Remote stereochemical control in asymmetric Diels-Alder reactions: Synthesis of the angucycline antibiotics, (-)-tetrangomycin and MM 47755

Article abstract of DOI:10.1016/S0040-4039(03)01228-0

The first asymmetric syntheses of the angucycline antibiotics, (-)-tetrangomycin and MM 47755, are achieved via a short efficient sequence starting from the chiral Lewis acid promoted Diels-Alder reaction of 5-hydroxy-1,4-naphthoquinone and (±)-(E)-5-dimethylphenylsilyl-5-methyl-1-(2′- trimethylsiloxyvinyl)cyclohexene 7 where an effective kinetic resolution of the latter, controlled by its remote stereocentre, is described.

Full text of DOI:10.1016/S0040-4039(03)01228-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5193–5196
Remote stereochemical control in asymmetric Diels–Alder
reactions: synthesis of the angucycline antibiotics,
(−)-tetrangomycin and MM 47755
John S. Landells, David S. Larsen* and Jim Simpson
Department of Chemistry, University of Otago, PO Box 56 Dunedin, New Zealand
Received 29 April 2003; revised 12 May 2003; accepted 19 May 2003
Abstract—The first asymmetric syntheses of the angucycline antibiotics, (−)-tetrangomycin and MM 47755, are achieved via a
short efficient sequence starting from the chiral Lewis acid promoted Diels–Alder reaction of 5-hydroxy-1,4-naphthoquinone and
( )-(E)-5-dimethylphenylsilyl-5-methyl-1-(2%-trimethylsiloxyvinyl)cyclohexene 7 where an effective kinetic resolution of the latter,
controlled by its remote stereocentre, is described. © 2003 Elsevier Science Ltd. All rights reserved.
The asymmetric Diels–Alder cycloaddition is one of the
most useful reactions available to the synthetic organic
chemist because of its ability to create four contiguous
chiral centres in one step.1 The source of asymmetry is
often incorporated into either the diene or dienophile,
or is from an asymmetric catalyst. Other stereogenic
centres in the cycloadduct are usually derived from
either of the reactants or are subsequently formed by
post-addition modifications. The former approach is
generally reliant on the availability of either dienes or
dienophiles in enantiomerically enriched or pure form.
We have previously demonstrated an alternative where
a chiral Lewis acid, derived from (S)-3,3%-diphenyl-1,1%-
binaphthalene-2,2%-diol and borane, promoted the
Diels–Alder reaction of 5-hydroxy-1,4-naphthoquinone
1 and the racemic diene ( )-2.2 The reaction gave an
effective kinetic resolution of the racemic diene partner
and the cycloadduct, obtained with 98% ee, was subse-
quently transformed into the angucyclinone antibiotics,
(+)-emycin A and (+)-ochromycinone 3. The stereo-
chemical outcome was explained by a double induction
process based on the facial reactivity of each of the
reactants. The facial selectivity of dienophile–Lewis
acid complex had been documented by Kelly et al.3 and
that of the diene was controlled by an allylic hydroxyl
group at the stereogenic centre adjacent to the dienyl
unit. Carren˜o et al. have adapted this approach for the
syntheses (+)-3 and (+)-rubiginone B2 4, both achieved
in 80% ee, using the cycloaddition of an enantiomeri-
cally pure sulfinylquinone dienophile as the source of
asymmetry to affect a kinetic resolution of a racemic
diene.4 The facial selectivity of the diene was also
controlled by an allylic substituent. In a further exten-
sion of this work, Carren˜o et al.5 have investigated the
kinetic resolution of a vinyl cyclohexene, possessing
protected tertiary hydroxyl functionality at the remote
C-5 position but lacking a C-3 allylic substituent, using
the same dienophile. After a series of transformations
they produced the angucyclinone analogue (−)-8-
deoxytetrangomycin 5 with 50% ee.
* Corresponding author. E-mail: dlarsen@alkali.otago.ac.nz
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01228-0

