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Biomimetic Polyene Cyclizations.

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Thanks are due to the many dedicated workers who have
helped in this research : Badreldin Ibrahim, Taisuke Matsuo,
Muthyala Ramaiah, Stuart K . Parton, Roberto Rittner, Ivan
tau lo^, Julie Barnerji, Judit Frank, Horst Wilde, Lemi Turker,
Hussein Dowlatshahi, and Gabi Sabounji.
Received: May 30, 1975 [A 91 IE]
German version. Angew. Chem. 88.41 (1976)
1.3-Dipolar Character of Six-membered Aromatic Rings. Part I7.-Part
16: Ref. [24].
See A . R . Kurrirzky and J . M. Layowski, Adv. Heterocycl. Chem. I,
311. 339 (1963); 2, 1. 27 (1963).
B! D. 011i.s and C . A. R ~ n i . ~ d eAdv.
~ i , Heterocycl. Chem. 19. in press.
R. Huisyen, Angew. Chem. 75, 604 (1963): Angew. Chem Int. Ed. Engl.
2, 565 (1963).
J . Hun:/ and M . SU~JTI,
Tetrahedron Lett. 1969, 3339.
R. Hui\ and H . Miirler, Angew. Chem. 81,621 (1969); Angew. Chem.
Int. Ed. Engl. 8. 604 (19691
The British Drug Houses Ltd., BDH Laboratory Chemicals Division:
Ion Exchange Resins. Poole, 5th Edit., 1965, p. 20.
A . R. Kurrri:k!, and Y Tukeirihi, J . Chem. Soc. C 1971, 874.
M . Kurplus, J. Chem. Phys. 30, 11 (1959).
7 N o x w in n. Ginsherg: Non-benzenoid Aromatic Hydrocarbons. Interscience, New York 1959, p. 339.
4. R . Kutrirzk!, and E Tukeuchi, J. Chem. Soc. C1971, 878.
N. D r i i ~ i i ~A,. R. Kariirrkj, and E Tukruchi, J. Chem. SOC. Perkin
I, 1972, 2054.
A modification ofthemethod described by W Hrjfe. personal communication.
N. DeiiJiis, A . R. Kurritzkr, and M . Ramaiuh, J. Chem. SOC. Perkin
1. 1975. 1506.
N . Dcwiis. A. R. Kutrirzkr, and M . Ramaiah, J. Chem. SOC. Perkin
1. in press
H. J . Barhw and E . Ltrnr, J. Chem. Soc. 1965, 1468; E. Lunr and
7 L. 7’hre/fit//,Chem. Ind. (London) 1964, 1805.
11. E. Anies and B. N o r i f t , J. Chem. Soc. C1969. 2355.
Th. Zincke and G. Miihlhausen. Ber. Dtsch. Chem. Ges. 3X, 3824 (1905):
see also C . F . Koelscli and J. J C‘urne!. J Am Chem. Soc. 72,2285 (1950)
S. K . Partou, Ph. D. Thesis, University of East Anglia 1975.
N. Dennis. A. R. Kutritzkj, 7: Mutruo, S. K . Put-ron, and E Tukeuchr,
J. Chem. Soc. Perkin I, 1Y74, 746.
J. Birrdon and I/. C. R . McLoughlin, Tetrahedron 21, 1 (1965).
L. Fried~iiunand F . M. Logidlo. J Am. Chem. Soc 85, 1549 (1963).
1231 N. Dennis, A. R. Kutritzky, S. K . Parto~i,and E Eikt,irclii, J. Chem.
SOC.Chem. Commun. 1972. 707.
N Dem7i.S. A. R. KorritzLy. and S. K . Partun, J. Chem. SOC.Perkin 1. in
G. U’irtiy and W Behtiisch, Chem. Ber. 91, 2358 (1958).
G. Witfig and B. Rrichrl, Chem. Ber. 96, 2851 (1963).
L. J. Kricku and J . M . Vernou. J. Chem. Soc. Perkin I, 1973. 766.
J . Nakuyama, 0. SLnamuru, and M. Yoshidu, Chem. Commun. 1970,
R . Gompper, G. Sryholri. and B. ScAiiioIhr. Angew. Chem. XO. 404 (196X):
Angew. Chem. Int Ed Engl. 7, 389 (i968).
M . Rumuiuh. Ph. D. Thesis, University of East Anglia 1974.
N . Dennis, A. R. Karritzki.. and S. K . Purron. J . Chem. Soc. Perkin
I, 1974, 750.
A. R . Knrrirzkr, H . 0.Tarliu~,and S. 7iirhu~1,J. Chem. Soc. 81970.
G P. Ford, B. Ih~uhirii,and A. R. Korrirzky, unpublished results.
