The diastereoselective syntheses of enantiopure benzo- and naphtho-pyrans related to the aphid insect pigments

Article abstract of DOI:10.1071/CH03286

An overview is presented of synthetic endeavours directed towards the assembly of the enantiopure quinone A and quinone A′, natural derivatives of the aphid insect pigments protoaphin-fb and protoaphin-sl. These are achieved through intramolecular diaster

Full text of DOI:10.1071/CH03286

Current Chemistry
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2004, 57, 329–333
The Diastereoselective Syntheses of Enantiopure Benzo- and
Naphtho-pyrans Related to the Aphid Insect Pigments
Robin G. F. GilesA
A Chemistry Department, Murdoch University, Murdoch WA 6150, Australia
(e-mail: rgiles@chem.murdoch.edu.au).
An overview is presented of synthetic endeavours directed towards the assembly of the enantiopure quinone A and
quinone Aꢀ, natural derivatives of the aphid insect pigments protoaphin-fb and protoaphin-sl. These are achieved
through intramolecular diastereoselective cyclization of tethered phenolic lactaldehydes.The conformational impli-
cations of the cyclization process are discussed. Model reactions allow the formulation of a more concise, convergent
route to these natural derivatives through the corresponding intermolecular reactions, in which the required com-
plementary diastereoselectivity is provided by the choice of either titanium or magnesium phenolates for reaction
with the ethoxyethyl-protected asymmetric lactaldehyde.
Manuscript received: 30 October 2003.
Final version: 16 January 2004.
Introduction
to the assembly of the dihydropyran ring of the enantiopure
quinones in both an intramolecular version that led to the
successful assembly of the quinones 1–4 themselves and in
an alternative intermolecular version where models were con-
sidered for the syntheses of these same quinones by a shorter,
more convergent route.
Naphtho[2,3-c]pyrans, and particularly their quinones, form
an extensive group of natural products, many of which pos-
sess an array of biological and pharmacological activities.[1,2]
The derivatives[3] quinone A 1 and quinone Aꢀ 2 (Scheme 1)
of aphid insect pigments have been nominated as examples
of potential bioreductive dialkylating agents.[4] The first syn-
theses of these quinones,[5] as well as those of their naturally
occurring C3 epimers 3 and 4,[6] are outlined. Also discussed
are related conformational observations as well as models for
a more concise, convergent assembly of these quinones.
For the intramolecular process, the phenolic lactaldehy-
des 11 and 15 were prepared from commercially available
2,5-dihydroxyacetophenone 5 and lactate from the chiral
pool as the source of asymmetry, Scheme 2. Preliminary
experimentsshowedthatthehydroquinonemonomethylether
correponding to the benzyl ether 12 (compound 12, MeO in
place of BnO) was unable to undergo oxidative demethyla-
tion with conventional reagents to yield the required quinone
13 on account of the crowded environment of the methoxy
group. Thus, acetophenone 5 was selectively silylated with
tert-butyldimethylsilyl chloride, the product regioselectively
brominated, and the remaining phenolic substituent benzy-
lated to yield the product 6 in an overall yield for the three
steps of 88%. The bromine atom was required to provide the
correct regioselectivity[8] for the construction of the diphe-
nolic aromatic ring in the final step of the reaction sequence.
The ketone function of 6 was reduced to the corresponding
alcohol, which was activated as the trichloroacetimidate
for reaction with lactate. With methyl (R)-lactate, the pair
of benzyl epimeric lactates 7 was obtained as an insep-
arable mixture, in an overall yield of 75% for the three
steps from ketone 6. Reduction of this mixture with lithium
aluminium hydride (a limited quantity to avoid the removal
of the aromatic bromine as well) gave the chromatographi-
cally separable pair of alcohols 8 (52%) and 9 (39%) in a
combined yield of 91%. Each of these alcohols was shown
to be enantiopure using both chiral lanthanide shift-reagent
Results and Discussion
Casiraghi and coworkers described[7] the complemen-
tary diastereoselectivity achieved when either titanium
or magnesium phenolates reacted with (R)-isopropylidene
glyceraldehyde. In the present case, these ideas were applied
OH
O
OH
O
1
4
O
O
3
HO
HO
O
OH
O
OH
1
2
OH
O
OH
O
O
O
HO
HO
O
OH
O
OH
3
4
Scheme 1.
