingen). or Siegfried -2.17" (c = 1.45, CHCl3), m.p.99-100", T h e s c l a r e o l u s e d ( o f R u s s j - a no r i g i n ) , Ia]'o ('"C-NMR). possible was not It + I0Z 13-epr-sclareol consisted of 90% sclareol and/or column chromatographv. sclareol content further by recrystallization
to
increase
the
(9) via deconposition 10. of its hypochlorrte L. Ambrox (la) from dihydroscTareoL (600 m1) was (77 B, 0,2\ (9) in pure ethanol mo1) dissolved Dihydrosclareol Sclareol 1.1 t4]. After g) at room temperature and atmospheric over 5Z Pd on carbon (0.6 hydrogenated Pressure. (peLroleum ether 80-100') 64 g (83% vield) of crysttiltration, concentration, and crystallization 0.85 0.78, (9) was obtained.- IH-NMR-360 MHz spectrumz 0.77, dihydrosclareol a11ine (m.p.107")
( 3 s , 3 H e a c h , r e s p e c t i v e l y H 3 C - 1 9 ,- L 7 , - 1 8 ) ; 0 . 8 8 ( t , J = 7 , H r C - 1 5 ) ; I . l 3 (s,
(s, HsC-i6);
1.15
HeC-20); 1.46 (q, J = 7, HzC-14).
(30 ml), 84 mmol), prepared A mixture of 2.8 molar aqueous sodium hypochlorite I.2 Anbrox (la). (9,9"3 g, 30 mmol), acetic acid (3.6 g, 60 mmol), and CC1,* accordlng to [9h], dihydrosclareol filtered. (30 m1) was stirred and at 0o for 3h. The organic layer was separated, washed (H20), and was i-mmediately titratj-on, It weighed 82.3 g and contai-ned 46.7 mmol hypochlorite by iodometric occurred exothermic reactlon solution 74 g were stirred at 30-35" for 3h. A slightly ruscd. Of this was conThe reaction solutlon was present at the end (by titratlon). and no more active chlorine (11.1 g), dlssolved slurry of 8OZ in anhydrous THF (20 m1), and poured onto a stirred centrated (0.8i tempeg, 29 mmol) in anhydrous THF (20 ml). The mlxture was heated at reflux NaH dispersion r a r r r r p f n r "3' .h t . o u r e d o n t o i c e a n d e x t r a c t e d the crude material with ether. After concentration, (7.8 g) was chromatographed on silica Fraction 2 gave 0.37 gel (100 g) using hexane/ether 4:I, (9) =0.52). g of l0% pure Ambrox (la) (yield based on dihydrosclareol via the hydroperoxides l2a/b. 2. Anbrox (la) (30.8 g, 0.1 mol), CH2C12 (200 ml), 7O7. aqueous A mixture of sclareol l2a/I2b. 2.1 Hydroperoxides (0.2 room stirred at g) was vj-gorously acid hydrogen peroxide (100 ml), and p-toluenesulphonic and concenwashed (H20), dri-ed (MgSOa), temDerature for 7 days. The organic layer was separated, which was chromatographed on with a Rotavapor (below 25o) to give 35 g of crude material trated
l 878
R. DnconzaNt
et al.
silica ge1 (Merck 0.2-0.063; 350 g) with cyclohexane/ether (7:3 ro 0:l). The firsr (6.9 fracrion g) consisted mainly of manoyl oxides 14a/b (7:3), Fracrion 2 (Ig.7 g) conrained rhe peroxides t 3 C N M R l2a, I2b,13, and unknown impurities (4OZ,2O7",2OZ,2OZ) as derermined lv (-CH=CH2) and the chromatographic separatlon descrlbed be1ow. yield of l2a/bz =3gZ based on sc1areo1. Fraction 3 (1,7 g) consisted of sclareol. Fraction 2 (I g) was chromatographed using trio commercially available fferck-columns connected 1n series Grosse B (310-23 mm), fi11ed wirh LiChropren@ Sl 60 (40-63 ILobarto-Fertigsaule, p m ) , A r t . n " 1 0 4 0 1] . S o l v e n t : c y c l o h e x a n e / e t h y 1 a c e t a t e 7:3; solvent pressure =20 psi. The epimers I2a/b (629 mg) were eluted (982 peroxide blz iodometric first rirrarion followed dlrecrly t19]) by 13 (205 mg, epimeric mixture). The mlxture l2a/b was recrvstallized frorn hexane (+25o to -20') t ' C N M R g i v e to 952 pure sample of l2a (m.p. 113-114'). It so became possible to r:un spectra and attribute chemlcal shift values to the hvdroperoxicles l2a, l2b, and 13, and Lo Lhe manoyl oxides l4a/b (see table).
-17'
and 2,
-17,
rH-NMR-360 12a MHz-spectrurn: 0.80, 0.81 , 0.87 (3s, 3H each, rc'spectlvely IJ3C-19, 1.19 (s, H3c-16); r.22 (s, H3c-20); 5.13 (dd, J = 11 and 2, HC-r5); 5.\g (dd, J = t8 HC-15); 6.04 (dd, J = 1l and 18, HC-14).
-18);
IH-NMR-360 12b }IHz spectrum: O.78 , O. r-9, 0.87 (3.s, 3H each, respectiveJ-y H3C-19, 1.20 (s, H3C-20); I,34 (s, H3C-16); 5.14 (dd, J = t1 and 2, HC_15); 5,19 (dd, J = tB HC-15); 5.81 (dd, J = t1 and 18. HC-14).
-18);
and 2,
13 (main isomer only') rtl-wtqn-:60IlHz specrrum:0.82,0.E4,0,88 (3s, e c t i v e l y H 3 c - 1 9 , - r 7 , - 1 8 ) ; 1 . 0 8 ( s , H 3 c - 2 0 ) ; r . 2 9 ( s , H : c - l 6 ) ; 5 . 0 1 ( ( l ( 1 ,. J = 1l 5.21 (dd, -t = 18 and 2, HC-l5); 5.93 (dd, J = 1t and i8. HC-14).