See discussion in A . R. Kurrirzkj, and J . M . Lagowski: The Principles
of Heterocyclic Chemistry. Academic Press, London 1967. p. 41 f.
A . F . Vimpe and N . F . Twitsyno. Zh. Obshch. Khim. 27. 3282 (1957);
Chem. Abstr. 52, 91 l2d (1958).
N. Deniiir, B. Ihraliiin, A . R. Kiirrirzk), I. G . 7aulor. and Y Taktwclii,
J. Chem. SOC.Perkin I 1974, 1883; N . Dennis, B. Ihrrrhini, A. R. K u t r i r z k j ,
and E Takcwchi, J. Chem. Soc. Cheni. Comrnun. 1973. 292.
N . Dennis, A. R. Kurritzkr. and S. K. POIYUJ~,
Chem. Pharm. Bull..
in press.
N. D~iiiiis. B. Ibrohirn, and A . R. Karrirzkr, J. Chem. SOC. Perkin
1. in press; J. Chem. Soc. Chem. Commun. 1974, 500.
N . Dennis, B. Ihrahiiii. and A. R. Kutrirzkr. J. Chem. SOC. Perkin
I,in press.
R. B. Woorli~ardandR. Hoffnian~.Angew. Chem. 81,797(1969),especially
p. 856: Angew. Chem Int. Ed. Engl. 8. 781 (1969). especially p. 840
[41] R . Susti~rannand H . Pi//.Angew. Chem. 84. 887 (1972): Angew. Chem.
Int. Ed Engl. / I , 838 (1972).
Biomimetic Polyene Cyclizations
By William S. J o h n s o n [ * ]
Certain polyenic substances having trans olefinic bonds in a 1,s relationship can be induced
to undergo stereospecific, non-enzymic, cationic cyclization to give polycyclic products with
all-trans (“natural”) configuration. These transformations appear to mimic in principle the
biogenetic conversion of squalene into polycyclic triterpenoids. Acetal and allylic alcohol functions are effective initiators for these cyclizations, and methylacetylenic end groups are particularly
useful terminators since they lead to five-membered rings. Thus a tetraenic acetal having
no chiral centers has been converted in a single step into a tetracyclic product having seven
such centers. The process is highly stereoselective, giving only two of 64 possible racemates.
Systems have also been developed for effecting the total synthesis of the steroid nucleus in
a single step starting from a substrate containing only one ring. The mechanism of these
biomimetic cyclizations and also that of their enzymic counterparts is still unknown, but the
balance of the evidence favors a synchronous process.
1. Introduction
The strategy for the total synthesis of polycyclic natural
products, particularly the steroid and polycyclic triterpenoids,
[*] Prof. Dr. W. S. Johnson
Department of Chemistry, Stanford University
Stanford, California 94305 (USA)
has involved, for the most part, step-by-step annelations, i. e.,
each new ring is formed one at a time“’. The biomimetic
approach differs in that the plan envisages the production
of a number of rings stereospecifically in a single step by
the ring closure of an acyclic chain having appositely placed
trans olefinic bonds, a process analogous to the known biogenetic conversion of squalene into polycyclic triterpenoids,
e.g., l a n ~ s t e r o l [the
~ ~ precursor
of cholesterol.
In 1955 Stork et a/.r31
and Eschenmoser et di4]
out that the stereochemical course of the biological cyclization
of squalene could be rationalized on stereoelectronic grounds.
Their important hypothesis, which immediately stimulated
serious biomimetic studies, can be illustrated by considering
the conversion of squalene oxide (I), which is a known biogenetic intermediate['], into the plant triterpenoid dammaradienol (2). The process may be regarded as a sequence of
trans-anti-parallel electrophilic additions to the olefinic bonds,
in the same stereochemical sense that bromine adds stereospecifically to alkenes. Thus protonation of the oxygen atom
of squalene oxide ( I ) generates an incipient cationic center
at C-2, which attacks the 6,7-olefinic bond, thereby initiating
formation of the cr bond between C-2 and C-7. Concomitantly,
the cationic center developing at C-6 starts an electrophilic
attack on the 10,ll-olefinic bond generating the o bond
between C-6 and C-I I, etc. The addition of C-2 and C-I 1
to the 6,7-olefinic bond occurs in the frans manner, yielding
the trans-fused ring system found in the product ( 2 ) . Thus
the all-trans geometry of the olefinic bonds in squalene results
in trans,trans,trans,trans,trans-fusion
of the four rings in product (2). A corollary to the hypothesis is that a cis olefinic bond
will give rise to a cis-fused ring system"].
