Formal synthesis of both atropomers of desertorin C and an example of chirality transfer from a biphenyl axis to a spiro centre and its reverse

C S I R O P U B L I S H I N G

Australian Journal

of Chemistry

Volume 53, 2000

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the Australian Academy of Science

Aust. J. Chem., 2000, 53, 487–506

Formal Synthesis of Both Atropomers of

Desertorin C and an Example of Chirality Transfer

from a Biphenyl Axis to a Spiro Centre and its Reverse

Robert W. Baker,^ARekha V. Kyasnoor,^BMelvyn V. Sargent,^B,C

Brian W. Skelton^Band Allan H. White^B

^ASchool of Chemistry, University of Sydney, Sydney, N.S.W. 2006.

^BDepartment of Chemistry, The University of Western Australia, Nedlands, W.A. 6907.

^CAuthor to whom correspondence should be addressed.

In connection with the synthesis of 4,4Ј,7,7Ј-tetramethoxy-5,5Ј-dimethyl-6,8Ј-bicoumarin (desertorin C) (11) in

enantiopure form, the diastereomeric ratios of the products of the reactions between 2-isopropyloxy-6-methoxy-4-

methylphenylmagnesium bromide (24) and (4S)-4-isopropyl-2-(2,3,5-trimethoxyphenyl)-4,5-dihydrooxazole (23),

between 2,4-dimethoxy-6-methylphenylmagnesium bromide (37) and (4S)-4-isopropyl-2-(2,3-dimethoxy-5-

methylphenyl)-4,5-dihydrooxazole (36), and between 2,4-dimethoxy-6-(t-butyldimethylsilyloxy)methylphenyl-

magnesium bromide (46) and the oxazole (36) were explored. The major product of the last mentioned reaction was

converted into (S,4S)-4-isopropyl-2-(2Ј-hydroxymethyl-4Ј,6,6Ј-trimethoxy-4-methyl-1,1Ј-biphenyl-6-yl)-4,5-

dihydroxazole (49), the axial configuration of which was confirmed by single crystal X-ray structural determina-

tion. The similar product (S,4S)-2-(2Ј,4Ј,6-trimethoxy-4,6Ј-dimethyl-1,1Ј-biphenyl-6-yl)-4,5-dihydrooxazole (43)

was converted into (S)-1-(2,4Ј,6Ј-trimethoxy-4,6Ј-biphenyl-2-yl)ethanone (57) which furnished (S)-1-(2Ј,4Ј,6-

trimethoxy-4,6Ј-dimethyl-1,1Ј-biphenyl-2-yl)acetamide (58) (43%) and (S)-2,7Ј-dimethoxy-3Ј,5Ј,6-trimethyl-

spiro[cyclohexa-2,5-diene-1,1Ј-(1H)isoindole]-4-one (61) (30%) on Schmidt rearrangement. The dienone (61) on

reduction and methylation regenerated the ketone (57). The methodology of Lipschutz was adapted for the synthe-

sis of both enantiomers of 1,1Ј-(2Ј,4-dihydroxy-6,6Ј-dimethoxy-2,4Ј-dimethylbiphenyl-3,3Ј-diyl)bisethanone (32)

and (83) which constitutes a formal synthesis of both enantiomers of desertorin C.

Keywords. Asymmetric synthesis; atropomers; chirality transfer; desertorin C.

A family of 4-methoxycoumarin dimers, all based on the

dihydric phenol orcinol (3,4-dihydroxytoluene) (1), which

are optically active on account of restricted rotation about the

biphenyl axis, has been isolated from lower fungi. These

bicoumarins fall into three groups: kotanin (3),

desmethylkotanin (4)¹and orlandin (5)²are symmetrical

4,4Јdimers of orcinol; isokotanins A (6),^3,4B (7)³and C (8)^3,4

are symmetrical 2,2Ј dimers of orcinol; and desertorinsA(9),

B (10) and C (11)⁵are unsymmetrical 2,4Ј dimers of orcinol.

Kotanin (3)¹and isokotanin A (6)⁶have been synthesized in

racemic form and, since we commenced the present work,

they have been synthesized in enantiopure (monochiral⁷)

form.^8,9

The synthesis of the unsymmetrical desertorin C (11) is a

more difficult task than that of its symmetrical isomers and

we achieved this in racemic form in 1988 by using oxazoline

chemistry.¹⁰Since then the absolute stereochemistry of the

desertorins has been determined by applying the Bijvoet

method to the bis-p-bromobenzoate of desertorin A (9).¹¹

Methylation of both desertorin A (9) and desertorin B (10)

yields desertorin C (11) so that the stereochemistry of B and

C is also established.

We now describe a formal total synthesis of both

atropomers of desertorin C. Preliminary accounts of this

work have appeared.^12,13

Our earlier synthesis of racemic desertorin C¹⁰used the

oxazoline (12) (Scheme 1) which was coupled with the

Grignard reagent derived from the bromo compound (13).

The product on functional group manipulation provided the

biphenyl (14) which, on acetylation to (15) and subsequent

selective demethylation, provided the diketone (16) which

had been obtained previously by hydrolytic degradation of

desertorin C.⁵This intermediate (16) was readily converted

into desertorin C in three steps.¹⁰

In order to adapt this synthetic route to provide an asym-

metric synthesis, an enantiopure oxazoline and a bromo

compound in which the two ether groups were differentiated

would be required. This latter could be achieved in com-

pound (20) (Scheme 2) where one of the ethers is a methyl

and the other an isopropyl ether. The diastereomeric ratio

(d.r.) and the stereochemical outcome of Meyers coupling

reactions of this type depend predominantly on the ability of

the substituents at the 2- and 6-positions of the phenyl

Grignard reagent to chelate to magnesium in the intermedi-

Manuscript received 11 October 1999

10.1071/CH99134

0004-9425/00/060487

488

R. W. Baker et al.

chelate than a methoxy group, as evidenced by the ability of

boron trichloride,²⁰titanium tetrachloride²¹and aluminium

trichloride²²to dealkylate an isopropoxy group in the pres-

ence of a methoxy group, it is predicted on mechanistic

grounds that the major diastereomer produced in such a cou-

pling reaction would be of the opposite absolute stereo-

chemistry to that required for the synthesis of desertorin C.

Nevertheless, we were intrigued by this possibility and, since

appropriate starting materials were to hand, we decided to

test it.

The synthesis of the required bromo compound (20) is

outlined in Scheme 2. 3-Methoxy-5-methylphenol (17)²³

was protected as its tetrahydropyranyl ether (18) and this

was allowed to react with butyllithium in the presence of

N,N,NЈ,NЈ-tetramethylethylenediamine (TMEDA). The resul-

tant lithium/hydrogen exchange product was treated with

1,2-dibromotetrafluoroethane and the crude product was

hydrolysed to afford the bromophenol (19).²⁴Isopropylation

then provided the required bromo compound (20).

ate complex.^14–19The best diastereomeric ratios have been

obtained when the chelating abilities of the two groups are

vastly different: a methoxy group, and a methyl group, or,

better, a t-butyldimethylsilyloxymethyl group, as the other

substituent.¹⁶Although an isopropoxy group is better able to

The synthesis of the required oxazoline (23) (Scheme 3)

commenced with the nitrile (21)¹⁰which, on hydrolysis with

powdered potassium hydroxide in boiling t-butyl alcohol,

smoothly gave the benzamide (22) which was converted into

its imidinium salt by treatment with triethyloxonium

tetrafluoroborate. Subsequent treatment²⁵with L-valinol²⁶

provided the oxazoline (23) in 75% yield. This was allowed

to react with an excess of the Grignard reagent (24) which

gave a chromatographically inseparable mixture of the

coupled oxazolines (25) and (26) in 74% yield as a viscous

oil which could not be induced to crystallize. The ¹H n.m.r.

spectrum of the mixture showed that the d.r. was 2.4:1 and,

although modest, it illustrates the sensitivity of the d.r. to

subtle changes in structure.

In order to establish the absolute configuration of the

major coupling product, the mixture of oxazolines (25) and

(26) was allowed to react with iodomethane and the resultant

methiodides were reduced to oxazolidines with sodium

borohydride. Mild acidic hydrolysis²⁷then afforded the

enantioenriched aldehyde (27) which easily underwent

thermal racemization since the magnitude of the specific

Synthesis of Both Atropomers of Desertorin C

489

rotation fell dramatically after three crystallizations from

dichloromethane/light petroleum. Reduction of the aldehyde

(27), which had been purified by chromatography but not

crystallized, afforded a mixture of the hydroxymethyl com-

pounds (28) and (31). In order to establish the enantiomeric

ratio (e.r.), the derived Mosher esters were prepared.

1

Fortuitously the H and ¹⁹F n.m.r. spectra of these diastere-

omeric esters were identical. However, when 1.4 mol. equiv.

of the chiral solvating agent (S)-1-(anthracen-9-yl)-2,2,2-tri-

fluoroethanol was added to a solution of the hydroxymethyl

compounds in deuteriochloroform, the signals of the

diastereotopic isopropyl methyl groups and one of the

methoxy groups of each enantiomer were clearly resolved.

This gave the e.r. as 2.8 : 1. It was thus confirmed that no

racemization had occurred during the deprotection and

reduction of the oxalozines (25) and (26). However, there is

the possibility that some enantiomeric enrichment had

occurred during the purification of the aldehyde and/or

alcohol by chromatography.²⁸

The enantioenriched alcohol (28) was converted to the

mesylate (29) which was reduced to the methyl compound

(30). The circular dichroism (c.d.) spectrum of this com-

pound, although weak, was similar to that of the (S)-com-

pound (77) so that it is concluded that the methyl compound

(30) and the major oxazoline (25) produced in the coupling

reaction also have the (S) configuration.

We now considered an alternative synthetic approach to

desertorin C, the retrosynthetic analysis of which is shown in

Scheme 4. The diacetyl compound (32) which has been

obtained by degradation from desertorin C⁵was the primary

goal. A logical precursor would then be the phenol (33).

Acetylation of this compound would be expected to occur at

the 5Ј-position¹⁰in one ring but the site of acetylation in the

other ring is open to speculation. In order to throw light on

this question, we acetylated the phenol (17) (Scheme 5). The

products proved to be the acetophenones (38) (46%)²⁹and

(39) (9%),³⁰so that acetylation of compound (33) is pre-

dicted to result in the desired compound (32). The phenol

(33) would be available in turn by Baeyer–Villiger oxidation

of the aldehyde (34) which would result from functional

group manipulation of the oxazoline (35). This oxazoline

would be predicted to be the major diastereomer produced in

the coupling reaction between the oxazoline (35) and the

Grignard reagent (37), since the substituents ortho to the

bromo substituent are a methyl and a methoxy group.

The oxazoline (36) was prepared from the benzoic acid

(40)³¹by, first, conversion into the acid chloride (41) which

was then treated with L-valinol.²⁶The resultant amide was

then cyclized to the oxazoline (36) (Scheme 6). This was

allowed to react with an excess of the Grignard reagent (37)

derived from the known bromo compound²³and the coupled

product was obtained as a viscous oil in 88% yield accompa-

nied by a trace of the demethylated oxazoline (42).³²The ¹H

n.m.r. spectrum of the coupled product demonstrated the

presence of the diastereomers (35) and (43). However, none

of the signals was resolved sufficiently to enable determina-

tion of the d.r., neither could the coupled product be obtained

crystalline, nor could it be separated by chromatography.

490

R. W. Baker et al.

Therefore it was converted into a mixture of the methiodides

(44) and (45) under mild conditions which would not be

expected to racemize this tetra-o-substituted biphenyl. The

¹H n.m.r. spectrum now showed well separated signals for

the two isomers in a d.r. of 7.3 : 1. Efforts to crystallize these

glass-like methiodides were not successful.

Mechanistic considerations lead to the prediction that the

major diastereomer (35) in the coupling reaction has the (S)

configuration. In order to provide concrete evidence for this

prediction, the following strategy was adopted. The coupling

reaction was repeated by using the Grignard reagent (46)

derived from the known bromo compound¹⁷since the

diastereomeric preference would be in the same sense.¹⁶In

the event, the coupled oxazolines (47) and (48) were

obtained as a chromatographically inseparable mixture in

64% yield. The demethylated oxazoline (42) was obtained in

26% yield and this observation and the lower yield of

coupled product reflect the greater steric demand of the sily-

loxymethyl substituent in (46) compared with the methyl

1

substituent in (37). The H n.m.r. spectral signals of the

coupled products (47) and (48) were not sufficiently

resolved to permit the determination of the d.r., but the addi-

tion of (S)-1-(anthracen-9-yl)-2,2,2-trifluoroethanol over-

came this difficulty and integration of the spectrum showed

that the d.r. was 8.5 : 1.

Desilylation of the coupled products by using tetrabutyl-

ammonium fluoride afforded a mixture of the crystalline

hydroxymethyl compounds (49) and (50) in which the d.r.

1

was unchanged as shown by integration of the H n.m.r.

spectrum. Fractional crystallization of this mixture allowed

the pure major diastereomer to be isolated, as shown by its

¹H n.m.r. spectrum. An X-ray crystal structure determination

on a single crystal of this diastereomer confirmed its (S) con-

figuration (Fig. 1). The close similarity of the c.d. spectrum

of this compound to that of the mixture of oxazolines (35)

and (43) confirmed that the major diastereomer was (35) and

also possessed the (S) configuration.

The mixture of methiodides (44) and (45) was now con-

verted by a similar method to that described above to a

mixture of the enantiomeric aldehydes (34) and (51). It was

found that, when this material crystallized from chloro-

form/light petroleum, the less soluble racemate, as shown by

its lack of optical rotation, crystallized first. The material

from the mother liquors was crystallized three times and

afforded the enantiopure aldehyde (34) which was reduced

with sodium borohydride to the alcohol (52). The unrecrys-

tallized aldehyde was also reduced to a mixture of the alco-

1

hols (52) and (53). When the H n.m.r. spectrum of this

material was determined in the presence of (S)-1-(anthracen-

9-yl)-2,2,2-trifluoroethanol, the e.r. proved to be 6.1 : 1 so

that little racemization had occurred during the removal of

the oxazoline. The above mixture of alcohols was also con-

verted into the derived Mosher esters (54) and (55). The ben-

zylic protons in the hydroxymethyl side chains of these

1

esters were well separated and the H n.m.r. spectrum

revealed a d.r. of 6.7 : 1, probably identical with the previous

value within experimental error, although the possibility of

enantiomeric enrichment cannot be dismissed. The alcohol

Synthesis of Both Atropomers of Desertorin C

491

492

R. W. Baker et al.

Fig. 1. A projection of molecule 1, as representative of the four

similar molecules of the asymmetric unit of the crystal structure of (49)

(general orientation, disposed so as to display the relative dispositions

of the various moieties). 20% thermal ellipsoids are shown for the non-

hydrogen atoms, hydrogen atoms having arbitrary radii of 0.1 Å. (In the

deposited data, atom numbers as displayed above are preceded by the

molecule number, n = 1–4.)

(52), obtained by reduction of the crystallized aldehyde (34),

was also converted into its Mosher ester, the ¹H n.m.r. spec-

trum of which demonstrated its optical purity. We have pre-

viously shown that the magnitude of the difference in the

chemical shifts of the side chain methylene protons in

Mosher esters of biarylmethanols such as (52) and (53) can

be used to determine their absolute configurations.¹⁹In

keeping with these observations, the ꢀꢁ_CH2for the (S) com-

pound (54) is 0.22 and that for the (R) compound (55) is 0.09.

Attempts^33,34to induce the aldehyde (34) to undergo

Baeyer–Villiger oxidation were unsuccessful. Treatment of

the aldehyde with m-chloroperoxybenzoic acid under a

variety of conditions did not yield any formate. This is pre-

sumably due to the effect of the m-methoxy group, since an

examination of the literature suggests that such compounds

give little or no formate.^33,35Another route to the phenol (33)

would be via a diazonium salt produced from the amine (59)

(Scheme 7) which could be obtained by a Schmidt rear-

rangement. Accordingly the enantioenriched aldehyde (34)

which had not beeen crystallized, and presumably therefore

had an e.r. of 6.1, was allowed to react at room temperature

with an excess of methylmagnesium iodide which gave a

separable mixture of alcohols (56) in the ratio 4.3: 1. A

portion of the mixture was separated and each alcohol on

oxidation gave the ketone (57) of the same specific rotation

so that they are epimeric at the stereogenic centre. Oxidation

of the mixture of alcohols (56) with pyridinium chlorochro-

mate gave the crystalline ketone (57), [ꢂ]²_D⁰–53.0°. This was

subjected to Schmidt rearrangement at 60° with sodium

azide in trichloroacetic acid. No product of alkyl migration³⁶

Synthesis of Both Atropomers of Desertorin C

493

could be detected and the expected arylamide (58) was iso-

lated in 43% yield. On hydrolysis, the amine (59), [ꢂ]²_D⁰

–33.0°, was obtained.

yielding the ketone (62). This ketone on methylation was

converted into the ketone (57), [ꢂ]²_D⁰–55.0°.