3H eacl-r, respand 2, HC-l5);
iH-NMR-360 14a I ' l H z s p e c t r u m ( c - f. [ 1 5 ] ) : 0.7g, 0.80, C.86 (3s, 3H eacir, rcsi)c'ctir.etr, l{3C-17, -18, -19); 1.28, 1.30 (2s, 3H each, H3C-16and H3C-20) 4,9I (rld, J = lI and 2, IIC-15); ; \.74 (dd, J = 18 and 2, HC-i5); 5.87 (dd,./ = 18 and 11, HC_14). 'IJ-NMR-360 'jli 14b l4Hzspectrum (cf. f 15l): 0.73, 0.7g,0.g6 ( is, each, respecliveLv Hjc-17, -18, -19); 1..14, 1.23 (2s, 3H each, H3c-16 and H3c-20); 4.89 (rJ, J = 11, HC-11): 4.9i ( d , . . 1= 1 8 , H C - i ) ) ; 6 . 0 1 ( c t d , J = 1 8 a r n d l l , IiC-14). ).2 (2a) :rom peroxide 12a. Pcroxidcs L2a/b (95:5; ir nrq, O.(118 mmol), dilgted Sclareol in anhvdrous el-her (5 ml) was treated wltfr trlphenylphospirine (9.4 rng, 0.036 rnmol) aL 2Oo dur i1g 24h. The reaction nixture was concenLrated and directly analyzed bl' tH-360 N1tlR. The spectrirm obtained was identicirl with thc specLrum of aLrthentic sclareor 2a/b (=95:5). 2.3 Ambrox (1") from the hydroperoxides l2a/b using the Fe(II)/Cu(II) redox couple. The peroxlde mixtrtre l2a/b (2:1, 982 pure by iodometric titration;0.47 g,1.45 mmol) was d-issolved in pure nrelhirnol (5 ml ) and treated with Cu(OAc)2. 2 H2o (0.435 g, 2 mmol) ancl FeSOa. 7 HrO (O.al7 g, 1.5 nrmol). The resr.rlting suspension was stirred at 50" f or 2h. The reaction mixt-ure was concentrated (below 2-5'), diluted with water, and extracted with ethr:r. The extract was washed (1120, dried ( M g S O , , ) , c t - r t r c e : n t r a t e d ,a n d I i l L e r e d through =1 g of silica ge1 with ether tc glve 0.355 g of crude material containi ng 60Z Ambrox (1a) (by capillary GC without lnternal standard). Chromatography of Lhe crude product (0.3 g) on silica gi-l' 120 g) rrsing cvclo_hexane/ether 9:1' gave 87 mg liOZ vield) of crvstalllne Ambrox (la), -23.6'. m . p . 7 O - 7 3 ' ( c v c : 1 o h e x a n " ) , I a ]':Do T h e .m" -" -i s- -s-i"nbn m a f e r i a l c-orrsisted mainly';f polymers. A sccortd experiment, using 6.2 nunolof l2a/b (2:71,10 nunolof Cu(OAc)2. 2 HzO, 7 m m < ; 1o f F e S O +. 7 H 2 O , 2 ( ) m 1 o f m e t h a n o l f o r 3 h a t 5 0 o g a v e a 3 3 2 j sol aled vleld of Ambrox ( la) .
2.4 Ambrox (ia) from the hydroperoxides 12a/b using thermal decomposition on1y. Fraction 2 of experj-ment 2.1 (50 mg containlng 0.095 mrnol of peroxides I2a/b (2:I')) was dissol.,,"d in cvclohexane (0.5 n1) and passed through a heated, emptv Prlrex tube (8 mm x 5 m) at a rate of approximatelv I mI/min. Three experiments at dlffe-rent temperatures (200', 2\0", 300") were performed. In alt cases terrible mixtures resul,ted , 250" giving the besL vield of Ambrox (la) ( < < . - . 2b y G C ) .
l 879
A short synthesisof Ambrox "
REFERENCES t1] l2l
t3]
t4]
G. Ohloff
in
Theimer Ed.,
E.T.
Chemistrv",
"Fragrance
M. Sro11 and M. Hlnder, He7v. Chin, ") Chin. Acta 1950, 33' 1308.
Academic Press,
Acta 1950, 33,
New York,
1251; b) M. Hinder
7982, p.
and M. Stol1,
535.
HeTr'.
e d . , v o l . 1 , C h a p m a na n d H a 1 1 , a) W. Klyne and J. Bucklngham, "At1as of Stereochemistry",2nd l37B; c) Lonclon, i978, p. 108; b) J.A. Barltrop and D.B. Biglev, Chen. and 1nd.1959, C. Via1, and F. Ndf, to be published. G.Bernardinel1l, L.
Ruzicka and M.M. Janot , He7v. Chin. Ruzicka, C.F. Seidel,
t5]
L.
t6]
G. Ohloff,
li. Giersch,
and L.L.
, 4 c t a 1 9 3 1, 1 4 ,
645.
Enge1, He1v. Chin. Acta 1942, 25, 62I,
W. Pickenhagen,
A. Furrer,
and B.
Frel,
He1v. Chin.
Acta
1985, 68,
2022. t7] IB]
,9]
tl0l
C. Vlal,
Firmenlch
J.K.
Kochl jn
"Free Radlcals",
1, .J.K. Kochi Ed.,
vol.
h.S. Trahanovsky and D.B. Macanlay, J. Cramer , .l. ()rp. Chen. l97I , 36 , i890.
a) J.
tt2]
C.Ciorclano, ,\. Belli,
i14]
results-
(--he,z. a ) S . L . S c h r e i b e r , T . S a m m i a k a , B . H u l i n , a n C G . S c h u l t e , I . A n '.[ e t r a h e S r c . 1 9 8 6 , 1 0 8 , 2 i 0 6 ; lron 1985, 4], 6Qjir; b) G. Cardinale, .J.A.M. Laan, D. van der Steen, and J.P. tiarC, 107,2980; d) T.L. )lacdonaldand .) S.L. Schreiber and W.-F. Liew, J. Am. Chem.ioc.1985, 102, e) S.L. Schreiber, J. Am. Chen.9oc,1980, D.E. O'De11, J. Org. Chem, 1981,46,1501; Helv, Chin. Acta I97I, 54, 2889; g) C. Walllng and R.T. 6163: f) .1. Becker and G. Ohloff, C1ark, J, An, Chen. Soc, 1974, q5, 4530; h) F.D. Greene, M.L. SaviLz, F.D. 0sterholz, H.H. j ) ' l . K . K o c h i , . 1. A m . C h e m . S o c . Larr, W.N. SmiLh, and P.M. Zanct, J. Org. Chen. 1963, 28, 5lt; (lhem. Soc. 1948' 70, BB, 1 9 6 2 , 8 4 , 1 1 9 3 ; . j ) . 1. U . R a l e v , F . F . R u s t , a n d h ' . E . V a r r g h a n , J . A n . 1 3 1 i 6 ; F . F . R u s t , F . H . S e u b o l d , a n d l l . E , . V i a u q h a n ,i L t i d , 9 5 ,
Ili]
f i3]
SA Geneva, unpublished
J.K. For reviews on alkoxy raclical B-scission see: a) J.K. Kochi in "Fre'e Radicals", vol.2, in "Advances in Koch1 Ed., John Wiley & Sons, 1913, p. 683; b) F. Mlnisci and A. Citterio C.H. Williams Ed., Hevden, London, 1980, p. 128; c) C. SosnovFree Ra{ical Chemlstry, vo1.6, ttOrganic Peroxidestt, vo1 . 2, D. Swern Ed., ir'llev-Interscience, sky and D.J. Rawlinson in 1971, p. 153; d) P. Gral' and A. Wi1llarms, Chen. Rev. 1959, 59, 239.