The first studies directed toward non-enzymic biogeneticlike polyene cyclization involved attempts to initiate cyclization by protonation of the terminal olefinic bond of a polyene
*I. The results were not promising['I. Seemingly,
much of the difficulty that has been encountered in the acidcatalyzed cyclization of such systems, including squalene, can
be attributed to the rather indiscriminate protonation of the
substrate, initiating a variety of other cyclizations in addition
to the desired reaction. Moreover, the relatively strong acidic
conditions generally employed are known to be conducive
to deprotonation (hence the production of partially cyclized
products) as well as to promoting reactions such as addition
to and isomerization of the olefinic bonds.
It was with the hope of obviating these difficulties that
we initiated, in 1960, a search for polyolefinic substrates con3'
taining an appropriately positioned functional group that
could be used to generate a cyclizable cationic carbon center
under conditions which would not otherwise affect the olefinic
bonds. This requirement appears to be fulfilled, at least in
part, by certain polyolefinic epoxides which have been examined extensively by can Tarnelen[']. Limitations in space
preclude a review of these most interesting studies in the
present paper. Other important studies that must be mentioned
are the free radical- and mercuric ion-initiated cyclizations
of M . Julia[lol, and the proton- and mercuric ion-initiated
cyclizations described by S H , J W O P S ~'I.~ [ '
Our very first investigations on the solvolysis of polyenic
sulfonate esters (see Section 2) gave useful mechanistic results;
however, the yields of cyclized products were extremely poor.
From an extensive search for groups more effective than sulfonate esters for initiating cationic polyene cyclizations, only
two good initiators emerged : the acetal function and the allylic
alcohol function. Our studies with these initiators are reviewed
2: Cyclization-Solvolysis of Polyenyl Sulfonate Esters
Careful product analyses have been made of the mixtures
obtained upon solvolysis of acyclic olefinic sulfonate esters
designed to produce mono-['21, bi-f' ' I , and tricyclic[141systems[''. Thus eleven,products were identified from the formolysis of the 5,9-decadienyl p-nitrobenzenesulfonate ( 3 ) . The
main component (after cleavage of the formate esters) was
'the monocyclic rrans alcohol ( 4 ) , produced in 3 5 ' x yield.
The major bicyclic component was trans,s~w-2-decalol ( 5 )
("natural configuration"). Moreover, all of the bicyclic material
(hydrocarbons as well as alcohols), which amounted to 12 %
yield, consisted exclusively of trans-decalin derivatives: no
cis products were
Formolysis of the geometric
isomer of ( 3 ) , having a cis instead of a trans internal olefinic
bond, gave a similar array of products except that they all
belonged to the opposite stereochemical series. In particular,
the bicyclic components, formed in 16 yield, all belonged
to the cis-decalin series[' 3b1. Although the yields of bicyclic
products were low, the stereospecificity of their formation
represented the first example of a system that followed the
theoretical predictions of Stork''] and E s c h e n m o ~ e r(see
~ ~ Sec~
tion 1).
The product from the acetolysis of the trienyl sulfonate
ester ( 6 ) , R=SO;C,H,-N02(p),
was estimated to consist
of approximately 20 acyclic material [ ( 6 ) , R = CH,CO],
40 y>monocyclic, 8-12 % bicyclic, and 2.8 % tricyclic substance~['~!
The tricyclic product, after cleavage of the acetates,
was shown to be exclusively the trans,trans,trans-alcohol(7)
Atignv. Chem. I n r . Ed. Eiigl.
Vol. 1 5 ( 1 9 7 6 ) No. /
as a mixture of C-2 epimers. Although the stereospecificity
of the reaction was encouraging, the low yield was completely
3. Cyclization of Polyenecarbaldehyde Acetals
After an exhaustive study of the cyclization of the transdienic acetal ( 8 ) [ " * 61, conditions were found for its essentially
quantitative conversion into trans-bicyclic materials, the major
product being the substance (9). It was also demonstrated
that the isomeric form of (8) with the cis internal olefinic
bond yielded only cis-decalin derivatives, in accordance with
the theoretical predictions (see Section 1).
the Wolff-Kishner reduction product with a substance synthesized from a naturally-derived D-homosteroid.