The spiroisoindolylcyclohexadienone (61) must arise by

rearside attack [(60), arrows] at the ipso position of the acti-

vated orcinol ring and thus has the (S) configuration. Similar

cross-conjugated spirocyclohexadienones, e.g. (63), have

been obtained previously from activated orcinol and

phloroglucinol type rings by intramolecular attack of a

neighbouring acylium ion.³⁷Attempts to determine the enan-

tiomeric purity of the spiro compound (61) were prevented

since it travelled as a single band on h.p.l.c. on two different

chiral columns [Chiralpak OT (+) and Pirkle type 1A]. In

view of the stability of the aldehyde (34) to thermal racem-

ization and the mild conditions involved in the preparation of

the ketone (57), the e.r. of this compound is likely to be

6.1 : 1. Since the specific rotation of the ketone (57) obtained

at the end of the sequence is the same, within experimental

error, as that of the initial ketone it may be concluded that

little racemization occurred throughout the sequence.

The cycle (57) (61) (57) thus involves the

intramolecular transfer of biphenyl axial chirality to a spiro

centre followed by the destruction of this centre and the

recreation of the biphenyl axis. Such intramolecular pro-

cesses which involve the transfer of stereogenecity by the

mutual destruction and creation of chiral elements have been

termed self-immolative.³⁹Examples in which the two chiral

elements are a biaryl axis and a carbon centre are rare.

Robinson recognized the first example of this process where

the chiral centres of thebaine are transferred to the chiral axis

of phenyldihydrothebaine.⁴⁰A few other examples of this

type have since been discovered in natural products chem-

istry^41,42and Meyers and Wettlaufer have described an

example of the transfer of a single chiral centre to a biaryl

axis in a synthetic compound.⁴³Examples of the transfer of

axial to central chirality and its reverse, and of central chi-

rality to axial chirality and its reverse, have been described

by Ohno and coworkers⁴⁴and by Straub and Goehrt,⁴⁵

respectively.

Another product, m.p. 190–192°, [ꢂ]²_D⁰30.0°, was also iso-

lated in 30% yield. The molecular formula was C₁₈H₁₉NO₃as

shown by the high resolution mass spectrum. The ¹³C n.m.r.

spectrum showed that a methoxy group had been lost, the

chemical shift of the carbonyl group had changed dramati-

cally, and there was a quaternary carbon at ꢁ_C79.31 which

suggested that a spirocyclohexadienone had been formed.

This proved to be the case and the detailed structural eluci-

dation was assisted by application of the ^COSY, HMQC, HMBC

and n.O.e. difference techniques which allowed the

spiroisoindolylcyclohexadienone structure (61) to be

advanced. The n.O.e. difference data are shown in Fig. 2 and

the HMBC data are shown in Table 1. That it was a cross-con-

jugated dienone rather than a linearly conjugated dienone

followed from the magnitude (1.3 Hz) of J_3,5in its ¹H n.m.r.

spectrum when compared with the dienones (63)³⁷(J_3,51.5

Hz) and (64)³⁸(J_3,52.2 Hz).

Further evidence for structure (61) came from cleavage of

the spiro C–N bond with zinc and acetic acid at room tem-

perature, the resultant ketimine suffering hydrolysis thereby

Attempts to convert the amine (59) via its diazonium salt

to the phenol (33) were not successful under a variety of con-

ditions. We therefore adopted a route based on chemistry

devised by Lipschutz and his coworkers⁴⁶in which the pre-

cursor to a biaryl is held together by a chiral tether. This

intermediate is used to generate a high diastereomeric excess

of the biaryl by oxidative coupling of a higher order

cyanocuprate. The chiral tether is then removed. We rea-

soned that this route should give rise to both enantiomers of

the degradation product (32) and this expectation was real-

ized.

Fig. 2. N.O.e. difference data for the spiro compound (61). The tail of

the arrow indicates the signal irradiated.

Table 1. HMBC correlations for the spiro compound (61)

Hydrogen

atom

Carbon atom

Two bond correlations Three bond correlations

The (S,S)-diol (65) (Scheme 8) was prepared from (R,R)-

tartaric acid⁴⁷and was next converted into its monosilyl ether

(66)⁴⁶by treatment with t-butyldimethylsilyl chloride in

N,N-dimethylformamide in the presence of imidazole.

Mitsunobu reaction⁴⁸of the monosilyl ether (66) using trib-

utylphosphine, diethyl azodicarboxylate and the bromophe-

nol (19) gave the expected aryl ether (67) in 68% yield.

Cleavage of the silyl ether in (67) was achieved with tetra-

butylammonium fluoride which gave the alcohol (68) in

Me 6

Me 4Ј

Me 2Ј

OMe 2

OMe 6Ј

3

5

5Ј

3Ј

6

4Ј

2Ј

1/7Ј; 5

5Ј

2Јa

2

6Ј

1/7Ј; 5

1/7Ј; 3

3Ј; 6Јa

2Ј; 5Ј; 6Јa

2

6Ј

494

R. W. Baker et al.

Synthesis of Both Atropomers of Desertorin C

495

Fig. 3. Conformation of the dioxocin (71).

90% yield. Another Mitsunobu reaction with the bromophe-

nol (69)²³now afforded the tethered precursor (70) in 45%

yield. This compound was now lithiated and converted into

the higher order cyanocuprate after the manner of Lipschutz

et al.⁴⁶This was treated with dry oxygen and workup pro-

vided the dibenzodioxocin (71) in 40% yield. That

intramolecular coupling had occurred was demonstrated by

the ¹H n.m.r. spectrum of the product (71) in which the signal

for one of the aryl methyl groups (Me 12; ꢁ_H2.16) was at sig-

nificantly higher field than that for the other aryl methyl

group (Me 3; ꢁ_H2.36) because it lies in the shielding zone of

the neighbouring aromatic ring.

In order that intramolecular coupling should occur, the

aryloxy substituents must be in close proximity in the transi-

tion state and it is likely, on account of the anomeric effect,

that they will adopt a gauche conformation so that the resul-

tant product will be the twist-boat–chair⁴²conformation (see

Fig. 3). Such an analysis also provides a rationalization of the

results obtained by Lipschutz et al.⁴⁶

Attempts to acetylate the dibenzodioxocin (71) with

acetic acid and trifluoroacetic anhydride at 0° gave a

complex mixture of products containing debenzylated com-

pounds. It was therefore decided to liberate the biphenyl

from its chiral tether. For this purpose we adopted a method

used by Lui and Zhong.⁸It involves standard threitol chem-

istry first described by H. O. L. Fischer and coworkers⁴⁹

whereby the 2,3-protected 1,4-diol is converted via the dito-

sylate into the diiodide. This is then treated with zinc in

ethanol as in Thiele’s preparation of 1,3-butadiene from 1,4-

dibromobut-2-ene.⁵⁰Accordingly, catalytic hydrogenation of

the dibenzodioxocin (71) yielded the diol (72) which was

converted sequentially into the ditosylate (73) and the diio-

dide (74) which yielded the biphenyldiol (75) on treatment

with zinc and ethanol.

In order to establish beyond doubt the absolute configura-

tion of the biphenyldiol (75), we attempted to grow a crystal

of the diiodide (74) suitable for an X-ray structural analysis.

These attempts were not successful. We therefore prepared

the dibenzoate (77) and measured its c.d. spectrum. The ¹L_a

transition band of the benzoate chromophore appeared at 228

nm in the electronic spectrum. The c.d. spectrum exhibited a

bisignate Cotton effect centred at 226 nm (ꢃꢀꢄ 33.3) with a

positive first band at 237 nm and a negative second band at

215 nm. This indicated a right-handed arrangement of the

two benzoate chromophores and hence positive chirality

between the long axes of these chromophores.⁵¹The (S) con-

figuration for the dibenzoate thus follows, and the (R) con-

figuration for the biphenyldiol. The diol appeared to be enan-

tiomerically pure as shown by the ¹H n.m.r. spectrum of the

derived bis-Mosher ester (78) and the fact that it travelled as

one band on two different chiral columns [Chiralpak OT (+)

and Pirkle type 1A].

Attention was now directed to the conversion of the

biphenyldiol (75) into the degradation product (32) of deser-

torin C. Acetylation of compound (75) cannot provide this

compound in view of the results obtained on acetylation of 3-

methoxy-5-methylphenol (17). The diol (75) was therefore

converted into its diisopropyl ether (76) and this was acet-

ylated with acetic acid and trifluoroacetic anhydride which

supplied an inseparable mixture of the diacetyl compounds

1

(79) and (80) in the ratio 1 : 1.2 as shown by the H n.m.r.

spectrum of the mixture. The major isomer (80) could be dif-

ferentiated from the minor isomer (79) since, in the ¹H n.m.r.

spectrum of the former, the signals for the isopropyl hydro-

gens of the isopropoxy group in an ortho relationship to an

acetyl group are at high field since they are in the shielding

zone of the carbonyl group. This mixture was subjected to

selective dealkylation with boron trichloride at –5–0° which

yielded a separable mixture of the triol (81) and the tetrol

(84). The structure of these compounds followed convinc-

1

ingly from their H n.m.r. spectra. That of the triol (81)

showed signals for two hydrogen-bonded hydroxy groups at

ꢁ_H11.87 and 12.45 and a free hydroxy group at ꢁ_H8.36. In

contrast, the spectrum of the tetrol (84) showed two hydro-

gen-bonded hydroxy groups at ꢁ_H11.80 and 13.42 and two

free hydroxy groups at ꢁ_H8.46 and 8.54.

Each of these compounds was separately methylated and

then selectively demethylated with boron trichloride to

afford the bisketones (32) and (83). As expected, the specific

rotations of the bisketones were opposite in sign. However,

the specific rotation of the bisketone (32) derived from the

tetrol (84) was lower, [ꢂ]²_D⁰34.0°, than the bisketone (83),

[ꢂ]²_D⁰–53.0°, derived from the triol (81). The c.d. spectra (see

Experimental section) of the two ketones are mirror images

of each other, but the amplitudes of the bands in (32) are

lower than those for (83). Attempts to determine the optical

purity of these compounds were frustrated since the anthra-

cenyl solvating agent was ineffective when applied to the

racemic ketone (16) synthesized previously.¹⁰This racemate

was not resolved on the Pirkle column.

The c.d. spectrum of the bisketone (32),⁵obtained by

degradation of desertorin C, contains bands at 227 and 270

496

R. W. Baker et al.

(3.3 ml, 29.3 mmol) in tetrahydrofuran (50 ml) at room temperature

under argon. The resulting orange solution was stirred for 4 h and then

cooled to 0°. 1,2-Dibromotetrafluoroethane (3.5 ml, 29.3 mmol) was

then added dropwise and the solution was stirred at room temperature

for 1 h and an excess of dilute hydrochloric acid was added. After 15 h,

workup with ethyl acetate gave a crude product which was purified by

flash chromatography with 2–5% ethyl acetate/light petroleum as

eluent. The phenol (19) crystallized from dichloromethane/light

petroleum as prisms (3.5 g, 71%), m.p. 70–71° (lit.²⁴70–72°).

nm, but the magnitude of these bands is much lower than that

for both of the synthetic ketones. However, the signs of the

bands for the degradation products are the same as those

observed in synthetic (32). The weak bands at longer wave-

length present in the synthetic compounds are not recorded

for the degradation product.⁵It is likely that the degradation

product (32) had undergone partial racemization under the

drastic conditions of its preparation which involved boiling

in basic aqueous dioxan.⁵The synthetic compound (32) must

also have undergone some racemization, probably at the

stage of the tetrol (84). The barrier to rotation in the triol (81)

would be higher than for the tetrol (84).

The stereochemical outcome of the Lipschutz cyclization

is thus in accord with the absolute configuration of deser-

torin C as determined by the Bijvoet method. The synthesis

of compounds (32) and (83) constitutes a formal synthesis of

both atropomers of desertorin C since the racemic ketone

(16) has already been converted into desertorin C.

1-Bromo-2-isopropyloxy-6-methoxy-4-methylbenzene (20)

The foregoing phenol (19) (10.0 g, 46.3 mmol), potassium carbon-

ate (10.0 g, 72.5 mmol) and 2-bromopropane (9.0 ml, 95.1 mmol) were

stirred together in N,N-dimethylformamide (250 ml) at 40° (bath) for

18 h. The usual workup gave a crude product which was distilled under

diminished pressure to yield the isopropyl ether (20) (9.3 g, 78%) as

an oil, b.p. 136–138° (oven)/0.8 mmHg (Found: C, 51.4; H, 5.8.

C₁₁H₁₅BrO₂requires C, 51.2; H, 5.5%). ꢁ_H1.36, d, J 5.8 Hz,

OCH(CH₃)₂; 2.31, dd, J 0.6 Hz, Me; 3.85, s, OMe; 4.53, septet, J 5.8

Hz, OCHMe₂; 6.36, m, W_h/23.8 Hz, HAr; 6.41, m, W_h/23.5 Hz, HAr.

Irradiation of the Me signal caused collapse of the aromatic signals to

an AB system, J_m2.0 Hz. ꢁ_C21.81 and 22.03 (×2), Me; 56.15, OMe;

72.03, OCHMe₂; 99.66, C 1; 105.53 and 109.25, C 3,5; 138.18, C 4;

155.39 and 156.75, C 2,6. m/z 260 (M⁺, 29%), 258 (M⁺, 27), 218 (98),

216 (100), 217 (13), 151 (14), 109 (11). v_max/cm^–12952, 2918, 2854,

1589, 1461, 1419, 1238, 1138, 1120, 809.

Experimental

Reactions were worked up, unless stated otherwise, by dilution with

water and extraction with the stated solvent, followed by washing with

acid or base as appropriate, water, and finally with saturated brine, and

then drying over anhydrous magnesium or sodium sulfate, the solvents

being removed under reduced pressure. Flash chromatography was per-

formed using B.D.H. silica gel (40–63 ꢅm). Radial chromatography

was performed on a Harrison Research Chromatatron by using plates

coated with Merck Kieselgel 60PF₂₅₄. Melting points were determined

2,3,5-Trimethoxybenzamide (22)

Powdered potassium hydroxide (10.0 g, 178.6 mmol) and the nitrile

(21) (10.0 g, 51.8 mmol)¹⁰were stirred and heated under reflux in t-

butyl alcohol (250 ml) for 1.5 h. The usual workup with

dichloromethane gave the amide (22) which crystallized from ethyl

acetate as needles (9.8 g, 90%), m.p. 110–111° (Found; C, 56.7; H, 6.1;

N, 6.7. C₁₀H₁₃NO₄requires C, 56.9; H, 6.2; N, 6.6%). ꢁ_H3.83, 3.868

and 3.874, each OMe; 6.41, bs, NHH; 6.65, d, J 3.0 Hz, H4; 7.19, d, J

3.0 Hz, H6; 7.99, bs, NHH. ꢁ_C55.66 and 55.99, each OMe; 61.40,

OMe 2; 103.98 and 104.55, C 4,6; 125.75, C 1; 142.22, C 2; 153.36 and

155.98, C 3,5; 166.99, C=O. m/z 211 (M⁺, 100%), 196 (60), 194 (13),

179 (13), 168 (17), 166 (12), 137 (17), 136 (39). v_max/cm^–13426, 3193,

1671, 1607, 1592, 1478, 1424, 1382.

with

a Kofler block. Optical rotations were measured on a

Perkin–Elmer 141 polarimeter with a 10 cm microcell. Circular dichro-

ism measurements were taken on a JASCO J-710 spectropolarimeter

for solutions in acetonitrile, unless stated otherwise. N.m.r. spectra

were determined in deuteriochloroform, unless stated otherwise, with a

Bruker AM-300 spectrometer at 300 MHz (¹H) or 75.5 MHz (¹³C).

Those determined at 500 MHz (¹H) or 125 MHz (¹³C) involved the use

of a Bruker ARX-500 instrument. The ^DEPTtechnique was used for

signal assignment of ¹³C n.m.r. spectra. ¹⁹F n.m.r. spectra were deter-

mined at 470 MHz with hexafluorobenzene (ꢁ_F–162.0) as internal stan-

dard. Infrared spectra were determined by means of thin films or

potassium bromide disks on a Biorad/Digilab FTS-45 Fourier-trans-

form spectrophotometer. Electronic spectra were determined for solu-

tions in methanol using a Hewlett Packard 8450A spectrophotometer.

Mass spectra were determined with a Fison VG Autospec instrument.

Light petroleum was a hexane fraction.

(–)-(4S)-4-Isopropyl-2-(2,3,5-trimethoxyphenyl)-4,5-

dihydrooxazole (23)

Triethyloxonium fluoroborate (1.92 ^M) in 1,2-dichloroethane (6.2

ml, 12.0 mmol) was added by syringe to a solution of the amide (22)

(2.0 g, 9.5 mmol) in dichloroethane (30 ml) under argon. The solution

was stirred at room temperature for 24 h and then ^L-valinol (1.3 g, 12.6

mmol)²⁶was added and the solution was boiled and stirred under reflux

for a further 24 h. The usual workup was followed by flash chromatog-

raphy with 20% ethyl acetate/light petroleum as eluent which gave the

2-(3-Methoxy-5-methylphenoxy)tetrahydropyran (18)

3,4-Dihydro-2H-pyran (3.5 ml, 35.9 mmol) was added to a stirred

solution of anhydrous toluene-p-sulfonic acid (35 mg) in dry tetrahy-

drofuran (50 ml) at 0° under argon. After 15 min, 3-methoxy-5-

methylphenol (17) (8.0 g, 58.0 mmol)²³and dihydropyran (9.6 ml, 98.3

mmol) were added simultaneously dropwise. The solution was stirred

at 0° for 20 h and then diluted with ether. Workup gave a yellow oil

which was distilled under diminished pressure to yield the pyran (18)

(11.0 g, 85%) as an oil, b.p. 120–122° (oven)/0.3 mmHg (Found: M⁺,

oxazoline (23) (2.0 g, 75%) as an oil, b.p. 210–215° (oven)/0.01 mmHg

12

(Found: M⁺, 279.1473.