A. Citterio,
John iirlev & S'rns, 10i3, p.
Org. Chen. 1973,38,
and F. Minisci,
J.
arg,
lq).
I 4 9 , - : t r) r i . - : i ' T r a h a n o v s k v a n d
Chen. 1979, 44,
2j14,
t'0xiclation
in 0rganic Chenristrv, Part A", K.B. \iiberg Ed., For reviews see: a) R. Crlcgee in Academlc Press, 1965, p. 271; b) G.M. Rubottom in Oxidat-jon in Organic Chemistrv' Part D", I d . S . T r a h a n o v s k y E d . , A c a d e m c. i P r e s s , L 9 8 2 , p . i ; c ) h : . S . T r a h a n o v s k i i n " I l e t h o d s i n F r e e R a r l i c a l C h e m l s t . r y " , v o J . 4 , E . S . H u y s e r E c i . , D c k k c r , I 9 7 3 , p . i 3 j ; d t ) 1. l - . ) l i h a i l o v i c a n d Z . C e k o r ,j ' c , . g y n t h e s r s 1 9 7 0 , 2 0 9 . j. .|n. Chem. Soc. 196A, 82, 2640; a ) D . 1 1 . l.l B a r t - o n , J . M . B e a t o n , [ , . E . C e 1 ] e r ' , a n d ] 1. ] 1. P e c h e t , jbid. 1 9 6 1 , 5 3 , 4 A 7 6 ; b ) i \ I. A k h t a r , D . H . R . B a r t o n , a n d G . S a m m e s, J , A n . C h e n . S o c . 1 9 6 5 , id., 8 7 , 4 6 0 I ; c ) P . K a b a s a k a l i : r n , E . R . T o w n l e y , a n d M . D . Y u d i s , J . A n . C h e n . S c , t c .1 9 6 2 , 8 4 , 2 7 I I ,
2716,2723. 1 9 6 1,
li74.
[] 5]
E. ldenkert. and P. Bcak, Chen. and Ind.
t16]
i'.W. hehrll and T. NishjCa in "Progr.ess jn the Chemistr"v of 0rganlc 36, ll. Herz et a1. fld,, Springer'-Vcr1ag, 1979, p. 1.
[17]
a) J.K. Kgc.hi and F.F. Rust, J. An, Chen, Soc. 1962, 84, Mare, and F.F'. Rusl , J. t\nt, Chen. Soc. 1960' 82, 1935.
flB]
,1.K. Kochi,
"0rganomctallic
119] R. Cri.egee in
3946; b)
\atural
I.
P r ' , l d L t c t . s " ,r . ' o L .
K t i r n a m , r t ol,l . E . D e L a
Academjc Pre'ss, i978, p. 52 and 59. Mechanismsand CataIisis", 'v'c-r1ag, 1953, p. 568. Stuttgarr-, G. Thieme
"Horrben-h'cvl.", ,,,rl1.2,
0040-4020187$1.00+.00 1987PergamonJournalsLtd.
A SHORTSYNTHESISOF AMBROX@ FROMSCLAREOLT
R E N ED E C O R Z A N TC,H R I S T I A NV I A L , a n d F E R D I N A N D NiF.' F i r m e n i c h S A , R e s e a r c hL a b o r a t o r i e s , C H - 1 2 1 1G e n e v a8
GEORCM E . hTIITESIDES H a r v a r d U n i v e r s i t y , D e p a r t m e n to f C h e m i s t r v , C a m b r i d g e ,M a s s a c h u s e t t s0 2 1 3 8
(Receiued in LlK 22 Dec'entber 1986\
AbsLract- - A th(,-step transformation of sclareol into Ambroy@(overall v'ra B-cleavage of an al,koxy radical intermediate II-l2Z) is described.
I n t r o d u c t i o n - A m b r o x o( 1 a ) I ) ,
one of
discovered by Hinder and Stoll
in 1950 f2a, bl.
p'ocess ( pr.cl'ci ug C.III
the most j-mportant ambergrr-s f ragrance It
is
sti11
, r . M n I l \ { a s te , m a x i m u mo v e r r l I L v i e l d
manufactured 522) of
yield
c h e nj c a l s
b1' a teciious
natural
I 1] ,
was
degradation
sclarer-,1
(D ,2)3)
Scheme i
IH t0
6
"l 2a
r\mbroxo la v)
Rc-asenLs: i ) CrO.,/AcOH; ii) v)
i 1) 2)
Dedicated
to
iso-i\mbrr-,x lb
150"/vactlrm;
Professor
K l 4 n O O ;i l j ) O r l A ; vi)
LiAlll//ether;
George Bijchi
on the
iv)
vil)
occasion
KoH. then HC1; B_naphrhtalenesul-fonic
of
his
65th
acid
birthdav.
Trade name of Firmenich SA for an ambergris fragrance chemlcal, whose Chem. lb.sfr. naphtho[2,r-b lfuran, dodecahydro-3a,6,6,9a-tetrarnethyl-, [ 3 a R - ( 3 a : r , 5 a B , 9 a o , 9 b B )] . L'hc:n,Abstr. narnes: 1-naphthalenepropanol , o,-ethenyldecahydro-2-hydroxy-o [ 1,t-(tolp*),2f3,4a8,8ao) ], and (l3R)-1abd-14-ene-g, i3-dto1.