© CSIRO 2004
10.1071/CH03286
0004-9425/04/040329

330
R. G. F. Giles
H
OBn
O
O
OBn
O
Br
Br
O
MeO2C
OH
TBSO
TBSO
5
6
7
OBn
OBn
OBn
Br
Br
Br
␣
O
O
O
ϩ
2
TBSO
OH
RO
O
TBSO
OH
10 R ϭ TBS
11 R ϭ H
8
9
O
BnO
O
aЈ
Br
Br
Br
O
O
O
e
eЈ
O
OH
HO
OH
O
OH
12
15
13
16
14
17
OBn
BnO
BnO
eЈ
eЈ
Br
Br
Br
␣
O
2
O
O
e
e
aЈ
eЈ
OH
HO
O
HO
HO
OH
Scheme 2.
NMR spectroscopy[9] and chiral HPLC. Swern oxidation
of the alcohol 8 afforded the aldehyde 10 in 88% yield.
No epimerization of the asymmetric centre α to the alde-
hyde was observed. This aldehyde 10 was desilylated and
the crude phenolic lactaldehyde 11 was cyclized as the tita-
nium phenolate[7,9c] to give the 2-benzopyran-4,5-diol 12
as the sole diastereoisomer in 75% overall yield for the two
steps. This product was shown to be the 1,3-trans-dimethyl
stereoisomer from the relatively low-field chemical shift of
Debenzylation through hydrogenolysis and oxidative dealky-
lation of the derived hydroquinone monomethyl ether com-
pleted the five-step transformation of diol 12 into quinone 14.
The quinones 13 and 14 were converted into quinoneA 1 and
quinone Aꢀ 2 respectively on reaction with 1-methoxy-1,3-
bis(trimethylsilyloxy)buta-1,3-diene[11] in purified yields of
29 and 20%.
Phenolic lactaldehyde 15, the (αR,2S) diastereoisomer
of 11, was obtained from 5 using the same sequence with
ethyl (S)-lactate. The titanium phenolate of 15 cyclized to
afford two C4 epimeric 2-benzopyran-4,5-diols, 16 and 17,
in a ratio of about 4 : 6 respectively and in a combined yield
of 81% for the two steps from the (αR,2S) diastereoisomer
of aldehyde 10. Each of these diols was transformed by the
method described above into the quinones 3 and 4 respec-
tively. The specific rotations of the naphthopyranquinones
(1–4) obtained through synthesis corresponded closely with
those obtained for the natural derivatives.[6]
The reason for the difference in degree of diastereos-
electivity on cyclization of the phenolic lactaldehydes 11
and 15 was considered. The former lactaldehyde gave the
2-benzopyran-4,5-diol 12 with complete diastereoselectivity,
whereas the latter lactaldehyde gave the pair of C4 epimeric
2-benzopyran-4,5-diols 16 and 17 with poor diastereo-
selectivity (ratio approximately 4 : 6). The transition state 18,
Scheme 3, for the conversion of 11 into 12 possesses a half-
chair conformation of the developing dihydropyran ring in
1
the proton H3 in the H NMR spectrum, and that the sub-
stituents at C3 and C4 were trans-diequatorial from the large
coupling constant between the corresponding vicinal protons.
Removal of the benzyl group of 12 through hydrogenolysis
followed by oxidation of the derived hydroquinone gave the
quinone 13 in an overall yield of 77% for the two steps.