C

15

¹H₂₁¹⁴N¹⁶O₄requires M⁺, 279.1471).

[ꢂ]²_D⁰–46.0° (c, 1.70 in CHCl₃). ꢁ_H(500 MHz) 0.96 and 1.04, each d, J

6.8 Hz, HC(CH₃)₂; 1.84–1.93, m, HCMe₂; 3.80, 3.81 and 3.84, each s,

OMe; 4.10–4.16, 5CHH, 4CH; 4.37–4.44, m, 5CHH; 6.59, d, J 2.9 Hz,

H4; 6.80, d, J 2.9 Hz, H6. ꢁ_C(125 MHz) 18.04 and 18.74, each Me;

32.68, CHMe₂; 55.61 and 55.99, each OMe; 61.48, OMe 2; 69.99, C 5;

72.39, C 4; 103.34 and 104.28, C 4,6; 122.88, C 1; 142.84, C 2; 154.04

and 155.59, C 3,5; and 162.38, C 2. m/z 279 (M⁺, 77%), 278 (22), 264

(22), 250 (30), 248 (21), 236 (82), 227 (14), 208 (33), 195 (47), 194

(27), 193 (100), 181 (54), 180 (20), 179 (32), 178 (57), 177 (78), 166

(13), 165 (37), 164 (15), 162 (17), 152 (12), 151 (14), 150 (20), 137

(15).

222.1257. ¹²C₁₃H₁₈¹⁶O₃requires M⁺, 222.1256). ꢁ_H1.52–1.73, 3H, m;

1

1.81–1.86, m, CH₂; 1.97, 1H, m; 2.83, s, Me; 3.60, m, H6Ј; 3.75, s,

OMe; 3.91, ddd, J_6Ј,6Ј= J_6Ј,5Ј= 9.2 Hz, J_6Ј,5Ј3.2 Hz, H 6Ј; 5.39, t, J 3.2,

H2Ј; 6.37, m, HAr; 6.44, dd, J_2,4= J_2,6= 2.0 Hz, H 2; 6.94, m, HAr. ꢁ_C

18.79, CH₂; 21.73, Me; 25.20 and 30.37, each CH₂; 55.16, OMe; 62.03,

CH₂; 96.32 and 99.82, C 2,2Ј; 108.21 and 109.53, C 4,6; 140.06, C 5;

158.08 and 160.52, C 1,3.

Coupling Reaction Between the Grignard Reagent (24) and the

Oxazoline (23)

2-Bromo-3-methoxy-5-methylphenol (19)

The Grignard reagent (24) was prepared from the bromo compound

(20) (2.0 g, 7.7 mmol) and magnesium turnings (250 mg, 10.3 mg-

atom) in tetrahydrofuran (12.0 ml) and was added dropwise under

Butyllithium (1.63 ^M) in hexane (18 ml, 29.3 mmol) was added

dropwise to a solution of the pyran (18) (5.0 g, 22.5 mmol) and ^TMEDA

Synthesis of Both Atropomers of Desertorin C

497

346.1780). [ꢂ]²_D⁰–8.3° (c, 1.24 in CHCl₃). ꢁ_H(500 MHz) 0.98 and 1.15,

each d, J 6.1 Hz, CH(CH₃)₂; 2.38, dd, J 0.6, 0.6 Hz, Me; 2.87, t,

J_OH,CH12.0 Hz, OH; 3.68, 3.69 and 3.87, each s, OMe; 4.21, d, J_{CH ,OH}

argon to a solution of the oxazoline (23) (980 mg, 3.5 mmol) in tetrahy-

drofuran (15.0 ml) at room temperature. The reaction mixture was then

boiled and stirred under reflux for 12 h, cooled, and quenched by the

addition of saturated ammonium chloride solution. Extraction with

ethyl acetate gave the crude product which was purified by flash chro-

matography with 30% ethyl acetate/light petroleum as eluent to give a

2.4 : 1 mixture of the diastereomeric oxazolines* (S)-(25) and (R,4S)-

(26) as a pale yellow gum (1.11 g, 74%). [ꢂ]²_D⁰–43.5° (c, 1.23 in

CHCl₃). For the major diastereomer (25): ꢁ_H(500 MHz) 0.79 and 0.84,

each d, J 6.7 Hz, HC(CH₃)₂; 1.07 and 1.09, each d, J 6.0 Hz,

OCH(CH₃)₂; 1.63, m, HCHMe₂; 2.34, s, Me; 3.64, 3.69 and 3.87, each

s, OMe; 3.77, dd, J_5,5= J_5,4= 8.1 Hz, CHH 5; 3.83, ddd, J 6.6 Hz, J_4,5

8.1 Hz, J_4,59.4 Hz, H4; 4.06, dd, J_5,58.6 Hz, J_5,49.4 Hz, CHH5; 4.27,

septet, J 6.1 Hz, OHCMe₂; 6.36 and 6.40, each bs, HAr; 6.60 and 7.02,

each d, J 2.3 Hz, HAr. ꢁ_C(125 MHz) 18.12, 18.80, 21.90, 22.08 and

22.41, each Me; 32.78, HCMe₂; 55.37, 55.74 and 55.85, each OMe;

70.21, C 5; 70.99, OCHMe₂; 72.17, C 4; 101.32, 104.79, 104.91 and

109.16, C 3,3Ј,5,5Ј; 113.87 and 117.45, C 1,1Ј; 137.93, C 4Ј; 156.57,

157.90, 158.56 and 159.14, C 2Ј,4,6,6Ј; 164.75, C 2. For the minor

diastereomer (26): ꢁ_H(500 MHz) inter alia, 0.80 and 0.85, each d, J 6.7

Hz, HC(CH₃)₂; 1.06 and 1.10, each d, J 6.0 Hz, OCH(CH₃)₂; 2.35, s,

Me; 3.67, s, OMe; 6.38, bs, HAr; 6.61 and 7.04, each d, J 2.3 Hz, HAr.

ꢁ_C(125 MHz) inter alia, 18.02, 18.74, 21.98, 22.09 and 22.11, each Me;

32.69, CHMe₂; 55.85, 55.87 and 55.94, each OMe; 70.57, C 5; 70.99,

OCHMe₂; 71.93, C 4; 101.51, 104.86, 104.91 and 108.44, C 3,3Ј,5,5Ј;

113.60, C 1 or C 1Ј; 130.47, C 4Ј; 156.11, 158.22, 158.60 and 159.11,

C 2,4,6,6Ј; 165.10, C 2.

2

12.0 Hz, CH₂OH; 4.23, septet, J 6.1 Hz, CHMe₂; 6.50, bs, HAr; 6.50, d,

J 2.4 Hz, HAr; 6.51, narrow m, HAr; 6.69, d, J 2.4 Hz, HAr. ꢁ_C21.78,

22.08 and 22.23, each Me; 55.22, 55.81 and 55.97, each OMe; 64.65,

CH₂OH; 72.53, CHMe₂; 98.48, 104.95, 106.18 and 110.77, C 3,3Ј,5,5Ј;

113.69 and 115.65, C1,1Ј; 138.92 and 141.57, C2,4Ј; 156.37, 158.23,

158.61 and 160.03, C 2Ј,4,6,6Ј. The enantiomeric ratio was estimated by

¹H n.m.r. spectroscopy at 500 MHz by the addition to the solution in

CDCl₃of 1.4 mol. equiv. of (S)-1-(anthracen-9-yl)-2,2,2-trifluoroethanol.

For the enantiomer (28): ꢁ_H0.95 and 1.11, each d, J 6.1 Hz; 2.38, s, Me;

3.67, 3.68 and 3.82, each OMe; 4.14–4.24, m, CHMe₂and CH₂OH; 6.49,

m, 2×HAr; 6.51, bs, HAr; and 6.63, d, J 2.4 Hz, HAr. For the enantiomer

(31): ꢁ_Hinter alia, 0.97 and 1.13, each d, J 6.1 Hz, CH(CH₃)₂, 3.66, s,

OMe.

(–)-(S)-2Ј-Isopropyloxy-2,4,6Ј-trimethoxy-4Ј,6-dimethyl-

1,1Ј-biphenyl (30)

A solution of methanesulfonyl chloride (38 mg, 0.33 mmol) in

dichloromethane (1.0 ml) was added dropwise to a stirred solution of

the foregoing alcohols (28) and (31) (95 mg, 0.27 mmol) and triethy-

lamine (8 drops) in dichloromethane (2.0 ml) at 0° under argon. After 1

h at 0°, the usual workup gave the crude mesylate (29) which was dis-

solved in tetrahydrofuran (2.0 ml) and added to a stirred solution of an

excess of lithium aluminium hydride in tetrahydrofuran (5.0 ml) at

room temperature. The solution was heated under reflux for 5 h, cooled,

and an excess of dilute hydrochloric acid was added. Workup with

(–)-(S)-2Ј-Isopropyloxy-4,6,6Ј-trimethoxy-1,1Ј-biphenyl-

2-carbaldehyde (27)

ethyl acetate gave

a crude product which crystallized from

The foregoing mixture of oxazolines (25) and (26) (286 mg, 0.67

mmol) and iodomethane (0.27 ml, 4.3 mmol) in nitromethane (6.0 ml)

were stirred and heated at 60° (bath) for 24 h. The solvent was removed

under reduced pressure and the residue was dissolved in tetrahydrofu-

ran/methanol (4 : 1 v/v, 5.0 ml) and cooled to 0°. A solution of sodium

borohydride (63 mg, 1.66 mmol) in tetrahydrofuran/methanol (2.0 ml)

was added to the stirred solution. After 1 h at 0°, an excess of 50%

aqueous ammonium chloride solution was added and the solution was

stirred for 2 h at 0°. Next, a solution of oxalic acid (420 mg) in water

(5.0 ml) was added and, after the solution was stirred for 1 h at room

temperature, the mixture was extracted with ether. The crude product

was purified by radial chromatography with 30% ethyl acetate/light

petroleum as eluent which gave the enantioenriched aldehyde (27) (117

mg, 51%) as pale yellow prisms (from dichloromethane/light

petroleum), m.p. 138–140° (Found: C, 69.6; H, 6.9. C₂₀H₂₄O₅requires

C, 69.8; H, 7.0%). [ꢂ]²_D⁰–1.5 (c, 1.0 in CHCl₃) before crystallization.

[ꢂ]²_D⁰–0.4 (c, 1.0 in CHCl₃) after three crystallizations. ꢁ_H1.10 and 1.11,

each d, J 6.0 Hz, OCH(CH₃)₂; 2.39, s, Me; 3.68, 3.73 and 3.86, each s,

OMe; 4.38, septet, J 6.0 Hz, HCMe₂; 6.44 and 6.46, each bs, HAr; 6.75

and 7.10, each d, J 2.5 Hz, HAr; 9.63, s, CHO. ꢁ_C21.90, 22.09 and

22.29, each Me; 55.46, 55.75 and 55.97, each OMe; 70.49, HCMe₂;

100.07, 104.60, 104.94 and 107.77, C 3,3Ј,5,5Ј; 108.78 and 122.19,

C 1,1Ј; 135.60 and 139.78, C 2,4; 156.70, 158.40, 158.91 and 159.82,

C 2Ј,4,6,6Ј; 193.36, C=O. m/z 344 (M⁺, 100%), 303 (28), 302 (93), 285

(11), 274 (25), 273 (20), 271 (21), 270 (14), 259 (32), 243 (32), 242

(16), 227 (22), 213 (11), 199 (13). v_max/cm^–12837, 1682, 1599, 1573,

1460, 1338, 1284, 1239, 1205, 1201, 1156, 1121, 1066, 995, 831, 640.

dichloromethane/light petroleum as prisms (67 mg, 74%) of the

biphenyl (30) (Found: C, 72.8; H, 7.7. C₂₀H₂₆O₄requires C, 72.7; H,

7.9%). The optical properties were determined on material that had not

been crystallized. [ꢂ]²_D⁰–4.0° (c, 1.00 in CHCl₃). ꢆ_max208, 228 infl, 251

infl, 280 infl nm (logꢄ 4.62, 4.16, 3.73, 3.49). C.d. ꢆ in nm (ꢀꢄ) 188

(2.4), 205 (–10.4), 211 (–4.3), 224 (–3.1), 241 (0.7), 247 (0.6), 255

(0.4). ꢁ_H0.98 and 1.03, each d, J 6.1 Hz, OCH(CH₃)₂; 1.93, s, Me 6;

2.29, s, Me 4Ј; 3.60, 3.62 and 3.74, each s, OMe; 4.29, septet, J 6.1 Hz,

OCHMe₂; 6.30 and 6.35, each bd, J_3’,5’2.4 Hz, H 3Ј,5Ј; 6.379 and 6.385,

each bs, H 3,5. ꢁ_C20.21, 22.09 (×2) and 22.21, each Me; 55.04 and

55.80×2, each OMe; 71.10, OCHMe₂; 97.00, 105.37, 105.97 and

109.57, C 3,3Ј,5,5Ј; 114.07 and 116.41, C 1,1Ј; 138.18 and 139.38,

C 4Ј,6; 156.62, 158.17, 158.55 and 159.27, C 2,2Ј,4,6Ј. m/z 330 (M⁺,

76%), 289 (18), 288 (100), 257 (16), 241 (11).

Acetylation of 3-Methoxy-5-methylphenol (17)

A solution of titanium(^IV) chloride (1.37 g, 7.2 mmol) in

dichloromethane (5.0 ml) was added at 0° to a stirred solution of acetic

anhydride (366 mg, 3.6 mmol) and the phenol (17) (150 mg, 1.1

mmol)²³in dichloromethane (10 ml). The solution was stirred at 0° for

1 h and then for 5 h at room temperature. The usual workup gave a crude

product which was purified by radial chromatography with 5–20%

ethyl acetate/light petroleum as eluent. The first band to be eluted gave

2-hydroxy-6-methoxy-4-methylacetophenone (39) (17.0 mg, 9%)

which crystallized from dichloromethane/light petroleum, m.p. 78–79°

(lit.³⁰79°). ꢁ_H2.28, s, Me; 2.62, s, MeCO; 3.85, s, OMe; 6.17, q, J 0.6

Hz, HAr; 6.37, q, J 0.6 Hz, HAr; 13.34, s, OH. ꢁ_C22.25, Me; 33.39,

COCH₃; 55.47, OMe; 102.33, C 5; 109.13, C 1; 110.95, C 3; 147.73,

C 4; 161.33, C 2; 164.69, C 6; 204.42, C=O. This was followed by 2-

hydroxy-4-methoxy-6-methylacetophenone (38) (83 mg, 46%) which

crystallized from dichloromethane/light petroleum, m.p. 80–81° (lit.²⁹

81°). ꢁ_H2.50, s, Me; 2.57, s, MeCO; 3.76, s, OMe; 6.221, dq, J_5,31.6,

J_5,Me0.7 Hz, H5; 6.245, d, J_3,51.6 Hz, H3; 13.55, s, OH. ꢁ_C25.05, Me;

32.89, COCH₃; 55.22, OMe; 98.90, C 3; 111.73, C 5; 114.99, C 1;

141.80, C 6; 164.25, C 2; 167.06, C 4; 203.89, C=O.

Reduction of the Aldehyde (27)

A solution of the aldehyde (27) (200 mg, 0.13 mmol), purified by

chromatography, but not crystallized, in tetrahydrofuran (2.0 ml) was

stirred at 0° and sodium borohydride (27 mg, 0.70 mmol) was added.

Workup after 2 h gave a crude product which was purified by radial

chromatography with 30% ethyl acetate/light petroleum as eluent

which gave a 2.8 : 1 mixture of the alcohols† (S)-(28) and (R)-(31) (189

mg, 94%) as a gum (Found: M⁺, 346.1769. ¹²C₂₀H₂₆¹⁶O₅requires M⁺,

1

* 4-Isopropyl-2-(2Ј-isopropyloxy-4,6,6Ј-trimethoxy-4Ј-methyl-1,1Ј-biphenyl-2-yl)-4,5-dihydroxazole.

† 2Ј-Isopropyloxy-4,6,6Ј-trimethoxy-4Ј-methyl-1,1Ј-biphenyl-2-methanol.