It is important to note that the products of all the biornimetic
cyclizations described above were racemic. Thus the tetracyclic
products represented by formula ( 1 4 ) contained an equal
amount of the mirror image of (14). The enzymic cyclization
of squalene, on the other hand, proceeds with total asymmetric
induction to produce only one enantiomeric form of the polycyclic products. In an effort to simulate this result in a nonenzymic process, we examined the case of the optically active
dienic acetal(Z5) derived from (- )-butanediol (R,R configura-
0 025 MSnCla
The next objective was to examine the possibility of forming
three rings from trienic acetals. Thus the trans,trans-acetal
(ZO), R = H, on treatment with stannic chloride in benzene,
was converted into a mixture of tricyclic products (1 Z ), R = H,
all ofwhich belonged to the trans,trans,Pans ("natural") stereochemical series['"! Similarly the acetal ( l o ) , R=CH,, was
converted, in 63 "/, yield, into the mixture of all-trans tricyclic
products (ZZ),R=CH,[161'.Surprisingly,when theacetal (ZO),
R = CH 3r was cyclized with stannic chloride in nitromethaneconditions which had been so successful with the dienic acetal
(8)-the reaction took a completely abnormal course involving rearrangement and yielded as the main product (44%
yield) the tricyclic substance (12), whose constitution was
established by single crystal X-ray diffraction analysis of a
derivative" 61.
tion)" *I. Treatment of ( 1 5 ) with stannic chloride in benzene
gave bicyclic products which were shown to have enantiomeric
ratios of92 :8. Thus a very high degree of asymmetric induction
has been realized. It will be interesting to see if this strong
induction is found in the tetracyclic series.
4. Cyclizations Promoted by the Allylic Cation
This type of cyclization is exemplified by the following
conversions161 which are catalyzed by formic acid :
(16) (17)[191, (18) ( 1 9 ) r 1 9201,
, and f2O) +(21)124"1.
stereospecific formation of the cis-fused ring system ( 1 9 ) from
(18) is the expected consequence of the known preference
for a cyclohexenyl cation to react with a nucleophile so as
to form a pseudo-axial bond [see (22) + (23)l.
To determine if four rings could be produced in a single
step, the cyclization of the tetraenic acetal (13) was examined[' ''. This substance, on treatment with stannic chloride
in pentane, was converted into a mixture of two crystalline
D-homosteroidal tetracyclic epimers ( Z 4 ) , which belonged
exclusively to the all-trans stereochemical series. This cyclization, which involves the production of no less than seven
asymmetric centers and in this sense is comparable to the
conversion of squalene into lanosterol, is remarkably stereoselective, yielding only two of 64 possible racemates. The constitution of (14) was established by degradation of the hydroxyethyl side-chain to give the 4-keto compound (the same
product was formed from each epimer), and then interrelating
The formation of two new rings by allylic cation promoted
cyclization is an efficient process. Thus the trienol ( 2 4 ) was
quantitatively converted, by the action of cold formic acid,
into a mixture of tricyclic products (25) and (1761. The
reaction was stereospecific with respect to the ring fusion
(trans,tran.s) as shown by separation and acid-catalyzed interconversion of each of the products, and by their reductive
transformation into the natural product ( *)-fichtelite
(27)I2 1 . 6 1 ,
2. L I A I H ~
tetracyclic hydrocarbon (34)[241.Ozonolysis of ( 3 4 ) gave
( 6 5 % yield) the triketo aldehyde ( 3 5 ) which still retained
the five new asymmetric centers that were generated in the
cyclization step. Substance (35) was finally converted, through
a double intramolecular aldol cyclodehydration, into (+)16,17-dehydroprogesterone ( 3 6 ) .
5. Cyclizations Involving Participation of Acetylenic
Bonds; Formation of Five-Membered Rings
Examples of the formation of three new rings follow. The
tetramethyl allylic alcohol function, as incorporated in the
substrate (28), is an effective cyclization
tricyclic material ( 2 9 ) is formed rapidly under exceedingly
mild conditions (52% yield). An example of the use of this
initiator to effect the total synthesis of a natural product
is the cyclization of the tetraenol (30), R = Si(CH,),t-C,H,,
which involves the formation of three new rings including
a seven-membered C-ring. The main product ( S I ) ,
R =Si(CH3)2t-C,H,, could be converted, via selective oxidation of the isopropylidene group followed by reduction and
deblocking, into (+)-serratenediol (32), a pentacyclic triterpenoid with nine asymmetric centers (256 possible race-
Because the five-membered ring widely occurs in natural
products, particularly in the D ring of steroids, it was of
special interest to search for systems which would give fivemembered ring closure in biomimetic processes. Since CC
triple bonds located in the 5,6-position relative to a developing
cationic center have a tendency to cyclize so as to give fiveit seemed reasonable to examine the behamembered
vior of such bonds as participants in polyene cyclizations.
The dienynol ( 3 7 ) was examined as a model system and
it did indeed undergo facile acid-catalyzed cyclization to give
exclusively the 6/5 trans-fused ring system in high
Thus upon treatment of (37) with formic acid, the en01 formate
5 mm
25 "C
The total synthesis of a steroid was effected via cyclization
of the tetraenol(33) which afforded (70 % yield) the crystalline
Anyew. Chon. I n t .