The C4 pseudoaxial epimer of 12 required for the syn-
thesis of quinone Aꢀ could not be obtained readily by
the cyclization of the magnesium phenolate[7] of phenolic
lactaldehyde 11, presumably owing to the inability of the
magnesium to coordinate effectively also to the additional
lactaldehyde oxygen. Alternatively, the hydroxy quinone 14,
the C4 epimer of 13, could be obtained from the benzopyran-
4,5-diol 12 in five steps in an overall yield of 61%, through
selective methylation of the phenolic hydroxy group at C5
and inversion of the stereochemistry of the C4 hydroxy
group by converting it into the C4 chloro derivative and
displacement of chlorine with aqueous silver nitrate.[10]

Diastereoselective Syntheses of Enantiopure Benzo- and Naphtho-pyrans
331
Br
Br
7
Me
H
Br
H
6
Me
OBn
H
Me
OBn
H
OBn
Me
8
Ti
O
O
5
1
O
O
O
4a
8a
4
O
2
O
Me
Ti
O
Ti
3
O
H
H
H
Si
Re
Si
Me
H
H
18
19
Scheme 3.
20
which all the substituents are in favoured orientations and,
therefore, a single diastereoisomer is produced. Thus, the
lactaldehyde carbonyl oxygen atom is pseudo-equatorial to
minimize the inter-oxygen distance for the coordination of
titanium in a reaction that involves intramolecular aryla-
tion of the Si face of the aldehyde. The methyl at C3 is
in the favoured equatorial orientation and the C1 methyl is
pseudo-axial to minimize peri-interactions with the neigh-
bouring benzyloxy substituent. The only difference between
this transition state and 19 for the cyclization of pheno-
lic lactaldehyde 15 into pyrans 16 and 17 [aside from the
diastereoisomeric conformation since the configuration of
the aldehyde is reversed from (R) in 11 to (S) in 15] is that
the developing C1 methyl adopts a pseudo-equatorial ori-
entation in 19. This gives rise to increased peri-interactions
with the neighbouring benzyloxy substituent and as a conse-
quence only about 60% of the molecules of the aldehyde 15
use this transition state to afford the pseudoequatorial C4
alcohol 17 (through arylation of the Re face of the alde-
hyde in the diastereoisomeric conformation). The remaining
40% of these molecules assume the alternative conformation
20 in which the developing C1 methyl adopts the pseudo-
axial orientation to minimize this peri-interaction at the
expense of the C3 methyl group becoming axial, while the
C4 oxygen atom remains pseudo-equatorial to minimize
the inter-oxygen coordination distance through arylation
of the alternative Si face of the aldehyde. On completion
of the reaction, hydrolysis of the titanium complex removes
this latter requirement which allows the conformation of
the derived dihydropyran ring to invert, so that the C1 and
C3 methyl groups become pseudo-equatorial and equatorial
respectively, andtheC4hydroxygroupbecomespseudo-axial
to provide the benzopyran-4,5-diol 16.[12]
these compounds from the starting material 5 were each of
the order of only 3% in view of the number of steps involved.
An alternative more concise, more convergent synthesis was
required in order to provide these compounds in signifi-
cant quantity for use in further experiments such as, for
example, the assembly of the protoaphins themselves, rather
than as an end in themselves. Casiraghi’s complementary
diastereoselectivity[7] wasthereforeinvestigatedinrelationto
the intermolecular assembly of the dihydropyran ring and, in
particular, the required complementary absolute stereochem-
istry of the C4 hydroxy group in the quinones A 1 and Aꢀ 2.
Preliminary experiments[14] on 7-benzyloxy-4,5-
dimethoxy-1-naphthol showed that its titanium naphtholate
reacts with the ethoxyethyl-protected (R)-lactaldehyde to
afford solely the adduct with the correct stereochemistry
for quinone A, while the corresponding magnesium naph-
tholate gives that solely for quinone Aꢀ, in yields of 63 and
78% respectively. (Each of these adducts was, however, a
pair of diastereoisomers arising from the asymmetry of the
ethoxyethyl protecting group.) It remained, therefore, only
to cyclize these adducts to the corresponding naphthopyrans
to complete the required ring system. Since this and related
naphthols useful in the current context would require several
steps for their assembly,[14,15] the commercially available 4-
methoxyphenol was chosen as a model to develop the reaction
sequence.