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J. S. Landells et al. / Tetrahedron Letters 44 (2003) 5193–5196
Krohn et al.6,7 have reported a concise synthesis of the
angucyclinone, ( )-tetrangomycin 6, which relied on the
thermally promoted Diels–Alder reaction of 5-hydroxy-
1,4-naphthoquinone 1 and diene ( )-7 to construct the
benz[a]anthraquinone ring system. They assumed that
the Diels–Alder reaction between 1 and 7 gave a mix-
ture of diastereoisomeric cycloadducts, however, our
examination of their reported experimental data indi-
cated the possibility that only one of the endo
diastereoisomers had been formed. This being the case,
the facial selectivity of diene 7 is presumed to arise
from the substituents at the remote C-5 chiral centre.
We now report a chiral Lewis acid promoted Diels–
Alder reaction of quinone 1 in which an effective
kinetic resolution of the diene partner ( )-7, controlled
by the remote C-5 stereogenic centre, resulted.
Figure 1.
ments (Scheme 1). The ligand, (S)-3,3%-diphenyl-1,1%-
binaphthalene-2,2%-diol, was recovered from the
reaction mixture in near quantitative yield. The struc-
ture of the major adduct 8a was based upon the
premise that the matched enantiomer of 7 reacted pref-
erentially to the less hindered Re face of 9 as depicted
in Figure 1. Aromatisation of the mixtures gave opti-
cally active angucyclinone 10, [h]D −42 to −52 (c 0.5,
Our initial aim was to determine the facial selectivity
exhibited by ( )-7. The thermal Diels–Alder reaction of
1 and 7 gave an 88:12 mixture of cycloadducts ( )-8a
and ( )-8b in 84% yield. This ratio was readily deter-
mined by integration of the signals for the 8-OH, H-5
and OTMS protons in the 1H NMR spectrum. A
similar ratio (91:9) of ( )-8a and ( )-8b was obtained
for the tetra-O-acetyl diborate promoted cycloaddition.
The structure of the major cycloadduct was consistent
with all NMR data and the relative stereochemistry at
C-3 was evident from strong NOE correlations between
the C-3 methyl group to H-2i and -4i and a weaker
correlation to H-12b. On this basis the more reactive
face of 7 is that syn to the ‘large’ phenyldimethylsilyl
group. The favoured approach of the dienophile is anti
to the pseudo-axial methyl group of 7, as depicted in
Figure 1, which minimises steric interactions in the
transition state.
1
CH2Cl2), in 82% yield. The ee was determined by H
NMR experiments using the chiral solvating agent,
(S)-2,2,2-trifluoro-1-(9-anthryl)ethanol, and ranged
from 67–78% depending on the ratio of 8a to 8b. The
fact that the ee was less than the de for the Diels–Alder
reaction suggests that either the facial selectivity of
complex 9 was not complete and the diene was reacting,
to a small extent, from its upper more hindered Si face
or a competing thermal reaction of 1 and ( )-7 was
occurring on workup. The next step in the sequence
involved the treatment of 10 with boron trifluoride
etherate which gave silyl fluoride 11 (90%). Subsequent
oxidation with hydrogen peroxide and potassium
fluoride gave tertiary alcohol 12 in 57% yield. Photo-
chemical oxidation of 12 in methanol gave tetran-
gomycin 6 in a 78% yield. The spectroscopic data were
identical to those reported by Krohn et al.6,7 for the
racemate. The ee was determined using NMR spec-
troscopy and found to range from 68–78%. The specific
rotation measured on a chloroform solution of 6 (68%
ee) was [h]D −67 (c 0.4, CHCl3). Of concern was the
Reaction of 1, via the chiral complex 9, and diene ( )-7
in dichloromethane at −78°C also gave 91:9 to 94:6 (de
82 to 88%) mixtures of 8a and 8b over repeated experi-
Scheme 1. Reagents, conditions and yields: (i) (S)-3,3%-diphenyl-1,1%-binaphthalene-2,2%-diol, BH3·THF, HOAc, CH2Cl2, −78°C,
94% (82–88% de); (ii) DBU, air, CH2Cl2, 82% (67–78% ee); (iii) BF3·Et2O, CH2Cl2, 90%; (iv) H2O2, KF, NaHCO3, THF–MeOH,
57%; (v) MeI, Ag2O, CH2Cl2, 25°C; (vi) hw, MeOH, 78% (68–78% ee).