Ed. Engl.
Vol. 1 5 ( 1 9 7 6 ) Nu. I
(39)[*] was produced in >90
yield. Hydrolysis yielded
the ketone ( 4 0 ) which has all of the structural features of
the C/D ring system of progesterone.
The cyclization of substance ( 3 7 ) involves either an intermediate or a transition state having the properties of a vinyl
cation (38). It is especially interesting that such cations can
be generated efficiently under extremely mild conditions (e.g.,
with 1 ”/, trifluoroacetic acid in a solvent at -78°C) from
a relatively stable ditertiary allylic cation. The energy for
this transformation probably is provided by the conversion
of 7c to G bonds.
The vinyl cation ( 3 8 ) proved to be exceedingly reactive.
Thus when it was generated in acetonitrile as the solvent,
the nitrile reacted as a nucleophile giving, after work-up,
the enamide (41 ) [ * ] [ 2 h ] . When stannic chloride in benzene-a
system that had been employed successfully for the cyclization
of olefinic acetals (see Section 3)-was used for the cyclization,
the benzene was trapped by the vinyl cation giving the substance (42)[*1F2’1. Trifluoroacetic acid in nitroethane-which
was the system of choice for the cyclization of the substrate
(33) (see Section 4)-effected cyclization with capture of the
nitroethane giving what proved to be the oxyimino compound
(43)[2x1.Another example of this type of cyclization is given
below, (5.3) +(68/. Cyclization with stannic chloride in dichloromethane gave a mixture of five- and six-membered ring
vinyl chlorides (44)[*1and (45)[29! With trifluoroacetic acid
in dichloromethane at - 78 “C, the cyclization proceeded to
give exclusively the six-membered ring chloride ( 4 5 ) , the “rearranged” vinyl cation evidently abstracting chloride ion from
the solvent[30! Finally it has been shown that the vinyl cation
(38) can react with an alkene, ie., isohexene, to give the
alkylation product ( 4 6 ) [ * ]thusdeveloping
the cholesterol-like
side-chain. Vinyl cations can also react intramolecularly with
olefinic bonds[261.A case of special interest is described below.
The cyclization of the cyclopentenol ( 4 8 ) , which is readily
prepared in several steps via conjugate addition of the sidechain fragment to the unsaturated ketone (47), proceeds,
presumably via the cation ( 4 9 ) which reacts with the olefinic
bond in the five-membered ring to form the 7-anti-norbornenyl
type cation (50). This tricyclic cation, on reaction with water
added during work-up, is converted into the crystalline alcohol
( 5 1 ) . Under optimal conditions (CF,CO,H, O’C, 3 min) the
yield for the conversion ( 4 8 ) + (51) is 75 ”/,. The structure
of the alcohol ( 5 1 ) was established by its transformation
(several steps) into the natural product longifolene ( 5 2 ) , which
was thus produced in 21 % overall yield from 2-isopropylidenecyclopentanone (47)[3’l.
Attention is now turned to the total synthesis of steroids
via the application of acetylenic participation in biomimetic
polyene cyclizations. The trienynol (53) appeared to be a
promising substrate for cyclization directly to the steroid nucleus. Indeed, under the indicated conditions. it was converted
(65% yield) into the pregnenone ( 5 5 ) which, in turn, was
readily transformed into progesterone (56)‘”’. Ethylene carbonate was added to the cyclization mixture to serve as a
nucleophile for capturing the vinyl cation, possibly in the
form of the stabilized cation ( 5 4 ) .
P r o g e s t e r o n e (56)
U p to this point the synthesis of the cyclization substrates
has been ignored. Attention is now turned to the preparation
of the trienynol (53)’331. A convergent approach was
employed, the key step being the Wittig condensation of the
phosphorane ( 5 7 ) with the aldehyde ( 5 8 ) . The Schlosser
modification of the Wittig reaction was used in order to
vroduce a trans olefinic bond in the product (59). The conversion of sltbstand (59) into the substrate (SCS) involved hydrolysis of the thio ketal to the unsaturated ketone which was
reduced with lithium tetrahydridoaluminate.
[*] The orientation of the substituents on the olefinic bond attached to
the five-memhcred ring is unknown.
Anyew Chcin.