Reaction[7] of the titanium phenolate of 4-methoxyphenol
with ethoxyethyl-protected (S)-lactaldehyde [readily pre-
pared[16] for the model reactions from the cheaper ethyl
(S)-lactate] gave the required adduct 21, Scheme 4, although
the reaction did not proceed to completion, and with only
93% diastereoselectivity. The mixture was therefore treated
with a catalytic quantity of camphorsulfonic acid to cyclize
the adduct 21 to the all-cis dioxolane 22 as the sole cis-
4,5-diastereoisomer. This cyclization was useful since it
selectively protected the benzylic hydroxy group and also
selectively expelled the ethoxy group as ethanol from the
adduct 21. The derived mixture was then acetylated, where-
upon chromatographic separation of the acetate 23, from the
acetates of the starting 4-methoxyphenol and of the minor
quantities (approx. 7%) of the diastereoisomeric trans-4,5-
dioxolanes 29 (see below), was achieved where this was not
possible for the precursor phenols or for the mixture of tosyl-
ates. The yield of acetate 23 was 15% over the three steps, or
52% based on consumed 4-methoxyphenol.
It has been long accepted that the C3 substituent (nor-
mally methyl or a fused γ-lactone ring methylene in these
naphthopyranquinones) prefers an equatorial orientation,
irrespective of the substitution at C1, C3, and C4. For the 1,3-
disubstituted system, an early example was provided by the
pair of C3 diastereoisomers eleutherin and isoeleutherin,[13]
for each of which the C3 methyl is known to be equatorial,
and this is achieved through inversion of the dihydropyran
ring of the latter molecule with respect to that of the former.
Nevertheless, three examples have recently been identified in
which the C3 methyl substituent is axial.[12] Its postulation
in transition state 20 is therefore not unreasonable.
The syntheses described above for the naturally derived
quinones 1–4 provide in principle for the assembly of all
eight stereoisomers, and all steps but the final Diels–Alder
reaction occur in excellent yields. Nevertheless, the yields of
Attempted isomerization[17,18] of the acetoxyaryldiox-
olane 23 into the corresponding 2-benzopyran with tita-
nium(iv) chloride yielded a complex mixture. This was
expected both in view of the presumed instability of the

332
R. G. F. Giles
MeO
HO
MeO
RO
MeO
RO
OEt
O
O
O
2
4
5
OH
OH
O
21
22 R = H
23 R = Ac
24 R = Ts
25 R = Ts
26 R = H
MeO
MeO
O
OEt
O
O
O
O
HO
OH
RO
O
OH
27
28
29 R = Ac
30 R = Ts
O
MeO
MeO
TsO
O
O
O
O
O
O
O
OH
TsO
OH
OH
OH
31
32
33
34
Scheme 4.
acetyl protection to the reaction conditions and also since the
related racemic 2,5-dimethoxyphenyldioxolane is known[18]
to undergo an unwanted ring-opening of the dioxolane to
afford chlorohydrins. This alternative reaction has been
ascribed[18] to the ortho-methoxy oxygen lone-pair electrons
facilitating the unwanted cleavage of the dioxolanyl O3/C4
bond. Conversion of the acetate 23 into the tosylate 24 was
anticipated to overcome this since this protection would be
more stable to the reaction conditions and also preferentially
involve this oxygen lone pair in delocalization over the sul-
fonyl group.This prediction was fulfilled since isomerization
of the tosylate 24 with titanium(iv) chloride gave the enan-
tiopure 2-benzopyran 25 in a yield of 44%, starting material
24, and some erythro-diol that was readily converted into 24.
Based on consumed 24 and recovered diol, the yield of 25
was 95%. Hydrolysis of the tosylate in 25 afforded the phenol
26 in a yield of 81%. Compound 26 was converted into the
enantiopure quinone 27[9c] in a yield of 91%.
respectively. Furthermore, it is known that the dioxolane C2
stereochemistry is not transferred to that at C1 of the product
2-benzopyrans, this being dependent instead on other factors,
including reaction temperature.[17,18] The acetate 29 was con-
verted into the tosylate 30 in a yield of 80% for the two steps
of hydrolysis and reprotection.