J. S. Landells et al. / Tetrahedron Letters 44 (2003) 5193–5196
5195
Figure 2. The molecular structure of 10.
fact that the specific rotation for the natural product
had a reported value of [h]D +42 (c 0.9, CHCl3).8,9 The
sign and the magnitude of this rotation, in comparison
to that measured by us, brings into doubt either the
original assignment of the structure of natural 6 or the
reporting of these data.
with the high facial selectivity of complex 9, results in
an effective kinetic resolution of the diene component.
We have demonstrated the utility of this approach with
the first asymmetric syntheses of (−)-tetrangomycin 6 in
31% overall yield with ee ranging from 68 to 78% and
(−)-MM 47755 13 in 28% overall yield with a 70% ee.
Recrystallisation of the reaction intermediates resulted
in an increase in their ee’s and gave (−)-6 with 98% ee.
An X-ray crystallographic study of 10 unambiguously
established the absolute configurations of (−)-6 and
(−)-13 as 3R. This synthesis required a stoichiometric
amount of the chiral Lewis acid to promote the pivotal
asymmetric Diels–Alder reaction. Further work investi-
gating the use of chiral Lewis acid catalysts to effect
kinetic resolutions of racemic dienes using Diels–Alder
reactions of the type described is warranted.
The related angucyclinone MM 47755 13, which is the
8-O-methyl congener of 6, has been independently iso-
lated by two groups.10,11 They reported the specific
rotations for 13 as [h]D −107 (c 0.5, MeOH) and −136
(c 0.04, MeOH), respectively. Treatment of the angucy-
clinone 12 (ee 70%) with methyl iodide and silver(I)
oxide gave, after photochemical oxidation of methyl
ether 14 in methanol, (−)-13 in a 70% yield for the two
steps. The specific rotation was measured as [h]D −69 (c
0.7, MeOH) and the ee was assessed as 70% by NMR
methods.
References
The stereochemical outcome of the cycloaddition was
based on the model for asymmetric induction for the
Diels–Alder reactions of 9 proposed by Kelly et al.3 in
conjunction with that for the facial selectivity of diene
7 determined from NMR data of adduct 8a. This in
turn led to the assignment of the absolute configura-
tions of (−)-6 and (−)-13 both as 3R. Unambiguous
confirmation for these assignments came from minor
modifications to the reaction sequence. Recrystallisa-
tion of 10 from hot hexanes increased the ee to 90%. A
further crystallisation of a small amount of this mate-
rial gave crystals suitable for an X-ray crystallographic
study12 the solution of which is shown in Figure 2. On
the basis of the crystallographic data the configuration
of 10 was determined as 3S and thus, those of (−)-6 and
(−)-13 as 3R. Continuation of the synthesis outlined in
Scheme 1 using 10 (90% ee), with recrystallisation of
each intermediate, gave (−)-tetrangomycin 6 with an
optical rotation [h]D −100 (c 0.26, MeOH) and with an
ee of 98%.
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In summary, we have shown that enantiomerically
enriched cycloadducts can be obtained from a chiral
Lewis acid Diels–Alder reaction of 1 and diene ( )-7.
The facial selectivity of ( )-7 is controlled by the
remote C-5 stereogenic centre which, in conjunction
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12. Crystal data and structure refinement for 10: C27H26O3Si,
M=426.57, monoclinic, space group P2(1), a=

5196
J. S. Landells et al. / Tetrahedron Letters 44 (2003) 5193–5196
,
17.597(16),
b=7.211(6),
c=18.494(17)
A,
i=
parameter 0.0(2); Flack, H. D. Acta Crystallogr. 1983,
A39, 876. Atomic coordinates, thermal parameters, and
bond lengths and angles have been deposited at the
Cambridge Crystallographic Data Centre (CCDC). Any
request to the CCDC for this material should quote the
full literature citation and deposition number CCDC
172389.
3
,
107.333(12)°, V=2240(3) A , Z=4, T=163(2) K, u(Mo-
,
Ka)=0.71073 A, 21414 reflections measured, 5706
unique (R(int)=0.1093), Bruker SMART CCD diffrac-
tometer, empirical absorption correction (SADABS),
v=0.131 mm−1. Final R indices R1[I>2|(I)]=0.0453,
final wR2(F2)=0.0812 (all data), absolute structure