Ed. Eiiqi. j Voi. 15 ( 1 9 7 6 ) No. 1
The phosphonium salt ( 6 4 ) , required for making the phosphorane ( 5 7 ) , was prepared from commercially available
Hagemann’s ester (60). Conversion to the ethylene ketal followed by reduction with lithium tetrahydridoaluminate, then
acid hydrolysis (which also effected dehydration) yielded the
dienone (61). This substance underwent a 1,6-Michael addition with malonic ester, giving the keto diester (62) which,
on hydrolytic decarboxylation followed by reaction with ethanedithiol, was converted into the thio ketal acid (63). This
acid has an asymmetric center (indicated by the asterisk)
and could be resolved into the ( + ) and ( - ) forms as the
salts of optically active a-methylbenzylamine. Use of the (+)
Another substrate that proved useful for synthesizing steroids is the cyclopentenol(71) which, on cyclization, prodpced
the crystalline ketone (72) in 71 % yield""b! Conversion
of this product, ljiu ozonolysis followed by intramolecular
aldol condensation (see above), into (_+)-progesterone was
effected in >SO% yield.
form of (63) in the remainder of the synthesis led to ( j-(56),
identical with natural progesterone.
The aldehyde ( 5 8 ) has been prepared in a variety of ways,
one of which involves the addition of 3-pentynylmagnesium
bromide to methacrolein. The resulting substituted allylic alcohol ( 6 5 ) was warmed with ethyl (or methyl) orthoacetate
containing 5 propionic acid which effected the stereospecific
orthoacetate Claisen
involving the intermediacy
of the ketene acetai (66). The resulting enyne ester (67)
was obtained in > 9 O x yield, and the olefinic bond was
> 98 yd in the trans ( E ) form.
O T , 3h
+ liImgJ
(67 /
In other cyclization studies the trienynol (53) was treated
with trichloroaceticacid in 2-nitropropane giving the oxyimino
compound (68)[281, analogous to the formation of substance
143) (see above). This product was converted by hydrogenolysis with lithium tetrahydridoaluminate into the diol (69)
which was transformed with periodate into the 17-keto compound and thence into testosterone benzoate[3s!
c-2 . 5 % KOH
The synthesis of the cyclopentenol (71) was effected by
the Wittig-Schlosser condensation of the aldehyde (58) (prepared as described above) with the phosphorane (73) as shown
in the flow sheet. The product (74) was hydrolyzed to the
diketone (75) which, in turn, was induced to undergo a basecatalyzed cyclodehydration, giving the unsaturated ketone
(76). Reaction of (76) with methyllithium gave the substrate
I '
1 7 1 ) +--
T e s t o s t e r o n e benzoate
When the trienynol ( 5 3 ) was treated with trjfluoroacetic
acid in 1,l-difluoroethane containing isohexene at - 60"C,
the resulting vinyl cation reacted with the olefin (see above)
to produce the adduct (70) in 30'x yield[36].The constitution
of this product was proved by interrelationship with material
produced from a natural steroid.
i 75)
The synthesis of the phosphonium salt ( 7 9 ) , required for
production of the aforementioned phosphorane (731, was
accomplished as summarized in the accompanying flow sheet.
The step of particular interest is the cleavage of the furan
ring of the alkylation product (77) under ketalization conditions, to give the diketal bromide (78).
The cyclization of a number of substrates of the type shown
by formula (80) has given only the t Icl-substitutedl*] products
[*J Steroid numherlng.
.41igew. Chein. lm. Ed. Engl.
Vd. 15 (19761 N o . I
1 1
2 . ICeHShP
1. H,Oe
2 OH”
(81), probably because the transition state that would lead
to the 1 1P-epimer involves serious non-bonded (1,3-diaxial
type) interactions, e. g., between the developing 1 1b-substituent
and the C-19 methyl. Thus in the case where R=CH3[371,
CH,CCI=CH213’1, and CH2CH=CH2[37’, the reaction
( 8 0 ) -+ (81 ), which proceeded more slowly requiring more
vigorous conditions than when R = H (see above), only one
stereoisomeric form of the cyclized products ( 8 7 ) was produced in 50-60”/, yields. The exclusive formation of the
1 la-epimer in the cyclization indicated that the reaction
involves total asymmetric induction. Thus if the substrate
(80) were obtained in one enantiomeric form with respect
to the asymmetric carbon holding the R group, the product
/ a / ) should be optically pure. Preliminary studies of
the cyclization of partially resolved substrate (SO),
R = CH ,CH=CH,, did indeed give an optically active tetracyclic product of undetermined enantiomeric purity1381.