498

R. W. Baker et al.

(–)-(4S)-4-Isopropyl-2-(2,3-dimethoxy-5-methylphenyl)-

(S,4S)-(44) and (R,4S)-2-(2Ј,4Ј,6-Trimethoxy-4,6Ј-dimethyl-1,1Ј-

4,5-dihydrooxazole (36)

biphenyl-2-yl)-3-methyl-4,5-dihydroxazolium Iodide (45)

The foregoing mixture of oxazolines (36) and (37) (0.74 g, 1.93

mmol) and iodomethane (1.64 g, 11.58 mmol) in nitromethane (10 ml)

was stirred at 60° under argon for 24 h. The nitromethane was re-

moved under reduced pressure and the residue was dissolved in

dichloromethane and washed with aqueous sodium thiosulfate. The

methiodides (44) and (45) (1.0 g, 99%) were obtained as a glass in the

ratio 7.3: 1. [ꢂ]²_D⁰–33.0° (c, 1.00 in CHCl₃). For the major diastereomer

(44): ꢁ_H(500 MHz) 0.62 and 0.87, d, J 6.9 Hz, HC(CH₃)₂; 2.19, d

septets, J 6.9 and 4.2 Hz, CHMe₂; 2.01, s, Me 6Ј; 2.50, s, Me 4; 3.17, s,

MeN; 3.65, 3.76 and 3.81, each s, OMe; 4.47, dd, J_5,59.4 Hz, J_5,47.0

Hz, CHH5; 5.13, dd, J_5,410.7 Hz, J_5,59.4 Hz, CHH5; 5.24, ddd, J_4,5

10.7 Hz, J_4,57.0 Hz, J 4.2 Hz, H 4; 6.34, d, J_3Ј,5Ј2.3 Hz, H 3Ј; 6.42, qd,

J_5Ј,3Ј2.3 Hz, J_5Ј,Me0.5 Hz; 7.05, bd, J 0.7, HAr; 7.44, qd, J 1.5 Hz, J 0.7

Hz, HAr. For the minor diastereomer (45): ꢁ_H(500 MHz) inter alia,

0.40 and 0.83, d, J 6.9 Hz, HC(CH₃)₂; 1.90, s, Me 6Ј; 3.19, MeN; 3.62,

3.73 and 3.79, each s, OMe; 4.33, m, CHH5; 5.22, m, H4; 5.32, m,

CHH5; 6.31, d, J_3Ј,5Ј2.3 Hz, H 3Ј; 6.39, qd, J_5Ј,3Ј2.3 Hz, J_5Ј,Me0.5 Hz,

H5Ј; 7.00, bd, J 0.7 Hz, HAr; 7.74, qd, J 1.5 and 0.7 Hz, HAr.

A mixture of 2,3-dimethoxy-5-methylbenzoic acid (40) (6.0 g, 30.6

mmol),³¹oxalyl chloride (5.0 ml, 57.0 mmol), 3 drops of N,N-dimethyl-

formamide and dichloromethane (80 ml) was stirred at room tempera-

ture for 15 h under argon. The solvent was removed under reduced

pressure and the resultant acid chloride (41) was dissolved in fresh

dichloromethane (35 ml) and added dropwise to a solution of ^L-valinol

(3.3 g, 32.3 mmol)²⁶and triethylamine (13.4 ml) in dichloromethane

(110 ml). The solution was stirred at room temperature under argon for

15 h and then worked up. To the crude product in dichloromethane (140

ml) a solution of thionyl chloride (5 ml) in dichloromethane (25 ml)

was added dropwise with stirring at 0° and the solution was then stirred

at room temperature for 15 h. The solution was cooled to 0° and water

was added. The usual workup gave a crude product which was heated

under reflux for 15 h with acetonitrile (120 ml), water (15 ml) and

potassium carbonate (6 g). Most of the acetonitrile was removed by

evaporation under reduced pressure. Workup with dichloromethane

gave a crude product which was purified by flash chromatography with

20% ethyl acetate/light petroleum as eluent. The oxazoline (36) (3.6 g,

45%) was obtained as a viscous oil which underwent slow decomposi-

tion after being allowed to stand at room temperature (Found: M⁺,

Coupling Reaction Between the Grignard Reagent (46) and the

Oxazoline (36)

263.1517. ¹²C₁₅H₂₁¹⁴N¹⁶O₃requires M⁺, 263.1521). ꢁ_H0.92 and 1.00,

1

each d, HC(CH₃)₂; 1.83, m, HCMe₂; 2.28, d, J 0.6 Hz, Me; 3.81 and

3.82, each s, OMe; 4.04–4.13, m, 2×HC_oxz; 4.32–4.41, m, HC_oxz; 6.78,

bd, J 2.0 Hz, HAr; 7.10, qd, J 2.0 and J 0.6 Hz, HAr. ꢁ_C18.08 and 18.75,

HC(CH₃)₂; 21.08, MeAr; 32.71, CHMe₂; 56.07, OMe 3; 61.39, OMe 2;

69.99, C 5; 72.37, C 4; 115.94 and 122.53, C 4,6; 122.69 and 133.61,

C 1,5; 146.37 and 152.96, C 2,3; 162.57, C 2. m/z 263 (M⁺, 68%), 262

(12), 234 (16), 221 (131), 220 (100), 192 (42), 179 (31), 178 (18), 177

(65), 176 (18), 165 (70), 163 (19), 162 (25), 161 (15), 149 (33).

The Grignard reagent (46), prepared from 1-bromo-2,4-dimethoxy-

6-(t-butyldimethylsilyloxy)methylbenzene (1.51 g, 4.20 mmol)¹⁷and

magnesium turnings (131 mg, 5.50 mg-atom) in tetrahydrofuran (9 ml),

was added by cannula to a stirred solution of the oxazoline (36) (0.50 g,

1.90 mmol) in anhydrous tetrahydrofuran (5 ml) under argon. The solu-

tion was heated and stirred under reflux for 20 h and worked up as

before. Flash chromatography with 10–20% ethyl acetate/light

petroleum as eluent gave first the oxazoline (42) (123 mg, 26%). This

was followed by a mixture of the diastereomers‡ (S,4S)-(47) and

(R,4S)-(48) (630 mg, 64%), as a viscous gum, in the ratio 8.5 : 1

(Found: C, 67.8; H, 8.4; N, 2.7. C₂₉H₄₃NO₅Si requires C, 67.7; H, 8.3;

N, 2.7%). [ꢂ]²_D⁰–53.3° (c, 0.81 in CHCl₃). ꢁ_H(500 MHz) –0.03, s,

Si(CH₃)₂; 0.75 and 0.80, each d, J 6.7 Hz, HC(CH₃)₂; 0.90, s,

Coupling Reaction Between the Grignard Reagent (37) and the

Oxazoline (36)

The Grignard reagent (37) was generated from 1-bromo-2,4-

dimethoxy-6-methylbenzene (2.6 g, 11.2 mmol)²³and magnesium turn-

ings (350 mg, 14.6 mg-atom) in tetrahydrofuran (15 ml) and it was

added dropwise to the oxazoline (36) (1.3, 4.9 mmol) in tetrahydrofu-

ran (15 ml) at room temperature under argon. After the solution was

stirred for 1 h at room temperature, it was heated and stirred under

reflux for 15 h and then cooled and quenched with saturated ammonium

chloride solution. Workup with ethyl acetate and flash chromatography

with 20–30% ethyl acetate/light petroleum as eluent gave first the

methylphenol (42)* which crystallized as plates, m.p. 62–63° (from

ethyl acetate/light petroleum). ꢁ_H0.91 and 0.97, each d, J 6.7 Hz,

HC(CH₃)₂; 1.76, m, HCMe₂; 2.26, d, J 0.5 Hz, Me; 3.86, s, OMe;

4.06–4.15, m, 2×HC_oxz; 4.34–4.43, m, HC_oxz; 6.76, bd, J 1.9, HAr; 7.02,

qd, J 1.9 and 0.7 Hz, HAr. ꢁ_C18.46, CH(CH₃)₂; 20.92, MeAr; 32.95,

CHMe₂; 56.03, OMe; 69.83, C 5Ј; 71.21, C 4Ј; 115.92 and 119.01,

C 3,5; 127.37×2, C 2,4; 147.89 and 148.03, C 1,6; 165.23, C 2Ј. Further

elution gave a mixture of the dihydrooxazoles† (S)-(35) and (R,4S)-(43)

SiC(CH₃)₃; 1.55, m, HCMe₂; 2.40, s, Me; 3.61, s, OMe; 3.68, dd, J_5,5

=

J_5,4= 8.1 Hz, CHH5; 3.69, s, OMe; 3.80, m, H 4; 3.84, s, OMe; 4.00,

m, CHH5; 4.35 and 4.39, AB, J 14.5 Hz, H₂COSi; 6.37 and 6.83, each

bd, J 2.4 Hz, HAr; 6.84 and 7.24, each bs, HAr. ꢁ_C(125 MHz) –5.40,

SiMe₂; 18.15 and 18.62, CH(CH₃)₂; 18.30, SiCMe₃; 21.54, Me; 25.91,

SiC(CH₃)₃; 32.69, HCMe₂; 55.14, 55.76 and 55.89, each OMe; 62.72,

OCH₂; 70.12, C 5; 72.31, C 4; 96.87 and 101.38, C 3Ј,5Ј; 113.78 and

122.45, C 3,5; 115.26 and 121.83, C 1,1Ј; 130.43, 138.33 and 142.55,

C 2,2Ј,4; 156.64, 157.64, 159.84, C 4,6,6Ј; 164.44, C 2. m/z 513 (M⁺,

100%), 483 (12), 482 (32) 457 (13), 456 (40), 370 (11), 368 (25), 269

1

(12), 265 (12). The diastereomeric ratio was estimated by H n.m.r.

spectroscopy at 500 MHz in CDCl₃solution in the presence of 1.2 mol.

equiv. of (S)-1-(anthracen-9-yl)-2,2,2-trifluoroethanol. For the major

diastereomer (47): ꢁ_H–0.04 and –0.03, each s, Si(CH₃)₂; 0.77 and 0.82,

each d, J 6.8 Hz, HC(CH₃)₂; 0.89, s, SiC(CH₃)₃, 1.62, m, HCMe₂; 2.33,

s, Me; 3.67, s, 2×OMe; 3.73, J_5,58.0 Hz, J_5,47.5 Hz, CHH5; 3.82, m,

H4; 3.84, s, OMe; 3.93, dd, J_5,49.6 Hz, J_5,58.0 Hz, CHH5; 4.36, bs,

H₂COSi; 6.39, bd, J 2.5, HAr; 6.60, bd, J 0.8 Hz, HAr; 6.84, bd, J 2.5

Hz, HAr; 7.15, dd, J 1.5 and 0.7 Hz, HAr. For the minor diastereomer

(48): ꢁ_Hinter alia, –0.014 and –0.012, s, Si(CH₃)₂; 0.70, d, J 6.8,

HC(CH₃)Me; 0.89, s, SiC(CH₃)₃; 6.31, bd, J 2.5, HAr; 6.81, bd, J 2.5,

HAr; 7.23, bdq, J 1.5 and J 0.7 Hz, HAr.

as a viscous oil (1.64 g, 88%) (Found: M⁺, 383.2097. ¹²C₂₃H₂₉¹⁴NO₄

1

requires M⁺, 383.2093). [ꢂ]²_D⁰–60.3° (c, 0.99 in CHCl₃). ꢆ_max206, 235

infl, 285 nm (logꢄ 4.74, 4.19, 3.65). C.d. ꢆ nm/ꢀꢄ 206 (8.8), 215

(–16.8), 244 (1.2), 258 (–3.0). ꢁ_H0.75 and 0.79 , each d, J 6.8 Hz,

HC(CH₃)₂; 1.55, m, CHMe₂; 1.95, s, Me 6Ј; 2.38, s, Me 4; 3.61, 3.70

and 3.79, each OMe; 3.65, dd, J_5,4= J_5,5= 8.0 Hz, CHH 5; 3.82, ddd,

J_4,59.6 Hz, J_4,58.0 Hz, J 6.4 Hz, H 4; 3.65, dd, J_5,49.6 Hz, J_5,58.0 Hz,

CHH5; 6.31, bd, J_3Ј,5Ј2.1 Hz, H 3; 6.37, bd, J_5Ј,3Ј2.1 Hz, H5Ј; 6.84, bd,

J 0.7 Hz, HAr; 7.21, qd, J 1.5 and J 0.7 Hz, HAr. ꢁ_C18.07 and 18.59,

HC(CH₃)₂; 20.24 and 21.46, each Me; 32.62, HCMe₂; 55.10, 55.82 and

55.93, each OMe; 70.10, C 5; 72.33, C 4; 95.94, C 3Ј; 105.82 and

113.96, C 5,5Ј; 122.35, C 3; 118.43 and 123.50, C 1,1Ј; 130.43, 138.02

and 139.02, C 2,4,6Ј; 157.19, 158.21 and 159.45, C 2Ј,6,6Ј; 164.64, C 2.

(–)-(S,4S)-4-Isopropyl-2-(2Ј-hydroxymethyl-4Ј,6,6Ј-trimethoxy-4-

methyl-1,1Ј-biphenyl-2-yl)-4,5-dihydrooxazole (49)

A solution of the oxazolines (47) and (48) (356 mg, 0.69 mmol) in

tetrahydrofuran (10 ml) was added dropwise to a stirred solution of

tetrabutylammonium fluoride (657 mg, 2.1 mmol) in tetrahydrofuran (2

ml) at 0°C. After 4.5 h at room temperature, ether was added and the

* (4-S)-2-(4Ј-Isopropyl-4Ј,5Ј-dihydrooxazol-2Ј-yl)-6-methoxy-4-methylphenol.

† 2-(2Ј,4Ј,6-Trimethoxy-4,6Ј-dimethyl-1,1Ј-biphenyl-2-yl)-4,5-dihydrooxazole.

‡ 4-Isopropyl-2-[2Ј,4Ј,6-trimethoxy-4-methyl-6Ј-(t-butyldimethylsilyloxy)methyl-1,1Ј-biphenyl-2-yl]-4,5-dihydrooxazole.

Synthesis of Both Atropomers of Desertorin C

499

solution was worked up. The crude product was subjected to radial

chromatography with 40–50% ethyl acetate/light petroleum as eluent

which afforded the diastereomers (49) and (50) as a solid (265 mg,

96%). Four crystallizations from ethyl acetate gave the pure oxazoline

(49) as prisms, m.p. 119–121° (Found: C, 69.0; H, 7.4; N, 3.4.

C₂₃H₂₉NO₅requires C, 69.2; H, 7.3; N, 3.5%). [ꢂ]²_D⁰–20.5° (c, 0.82 in

CHCl₃). ꢆ_max206, 235 infl, 285 nm (logꢄ 4.74, 4.19, 3.65). C.d. ꢆ in nm

(ꢀꢄ) 199 (7.4), 213 (–23.3), 237 (6.5), 286 (–2.6). ꢁ_H0.49 and 0.59,

each d, J 6.7 Hz, HC(CH₃)₂; 1.26, septet, HCMe₂; 2.38, s, Me; 3.55,

3.67 and 3.81, each OMe; 3.83–3.94, 2×H-C_oxz; 4.20 and 4.25, AB, J

10.5 Hz, OCH₂; 4.24, dd, J 9.0 and 7.4 Hz, H-C_oxz; 6.39 and 6.69, each

d, J 2.4 Hz, HAr; 6.85, bd, J 0.9 Hz, HAr; 7.08, qd, J 1.5 and 0.7 Hz,

HAr. ꢁ_C17.39 and 18.21, HC(CH₃)₂; 21.56 Me; 32.72, HCMe₂; 55.37,

55.81 and 55.98, each OMe; 64.26, OCH₂; 70.39, C 5; 71.99, C 4; 98.56

and 105.65, C 3Ј,5Ј; 114.21 and 121.58, C 3,5; 117.92 and 122.74,

C 1,1Ј; 129.87, 138.51 and 142.05, C 2,2Ј,4; 156.63, 157.49 and 160.22,

C 4Ј,6,6Ј; 164.46, C 2. m/z 399 (M⁺, 46%), 369 (23), 368 (100), 234

(15), 149 (18), 97 (14). v_max/cm^–13438, 3354, 2960, 2916, 2839, 1618,

1577, 1487, 1470, 1417, 1346, 1319, 1245, 1229, 1198, 1158, 1137,

1089, 1066, 1001, 932.

qd, J_5Ј,3Ј2.4 Hz, J_5Ј,Me0.4 Hz, H5Ј; 6.75 and 6.98, each bs, H3,5. ꢁ_C

20.15 and 21.71, each Me; 55.16, 55.77 and 55.85, each OMe; 63.94,

OCH₂; 95.58, C 3Ј; 105.93, 111.42 and 121.66, C 3,5,5Ј; 117.23 and

121.89, C 1,1Ј; 138.60, 139.54 and 140.64, C 2,4,6Ј; 157.11, 157.70 and

159.79, C 2Ј,4Ј,6. In the presence of 1.2 mol. equiv. of (S)-1-(anthracen-

9-yl)-2,2,2-trifluoroethanol: ꢁ_H(500 MHz) 1.90, s, Me 6Ј; 2.39, s, Me 4;

3.66, 3.69 and 3.83, each s, OMe; 4.17, s, OCH₂; 6.42 and 6.47, each

bd, J 2.4 Hz, H 3Ј,5Ј; 6.75 and 6.98, each bs, H3,5. m/z 302 (M⁺, 79%),

284 (25), 269 (15), 241 (13), 153 (15), 152 (100). v_max/cm^–13371, 2958,

2838, 1604, 1576, 1464, 1413, 1334, 1275, 1204, 1153, 1094, 1048,

1037, 1001.