3 ) The relative given
in
[3a,
is:
,2,5,5,8a-pentamethyl-,
and absolute configuration (2a) (and 13-epr-sc1are.1) of sclareol b], and has been confirmed by x-ray crysrallography i:.].
1871
name
is
drawn as
R. Dsconzevr et al.
t8'72 rhe
n rincinal ts_ - ".-rr-_
s" - o u- r c e
of
reactions
4,
and
which
acid,
produce
routes
to
conditlons
4
cyclizes
Ia
to
5 and 6 with
but
more stable,
the
vra
[2])
5
1s
diol
6
much weaker
olfactively
( la)
Ambrox
since
Ambrox (1a).
into
in
steps these
acid-catalyzed under
readlly
isomerizes (lU1
iso-Ambrox
[6]
two
Although
flnal
the
acid
Lhe acetoxy
transformed
flnally
sLereochemlstrv,
correct
the
care
special
needs
Lactone
t5].
cyclizatlon
ozone Lo yield
is
a sequence
using
indirectly
or
[4], (3),
oxide
sclareol
5
lactone
to
intermediates
6
give
(2a)
sclareol
AccordinSlY,
L.).
scfarea
chromium trloxide
using
directly
and acid-catalyzed
the
of
cyclization
sage (Salvia
clary
permanganate to
comprising
(LlA1H4 reduction
ls
5 either
lactone
degraded to
which
of
acid
wlth
together
other
compounds[7].
(rhpme
2
Ret
rncvnLheL
i c
s
anafVsi
OH
6o v
qs-+$,"-)$'-i-6$ 1a
2a
publication
This vra
presumably (cf.
(la)
Lertiary
its
retrosynthetic
giving There
j-nto ketones
(S-cteavage)
radicals
alkoxy
i,
analysis).
ra<Jical
oxygen-centred
scheme 2t
in is
process
degradation
fragmentative
a
describes
two
radicals
and alkl'1
t9].
tBl
pure
Ambrox
tlre fragmenLation of
.n
I iterature
(2a),
sclareol
slereochemicalLy
steps
amplc
of
Wlth
non-identical
t')?
groups
aIkyI
being
of
the
f]
(scheme 3,
eqn.
such
(1)).
present
as
This
j-ons Lo g-Lve ulti-mately nucleophile
to
attached is
$-cleavage
favour
(scheme 3,
ether,
Q));
Schene
0.
most
R'
+
stable
I
R'),
alky1
under the
further
an alcohol
or
sonetimes also
ls
an olefin
atom the
of
be oxidized
needs to
, an a1kyl
ha1lde
eqn,
formatlon
the
a1ky1 radical
an alky1
carbon
ox)'gen-carryrng
the
to
(R'
etc. '
t-he selectivity radical reactlon
depending
[9g,
h,
conditon
the
obtained.
3
0
I
*
*t,t(*'
?. R"
+
nrAn2
(1)
R-
*hrl. [*r.l' LJ g
metal
Results
oxidants
red on
direct
slmplicity,
lithium
S.l".tively
oxidation
a series
of
i- were rried
radical
alcoholate
were isolated
4)
may be used instead
is
(2)
best
. ^ II out bv Cu" alrhough other
carried
[ 10].
and discussion
1, ALtenpted For
radical
a carbon-centred
of
The oxidation
R3-Nu
*
l4))
of
scTareol
firsr.
C"rV
gave
(2a)
oxidations
di-rect
no
[11], useful
of
sclareol
c,,rr /s2082results;
of
2a with
BuLi
[12],
starting
on1y.
formed by treatment
(2a)
[7].
likely Pb(oAc)o material
to
generaLe the
[13.], and air and/or
oxygen-cent(in
complicated
this
case
mixtures
A short synthesisof Ambroxh
l 873 0c1
0Li
\
2.
(Ia)
Anbrox
A second
fron
approach
chlorites
h].
[9g,
(9)
dihydrosclareoL to
However,
the
cal
bond. 0n the
intermediate =0.52
other
10,
hand,
followed
of
Ambrox (la)
A1ky1 nitrite
homolysis
to
deconposiLion by the
necessary
aBents, such as sodium hypochlorite double
via
j- was offered
radlcaf
and tert-butyl
together
of
the
saturaLed
10.
of
preferentially
alcohol
9 [4]
the
the
vinvl
hypotheti-
chloride
f1?)
led
(scheme 4).
products
Ambrox (la)
nor give
hypo-
chlorinating
give
to
(via
unknown decomposition did
t-ertiary
attacked
elther.
lt
oil
..i43
of
be inaccesslble:
and base treatment
A1k0-N=O,iheat l14l)
9, ltr'tnt
to
hypochlorite,
a multitude
(A1k0-N=0/Ir/hv,
hypochlorrte
its
proved
8
decomposition
wlth
of
documented decomposltion
hypochlorite
chlorination
by thermal
well
oc1 i)
.Lq} -----\o-
rr)
_+
iij)>
. 2a
l0
.ji'l
-f4,,,:l
,\o, J iii
Reagcnt-s: i)
.^tm
w
iv)
-{r>
lt
lr7,Pd-C/lrt0ll;
ii)
la
, r 1u1( i o u s
i v ) N ; r l l / ' f l l [ , 3 l r r c f I i r x.
r? .
sA^-; re y, , n- Lt n e s r s-
a^ ^n) a d e c o n p o s i t i o n
A major
difficulty
lack
selectivity
of
^ ^ ^ f a c e L ,y, l1 a^ +Li t o^ n- .
hand
the
oxide
^ C o L
in
for
sclareol
a11y1ic
when either
treated
rather
Reaction amount of
of
of
l2a
rnanoyl oxides 952 pure
and
1:l
114')
as
opposed
mixture
of
should
to
the
the
two
undergo
than
13.
peroxide metals (2a/b,
acld
at
(2:1)
[15].
and 9OZ pure
positional
alcohol
with
a
TiIII,
gave
1itt1e
Chromatography
so
(Scheme 5). seems to
a1coho1.
monoacetaLes t7l. displacement
and
therefore
readily
give
und vlrI
the
382 isolated
of
the
give
of
the
the
radicals
a catalytic two eprmerlc
hydroperoxide al-1owed the
were characterized
per-
pyrolyzed.
or
presence yield
other
hydrogen
oxygen-centred
undesired
and crysrallizarion
On the
with
k]
be the
Srmilarly,
selectively
[9i,
in
13. The new peroxides
(la) far
tertiary
7OZ aqueous HrO, in
room temperature
together
non-allv1ic
Hvdroperoxides
with
to Anbrox
dlscussed
nucleophilic
such as Furr, 9:l)
route
reactions
non-a1l-y1ic.