The tosyloxyaryldioxolane 30 was isomerized with tita-
nium(iv) chloride, whereupon a readily chromatographically
separable mixture of the two C1 epimeric 2-benzopyrans 31
and 32 was obtained in yields of 44 and 14% respectively,
or 66 and 21% based on consumed starting material 29 and
recovered threo diol. Each of these was converted into the
corresponding quinones 33 and 34 in yields, as before, of
approx. 75% for the two steps.
The isolation of starting material in each of the reactions
leading to the formation of the adducts 21 and 28, each with
approx. 93% diastereoselectivity, presumably occurred as a
consequence of the poorer electron availability on the metal
phenolates in comparison with that of the metal naphtho-
lates of 7-benzyloxy-4,5-dimethoxy-1-naphthol, where the
reactions proceeded in very reasonable yields with complete
diastereoselectivity. Insufficient electron availability may
also lead to the isolation of starting material and diol in
the isomerization of the aryldioxolanes 24 and 30 into the
2-benzopyrans 25, 31, and 32.
Treatment[7] of the magnesium phenolate of 4-methoxy-
phenol with ethoxyethyl-protected (S)-lactaldehyde gave the
expected adduct 28, although once again the reaction did not
proceedtocompletion, andoccurredwithonly93%diastereo-
selectivity. Cyclization of this adduct as before provided the
4,5-trans dioxolane as a mixture of C2 epimers[17,18] in a
ratio of 84 : 16. The complete reaction mixture was again
acetylated to form the acetate 29 that allowed its chromato-
graphic separation from the acetate of 4-methoxyphenol and
minor quantities (approx. 7%) of the all-cis dioxolane 23.
In this case, the yield of 29 was 36% over the three steps,
or 70% based on consumed 4-methoxyphenol. The produc-
tion of a single diastereoisomer for the all-cis dioxolane 23
in contrast to a pair of C2 epimers for the 4,5-trans diox-
olane 29 was consistent with related observations[17,18] for
the formation of dioxolanes from erythro and threo diols
Conclusions
The first syntheses of all eight stereoisomers of the enan-
tiopure aphid insect pigment derivatives 1–4 are established
using lactate from the chiral pool as the source of asymme-
try. In all but the last step the yields are extremely high in
a sequence that involves formation of the dihydropyran ring
through an intramolecular ring closure.The specific rotations

Diastereoselective Syntheses of Enantiopure Benzo- and Naphtho-pyrans
333
of the synthetic materials agree closely with those observed
for the natural derivatives.[6] For the transition state leading to
the dihydropyran half-chair of the product benzopyrans the
C3 methyl group is prepared to adopt the axial orientation
when 1,8- and 4,5-peri-interactions are appropriate.
[3] D. W. Cameron, R. I. T. Cromartie, D. G. I. Kingston, A. R. Todd,
J. Chem. Soc. 1964, 51.
[4] H. W. Moore, Science 1977, 197, 527.
[5] R. G. F. Giles, I. R. Green, F. J. Oosthuizen, C. P. Taylor, Tetrahe-
dron Lett. 2001, 42, 5753. doi:10.1016/S0040-4039(01)00955-8
[6] D. W. Cameron, unpublished results.
Models are used to establish a shorter, more conver-
gent synthesis of these enantiopure naphthopyranquinones.
These model reactions based on 4-methoxyphenol and the
ethoxyethyl protected derivative of either enantiomer of
enantiopure lactaldehyde lead to the formation of the parent
2-benzopyran-5,8-quinones 27, 33, and 34 related to com-
pounds 1–3. For the natural derivatives themselves, a short,
seven-step assembly of these targets is envisaged in which the
requiredcomplementarydiastereoselectivityatC4inquinone
A 1 and quinone Aꢀ 2 is achieved through reaction of either
the titanium or magnesium naphtholate of 5,7-dibenzyloxy-
4-methoxy-1-naphthol and the lactaldehyde. Ready cycliza-
tion of the derived adducts to the dioxolanes and tosylation
of the naphthol would provide 4-naphthyldioxolanes that
would be isomerized to the naphthopyran ring system. The
targets would then be available through detosylation, oxida-
tive dealkylation, and finally debenzylation of the phenolic
ethers.