(S)-(54) and (R)-1-(2Ј,4Ј,6-Trimethoxy-4,6Ј-dimethyl-1,1Ј-biphenyl-2-

yl)methyl (R)-ꢂ-Trifluoromethyl-ꢂ-methoxyphenylacetate (55)

Method ^A. (+)-(S)-Mosher acid chloride (11.7 mg, 0.05 mmol)

was added by syringe to a solution of the alcohols (52) and (53) (10 mg,

0.033 mmol) in carbon tetrachloride (200 ꢅl) and pyridine (200 ꢅl)

under argon. Workup after 12 h with ether and dilute hydrochloric acid

gave a crude product which was purified by flash chromatography with

10% ethyl acetate/light petroleum as eluent. The esters (54) and (55) (11

mg) were obtained in the ratio 6.7: 1. For the major diastereomer (54):

see below. For the minor diastereomer (55): ꢁ_H(500 MHz) inter alia,

1.85, s, Me 6Ј; 3.51, narrow m, OMe; 3.64 and 3.83, each s, OMe; 4.90

and 4.99, AB, J 12.8 Hz, OCH₂. ꢁ_F–72.43 (resolution enhancement).

Method ^B. The pure alcohol (52) was converted, as above, into the

Mosher ester (54). ꢁ_H(500 MHz) 1.87, s, Me 6Ј; 2.34, s, Me 4; 3.48,

narrow m, OMe; 3.62, 3.69 and 3.84, each s, OMe; 4.85 and 5.07, AB,

J 12.7 Hz, OCH₂; 6.37, d, J_3Ј,5Ј2.4 Hz, H 3Ј; 6.43, qd, J_5Ј,3Ј2.4 Hz, J_5Ј,Me

0.4 Hz, H5Ј; 6.75, bd, H3,5; 7.38, m, Ph. ꢁ_F–72.42.

Deprotection of the Oxazolines (47) and (48)

A mixture of the oxazolines (35) and (43) (639 mg, 1.67 mmol) was

converted as before into the methiodides (44) and (45). A solution of

these compounds in tetrahydrofuran/methanol (4: 1, v/v, 8 ml) was

stirred and cooled to 0° and a solution of sodium borohydride (273 mg,

7.2 mmol) in tetrahydrofuran/methanol (8 ml) was added dropwise.

After 1 h at 0°, an excess of 50% aqueous ammonium chloride was

added and the mixture was stirred for 2 h and worked up with ether. The

crude oxazolidines were dissolved in aqueous tetrahydrofuran (1: 1 v/v,

8 ml) and treated with oxalic acid dihydrate (1.05 g). The solution was

stirred for 10 h at room temperture and the disappearance of the oxazo-

lidines was monitored by t.l.c. by spraying with DragendorffЈs reagent.

Workup with ether gave a crude product which was purified by radial

chromatography with 10–20% ethyl acetate/light petroleum as eluent.

This afforded a mixture of the aldehydes (34) and (51) (261 mg, 52%),

m.p. 73–75°. [ꢂ]²_D⁰–74.4° (c, 1.4 in CHCl₃). When this material was

crystallized from chloroform/light petroleum, the less soluble racemate

crystallized first. Crystallization of material from the mother liquors

afforded the aldehyde (34)* as prisms, m.p. 89–91° (Found: C, 71.8; H,

6.5. C₁₈H₂₀O₄requires C, 72.0; H, 6.7%). [ꢂ]²_D⁰–91.9° (c, 1.0 in CHCl₃).

ꢁ_H1.95, s, Me 6Ј; 2.43, s, Me 4; 3.63, 3.74 and 3.82, each s, OMe; 6.38

and 6.45, AB, J 2.1 Hz, H3Ј,5Ј; 7.00 and 7.42, each bs, HAr; 9.57, s,

CHO. ꢁ_C20.37 and 21.59, each Me; 55.20, 55.63 and 55.97, each OMe;

95.83, C 3Ј; 106.38, 117.34 and 119.10, C 3,5,5Ј; 114.09 and 127.83,

C 1,1Ј; 135.17, 138.62 and139.76, C 2,4,6Ј; 157.37, 158.33 and 160.30,

C 2Ј,6,6Ј. m/z 300 (M⁺, 100%), 272 (16), 257 (55), 241 (18). v_max/cm^–1

1689, 1604, 1578, 1466, 1322, 1309, 1274, 1149.

(S,1R) and (S,1S)-1-(2Ј,4Ј,6-Trimethoxy-4,6Ј-dimethyl-1,1Ј-biphenyl)-

2-ethanol (56)

The mixture of aldehydes (34) and (51) (381 mg, 1.27 mmol), puri-

fied by chromatography but not crystallized, was dissolved in tetrahy-

drofuran (10 ml) and stirred and cooled at –78° during the dropwise

addition of methylmagnesium iodide (0.64 ^M) in ether (5 ml) and the

solution was stirred at –78° for 1 h and at room temperature for 5 h.

Workup with saturated ammonium chloride gave a crude product (363

mg, 91%) as a gum which was a mixture of epimeric alcohols (56) in

the ratio 4.3: 1 (Found: C, 72.4; H, 7.5. C₁₉H₂₄O₄requires C, 72.1; H,

7.7%. [ꢂ]²_D⁰–46.0° (c, 1.0 in CHCl₃). A portion of the mixture was sep-

arated by radial chromatography with 10–40% ethyl acetate/light

petroleum as eluent. This gave first the minor epimer. [ꢂ]²_D⁰1.3° (c, 1.2

in CHCl₃). ꢁ_H1.27, d, J 6.4 Hz, HOCHCH₃; 1.60, bd, J 2.9 Hz, OH;

1.93, s, Me 6Ј; 2.40, s, Me 4; 3.64, 3.67 and 3.82, each s, OMe; 4.45, dq,

J 6.4 and 2.9 Hz, HOCHMe; 6.43 and 6.48, AB, J_3Ј,5Ј2.4 Hz, H 3Ј,5Ј;

6.69, d, J 1.5 Hz, HAr; 7.04, bs, HAr. ꢁ_C20.38, 21.95 and 24.08, each

Me; 55.16, 55.41 and 55.87, each OMe; 67.48, HOCHMe; 96.09, C 3Ј;

106.23, 110.98 and 117.94, C 3,5,5Ј; 117.25 and 121.15, C 1,1Ј; 138.62,

138.85 and 145.42, C 2,4,6Ј; 156.89, 157.30 and 159.70, C 2Ј,4Ј,6.

Further elution gave the major epimer. [ꢂ]²_D⁰–49.2° (c, 1.1 in CHCl₃). ꢁ_H

1.28, d, J 6.4 Hz, HOCHCH₃; 1.90, s, Me 6Ј; 2.42, s, Me 4; 2.40, bs,

OH; 3.66, 3.68 and 3.82, each s, OMe; 4.45, q, J 6.4 Hz, HOCHMe;

6.42, d, J_3Ј,5Ј2.4 Hz, H3Ј; 6.47, qd, J_5Ј,3Ј2.4 Hz, J_5Ј,Me0.4 Hz, H 5Ј; 6.71,

d, J 0.8 Hz, HAr; 7.04, bs, HAr. ꢁ_C20.15, 21.86 and 22.18, each Me;

55.09, 55.69 and 55.73, each OMe; 66.75, HOCHMe; 96.39, C 3Ј;

106.84, 117.88 and 119.10, C 3,5,5Ј; 117.23 and 127.28, C 1,1Ј; 138.62,

139.74 and 145.01, C 2,4,6Ј; 156.74, 157.34 and 159.61, C 2Ј,4Ј,6.

(–)-(S)-(52) and (R)-2Ј,4Ј,6-Trimethoxy-4,6Ј-dimethyl-1,1Ј-biphenyl-

2-methanol (53)

Method ^A. A mixture of aldehydes (34) and (51) (37 mg, 0.13

mmol), purified by chromatography but not crystallized, in ethanol (1

ml) was reduced in the usual way with sodium borohydride (5 mg, 0.13

mmol). The usual workup gave a product which was purified by radial

chromatography to give the alcohols (52) and (53) (36 mg, 97%) in the

ratio 6.1 : 1, as a solid. [ꢂ]²_D⁰–32.6° (c, 1.62 in CHCl₃). The e.r. was esti-

mated by the ¹H n.m.r. spectrum determined at 500 MHz in the presence

of 1.2 mol. equiv. of (S)-1-(anthracen-9-yl)-2,2,2-trifluoroethanol in

CDCl₃. For the major enantiomer (52): see below. For the minor enan-

tiomer (53), inter alia, ꢁ_H1.91, s, Me 6Ј; 2.41, s, Me 4; 3.63, s, OMe;

6.94, bs, HAr.

Method ^B. The pure aldehyde (34) was reduced in the same way

and the alcohol (52)† crystallized as prisms from ethyl acetate/light

petroleum, m.p. 94–96° (Found: C, 71.4; H, 7.3. C₁₈H₂₂O₄requires C,

71.5; H, 7.2%). ꢁ_H1.87, bs, OH, 1.92, s, Me 6Ј; 2.41, s, Me 4; 3.68, 3.70

and 3.83, each s, OMe; 4.20, s, OCH₂; 6.43, bd, J_3,5Ј2.4 Hz, H3Ј; 6.47,

(–)-(S)-1-(2Ј,4Ј,6-Trimethoxy-4,6Ј-dimethyl-1,1Ј-biphenyl-2-

yl)ethanone (57)

A solution of the foregoing mixture of epimeric alcohols (56) (303

mg, 0.96 mmol) in dichloromethane (3 ml) was added under argon at

room temperature to a stirred mixture of anhydrous sodium acetate (121

mg, 1.44 mmol) and pyridinium chlorochromate (311 mg, 1.44 mmol)

in dichloromethane (15 ml). After 7 h, the solution was diluted with

ether and passed through a short column of silica gel with more ether as

* (–)-(S)-2Ј,4Ј,6-Trimethoxy-4,6Ј-dimethyl-1,1Ј-biphenyl-2-carbaldehyde.

† (–)-(S)-2Ј,4Ј,6-Trimethoxy-4,6Ј-dimethyl-1,1Ј-biphenyl-2-methanol.

500

R. W. Baker et al.

eluent. Workup and radial chromatography with 20% ethyl acetate/light

petroleum as eluent gave the ketone (57) (252 mg, 83%) which crystal-

lized from chloroform/light petroleum as rosettes of needles, m.p.

80–82° (Found: C, 72.4; H, 6.8. C₁₉H₂₂O₄requires C, 72.6; H, 7.1%).

[ꢂ]²_D⁰–53.0° (c, 1.3 in CHCl₃) (before recrystallization). [ꢂ]²_D⁰–49.0° (c,

1.3 in CHCl₃) (after three crystallizations). ꢆ_max204, 221 infl, 241 infl,

285, 308 (logꢄ 4.61, 4.28, 3.95, 3.40, 3.43). C.d. ꢆ in nm (ꢀꢄ) (on mate-

rial with [ꢂ]²_D⁰–49.0°) 205 (8.0), 219 (–19.6), 239 (8.7). ꢁ_H1.94, 1.97

and 2.41, each s, Me; 3.66, 3.73 and 3.82, each s, OMe; 6.38, d, J_3Ј,5Ј2.4

Hz, H 3Ј; 6.44, qd, J_5Ј,3Ј2.4 Hz, J_5Ј,Me0.4 Hz, H 5Ј; 6.50, bd, J 0.7 Hz,

HAr; 7.04, qd, J 1.8 Hz, J 0.7 Hz, HAr. ꢁ_C20.18 and 21.57, each Me;

29.20, COCH₃; 55.11, 55.55 and 55.96, each OMe; 96.12, C 3Ј; 106.37,

114.39 and 120.19, C 3,5,5Ј; 117.39 and 121.58, C 1,1Ј; 138.43, 139.27

and 142.67, C 2,4,6Ј; 157.07, 157.94 and 160.09, C 2Ј,4Ј,6; 203.63,

C=O. m/z 316 (M⁺, 76%), 298 (31), 283 (17), 273 (21), 258 (11), 153

(12), 152 (10). v_max/cm^–11685, 1606, 1457, 1313, 1210, 1060.

acetate/light petroleum as eluent gave the ketone (57) (7 mg, 82%) with

spectroscopic properties identical to those above. [ꢂ]²_D⁰–55.0 (c, 0.4 in

CHCl₃). C.d. ꢆ in nm (ꢀꢄ) 207 (7.2), 220 (–24.2), 239 (8.9).

(–)-(S)-2Ј,4Ј,6-Trimethoxy-4,6Ј-dimethyl-1,1Ј-biphenyl-2-amine (59)

A solution of the amide (58) (91 mg, 0.28 mmol) and potassium

hydroxide (300 mg, 0.53 mmol) in dimethylsulfoxide and water (3 : 1

v/v, 4 ml) was stirred and heated at 90° for 7 h. The usual workup gave

a crude product which was purified by radial chromatography with 30%

ethyl acetate/light petroleum as eluent; this afforded the amine (59) (68

mg, 85%) which formed prisms from ethyl acetate, m.p. 129–130°

(Found: C, 70.9; H, 7.1; N, 4.7. C₁₇H₂₁NO₃requires C, 71.1; H, 7.4; N,

4.8%).[ꢂ]²_D⁰–33.0 (c, 1.1 in CHCl₃). ꢆ_max208, 248 infl, 282 (logꢄ 4.60,

4.16, 3.46). C.d. ꢆ in nm (ꢀꢄ) 192 (5.5), 222 (–12.8), 239 (8.4), 280

(–1.4). ꢁ_H2.02, s, Me 6Ј; 2.30, s, Me 4; 3.36, bs, NH₂; 3.66, 3.69 and

3.82, each s, OMe; 6.23, bs, HAr; 6.27, qd, J 1.4 and 0.7 Hz, HAr; 6.41,

bd, J 2.4 Hz, HAr; 6.47, qd, J 2.4 and 0.4 Hz, HAr. ꢁ_C19.95 and 21.84,

each Me; 55.14, 55.66 and 55.93, each OMe; 96.58, C 3Ј; 102.40,

106.70 and 108.99, C 3,5,5Ј; 108.87 and 115.50, C 1,1Ј; 138.46, C 2;

140.29, 145.23, C 4,6Ј; 157.94, 158.60 and 159.84, C 2Ј,4Ј,6. m/z 287

(M⁺, 100%), 256 (34), 241 (19), 150 (17). v_max/cm^–13438, 3354, 2960,

2916, 2839, 1618, 1577, 1487, 1470, 1417, 1345, 1319, 1245, 1229,

1198, 1158, 1137, 1089, 1066, 931.

Schmidt Rearrangement of the Ketone (57)

Sodium azide (77 mg, 1.19 mmol) was added in portions to a stirred

molten mixture of anhydrous trichloroacetic acid (1.2 g) and the ketone

(57) (240 mg, 0.77 mmol), which had been purified by chromatography

but not crystallized, at 60°. After 27 h at 60° the reaction mixture was

diluted with ethyl acetate and worked up. The crude product was puri-

fied by radial chromatography with 30% ethyl acetate/light petroleum

(2S,3S)-1,4-Bis(benzyloxy)-3-t-butyldimethylsilyloxybutan-2-ol (66)

as eluent. This gave first the acetamide (58)* (109 mg, 43%) as a gum

12

(Found: M⁺, 329.1621.

C

19

¹H₂₃¹⁴N¹⁶O₄requires M⁺, 329.1627).

t-Butyldimethylsilyl chloride (5.0 g, 33.1 mmol) was added to a

stirred solution of the diol (65) (10.0 g, 33.1 mol)⁴⁷and imidazole (4.5

g, 66.2 mmol) in N,N-dimethylformamide (25 ml) at room temperature.

After 15 h, the usual workup gave a crude product which was purified

by flash chromatography with 2–30% ethyl acetate/light petroleum as

eluent. The silyl ether (66) (10.5 g, 76%)⁴⁶was obtained as an oil. ꢁ_H

0.06 and 0.07, each s, Si(CH₃)₂; 0.88, s, SiC(CH₃); 3.47, dd, J_4,49.6 Hz,

J_4,35.8 Hz, CHH4; 3.50, bd, J_1,16.1 Hz, CH₂1; 3.59, dd, J_4,49.6 Hz, J_4,3

6.1 Hz, CHH4; 3.90 and 4.00, each td, H2,3; 4.53, bd, J 7.9 Hz,

CH₂Ph; 7.27–7.37, m, Ph. ꢁ_C–5.11 and –4.38, Si(CH₃)₂; 18.02,

SiCMe₃; 25.77, SiC(CH₃)₃; 70.53 and 70.64, C 2,3; 70.97 and 71.70,

C 1,4; 73.23 and 73.33, each CH₂Ph; 127.59, 2×PhCH; 127.73, 4×

PhCH; 128.28, 4×PhCH; 137.98, 2×PhC.

[ꢂ]²_D⁰–54.0° (c, 0.9 in CHCl₃). ꢁ_H1.92, 1.97 and 2.41, each Me; 3.69,

3.70 and 3.85, each s, OMe; 6.44 and 6.45, b AB, J 1.6 Hz, HAr; 6.58

and 6.76, each bs, HAr; 7.79, bs, NH. ꢁ_C20.01, 22.12 and 24.76, each

Me; 55.11, 55.79 and 55.84, each OMe; 96.49, C 3Ј; 106.95, 107.96 and

113.98, C 3,5,5Ј; 112.97 and 113.84, C 1,1Ј; 136.73, 138.87 and 140.61,

C 2,4,6Ј; 157.02, 158.32 and 160.38, C 2Ј,4Ј,6; 168.01, C=O. m/z 329

(M⁺, 100%), 287 (25), 256 (27), 241 (11), 240 (12), 192 (34), 150 (10).