14a and 14b (7:3)
12a (m.p.
a viable
corresponding
sclareot
12b
l2a/b:
and chlorination
sclareol
transition
p-toluenesulphonic
hydroperoxides the
in the
with
hydroperoxide
a11y1ic
gave a
than
l2a/b
of
oxidation
the
alcohol
much faster
hydroperoxides
the
bv a)
13 and
isolation
iodometric
R. Drconza.Nr et al.
t874
S c h e m e5
i) __l>
\
ooH
OH
OH
d$d"' 13 Reagents:
7OZ aquenus I{.()"/p- l sOil/Cl{rC1.r;
i)
to
and hydroxy
the
o and b-carbon
t'C-NMR
b)
function
(Table)
exhibits
of
(nr
match) thc
meric
at
diffcrence
could
all
I2a
back
of
by-product
fL rL -I E, a rL ,W' U^ -I I -I d- T^I "U r} A values
tlon
This
hydroperoxide
the
of
carbon
the
the two
atoms of
suggests
posiLion
that
atoms C-9,
the
C-l3 major
by
mixture
the
function
on the
hvdroperoxide
C-13,
hydroperoxj-des the
12b 13-epr-sclareol
(reduction
the
of
shift
The
hydroperoxide/terr-butanol.
Za/2b for
Ad-values other
of
hydroperoxv
valuable
C-14,
pal rs
hydroperoxlde
funcLion
exactly
and C-16 para11e1 are
and 2a/b
l2a/b
12a has sclareol Chemical
configuration.
opposed
differenr-es
shift
C-15,
12b which
12a and
epimeric
as
neighbouring
also
epi-
no shift configu-
transformation
th:-s assignrnent. Structure 1? 1 l3 (without stereochemical assignmenL) was evidenL Irom'-C and'H-NMR spectra rrrd 'l? ' ' C N M R ^-ides (I4a/b) were identif ied by compar-ison of therr values wilh the reporUA-
into
2a
triphenvlphosphine)
corroborated
I l) l. When the
f"II/CuII
the
be detected.
and the minor
ration of
ted
For
The
obtained.
and diagnostically
tert-buty1
C-13 epimers
corresponding
C-l3.
mixtures
localization
atoms allowing
between the
the
a typrcal
by using Lhe known reference pair A6 observed
ItZOIC\OH, 2hl50'
Cu(0Ac)r.21{rOll'eSO 4.7
ri)
titration
14tr
Ii7]
(250',
Ambrox (ta)
contact
of
two hydroperoxides
(=3OZ isolated
ti,me =l0s)
1ed onlv
yield) to
traces
l2a/b
was direcrly of
(2:l)
reacted
with
formed (scheme 5).
Ambrox (la)
and a multitude
the
redox couple
Thermal decomposiof
unknown prod-
ucts. Mechanistically, lined
gether
in
the
catalyLic
deconnposiLion of
l2a/b
mighr
be rationaljzed
as
out-
scheme 6 ln
with
analoCy known, related reactions [7a] [Bu] [9a, i] t10l t171. !g In step (1) Fett cleaves the hydroperoxide to give the radical intermediate i . III Fe^--. In step (2) the free radical fragments into the radical intermediate i
toii
I875
A short svnthesisof Ambrox* c'.l
c\ O
N
l--
\O
O\
$$\to'tnca
C\
c . ] N C \ N N
tn
trl
\a
Ln
\t
o-1
C\
C\
c\l
N
C{
(\l
\t
\t
ca
\t
\t
c'
'rl X c l. c,
ca ca
ca ca
ca ci
ca ca
./-r ca
ca ca
-o
'ou
o ii
E -J-Jta\OL^O
r-
ra)
r^
a
tn
La
tr\
\o
: {
r)
-o
I
O q)
Latnc!C!Gtca\O@ ca
r/) \O cr' --c\NNNNol
'-
\O
Lr iJ
C-.i
@
o
@@clcC@Nc!r Ln o@ci$oo\
C
O
o, ,c
\1
E
\OO,@NO'C1)
-t
\O \O -t $\acn-t\t$\Ts
.$$
a-'l
O
t'
I C)
CC
l\
c!
c-'l
ca l--
--l tt-
a^
\
CFJ
rn
O'\
c\l
O
tn
ca r--
ca '--
ca r-
-T @
$ @
-t t\
cl c-
: : .-
N N
l'-
cC
O'
tn
\O
C.l
r^\toa-ta-T -Jjc^\t:^3-
N
N
O,
@
Lr\
@
Cn
r-'
CO
a^
a^
I
$ N q*i
o
(-cao.'-1
O
':
CL^
O,C,@c..r_C. ol -
ac a-'
a-
u
\
!J a
r\o.'\Otij$@\C
A-)
\O
\O
NNC\!nLn@ \O \C \O
tr\
ul
Lr\
'1.
L^
a tr A) !
r\
\C
cY-r
-'l
C
C
-1 n
\t F-
L/l r\
\C Cla
L^ l--
.C r\
c I
: a-? f,> a ri 'o
c\l
U 9
\t-t\t\O"c' +-3$o1\t$
=
{ Laultac..lOO
U) AJ
c.J
U C-'.1
N t
aJ
N
C'J
c'l
--z -4.
= i3
OJ i
t
CtcL^Lf \O ln
\O L^
\C ta1
ul !r'l
\O Lr)
\O Ltl
N€ aa
a
'i3 o.lNNc^$ ca ca
a
al (-)
ca c]
ci ca
cil cl
u
!r ::
ca o-l
>a
U
a CJU
O O O O N N
(-)
C..l
-$
aJ
c!
N
-r
-t
-t
C\i
C\
\i
\t
9! !i CJ
(n tn
tn
-f,
In
\O
Y !,
It-
C, (ts^ qc -O+
co@@ccco@
'- c' ?l l l ( - )
'E \O
\O
c,.\ O'. -caca-Jalca
O\
Ir-
0
tn O
O\
q
.C-
=E z.o z (a
C,
OLn ca c!
o'u dod,6co-ot!-0 <jo.NNo\c{Ncn$\t Eo C')
a^ u
!a-
1816
et al.