6. Concerning the Mechanism of Polyene Cyclizations
In the cyclization (86) (87)L3’1 the reaction appeared
to be even slower than those mentioned above, requiring
more severe conditions, perhaps because the nucleophilicity
of the disubstituted olefinic bond was attenuated by the negative inductive effect of the allylic hydroxyl group. The best
yield of the cl-hydroxy tetracyclic product that has been produced to date is 40 %[4”1. Even so, a relatively efficient totally
synthetic pathway to cortisone from simple chemicals has been
defined’3y1as follows:
The aldehyde ( 8 3 ) was prepared by reaction of the aforementioned allylic alcohol ( 6 5 ) with thionyl chloride to afford
the allylically transposed chloride which, in turn, was condensed with the anion of dithiane. Hydrolysis of the product
gave the aldehyde (83). The diketal acetylene ( 8 2 ) was produced by reaction of lithium acetylide with the lower homolog
of the diketal bromide (78). Conversion of the tetracyclic
product ( 8 7 ) into 1 1cr-hydroxyprogesterone (88) was carried
out via the oxidation-cyclodehydration sequence describec)
above [(7_7) + ( 5 6 ) ] . The substance (88) is a known intermediate in the commercial synthesis (ca. 50% overall yield) of
hydrocortisone acetate. Although the yields have not been
The question of the mechanism of stereospecific cationic
polyene cyclizations, whether enzymic or biomimetic, has been
open to debate. O n the one hand, the intermediacy of partially
cyclized cations (classical or bridged) has been shown to be
consistent with the observed stereochemical course of such
O n the other hand, a concerted process in
which all of the new C C bonds are formed synchronously
represents an equally satisfactory rationalization of the facts.
There has been very little direct evidence obtained for deciding
between the “stepwise” and the “synchronous” mechanisms;
however, at the present time the balance (see below) is somewhat in favor of the latter.
It has been demonstrated by deuterium incorporation experiments that certain enzymic[421as well as b i ~ m i m e t i d ~ ~ ]
polyene cyclizations d o not involve partially cyclized olefinic
intermediates which would require reprotonation (and consequent deuterium incorporation) in order for the cyclization
to continue. This finding, however, does not preclude a stepwise
process involving cations which do not deprotonate.
Kinetic studies of solvolysis of a series of substituted dienic
p-nitrobenzenesulfonates (see formula ( 3 ) above) in both acetic
and in t r i f l u ~ r o e t h a n o l [have
~ ~ ~ shown small, but
incremental, rate enhancements by substituting the vinyl hydrogens of the terminal olefinic bond by methyl groups. These
effects represent a necessary, but not sufficient, condition for
the synchronous mechanism. Other results consistent with
the synchronous process are presented below.
In connection with a total synthesis of estrone (92) from
(89)[461,a thorough study was made of the key step, namely
optimized for a number of steps, the overall yield of ( 8 8 )
at the present stage of refinement is 15.4% in 16 steps from
methacrolein and 2-methylfuran. The preparation and cyclization of the resolved form of the substrate (86) is under study.
the Lewis acid-catalyzed biomimetic cyclization (119) 4( 9 0 )
which proceeds in high yield. In addition to the product
(90), there was always obtained some of the isomer resulting
from cyclization ortho, instead of para, to the OR group.
The paralortho ratio varied depending on the nature of the
allylic leaving group in the
For example, in
the case of (89) having a free hydroxyl group, the ratio
was 8.4; on the other hand, when the leaving group was
trimethylsilyloxy the ratio was 2.6. Thus the effect of the
leaving group is “felt” in the bonding of the aromatic nucleus
to the internal olefinic bond, suggestive of a synchronous
process. Moreover, kinetic studies of the cyclization of the
substrate ( 8 9 ) having other groups (i.e., CH3, H, CF,) in
place of OH in the aromatic nucleus gave decreasing rates
as the groups became more ele~tronegative~~’~.
These findings
are also consistent with a synchronous process. Although
the evidence points strongly toward a synchronous process
in the case of the cyclization ( 8 9 ) + ( 9 0 ) , it should be emphasized that this result does not constitute proof that all cationic
polyene cyclizations are synchronous.
7. Conclusion
Acid-catalyzed biomimetic polyene cyclization of acyclic
chains is a viable synthetic tool for the stereospecific formation
of polycyclic systems. Acetal as well as allylic alcohol functions
are useful initiators for these cyclizations, and methylacetylenic
end groups are particularly useful terminators which can give
exclusive five-membered ring formation, and thus make possible the total synthesis of the steroid nucleus in a single
step starting from a one-ring substrate.
The stereochemical course of natural, enzymic polyene cyclizations may to some extent be guided by the same effects
that seem to control the non-enzymic processes, i. c., the course
of the reaction results from trans-anti-parallel electrophilic
addition to the olefinic functions according to the prediction
of Stork et
and Eschenmoser et al.13b!