Further elution with ethyl acetate afforded the ketone (61)† as pale

yellow prisms (66 mg, 30%) from ethyl acetate, m.p. 190–192° (Found:

12

M⁺, 297.1356.

C

¹H₁₉¹⁶O₃requires M⁺, 297.1364). [ꢂ]²_D⁰30.0° (c,

18

0.6 in CHCl₃). ꢆ_max218, 234 infl, 256 infl, 294 infl nm (logꢄ 4.36, 4.23,

4.00, 3.68). C.d. ꢆ in nm (ꢀꢄ) 218 (–8.3), 236 (16.7), 274 (–2.9). ꢁ_H

(500 MHz) 1.28, d, J_Me,51.3 Hz, Me 6; 2.46, s, Me 4Ј; 2.55, s, Me 2Ј;

3.50, s, OMe 2; 3.71, s, OMe 6Ј; 5.73, d, J_3,51.3 Hz, H 3; 6.26, qd, J_5,3

= J_5,Me= 1.3 Hz, H 5; 6.71, s, H 5Ј; 6.97, s, H 3Ј. ꢁ_C(125 MHz) 16.67,

Me 6; 16.72, Me 4Ј; 21.83, Me 2Ј; 55.55 and 55.95, each OMe; 79.31,

C 1/7Ј; 102.97, C 3; 113.24, C 5Ј; 114.28, C 3Ј; 128.26, C 5; 134.90,

C 6Јa, 141.69, C 4Ј, 143.69, C 2Јa; 149.87, C 6; 154.28, C 6Ј; 170.89,

C 2; 175.69, C 2Ј; 188.13, C 4. m/z 297 (M⁺, 100%), 282 (32), 269 (16),

268 (15), 254 (37), 238 (12), 226 (16). v_max/cm^–12917, 2845, 1666,

1629, 1608, 1578, 1380, 1354, 1338, 1306, 1264, 1218, 1181, 1150,

1067, 938, 873, 839.

(–)-(2R,3S)-1,4-Bis(benzyloxy-2-(2-bromo-3-methoxy-5-

methylphenyl)oxy-3-t-butyldimethylsilyloxybutane (67)

Tributylphosphine (90%, 8.58 ml, 31.0 mmol) was added dropwise

to a stirred solution of diethyl azodicarboxylate (5.0 ml, 31.0 mmol) in

tetrahydrofuran (40 ml) at 0–4° under argon. The resulting pale yellow

solution was stirred at 0° for 15 min and then added slowly by cannula

to a stirred solution of the bromophenol (19) (4.5 g, 20.7 mmol) and the

silyl ether (66) (8.6 g, 20.70 mmol) in tetrahydrofuran (100 ml) at 0–4°.

The solution was stirred at room temperature for 24 h and then most of

the solvent was removed by evaporation under reduced pressure. The

solution was diluted with ether and washed with dilute aqueous sodium

hydroxide. Flash chromatography of the crude product with 5–15%

(S)-1-(4Ј-Hydroxy-2Ј,6-dimethoxy-4-6Ј-dimethyl-1,1Ј-biphenyl-2-

yl)ethanone (62)

The spiro compound (61) (12 mg, 0.06 mmol) and zinc dust (80 mg)

were stirred for 15 h at room temperature in glacial acetic acid (2 ml).

ethyl acetate/light petroleum as eluent afforded the silyl ether (67) (8.7

12

g, 68%)⁸as an oil (Found: M⁺, 615.2141.

C

32

¹H₄₄⁷⁹BrO₅Si requires

M⁺, 615.2139). [ꢂ]²_D⁰–10.5° (c, 0.9, in CHCl₃). ꢁ_C(500 MHz) 0.05 and

0.06, each s, Si(CH₃)₂; 0.85, s, SiC(CH₃)₃; 2.71, s, Me; 3.60, dd, J_4,49.8

Hz, J_4,34.9 Hz, CHH4; 3.64, dd, J_4,49.8 Hz, J_4,35.2 Hz, CHH4; 3.78,

dd, J_1,110.8 Hz, J_1,26.1 Hz, CHH1; 3.86, s, OMe; 3.88, dd, J_1,110.8 Hz,

J_1,23.4 Hz, CHH1; 4.19, bdd, m, H3; 4.47, bs, CH₂Ph; 4.57 and 4.59

AB, J 12.0 Hz, CH₂Ph; 4.68, 1H, ddd, J_2,39.6 Hz, J_2.16.1 Hz, J_2,13.4

Hz, H 2; 6.43, bd, J 0.8 Hz, HAr; 6.61, qd, J 1.6 and J 0.8 Hz;

7.24–7.36, PhH. ꢁ_C–4.87 and –4.66, Si(CH₃)₂; 18.04, SiC(CH₃)₃;

21.85, Me; 25.80, SiC(CH₃)_3;56.32, OMe; 69.45, OCH₂1; 71.44, C 2;

71.64, OCH₂3; 73.33 and 73.46, each CH₂Ph; 79.94, C 3; 98.94, C 2;

105.63 and 108.85, C 4,6; 127.37, 2×PhCH; 127.59, 4×PhCH; 128.22,

4×PhCH; 138.22, C 5; 138.35×2, PhC; 155.99 and 156.75, C 1,3. m/z

The usual workup gave the ketone (62) (12 mg, 79%) as a gum (Found:

12

M⁺, 300.1374.

C

¹H₂₀¹⁶O₄requires M⁺, 300.1362). ꢁ_H1.92, s,

18

Me 6Ј; 1.96, s, COMe; 2.41, s, Me 4; 3.64 and 3.73, each s, OMe; 5.24,

bs, OH; 6.33, d, J_3Ј,5Ј2.4 Hz, H 3Ј; 6.35, qd, J_5Ј,3Ј2.4 Hz, J_5Ј,Me0.4 Hz,

H5; 6.89, bd, J 0.7 Hz, HAr; 7.03, qd, J 1.6 and J 0.7 Hz, HAr. ꢁ_C19.93

and 21.62, each Me; 29.26, COCH₃; 55.59 and 55.99, each OMe;

96.74, C 3Ј; 108.97, 114.51 and 120.25, C 3,5,5Ј; 117.18 and 121.49,

C 1,1Ј; 138.53, 139.55 and 142.67, C 2,4,6Ј; 156.21, 157.06 and 158.08,

C 2Ј,4Ј,6; 203.98, C=O. m/z 300 (M⁺, 100%), 285 (26), 270 (24), 269

(12), 257 (12), 226 (15), 177 (39). This ketone (62) (8 mg) was methy-

lated at room temperature with iodomethane and potassium carbonate

in acetone. Workup and radial chromatography with 20% ethyl

* (–)-(S)-N-(2Ј,4Ј,6-Trimethoxy-4,6Ј-dimethyl-1,1Ј-biphenyl-2-yl)acetamide.

† (+)-(S)-2,6Ј-Dimethoxy-2Ј,4Ј,6-trimethylspiro(cyclohexa-2,5-diene-1,7Ј-[1ЈH]isoindol)-4-one.

Synthesis of Both Atropomers of Desertorin C

501

617 (M⁺, 57%), 615 (M⁺, 54), 559 (13), 557 (12), 309 (14), 307 (21),

275 (16), 273 (16), 231 (49), 229 (50), 227 (19), 201 (79), 182 (15), 181

(100), 171 (45), 161 (53), 159 (21), 145 (25), 143 (28), 131 (28), 129

(25), 117 (55).

11.0 Hz, OCH₂; 3.74 and 3.75, each s, OMe; 4.06–4.12, m, H6,7; 4.56

and 4.58, AB, J 11.9 Hz, CH₂Ph; 4.57 and 4.59, AB, J 12.2 Hz, CH₂Ph;

6.56, bd, J 0.9 Hz, HAr; 6.61, bs, 2×HAr; 6.68, qd, J 1.4 and 0.7 Hz,

HAr; 7.26–7.36, m, PhH. ꢁ_C(125 MHz) 20.53 and 21.72, each Me;

55.16 and 55.39, each OMe; 70.56 and 70.62, each OCH₂; 73.58 and

73.66, each CH₂Ph; 85.06 and 85.55, C 6,7; 104.68, 107.75, 111.69 and

115.07, C 2,4,9,11; 116.37 and 120.02, C 12a,12b; 127.62, PhCH;

127.65, 2×PhCH; 127.68, PhCH; 127.75, 128.35 and 128.38, each

2×PhCH; 137.97 and 138.07, each PhC; 139.28 and 139.72, C 3,12;

157.12, 159.51, 159.59 and 159.75, C 1,4a,8a,10. m/z 540 (M⁺, 45%),

341 (22), 256 (11), 241 (11), 91 (100).

(–)-(2R,3S)-1,4-Bis(benzyloxy)-3-(2-bromo-3-methoxy-5-

methylphenyl)oxybutan-2-ol (68)

A solution of the silyl ether (67) (6.3 g, 10.2 mmol) and tetrabutyl-

ammonium fluoride (4.8 g, 15.2 mmol) in tetrahydrofuran (75 ml) was

stirred at room temperature for 1 h. Water was then added and the

mixture was extracted with ether. Flash chromatography of the crude

product with 10–20% ethyl acetate/light petroleum as eluent gave the

(+)-(S,6R,7R)-1,10-Dimethoxy-3,12-dimethyl-6,7-

dihydrodibenzo[e,g][1,4]dioxocin-6,7-dimethanol (72)

butanol (68) (4.62 g, 90%) as a viscous oil (Found: M⁺, 500.1186.

12

C

26

¹H₂₉⁷⁹Br¹⁶O₅requires M⁺, 500.1198). [ꢂ]²_D⁰–26.1° (c, 0.7 in

A solution of the foregoing dioxocin (71) (700 mg, 1.3 mmol) in

ethyl acetate (12 ml) containing a drop of acetic acid was stirred with

palladized charcoal (10%, 40 mg) under an atmosphere of hydrogen

until absorption ceased. The crude product was subjected to radial chro-

matography with 40–50% ethyl acetate/light petroleum as eluent. The

CHCl₃). ꢁ_H2.18, s, Me; 3.65, d, J_1,24.2 Hz, CHH 1; 3.65, d, J_1,24.9 Hz,

CHH1; 3.74, dd, J_4,410.6 Hz, J_4,35.3 Hz, CHH 4; 3.80, s, OMe; 3.82,

dd, J_4,410.6 Hz, J_4,33.8 Hz, CHH4; 4.07, ddd, J_2,36.5 Hz, J_2,14.9 Hz,

J_2,14.2 Hz, H2; 4.48, m, H 3; 4.50 and 4.49, AB, J 11.7 Hz, CH₂Ph;

4.51, s, CH₂Ph; 6.45, qd, J 2.8 and 0.6 Hz, HAr; 6.61, narrow m, HAr;

7.21–7.29, PhH. ꢁ_C21.86, Me; 56.31, OMe; 69.67 and 70.44, OCH₂1,4;

70.59 and 79.40, C 2,3; 73.35 and 73.52, each CH₂Ph; 99.40, C 2;

106.20 and 109.58, C 4,6; 127.57, 2×PhCH; 127.67, 4×PhCH; 128.32,

4×PhCH; 137.82, 137.93 and 138.58, 2×PhC, C 5; 155.67 and 156.70,

C 1,3.

diol (72) (438 mg, 94%) was obtained as a gum (Found: M⁺, 360.1573.

12

C

20

¹H₂₄¹⁶O₆requires M⁺, 360.1572). [ꢂ]²_D⁰12.0° (c, 1.2 in CHCl₃). ꢁ_H

2.05, bs, 2×OH; 2.18, s, Me 12; 2.38, s, Me 3; 3.61–3.68 and 3.75–3.80,

each m, OCH₂; 3.78 and 3.80, each s, OMe; 3.98–4.00, m, H6,7; 6.55,

bd, J 2.5 Hz, HAr; 6.60, bs, HAr; 6.64, qd, J 1.5 and 0.7 Hz, HAr; 6.66,

qd, J 2.5 and 0.6 Hz, HAr. ꢁ_C20.46 and 21.70, each Me; 55.30 and

55.44, each OMe; 62.77, 2×CH₂OH; 85.78 and 85.96, C 6,7; 104.70,

108.04, 111.94 and 114.89, C 2,4,9,11; 116.31 and 119.92, C 12a,12b;

139.76 and 139.93, C 3,12; 157.16, 158.84, 159.05 and 159.80,

C 1,4a,8a,10. m/z 360 (M⁺, 100%), 287 (11), 285 (14), 275 (12), 274

(55), 259 (21), 257 (23), 256 (13), 243 (19), 242 (18), 241 (21), 227

(14), 213 (11), 199 (11), 176 (18), 151 (26), 128 (16), 115 (13).

(2R,3R)-1,4-Bis(benzyloxy)-2-(2-bromo-3-methoxy-5-

methylphenyl)oxy-3-(2Ј-bromo-5Ј-methoxy-3Ј-

methylphenyl)oxybutane (70)

This was prepared in the same way as compound (67) from the fore-

going butanol (68) and the phenol (69)²³except that the reaction time

was 48 h. The ether (70) (45%) crystallized from light petroleum as

prisms, m.p. 54–56° (Found: C, 58.0; H, 5.3; Br, 22.8. C₃₄H₃₆Br₂O₆

requires C, 58.3; H, 5.2; Br, 22.8%). The specific rotation was too small

to measure. ꢁ_H(500 MHz) 2.25 and 2.36, each s, Me; 3.64 and 3.85,

each s, OMe; 3.84, dd, J_1,110.4 Hz, J_1,25.2 Hz, CHH 1; 3.86, dd, J_4,4

10.4 Hz, J_4,35.2 Hz, CHH 4; 4.00, dd, J_1,110.4 Hz, J_1,24.8 Hz, CHH1;

4.01, dd, J_4,410.4 Hz, J_4,34.8 Hz, CHH4; 4.77 and 4.80, each ddd, J 5.2,

4.8 and 4.8 Hz, H 2,3; 4.50 and 4.49, AB, J 11.7 Hz, CH₂Ph; 4.51, s,

CH₂Ph, 6.37, bd, J 0.9 Hz, HAr; 6.45, qd, J 2.8 and 0.6 Hz, HAr; 6.59,

bd, J 2.8 Hz, HAr; 6.61, bqd, J 1.6 and 0.9 Hz, HAr; 7.21–7.29, m, PhH.

ꢁ_C(125 MHz) 21.79 and 23.58, each Me; 55.31 and 56.29, each OMe;

68.40 and 68.48, each OCH₂; 73.50, 2×CH₂Ph; 78.58 and 78.72; C 2,3;

99.67, C 2; 100.14, 106.26, 109.26 and 109.46, C 4,4Ј,6,6Ј; 106.89,

C 2Ј; 127.51 and 127.52, each PhCH; 127.63 and 127.66, each

2×PhCH; 128.22, 4×PhCH; 137.91, 137.93, 138.49 and 139.73, C 3Ј,5,

2×CPh; 155.74, 155.91, 156.72 and 159.09, C 1,1Ј,3,5Ј.

(–)-(S,6R,7R)-6,7-Bis(toluene-4-sulfonyloxymethyl)-1,10-dimethoxy-

3,12-dimethyl-6,7-dihydrodibenzo[e,g][1,4]dioxocin (73)

p-Toluenesulfonyl chloride (572 mg, 3.0 mmol) was added in por-

tions at 0° to a stirred solution of the diol (72) (368 mg, 1.1 mmol) in

pyridine (5 ml). After 7 h at 0°, workup gave a crude product which was

purified by radial chromatography to give the ditosylate (73) (526 mg,

76%) as a gum (Found: M⁺, 668.1741. ¹²C₃₄H₃₅

O

³²S₂requires M⁺,

1

16

10

668.1750). [ꢂ]²_D⁰–17.4° (c, 0.7 in CHCl₃). ꢁ_H2.21, s, Me 12; 2.34, Me 3;

2.42 and 2.43, each s, Me; 3.73 and 3.76, each s, OMe; 3.99–4.12, m,

2×OCH₂; 4.14–4.19, m, H 6,7; 6.47, d, J 2.5 Hz, H2 or H4; 6.25 and

6.55, each bs, H 9,11; 6.61, bd, J 2.5 Hz, H2 or H4; 7.33–7.80,

2×AAЈBBЈ, TsH. ꢁ_C20.23 and 21.66, Me 3,12; 21.61, 2×Me; 55.20 and

55.41, each OMe; 69.03 and 69.08, each CH₂S; 82.21 and 82.59, C 6,7;

104.28, 108.26, 112.11 and 114.46, C 2,4,9,11; 115.96 and 119.48,

C 12a,12b; 127.95 and 129.99, each 4×TsCH; 132.35, 2×TsC; 139.75

and 139.90, C 3,12; 145.24, 2×TsC; 157.05, 158.36, 159.61 and 159.73,

C 1,4a,8a,10. m/z 668 (M⁺, 32%), 624 (33), 580 (18), 497 (19), 496

(25), 482 (12), 453 (14), 341 (16), 326 (33), 325 (100), 324 (17), 311

(15), 309 (11), 297 (12), 285 (24), 281 (11), 269 (11), 267 (11), 257

(18), 256 (29), 242 (13), 241 (25), 213 (13), 199 (19), 176 (17), 175

(21), 171 (26), 155 (27), 127 (16), 115 (12), 92 (14), 91 (85).