R. Dnconznvr
Schene 6
.'^l I
I
r)z\. | |
V|.'/
o'
ooH - l a ' a
.
t"
rl''
\ t' o H
-re -rr -
r |
\av .\H
.,\H
I |
I\ [" oH
+
F.IrI
+
oH
(r)
i
l2a ot
-^-fll \-. ( -l. J,^,,I I tuH
.
(
^1,.-
-+
-.\ H
.^l^l" I
|
+
["oH
i
.-\?
-.\H ii
i
(' llr
(* cuTI -.
-\r\..
ll["oH>ll["oH+
..
L
cur
(3a)
\d-'l
-.\H
,{H ii
iv
(
f
tu"-
f'FJ'*, .\H
currrLn
^trAIJ
IT
ll+
(
dry
t t
-
J,
I
-...-w
llr'oH4 -\u
(4a)
la
iv
.^currrLn
^A# I
I
I
___-.____-.>-
.'\H
-N
>o'
+ cul
1a
FeIrI
+
cuI -+
F.rI
+
cuTI
(s)
t877
A short synthesisof Ambrox!
ketone.
vinyl
and methyl
The (an electron the
tively, species cess.
v
could
and
catalytic
in
be isolated,
step
step of
in
(4b)). iron
radical
ii
which
then
(3a))
radical
Finatly, and
contrast
of
(step
copper.
to
might
ii
elimlnation
upon reductive
(3b)
steDs
sequence
process,
ring-closing
which
primary
carbon-centred
transfer
simllar
It
involve
p"II
the give
cyclic,
that
(step
ur" neither
(a
ligand
regenerated olefin
( a)).
iv
Alterna-
organocopper(III)
transient
Ambrox (Ia)
ion
carbonium
the
to
Ambrox (la)
to
und CuII
noteworthy
cases [9a]
Uy CuII
oxidized
cyclizes
Cu'would
(5)), is
is
pro-
transfer
maklng the
15 nor
whole
chloride
1l
i10].
#* t5
Acknowledgements. The authors are jndebted
to Dr.
B. Maurer for
helpful
Experinerttal
discusslons.
Part
Generalities expressed are Chernical shifts NMR spectra are measured in CDC13 orr B Eruker WH 360 instrument. 'in nnm (A seal.) downfield Irom tetramethylsilane d s singleL, standard; abbreviations: as internal the assignmenLs of methvl q quadruplet, couplj.ng consLant (Hz); J spin-spin douh1er., L rriplet, t'C-NMR/tH-t'tt'tR IH-NMR (GC) was Gas chromatography correlation. srouDS in specLra were based or, 530 mu x 5m. Column using Methvl Srlicone carrj-ed out on a HewLett-Packard series 5890A instrument A11 reactions 0.063-0.200mm). gel Merck (particle size chromatography was performed on silica were carrj-ed out under argon. Pure solvents and reagents were purchased from Fluka (CH 9470 Buchs) (CH 4800 - Zofingen). or Siegfried -2.17" (c = 1.45, CHCl3), m.p.99-100", T h e s c l a r e o l u s e d ( o f R u s s j - a no r i g i n ) , Ia]'o ('"C-NMR). possible was not It + I0Z 13-epr-sclareol consisted of 90% sclareol and/or column chromatographv. sclareol content further by recrystallization
to
increase
the
(9) via deconposition 10. of its hypochlorrte L. Ambrox (la) from dihydroscTareoL (600 m1) was (77 B, 0,2\ (9) in pure ethanol mo1) dissolved Dihydrosclareol Sclareol 1.1 t4]. After g) at room temperature and atmospheric over 5Z Pd on carbon (0.6 hydrogenated Pressure. (peLroleum ether 80-100') 64 g (83% vield) of crysttiltration, concentration, and crystallization 0.85 0.78, (9) was obtained.- IH-NMR-360 MHz spectrumz 0.77, dihydrosclareol a11ine (m.p.107")
( 3 s , 3 H e a c h , r e s p e c t i v e l y H 3 C - 1 9 ,- L 7 , - 1 8 ) ; 0 . 8 8 ( t , J = 7 , H r C - 1 5 ) ; I . l 3 (s,
(s, HsC-i6);
1.15
HeC-20); 1.46 (q, J = 7, HzC-14).
(30 ml), 84 mmol), prepared A mixture of 2.8 molar aqueous sodium hypochlorite I.2 Anbrox (la). (9,9"3 g, 30 mmol), acetic acid (3.6 g, 60 mmol), and CC1,* accordlng to [9h], dihydrosclareol filtered. (30 m1) was stirred and at 0o for 3h. The organic layer was separated, washed (H20), and was i-mmediately titratj-on, It weighed 82.3 g and contai-ned 46.7 mmol hypochlorite by iodometric occurred exothermic reactlon solution 74 g were stirred at 30-35" for 3h. A slightly ruscd. Of this was conThe reaction solutlon was present at the end (by titratlon). and no more active chlorine (11.1 g), dlssolved slurry of 8OZ in anhydrous THF (20 m1), and poured onto a stirred centrated (0.8i tempeg, 29 mmol) in anhydrous THF (20 ml). The mlxture was heated at reflux NaH dispersion r a r r r r p f n r "3' .h t . o u r e d o n t o i c e a n d e x t r a c t e d the crude material with ether. After concentration, (7.8 g) was chromatographed on silica Fraction 2 gave 0.37 gel (100 g) using hexane/ether 4:I, (9) =0.52). g of l0% pure Ambrox (la) (yield based on dihydrosclareol via the hydroperoxides l2a/b. 2. Anbrox (la) (30.8 g, 0.1 mol), CH2C12 (200 ml), 7O7. aqueous A mixture of sclareol l2a/I2b. 2.1 Hydroperoxides (0.2 room stirred at g) was vj-gorously acid hydrogen peroxide (100 ml), and p-toluenesulphonic and concenwashed (H20), dri-ed (MgSOa), temDerature for 7 days. The organic layer was separated, which was chromatographed on with a Rotavapor (below 25o) to give 35 g of crude material trated
l 878
R. DnconzaNt
et al.