[7] (a) G. Casiraghi, M. Cornia, G. Casnati, G. G. Fava,
M. F. Belicchi, L. Zetta, J. Chem. Soc., Chem. Commun.
1987, 794.
(b) G. Casiraghi, M. Cornia, G. Rassu, J. Org. Chem. 1988,
53, 4919.
[8] (a) J. Banville, P. Brassard, J. Chem. Soc., Perkin Trans. 1 1976,
1852.
(b) D. W. Cameron, G. I. Feutrill, D. J. Hodder, J. Chem. Soc.,
Chem. Commun. 1978, 688.
(c) J. Savard, P. Brassard, Tetrahedron Lett. 1979, 4911.
doi:10.1016/S0040-4039(01)86747-2
(d) D. W. Cameron, C. Conn, G. I. Feutrill, Aust. J. Chem. 1981,
34, 1945.
[9] (a) W. H. Pirkle, D. J. Hoover, Top. Stereochem. 1982, 13, 263.
(b) R. M. Silverstein, G. C. Bassler, T. C. Morril, Spectrometric
Identification of Organic Compounds, 5th edn 1991, pp. 198–
201 (John Wiley & Sons: New York, NY).
(c) R. G. F. Giles, C. A. Joll, J. Chem. Soc., Perkin Trans. 1
1999, 3039. doi:10.1039/A901457H
[10] J. F. Elsworth, R. G. F. Giles, I. R. Green, J. E. Ramdohr,
S. C. Yorke, J. Chem. Soc., Perkin Trans. 1 1988, 2469.
[11] T.-H. Chan, P. Brownbridge, J. Am. Chem. Soc. 1980, 102, 3534.
[12] R. Aggarwal, A. A. Birkbeck, C. B. de Koning, R. G. F. Giles,
I. R. Green, S.-H. Li, F. J. Oosthuizen, Tetrahedron Lett. 2003,
44, 4535. doi:10.1016/S0040-4039(03)00986-9
[13] (a) H. Schmid, A. Ebnöther, Helv. Chim. Acta 1951, 34, 561.
(b) H. Schmid, A. Ebnöther, Helv. Chim. Acta 1951, 34, 1041.
[14] R. G. F. Giles, C. A. Joll, M. V. Sargent, D. M. G. Tilbrook,
J. Chem. Soc., Perkin Trans. 1 1999, 3029. doi:10.1039/
A901456J
Acknowledgments
Financial support from the Australian Research Council and
the Senate of Murdoch University is acknowledged.
References
[15] R. G. F. Giles, A. B. Hughes, M. V. Sargent, J. Chem. Soc.,
Perkin Trans. 1 1991, 1581.
[1] (a) R. H. Thomson, Naturally Occurring Quinones, 2nd edn
1971 (Academic Press: London).
[16] T. Hiyama, K. Nishide, K. Kobayashi, Tetrahedron Lett. 1984,
25, 569. doi:10.1016/S0040-4039(00)99940-4
[17] R. G. F. Giles, R. W. Rickards, B. S. Senanayake, J. Chem.
Soc., Perkin Trans. 1 1996, 2241. doi:10.1039/P19960002241
[18] R. G. F. Giles, R. W. Rickards, B. S. Senanayake, J. Chem.
Soc., Perkin Trans. 1 1997, 3361. doi:10.1039/A704543C
(b) R. H. Thomson, Naturally Occurring Quinones III, Recent
Advances, 3rd edn 1987 (Chapman & Hall: London).
(c) R. H. Thomson, Naturally Occurring Quinones IV, Recent
Advances, 4th edn 1997 (Chapman & Hall: London).
[2] M. A. Brimble, L. J. Duncalf, M. R. Nairn, Nat. Prod. Rep.
1999, 16, 267. doi:10.1039/A804287J