(–)-(S,6R,7R)-6,7-Bis(benzyloxymethyl)-1,10-dimethoxy-3,12-

dimethyl-6,7-dihydrodibenzo[e,g][1,4]dioxocin (71)

Butyllithium (1.62 ^M) in hexane (5.91 ml, 9.6 mmol) was added

dropwise to a stirred solution of the foregoing dibromo compound (70)

(1.60 g, 2.3 mmol) in tetrahydrofuran (40 ml) at –78° under argon. The

resulting yellow solution was stirred at –78° for 1 h and then transferred

slowly by cannula to a suspension of copper(^I) cyanide (210 mg, 2.3

mmol) in tetrahydrofuran (40 ml) at –78°. The reaction mixture was

stirred at –78° for 15 min and then ^TMEDA(1.2 ml, 7.5 mmol) was added

dropwise. The mixture was allowed to warm to –40° and stirred at that

temperature for 1 h. The resultant clear yellow solution was cooled to

–78° and dry oxygen was bubbled through the solution for 3 h.

Methanol and saturated aqueous ammonium chloride (4 ml) were added

and, after the solution was allowed to warm to room temperature, it was

poured into 10% aqueous ammonia (100 ml) saturated with ammonium

chloride. After the solution was stirred for 0.5 h, the organic layer was

separated and the aqueous layer was extracted with ether. The crude

product was purified by radial chromatography with 5% ethyl

(+)-(S,6R,7R)-6,7-Bis(iodomethyl)-1,10-dimethoxy-3,12-dimethyl-6,7-

dihydrodibenzo[e,g][1,4]dioxocin (74)

A solution of the ditosylate (73) (520 mg, 0.8 mmol) in acetone (8

ml) was stirred and heated under reflux with powdered sodium iodide

(1.6 g, 10.7 mmol) for 5 h. The usual workup followed by radial chro-

matography with 15% ethyl acetate/light petroleum as eluent, gave the

diiodide (74) (410 mg, 91%) as plates, from dichloromethane/light

petroleum, m.p. 155–157° (Found: C, 41.3; H, 4.0; I, 44.0. C₂₀H₂₂I₂O₄

requires C, 41.4; H, 3.8; I, 43.7%). [ꢂ]²_D⁰36.5° (c, 0.7 in CHCl₃). ꢁ_H(500

MHz) 2.16, s, Me 12; 2.39, s, Me 3; 3.59–3.72 and 3.68–3.72, each m,

OCH₂; 3.75 and 3.82, each s, OMe; 4.03–4.05, m, H6,7; 6.05, bd, J 0.5

Hz, HAr; 6.65, bqd, J 2.6 and 0.5 Hz, HAr; 6.71, bd, J 2.6 Hz, HAr;

6.77, qd, J 1.4 and 0.4 Hz, HAr. ꢁ_C(125 MHz) 4.70 and 4.72, each

CH₂I; 20.51 and 21.86, each Me; 55.30 and 55.43, each OMe; 87.24 and

87.75, C 6,7; 104.55, 108.30, 111.97 and 114.39, C 2,4,9,11; 139.64 and

acetate/light petroleum as eluent. The dioxocin (71) was obtained as a

12

viscous oil (490 mg, 40%) (Found: M⁺, 540.2524.

C

¹H₃₆¹⁶O₆

34

requires M⁺, 540.2512). [ꢂ]²_D⁰–28.8° (c, 1.3 in CHCl₃). ꢁ_H(500 MHz)

2.16, s, Me 12; 2.36, s, Me 3; 3.57–3.61, m, OCH₂; 3.69, bdd, J 11.0 and

502

R. W. Baker et al.

139.83, C 3,12; 157.04, 158.60; 158.80 and 159.64, C 1,4a,8a,10. m/z

580 (M⁺, 88%), 454 (23), 453 (100), 327 (10), 326 (33), 325 (54), 311

(20), 286 (17), 285 (96), 257 (26), 256 (20), 242 (12), 241 (24), 229

(17), 213 (14), 198 (12), 176 (12), 175 (41), 141 (12), 128 (16), 115

(16).

(–)-(S)-2,2Ј-Diisopropyloxy-4Ј,6-dimethoxy-4,6Ј-dimethyl-1,1Ј-

biphenyl (76)

A solution of the diol (75) (125 mg, 0.5 mmol) and 2-bromopropane

(450 mg, 3.6 mmol) in N,N-dimethylformamide (4 ml) was stirred

under argon at 45° with potassium carbonate (500 mg, 3.6 mmol) for 48

h. The usual workup, followed by radial chromatography, yielded the

biphenyl (76) (122 mg, 68%) as an oil (Found: M⁺, 358.2140.

(–)-(R)-4Ј,6-Dimethoxy-4,6Ј-dimethyl-1,1Ј-biphenyl-2,2Ј-diol (75)

12

11

C

22

H

30

¹⁶O₄requires M⁺, 358.2144). [ꢂ]²_D⁰–6.0° (c, 0.5 in CHCl₃).

A solution of the diiodide (74) (382 mg, 0.7 mmol) in ethanol (8 ml)

was stirred and heated under reflux for 1 h with activated zinc (4.0 g).

Workup in the usual way and radial chromatography with 30–40% ethyl

acetate/light petroleum as eluent gave the diol (75) (145 mg, 80%)

which formed prisms from ethyl acetate, m.p. 134–136° (Found: M⁺,

ꢆ_max208, 229 infl, 250 infl, 280 nm (logꢄ 4.80, 4.35, 3.92, 3.67). C.d.

ꢆ in nm (ꢀꢄ) 193 (6.5), 212 (–14.1), 221 infl (–4.2), 235 (2.6), 248

(2.2), 261 (0.8). ꢁ_H(500 MHz) 1.03, 1.05, 1.07 and 1.09, each d, J 6.1

Hz, 2×CH(CH₃)₂; 1.88, s, Me 6Ј; 2.35, s, Me 4; 3.66 and 3.79, each s,

OMe; 4.20 and 4.21, each septet, J 6.1 Hz, HC(CH₃)₂; 6.35, bd, J 2.4

Hz, HAr; 6.40, bs, HAr; 6.41, bs, HAr; 6.42, bd, J 2.4 Hz, HAr. ꢁ_C(125

MHz) 20.35 and 22.07, each Me; 22.12, 2×CH(CH₃)₂; 55.07 and 55.79,

each OMe; 70.97, 2×CHMe₂; 99.67, 105.07, 106.69 and 109.40,

C 3,3Ј,5,5Ј; 137.86 and 139.58, C 4,6Ј; 156.50, 156.99, 158.28 and

158.95, C 2,2Ј,4Ј,6. m/z 358 (M⁺, 77%), 316 (30), 275 (21), 274 (100),

259 (21), 243 (18), 242 (11).

274.1206. ¹²C₁₆H₁₈¹⁶O₄requires M⁺, 274.1205). [ꢂ]²_D⁰–27.0° (c, 0.7 in

1

CHCl₃), ꢆ_max207, 230 infl, 250 infl, 280 nm (logꢄ 4.74, 4.37, 3.95,

3.75). C.d. ꢆ in nm (ꢀꢄ) 195 (4.2), 214 (–2.6), 232 (2.2), 248 (–1.0). ꢁ_H

(500 MHz) 2.01, s, Me 6Ј; 2.37, s, Me 4; 3.73 and 3.80, each s, OMe;

4.89, bs, 2×OH; 6.41, bd, J 0.6 Hz, HAr; 6.47, bd, J 2.2 Hz, HAr; 6.50,

bs, HAr; 6.65, bqd, J 2.5 and 0.6 Hz, HAr. ꢁ_C19.94 and 21.96, each Me;

55.20 and 55.81, each OMe; 98.55, 104.38, 108.94 and 109.04,

C 3,3Ј,5,5Ј; 105.35 and 109.11, C 1,1Ј; 140.70 and 141.24, C 4,6Ј;

154.79, 155.40, 158.18 and 160.98, C 2,2Ј,4Ј,6. m/z 274 (M⁺, 100%),

259 (32), 243 (22), 199 (10), 137 (14). The Mosher ester (78), prepared

in a similar manner to that described above, had ꢁ_H(500 MHz) 2.03,

Me 6Ј; 2.38, Me 4; 3.28, bd, OMe; 3.66 and 3.79, each s, OMe; 6.49, bd,

J 2.5 Hz, HAr; 6.50, dd, J 1.4 and 0.7 Hz, HAr; 6.58, bs, HAr; 6.65, bdd,

J 2.5 and 0.6 Hz, HAr; 7.20–7.25, m, 5×PhH; 7.30–7.34, m, 5×PhH. ꢁ_F

–72.98, –72.74.

(S)-1,1Ј-(6,6Ј-Diisopropyloxy-2,4Ј-dimethoxy-2Ј,4-dimethyl-1,1Ј-

biphenyl-3,3Ј-diyl)bisethanone (79) and (S)-1,1Ј-(2,6Ј-

Diisopropyloxy-2,4Ј-dimethoxy-2Ј,4-dimethyl-1,1Ј-biphenyl-3,3Ј-

diyl)bisethanone (80)

Trifluoroacetic anhydride (0.7 ml, 5.0 mmol) was added dropwise at

0° to a stirred solution of the biphenyl (76) (100 mg, 0.3 mmol) in

dichloromethane (3 ml) and acetic acid (100 mg). The solution was

stirred at room temperature and then worked up. Purification of the

crude product by flash chromatography with 10% ethyl acetate/light

petroleum as eluent afforded a mixture of the ketones (79) and (80) as

(–)-(S)-4Ј,6-Dimethoxy-4,6Ј-dimethyl-1,1Ј-biphenyl-2,2Ј-

diyl Dibenzoate (77)

prisms (85 mg, 69%) in the ratio 1: 1.2 (Found: M⁺, 442.2357.

12

C

26

¹H₃₄¹⁶O₆requires M⁺, 442.2355). For the major isomer (80): ꢁ_H

A solution of the diol (75) (7 mg, 0.03 mmol) and excess benzoyl

chloride in pyridine (1 ml) was stirred at room temperature for 15 h. The

usual workup followed by radial chromatography with 2–15% ethyl

0.77 and 0.80, each d, J 6.1 Hz, HC(CH₃)₂2; 1.11 and 1.12, each d, J

6.1 Hz, HC(CH₃)₂6Ј; 1.89, bs, Me 2Ј; 2.24, d, J 0.6 Hz, Me 4; 2.4251

and 2.4257, each s, COCH₃; 3.63 and 3.78, each s, OMe; 3.55, septet, J

6.1 Hz, HCMe₂2; 4.39, septet, J 6.1 Hz, HCMe₂6Ј; 6.29 and 6.43, each

bs, HAr. For the minor isomer (79): ꢁ_H(500 MHz) 1.09, 1.10, 1.11 and

1.12, each d, J 6.1 Hz, CH(CH₃)₂; 1.85, bs, Me 2Ј; 2.22, bd, J 0.6 Hz,

Me 4; 3.25 and 3.78, each s, OMe; 4.28 and 4.33, each septet, J 6.1 Hz,

HCMe₂; 6.32 and 6.43, each bs, HAr. m/z 442 (M⁺, 34%), 400 (10),

344 (22), 343 (100), 327 (11), 326 (25), 311 (17).

acetate/light petroleum as eluent gave the dibenzoate (77) (8.5 mg,

12

70%) as prisms (Found: M⁺, 482.1720.

C

30

¹H₂₆¹⁶O₆requires M⁺,

482.1729). [ꢂ]²_D⁰–23.0° (c, 0.5 in CHCl₃). ꢆ_max228 and 274 nm (logꢄ

4.55, 4.55). C.d. ꢆ in nm (ꢀꢄ) 188 (–37.6), 199 (53.6), 215 (–9.0), 237

(24.3), 258 (6.9). ꢁ_H2.15, s, Me 6Ј; 2.35, Me 4; 3.64 and 3.75, each s,

OMe; 6.58, bs, HAr; 6.67, bqd, J 2.5 and 0.5 Hz, HAr; 6.72, bd, J 2.5

Hz, HAr; 6.73, bqd, J 2.0 and 0.6 Hz, HAr; 7.35–7.56, m, 10×PhH. ꢁ_C

19.99 and 21.77, each Me; 55.27 and 55.81, each OMe; 105.38, 109.28,

113.28 and 115.23, C 3,3Ј,5,5Ј; 115.46 and 118.06, C1,1Ј; 128.34,

4×mPhCH; 129.93, 4×oPhCH; 133.18, 2×pPhCH; 139.33, 140.34,

149.62 and 157.96, C 2,2Ј,4,4Ј,6,6Ј and 2×PhC 1; 164.45 and 164.78,

each C=O. m/z 482 (M⁺, 100%), 171 (10).

Dealkylation of Compounds (79) and (80)

Boron trichloride (170 mg, 1.5 mmol) in dichloromethane (0.5 ꢅl)

was added to a stirred solution of the foregoing ketones (80 mg, 0.18

mmol) in dichloromethane (3 ml) at –5°. The solution was stirred at

room temperature for 2 h and then worked up. The crude product was

Table 2. Selected molecular non-hydrogen geometries for compound (49)

Atoms

Mol. 1

Mol. 2

Mol. 3

Mol. 4

Mean

Distances (Å)

O(10)–C(2)

O(1)–C(5)

C(2)–N(3)

C(2)–C(2Ј)

N(3)–C(4)

C(4)–C(5)

C(4)–C(4Ј)

C(1Ј)–C(1ЈЈ)

C(1Ј)–C(2Ј)

C(2Ј)–C(3Ј)

C(3Ј)–C(4Ј)

C(4Ј)–C(5Ј)

C(5Ј)–C(6Ј)

C(1Ј)–C(6Ј)

1.35(1)

1.465(9)

1.25(1)

1.492(8)

1.490(7)

1.52(1)

1.481(8)

1.405(9)

1.39(1)

1.384(9)

1.418(9)

1.36(1)

1.402(8)

1.36(1)

1.45(1)

1.25(1)

1.484(9)

1.489(9)

1.50(1)

1.344(1)

1.47(1)

1.28(1)

1.48(1)

1.51(1)

1.50(1)

1.49(1)

1.380(9)

1.41(1)

1.37(1)

1.41(1)

1.347(9)

1.49(1)

1.25(1)

1.505(9)

1.51(1)

1.50(1)

1.51(2)

1.49(1)

1.388(9)

1.40(1)

1.38(1)

1.37(1)

1.36(1)

1.427(9)

1.350(7)

1.47(2)

1.26(1)

1.49(1)

1.51(1)

1.52(2)

1.4895(7)

1.40(1)

1.380(7)

1.39(3)

1.37(1)

1.41(1)

1.53(1)

1.477(9)

1.408(9)

1.390(9)

1.384(9)

1.409(9)

1.378(9)

1.414(9)

Synthesis of Both Atropomers of Desertorin C

503

Table 2 (Continued)

Mol. 2

Atoms

Mol. 1

Mol. 3

Mol. 4

Mean

Distances (Å) (continued)

C(6Ј)–O(6Ј)

1.375(8)

1.394(8)

1.39(1)

1.38(1)

1.37(1)

1.38(1)

1.406(9)

1.37(1)

2.837(9)

1.385(7)

1.39(1)

1.37(1)

1.39(1)

1.37(1)

1.404(9)

1.38(1)

2.86(1)

1.356(8)

1.39(1)

1.41(1)

1.37(1)

1.39(1)

1.38(1)

1.39(1)

1.362(9)

2.83(1)

1.362(8)

1.40(1)

1.41(1)

1.37(1)

1.38(1)

1.39(1)

1.40(1)

1.365(9)

2.83(1)

1.37(1)

1.394(5)

1.40(1)

1.373(5)

1.37(1)

1.38(1)

1.400(7)

1.37(1)

2.84(1)

C(1ЈЈ)–C(2ЈЈ)

C(2ЈЈ)–C(3ЈЈ)

C(3ЈЈ)–C(4ЈЈ)

C(4ЈЈ)–O(4ЈЈ)

C(4ЈЈ)–C(5ЈЈ)

C(5ЈЈ)–C(6ЈЈ)

C(1ЈЈ)–C(6ЈЈ)

C(6ЈЈ)–O(6ЈЈ)

O(21ЈЈ)···N(3)

Angles (degrees)

C(2)–O(1)–C(5)

O(1)–C(2)–C(2Ј)

O(1)–C(2)–N(3)

C(21)–C(2)–N(3)

C(2)–N(3)–C(4)

N(3)–C(4)–C(5)

N(3)–C(4)–C(41)

C(5)–C(4)–C(41)

C(4)–C(41)–C(42)

C(4)–C(41)–C(43)

C(42)–C(41)–C(43)

O(1)–C(5)–C(4)

104.7(6)

105.1(8)

113.9(7)

118.6(6)

127.4(7)

107.0(7)

103.7(6)

113.3(6)

117.2(7)

110.2(8)

110.1(8)

114(1)

106.0(6)

104.8(6)

105.2(6)

114.3(7)

119.3(5)

126.1(7)

107.5(6)

103.2(6)