silica ge1 (Merck 0.2-0.063; 350 g) with cyclohexane/ether (7:3 ro 0:l). The firsr (6.9 fracrion g) consisted mainly of manoyl oxides 14a/b (7:3), Fracrion 2 (Ig.7 g) conrained rhe peroxides t 3 C N M R l2a, I2b,13, and unknown impurities (4OZ,2O7",2OZ,2OZ) as derermined lv (-CH=CH2) and the chromatographic separatlon descrlbed be1ow. yield of l2a/bz =3gZ based on sc1areo1. Fraction 3 (1,7 g) consisted of sclareol. Fraction 2 (I g) was chromatographed using trio commercially available fferck-columns connected 1n series Grosse B (310-23 mm), fi11ed wirh LiChropren@ Sl 60 (40-63 ILobarto-Fertigsaule, p m ) , A r t . n " 1 0 4 0 1] . S o l v e n t : c y c l o h e x a n e / e t h y 1 a c e t a t e 7:3; solvent pressure =20 psi. The epimers I2a/b (629 mg) were eluted (982 peroxide blz iodometric first rirrarion followed dlrecrly t19]) by 13 (205 mg, epimeric mixture). The mlxture l2a/b was recrvstallized frorn hexane (+25o to -20') t ' C N M R g i v e to 952 pure sample of l2a (m.p. 113-114'). It so became possible to r:un spectra and attribute chemlcal shift values to the hvdroperoxicles l2a, l2b, and 13, and Lo Lhe manoyl oxides l4a/b (see table).
-17'
and 2,
-17,
rH-NMR-360 12a MHz-spectrurn: 0.80, 0.81 , 0.87 (3s, 3H each, rc'spectlvely IJ3C-19, 1.19 (s, H3c-16); r.22 (s, H3c-20); 5.13 (dd, J = 11 and 2, HC-r5); 5.\g (dd, J = t8 HC-15); 6.04 (dd, J = 1l and 18, HC-14).
-18);
IH-NMR-360 12b }IHz spectrum: O.78 , O. r-9, 0.87 (3.s, 3H each, respectiveJ-y H3C-19, 1.20 (s, H3C-20); I,34 (s, H3C-16); 5.14 (dd, J = t1 and 2, HC_15); 5,19 (dd, J = tB HC-15); 5.81 (dd, J = t1 and 18. HC-14).
-18);
and 2,
13 (main isomer only') rtl-wtqn-:60IlHz specrrum:0.82,0.E4,0,88 (3s, e c t i v e l y H 3 c - 1 9 , - r 7 , - 1 8 ) ; 1 . 0 8 ( s , H 3 c - 2 0 ) ; r . 2 9 ( s , H : c - l 6 ) ; 5 . 0 1 ( ( l ( 1 ,. J = 1l 5.21 (dd, -t = 18 and 2, HC-l5); 5.93 (dd, J = 1t and i8. HC-14).
3H eacl-r, respand 2, HC-l5);
iH-NMR-360 14a I ' l H z s p e c t r u m ( c - f. [ 1 5 ] ) : 0.7g, 0.80, C.86 (3s, 3H eacir, rcsi)c'ctir.etr, l{3C-17, -18, -19); 1.28, 1.30 (2s, 3H each, H3C-16and H3C-20) 4,9I (rld, J = lI and 2, IIC-15); ; \.74 (dd, J = 18 and 2, HC-i5); 5.87 (dd,./ = 18 and 11, HC_14). 'IJ-NMR-360 'jli 14b l4Hzspectrum (cf. f 15l): 0.73, 0.7g,0.g6 ( is, each, respecliveLv Hjc-17, -18, -19); 1..14, 1.23 (2s, 3H each, H3c-16 and H3c-20); 4.89 (rJ, J = 11, HC-11): 4.9i ( d , . . 1= 1 8 , H C - i ) ) ; 6 . 0 1 ( c t d , J = 1 8 a r n d l l , IiC-14). ).2 (2a) :rom peroxide 12a. Pcroxidcs L2a/b (95:5; ir nrq, O.(118 mmol), dilgted Sclareol in anhvdrous el-her (5 ml) was treated wltfr trlphenylphospirine (9.4 rng, 0.036 rnmol) aL 2Oo dur i1g 24h. The reaction nixture was concenLrated and directly analyzed bl' tH-360 N1tlR. The spectrirm obtained was identicirl with thc specLrum of aLrthentic sclareor 2a/b (=95:5). 2.3 Ambrox (1") from the hydroperoxides l2a/b using the Fe(II)/Cu(II) redox couple. The peroxlde mixtrtre l2a/b (2:1, 982 pure by iodometric titration;0.47 g,1.45 mmol) was d-issolved in pure nrelhirnol (5 ml ) and treated with Cu(OAc)2. 2 H2o (0.435 g, 2 mmol) ancl FeSOa. 7 HrO (O.al7 g, 1.5 nrmol). The resr.rlting suspension was stirred at 50" f or 2h. The reaction mixt-ure was concentrated (below 2-5'), diluted with water, and extracted with ethr:r. The extract was washed (1120, dried ( M g S O , , ) , c t - r t r c e : n t r a t e d ,a n d I i l L e r e d through =1 g of silica ge1 with ether tc glve 0.355 g of crude material containi ng 60Z Ambrox (1a) (by capillary GC without lnternal standard). Chromatography of Lhe crude product (0.3 g) on silica gi-l' 120 g) rrsing cvclo_hexane/ether 9:1' gave 87 mg liOZ vield) of crvstalllne Ambrox (la), -23.6'. m . p . 7 O - 7 3 ' ( c v c : 1 o h e x a n " ) , I a ]':Do T h e .m" -" -i s- -s-i"nbn m a f e r i a l c-orrsisted mainly';f polymers. A sccortd experiment, using 6.2 nunolof l2a/b (2:71,10 nunolof Cu(OAc)2. 2 HzO, 7 m m < ; 1o f F e S O +. 7 H 2 O , 2 ( ) m 1 o f m e t h a n o l f o r 3 h a t 5 0 o g a v e a 3 3 2 j sol aled vleld of Ambrox ( la) .