Special thanks are due to my numerous collaborators who
have made many significant contributions to the planning ofthis
research endeavor, and who were completely responsible for
its reduction to practice. I wish also to thank the National
Institutes of Health and the National Science Foundation who
have afforded the major financial support to our program.
Received: July 14. 1975 [A 93 IE]
German version: Angew. Chem. 88, 33 (1976)
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Bacteriorhodopsin as an Example of a Light-Driven Proton Pump[**]
By Dieter O e s t e r h e l t [ * l
Apart from the long known visual pigments, another retinal protein complex exists in nature,
ciz. bacteriorhodopsin from halobacteria. In contrast to the visual pigments such as the rhodopsins, which act as light sensors in the eye, bacteriorhodopsin actually transforms light energy.
This energy conversion is connected with the asymmetric incorporation of bacteriorhodopsin
in the lattice structure of the purple membrane which forms patches on the cell surface of
halobacteria. Alongside the chlorophyll system, the purple membrane system represents the
second light energy conversion principle to be discovered in living nature. Bacteriorhodopsin
acts as a light-driven proton pump or as the main component of such a pump system. Absorption
of light triggers off a cycle of reactions coupled with the spatially oriented uptake and release
of a proton. In the intact cell an electrochemical gradient is thus built up across the cell
membrane of the bacterium in which part of the absorbed light energy is stored and which
is not dependent upon redox processes as in the case of respiration or photosynthesis. This
electrochemical gradient can supply the energy required for ATP synthesis in the cell; a reversible
proton-translocating ATPase serves as catalyst system.
1. Introduction
The questions of biological conservation and conversion
of energy have long played an important role in bioenergetics.
The universal storage form of energy is adenosine triphosphate
(ATP)[”: it stores chemical energy in the form of a high
phosphate transfer potential and the free energy of hydrolysis
of its phosphoric anhydride bonds serves to drive endergonic
processes in the cell, for instance the biosynthesis of endogenous substances and the energy-dependent uptake of
nutrients and salts against prevailing concentration gradients.
Two pathways have hitherto been known for energy storage
by ATP synthesis:
1 ) Substrate level phosphorylation of adenosine diphosphate (ADP) and
2) electron transport chain phosphorylations (oxidative and
photophosphorylation) of ADP.
During energy storage by substrate level phosphorylation,
enzyme-catalyzed reactions raise the phosphorylation potential of organic phosphates until ADP can be phosphorylated.
The energy required for this kind ofATP formation is supplied
by the free energy of intramolecular redox reactions, e.g.
in lactic acid fermentation where one mole of glucose is transformed into two moles of lactate.
In contrast, energy storage by oxidative phosphorylation
involves transfer of the electrons of an oxidizable substrate,
e.g. lactate, oia a chain of intermediate carriers-termed
respiratory chain-to atmospheric oxygen. Thus here too,
redox energy is transformed into the free energy of formation
[*] Prof. Dr. D. Oesterheltlnstitut fur Biochemie der Universitiit
87 Wurzhurg. Rontgenring I 1 (Germany)
[**I Based on a lecture delivered at the “Chemiedozenten-Tagung”, Dusseldorf. April 1975.
of a phosphoric anhydride bond in the ATP molecule, but
cia intermolecular processes. The way in which ATP synthesis
I S coupled to oxidation of a substrate molecule has not yet
been completely elucidated. In photophosphorylation (e.9.
in bacteria), light absorption in a chlorophyll molecule effects
release of an electron which then finds its way back to the
chlorophyll via an electron transport chain resembling the
respiratory chain. Again, phosphorylation of ADP is coupled
to this electron flow. It is called cyclic photophosphorylation.
The bacteriorhodopsin system, the subject of this paper, differs from the previously known types of biological energy storage. Neither the raising of a phosphorylation potential nor’a
transport of electrons is coupled to its light energy converting
function. All available evidence indicates that the absorbed
light energy is not initially transformed into redox energy
but directly into the energy of an electrochemical gradient
which then drives the ATP synthesis. Before going into details
about bacteriorhodopsin as a light-driven proton pump, we
shall first consider the fundamental difference between substrate level phosphorylation and electron transport chain
phosphor y lation.
2. Pathways of ATP Formation
The formation of phosphoenolpyruvate (2) from 2-phosphoglycerate ( I ) by dehydration and subsequent ATP formation with liberation of pyruvate ( 4 ) (Fig. l ) may be cited
as an example of substrate level phosphorylation. The high
phosphorylation potential of phosphoenolpyruvate arises from
the proclivity of the nascent enol form ( 3 ) of the pyruvate
to transform into the keto form ( 4 ) .The free energy of hydrolysis of ATP is 7 kcal/mol. but that of phosphoenolpyruvate
12 kcal/mol.
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