113.1(6)

117.9(7)

111.0(8)

109.7(7)

112.0(3)

105.2(6)

122.2(5)

121.5(6)

116.3(6)

121.3(5)

121.2(6)

117.5(5)

121.8(6)

116.9(6)

121.3(6)

121.7(6)

121.1(6)

122.6(6)

114.0(6)

123.4(5)

116.9(6)

121.5(5)

121.0(4)

117.5(6)

120.9(6)

120.5(6)

118.5(8)

114.3(5)

120.3(8)

119.4(7)

125.0(9)

115.6(7)

121.3(7)

120.5(7)

115.1(6)

124.4(7)

117.4(6)

116.6(6)

118.0(7)

125.3(7)

106.7(6)

104.4(6)

112.2(6)

115.7(8)

113.0(7)

111.8(9)

107.7(8)

104.3(6)

124.2(6)

118.4(5)

117.2(6)

120.7(6)

120.2(6)

119.1(6)

121.4(6)

117.8(7)

121.7(7)

120.5(7)

122.4(7)

120.4(6)

115.3(6)

124.3(6)

117.6(7)

123.5(7)

118.2(6)

118.3(6)

120.2(7)

120.5(7)

119.2(7)

114.3(7)

119.9(7)

120.6(7)

124.7(7)

114.7(8)

119.1(8)

121.9(7)

116.0(7)

122.2(8)

118.8(8)

114.1(6)

118.8(6)

127.1(6)

107.0(6)

103.3(7)

110.1(7)

116.3(9)

111.5(8)

111.3(9)

111.2(9)

104.0(6)

124.4(6)

119.8(6)

115.6(6)

121.7(6)

120.3(6)

118.0(6)

120.8(6)

118.2(7)

120.9(6)

120.8(7)

121.7(7)

122.0(6)

131.1(6)

124.9(6)

117.3(7)

122.3(7)

119.4(6)

118.4(7)

120.4(8)

120.0(7)

119.5(7)

111.7(7)

119.3(7)

121.5(7)

124.1(7)

114.4(8)

119.4(8)

121.0(6)

114.8(7)

124.2(8)

117.5(7)

114.7(13)

118.7(5)

126.5(10)

107.1(3)

103.7(5)

112.2(15)

116.8(10)

111.4(12)

110.7(10)

111(3)

105.4(6)

124.4(5)

119.9(6)

115.6(6)

121.0(6)

120.9(6)

118.1(5)

122.4(6)

117.7(6)

122.7(6)

119.5(6)

119.7(6)

123.4(6)

113.6(6)

122.9(6)

116.8(6)

121.4(6)

120.9(7)

117.7(6)

120.8(6)

121.1(6)

118.1(7)

112.9(6)

120.2(8)

120.3(7)

125.6(8)

114.1(7)

119.5(7)

121.6(8)

115.0(6)

123.4(6)

117.1(5)

104.7(7)

123.8(11)

119.9(13)

116.2(8)

121.2(4)

120.7(5)

118.2(7)

121.6(7)

117.7(5)

121.7(8)

120.6(9)

121.2(11)

122.1(13)

114.0(9)

123.9(9)

117.2(4)

122.2(10)

119.9(13)

118.0(4)

120.6(3)

120.5(5)

118.8(6)

113.3(13)

119.9(5)

120.5(9)

124.9(6)

114.7(6)

119.8(10)

121.3(6)

115.2(5)

123.6(10)

117.7(8)

C(1ЈЈ)–C(1Ј)–C(2Ј)

C(1ЈЈ)–C(1Ј)–C6Ј)

C(2Ј)–C(1Ј)–C(6Ј)

C(1Ј)–C(2Ј)–C(3Ј)

C(1Ј)–C(2Ј)–C(2)

C(3Ј)–C(2Ј)–C(2)

C(2Ј)–C(3Ј)–C(4Ј)

C(3Ј)–C(4Ј)–C(5Ј)

C(3Ј)–C(4Ј)–C(41Ј)

C(5Ј)–C(4Ј)–C(41Ј)

C(4Ј)–C(5Ј)–C(6Ј)

C(5Ј)–C(6Ј)–C(1Ј)

C(1Ј)–C(6Ј)–O(6Ј)

C(5Ј)–C(6Ј)–O(6Ј)

C(6Ј)–O(6Ј)–C(61Ј)

C(1Ј)–C(1ЈЈ)–C(2ЈЈ)

C(1Ј)–C(1ЈЈ)–C(6ЈЈ)

C(2ЈЈ)–C(1ЈЈ)–C(6ЈЈ)

C(1ЈЈ)–C(2ЈЈ)–C(3ЈЈ)

C(1ЈЈ)–C(2ЈЈ)–C(21ЈЈ)

C(3ЈЈ)–C(2ЈЈ)–C(21ЈЈ)

C(2ЈЈ)–C(21ЈЈ)–O(21ЈЈ)

C(2ЈЈ)–C(3ЈЈ)–C(4ЈЈ)

C(3ЈЈ)–C(4ЈЈ)–C(5ЈЈ)

C(3ЈЈ)–C(4ЈЈ)–O(4ЈЈ)

C(5ЈЈ)–C(4ЈЈ)–O(4ЈЈ)

C(4ЈЈ)–C(5ЈЈ)–C(6ЈЈ)

C(1ЈЈ)–C(6ЈЈ)–C(5ЈЈ)

C(1ЈЈ)–C(6ЈЈ)–O(6ЈЈ)

C(5ЈЈ)–C(6ЈЈ)–O(6ЈЈ)

C(6ЈЈ)–O(6ЈЈ)–C(61ЈЈ)

Torsion angles (degrees)

N(3)–C(4)–C(41)–C(42)

N(3)–C(4)–C(41)–C(43)

C(1Ј)–C(2Ј)–C(2)–N(3)

C(1Ј)–C(6Ј)–O(6Ј)–C(61Ј)

C(2Ј)–C(1Ј)–C(1ЈЈ)–C(2ЈЈ)

C(1ЈЈ)–C(2ЈЈ)–C(21ЈЈ)–O(21ЈЈ)

C(1ЈЈ)–C(6ЈЈ)–O(6ЈЈ)–C(61ЈЈ)

C(3ЈЈ)–C(4ЈЈ)–O(4ЈЈ)–C(41ЈЈ)

58(1)

–66.4(9)

–64(1)

176.5(7)

92.0(8)

–91.0(8)

–178.4(6)

–9(1)

60(1)

–65.9(9)

–50(1)

–174.4(7)

92.6(9)

–91.8(8)

177.6(5)

–10(1)

58(1)

–63.8(9)

–43(1)

161.5(8)

104.9(9)

–70.8(9)

167.1(7)

1(1)

64(1)

–60.7(9)

–30(1)

–176.1(8)

95.1(9)

–83.8(8)

–178.6(6)

–14(1)

60(3)

64(3)

47(14)

177(10)

96(6)

84(10)

178(6)

–8(5)

504

R. W. Baker et al.

Table 3. Substituent atom deviations and interplanar dihedral angles for compound (49)

Mol. 1 Mol. 2 Mol. 3 Mol. 4

Substituent atom deviations, ꢁ, from the ring planes (Å)

The heterocyclic ring (ꢇ²(C₃NO) is given)

ꢇ²

3.4

11.7

42

127

ꢁ(2Ј)

ꢁ(41)

ꢁ(42)

ꢁ(43)

–0.08(1)

1.11(2)

2.46(2)

0.84(2)

–0.02(1)

1.17(2)

2.52(2)

0.97(2)

–0.06(2)

1.25(1)

2.55(1)

1.22(2)

0.02(2)

1.38(2)

2.60(2)

1.47(2)

The primed ring

ꢁC(1ЈЈ)

ꢁC(2)

ꢁO(6Ј)

ꢁC(41Ј)

0.04(1)

0.03(1)

0.04(1)

0.09(1)

0.01(1)

0.00(1)

0.02(1)

–0.05(1)

0.19(1)

–0.08(1)

–0.03(1)

0.03(2)

0.17(1)

–0.02(1)

–0.04(1)

0.01(1)

The doubly primed ring

ꢁC(1Ј)

0.08(1)

0.03(1)

0.01(1)

1.33(1)

0.03(1)

–0.02(1)

–0.12(1)

0.09(1)

1.34(1)

–0.05(1)

0.03(1)

0.06(1)

0.03(1)

1.37(1)

0.06(1)

0.03(1)

ꢁC(21ЈЈ)

ꢁO(21ЈЈ)

ꢁO(4ЈЈ)

ꢁO(6ЈЈ)

0.02(1)

1.33(1)

0.09(1)

–0.04(1)

Interplanar dihedral angles (degrees)

Unprimed/primed

Unprimed/doubly primed

Primed/doubly primed

67.7(3)

61.7(3)

88.2(3)

72.l(3)

48.8(3)

89.6(3)

39.6(3)

74.4(4)

80.5(3)

27.0(3)

76.6(4)

87.2(3)

Fig. 4. Unit cell contents of compound (49) projected down a.

Synthesis of Both Atropomers of Desertorin C

505

purified by p.l.c. with 40–50% dichloromethane/light petroleum as

hydrogen atoms being observed in difference maps. Conven-

developing solvent. The band of higher R_Fafforded the ketone (81)*

tional residuals R and R_w(statistical weights derivative of

(21.5 mg, 35%) which decomposed at 120° on attempted m.p. determi-

ꢉ²(I_diff)+0.0004ꢉ⁴(I_diff)) on |F| were 0.052 and 0.061. The absolute con-

figuration was assigned from the chemistry. Neutral atom complex scat-

tering factors were employed; computation used the Xtal 3.4 program

system.⁵²Pertinent results are given in Fig. 4 and Tables 2 and 3 (full

atomic parameters, non-hydrogen geometries, and structure factors

have been deposited).‡

12

nation (Found: M⁺, 344.1259.

C

¹H₂₀¹⁶O₆requires M⁺, 344.1260).

19

[ꢂ]²_D⁰–61.0° (c, 1.0 in acetone). ꢁ_H[(CD₃)₂CO; 500 MHz] 2.13, s, Me 2Ј;

2.63, d, J 0.5 Hz, Me 4; 2.56 and 2.64, each s, COMe; 3.77, s, OMe;

6.31, bd, J 0.4 Hz, HAr5; 6.59, bs, HAr5Ј; 8.36, 11.87 and 12.45, each

s, OH. ꢁ_C[(CD₃)₂CO; 125 Mz] 19.80 and 24.58, each Me; 33.06 and

33.21, each COCH₃; 56.09, OMe; 101.50 and 107.53, C 5,5Ј; 113.36,

115.19, 117.89 and 118.50 C 1,1Ј,3,3Ј; 161.03, 162.54, 162.86 and

163.26, C 2,4Ј,6,6Ј; 205.17 and 205.45, each C=O. m/z 344 (M⁺, 55%),

330 (26), 329 (100), 311 (19), 287 (20), 157 (15). This was followed by

the ketone (84)† (18.2 mg, 30%) as needles, m.p. 198–200° (Found:

Crystal Data

C₂₃H₂₉NO₅, M 399.5. Monoclinic, space group P2₁, (C²₂, No. 4), a

8.658(3), b 31.404(6), c 16.238(3) Å, ꢊ 96.44(2)°, V 4387 Å³. D_c(Z = 8)

1.20₉g cm^–3; F(000) 1712. ꢅ_Mo0.8 cm^–1; specimen: 0.95 by 0.70 by

0.22 mm. n_v1045; |ꢀꢋ_max| 0.31(2) e Å^–3.

M⁺, 330.1088. ¹²C₁₈H₁₈¹⁶O₆requires M⁺, 330.1103). [ꢂ]²_D⁰32.8 (c, 0.9

1

in acetone). ꢁ_H[(CD₃)₂CO; 500 MHz] 2.18, s, Me 2Ј; 2.56 and 2.64,

each s, COMe; 2.59, bd, J 0.5 Hz, Me 4; 6.31, bd, HAr; 6.41, bd, J 0.7

Hz, HAr; 8.46, 8.54, 11.80 and 13.42, each s, OH. ꢁ_C[(CD₃)₂CO; 125

MHz] 19.72 and 24.83, each Me; 33.03 and 33.12, each COCH₃;

101.67 and 112.45, C 5,5Ј; 109.94, 114.29, 115.96 and 118.79,

C 1,1Ј,3,3Ј; 161.36, 161.47, 163.30 and 165.34, C 2,4Ј,6,6Ј; 205.04 and

205.24, each C=O. m/z 330 (M⁺, 35%), 329 (19), 316 (18), 315 (100),

297 (14), 273 (16).

Comment

The results of the room-temperature single-crystal X-ray study are

consistent with the stoichiometry, connectivity and stereochemistry

implied by the formulation of compound (49), the absolute configura-

tion being defined by the chemistry via incorporation of the ^L-valine

residue. Four independent molecules comprise the asymmetric unit of

the structure, a loose pseudo-symmetry being evident in the crystal

packing (Fig. 4) in the space group P2₁. The four molecules present

very similarly in aspect, the principal factor affecting their overall

demeanour apparently being the hydrogen bonds between the CH₂OH

substituents and the adjacent valine nitrogen; O···N distance was about

2.84 Å (Table 2), with CH₂OH being consistently twisted well out of the

ring plane toward the heterocycle. Adopting the centroid of the primed

ring as a loose datum for a ‘quasi-2 axis’ relating the two substituent

rings, we see in the cell diagram that, vis-à-vis the polarity of the struc-

ture, molecules 1 and 2 lie disposed about the ac plane (i.e. at y Ϸ 0 (and

y Ϸ 1/2)) and molecules 3, and 4 lie about the planes y Ϸ 1/4 and

3/4,with the intramolecular poles of molecules 1 and 3 opposed to those

of molecules 2 and 4. Although a matter of degree rather than funda-

mental conformational change, the molecules within these two layers,

designated type A and B respectively, differ considerably in respect of

the disposition of the substituent rings vis-à-vis the central ring, the het-

erocyclic component of molecules B lying more nearly coplanar

(‘flatter’), vis-à-vis the central ring, than those of molecules A. The dis-

position of the doubly primed ring also changes concomitantly but

rather less perceptibly, with O(H)···N remaining constant, lying more

nearly normal to the central ring in molecules B. In respect of sub-

stituent detail, the isopropyl substituent of the valine residue adopts a

similar disposition throughout all four molecules, while similar angular

asymmetries are found at C(2), C(2Ј), C(4Ј), C(6Ј), C(2ЈЈ), C(4ЈЈ) and

C(6ЈЈ) (Table 2), with those at the group attachments being the most dis-

parate and in the manner expected.

(–)-(R)-1,1Ј-(2,4Ј-Dihydroxy-6,6Ј-dimethoxy-2Ј,4-dimethyl-1,1Ј-

biphenyl-3,3Ј-diyl)bisethanone (83)

Asolution of the trihydroxy bisketone (81) (20.6 mg, 0.06 mmol) and

excess iodomethane in N,N-dimethylformamide (1 ml) was stirred with

potassium carbonate (50 mg, 0.4 mmol) under argon for 15 h at 40°. The

usual workup gave compound (82) which was demethylated by treat-

ment with boron trichloride (14.5 mg, 0.13 mmol) in dichloromethane (3

ml) at 5°. The solution was stirred for 1 h at room temperature and then

worked up. The crude product was purified by radial chromatography

with 25–30% ethyl acetate/light petroleum as eluent which gave the

dihydroxy bisketone (83) (16.5 mg, 82%), m.p. 145–146° (Found: M⁺,

358.1411. ¹²C₂₀H₂₂⁶O₆requires M⁺, 358.1416). [ꢂ]²_D⁰–53.0° (c, 0.8 in

1

acetone). ꢆ_max200, 219 infl, 232 infl, 240, 285, 333 infl nm (logꢄ 4.50,

4.30, 3.70, 4.31, 4.15, 3.78). C.d. ꢆ in nm (ꢀꢄ) 196 (–19.8), 216 (52.7),

230 (33.5), 276 (14.7), 295 (–7.5), 335 (–5.2). ꢁ_H(500 MHz) 2.13, bs,

Me 2Ј; 2.58, Me 4; 2.65, s, 2×COMe; 3.67 and 3.76, each s, OMe; 6.39

and 6.58, each bs, HAr; 12.05 and 12.54, each s, OH. ꢁ_C(125 MHz)

19.65 and 24.71, each Me; 33.05 and 33.26, each COCH₃; 55.96 and

56.09, each OMe; 98.01 and 107.50, C 5,5Ј; 112.09, 116.54, 117.61 and

118.52, C1,1Ј,3,3Ј; 140.69 and 142.55, C 2Ј,4; 162.31, 162.76, 162.98

and 163.71, C 2,4Ј,6,6Ј; 205.35 and 205.55, each C=O. m/z 358 (M⁺,

53%), 344 (22), 343 (100), 301 (16), 164 (14).

(+)-(S)-1,1Ј-(2,4Ј-Dihydroxy-6,6Ј-dimethoxy-2Ј,4-dimethyl-1,1Ј-

biphenyl-3,3Ј-diyl)bisethanone (32)

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Article Doi

Formal synthesis of both atropomers of desertorin C and an example of chirality transfer from a biphenyl axis to a spiro centre and its reverse

DOI: 10.1071/CH99134

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Full text of DOI:10.1071/CH99134

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