2.4 Ambrox (ia) from the hydroperoxides 12a/b using thermal decomposition on1y. Fraction 2 of experj-ment 2.1 (50 mg containlng 0.095 mrnol of peroxides I2a/b (2:I')) was dissol.,,"d in cvclohexane (0.5 n1) and passed through a heated, emptv Prlrex tube (8 mm x 5 m) at a rate of approximatelv I mI/min. Three experiments at dlffe-rent temperatures (200', 2\0", 300") were performed. In alt cases terrible mixtures resul,ted , 250" giving the besL vield of Ambrox (la) ( < < . - . 2b y G C ) .
l 879
A short synthesisof Ambrox "
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t3]
t4]
G. Ohloff
in
Theimer Ed.,
E.T.
Chemistrv",
"Fragrance
M. Sro11 and M. Hlnder, He7v. Chin, ") Chin. Acta 1950, 33' 1308.
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New York,
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HeTr'.
e d . , v o l . 1 , C h a p m a na n d H a 1 1 , a) W. Klyne and J. Bucklngham, "At1as of Stereochemistry",2nd l37B; c) Lonclon, i978, p. 108; b) J.A. Barltrop and D.B. Biglev, Chen. and 1nd.1959, C. Via1, and F. Ndf, to be published. G.Bernardinel1l, L.
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,9]
tl0l
C. Vlal,
Firmenlch
J.K.
Kochl jn
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a) J.
tt2]
C.Ciorclano, ,\. Belli,
i14]
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(--he,z. a ) S . L . S c h r e i b e r , T . S a m m i a k a , B . H u l i n , a n C G . S c h u l t e , I . A n '.[ e t r a h e S r c . 1 9 8 6 , 1 0 8 , 2 i 0 6 ; lron 1985, 4], 6Qjir; b) G. Cardinale, .J.A.M. Laan, D. van der Steen, and J.P. tiarC, 107,2980; d) T.L. )lacdonaldand .) S.L. Schreiber and W.-F. Liew, J. Am. Chem.ioc.1985, 102, e) S.L. Schreiber, J. Am. Chen.9oc,1980, D.E. O'De11, J. Org. Chem, 1981,46,1501; Helv, Chin. Acta I97I, 54, 2889; g) C. Walllng and R.T. 6163: f) .1. Becker and G. Ohloff, C1ark, J, An, Chen. Soc, 1974, q5, 4530; h) F.D. Greene, M.L. SaviLz, F.D. 0sterholz, H.H. j ) ' l . K . K o c h i , . 1. A m . C h e m . S o c . Larr, W.N. SmiLh, and P.M. Zanct, J. Org. Chen. 1963, 28, 5lt; (lhem. Soc. 1948' 70, BB, 1 9 6 2 , 8 4 , 1 1 9 3 ; . j ) . 1. U . R a l e v , F . F . R u s t , a n d h ' . E . V a r r g h a n , J . A n . 1 3 1 i 6 ; F . F . R u s t , F . H . S e u b o l d , a n d l l . E , . V i a u q h a n ,i L t i d , 9 5 ,
Ili]
f i3]
SA Geneva, unpublished
J.K. For reviews on alkoxy raclical B-scission see: a) J.K. Kochi in "Fre'e Radicals", vol.2, in "Advances in Koch1 Ed., John Wiley & Sons, 1913, p. 683; b) F. Mlnisci and A. Citterio C.H. Williams Ed., Hevden, London, 1980, p. 128; c) C. SosnovFree Ra{ical Chemlstry, vo1.6, ttOrganic Peroxidestt, vo1 . 2, D. Swern Ed., ir'llev-Interscience, sky and D.J. Rawlinson in 1971, p. 153; d) P. Gral' and A. Wi1llarms, Chen. Rev. 1959, 59, 239.
A. Citterio,
John iirlev & S'rns, 10i3, p.
Org. Chen. 1973,38,
and F. Minisci,
J.
arg,
lq).
I 4 9 , - : t r) r i . - : i ' T r a h a n o v s k v a n d
Chen. 1979, 44,
2j14,
t'0xiclation
in 0rganic Chenristrv, Part A", K.B. \iiberg Ed., For reviews see: a) R. Crlcgee in Academlc Press, 1965, p. 271; b) G.M. Rubottom in Oxidat-jon in Organic Chemistrv' Part D", I d . S . T r a h a n o v s k y E d . , A c a d e m c. i P r e s s , L 9 8 2 , p . i ; c ) h : . S . T r a h a n o v s k i i n " I l e t h o d s i n F r e e R a r l i c a l C h e m l s t . r y " , v o J . 4 , E . S . H u y s e r E c i . , D c k k c r , I 9 7 3 , p . i 3 j ; d t ) 1. l - . ) l i h a i l o v i c a n d Z . C e k o r ,j ' c , . g y n t h e s r s 1 9 7 0 , 2 0 9 . j. .|n. Chem. Soc. 196A, 82, 2640; a ) D . 1 1 . l.l B a r t - o n , J . M . B e a t o n , [ , . E . C e 1 ] e r ' , a n d ] 1. ] 1. P e c h e t , jbid. 1 9 6 1 , 5 3 , 4 A 7 6 ; b ) i \ I. A k h t a r , D . H . R . B a r t o n , a n d G . S a m m e s, J , A n . C h e n . S o c . 1 9 6 5 , id., 8 7 , 4 6 0 I ; c ) P . K a b a s a k a l i : r n , E . R . T o w n l e y , a n d M . D . Y u d i s , J . A n . C h e n . S c , t c .1 9 6 2 , 8 4 , 2 7 I I ,
2716,2723. 1 9 6 1,
li74.
[] 5]
E. ldenkert. and P. Bcak, Chen. and Ind.
t16]
i'.W. hehrll and T. NishjCa in "Progr.ess jn the Chemistr"v of 0rganlc 36, ll. Herz et a1. fld,, Springer'-Vcr1ag, 1979, p. 1.
[17]
a) J.K. Kgc.hi and F.F. Rust, J. An, Chen, Soc. 1962, 84, Mare, and F.F'. Rusl , J. t\nt, Chen. Soc. 1960' 82, 1935.
flB]
,1.K. Kochi,
"0rganomctallic
119] R. Cri.egee in
3946; b)
\atural
I.
P r ' , l d L t c t . s " ,r . ' o L .
K t i r n a m , r t ol,l . E . D e L a
Academjc Pre'ss, i978, p. 52 and 59. Mechanismsand CataIisis", 'v'c-r1ag, 1953, p. 568. Stuttgarr-, G. Thieme
"Horrben-h'cvl.", ,,,rl1.2,
