Total synthesis of (+)-rugulosin and (+)-2,2′-epi-cytoskyrin A through cascade reactions

Article abstract of DOI:10.1002/anie.200503678

(Chemical Equation Presented) The cytoskyrin cascade: The total syntheses of the bisanthraquinones 2 (+)-2,2′-epi-cytoskyrin A (R² = OMe) and (+)-rugulosin (R² = Me) has been achieved through a cascade sequence from anthradihydroquin

Full text of DOI:10.1002/anie.200503678

Angewandte
Chemie
Natural Product Synthesis
DOI: 10.1002/anie.200503678
Total Synthesis of (+)-Rugulosin and (+)-2,2’-epi-
Cytoskyrin A through Cascade Reactions**
K. C. Nicolaou,* Yee Hwee Lim,
Charles D. Papageorgiou, and Jared L. Piper
We have previously reported[1] the development of the
“cytoskyrin cascade” as a facile and efficient entry into the
growing class of modified bisanthraquinones that includes
cytoskyrin A (1a),[2] graciliformin (1b),[3] and rugulosin (2b;
Figure 1).[1c,4] Isolated from a number of fungi and lichens,[4b]
Figure 1. Selected naturally occurring modified bisanthraquinones.
the latter compound (2b)was recently found to exhibit anti-
HIV properties,[5] in addition to its originally reported
cytotoxic activity[4b] that it shares with cytoskyrin A (1a).[2]
Given the occurrence of both graciliformin (1b)and rugulo-
sin (2b)in nature, it will not be surprising if 2,2 ’-epi-
cytoskyrin A (2a)is someday discovered as a natural product,
for its structural relationship to cytoskyrin A (1a)is the same
as that of 2b to 1b. The multistep “cytoskyrin cascade” was
demonstrated on a model system that differed from the
[*] Prof. Dr. K. C. Nicolaou, Y. H. Lim, Dr. C. D. Papageorgiou,
Dr. J. L. Piper
Department of Chemistry and
The SkaggsInstitute for Chemical Biology
The Scripps Research Institute
10550 North Torrey PinesRoad, La Jolla, CA 92037 (USA)
Fax: (+1)858-784-2469
E-mail: kcn@scripps.edu
and
Department of Chemistry and Biochemistry
University of California, San Diego
9500 Gilman Drive, La Jolla, CA 92093 (USA)
[**] We thank Dr. D. H. Huang, Dr. G. Siuzdak, and Dr. R. K. Chadha for
NMR spectroscopic, mass spectrometric, and X-ray crystallographic
assistance, respectively. Financial support for this work was
provided by grantsfrom the National Institutesof Health (USA) and
the Skaggs Institute for Chemical Biology, a predoctoral fellowship
from the A*STAR NSS Overseas PhD Scholarship (to Y.H.L.), and a
postdoctoral fellowship from the George E. Hewitt Foundation (to
J.L.P.).
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natural products by the absence of a hydroxy group at the C2
and C2’ positions (see Figure 1). The presence of these
hydroxy groups was considered to be problematic for a total
synthesis involving dimerization of two monomeric units, as
their elimination was anticipated to be favored by aromatiza-
tion, and hence facile. Although nature is probably carrying
out this dimerization process with a hydroxy group in place, a
recent report[1b] confirmed that attempts to synthesize the
monomeric anthradihydroquinone featuring a benzyl-pro-
tected hydroxy group at the C2 and C2’ positions resulted in
elimination of benzyl alcohol. Herein, we report the first
biomimetic, asymmetric total synthesis of (+)-2,2’-epi-cytos-
kyrin A (2a)and ( +)-rugulosin (2b)through the “cytoskyrin
cascade”, under conditions that successfully overcome the
above-mentioned challenges.
There are four possible spatial arrangements (A–D)for
the dimerization of the monomeric anthraquinones, two endo
(A, B)and two exo (C, D)arrangements, which are further
distinguished by the faciality of approach, the one from the
top (B, D)and the one from below ( A, C), as demonstrated in
Figure 2. The two endo alignments (A and B)are equivalent
and are unlikely, if not impossible, due to structural con-
straints. The exo-syn arrangement (C)would place the two
substituted hydroxy groups (OR1)in a syn arrangement
resulting in the build-up of significant steric congestion and
should, therefore, be disfavored. A pathway through such an
arrangement would form ent-cytoskyrin (ent-1a)and ent-
graciliformin (ent-1b)through the intermediacy of O-bridged
dimers 3. The alternative exo-anti arrangement (D), places
these two interfering groups opposite to each other, hence
minimizing the steric congestion and allowing the generation
of 2,2’-epi-cytoskyrin A (2a)and rugulosin ( 2b). It is inter-
esting to note that while the chirality of the monomeric
anthraquinone is responsible for determining the absolute
configuration of the cage, the diastereoselectivity of the
dimerization step controls the relative stereochemistry of the
C2 and C2’ centers relative to the rest (epimeric stereo-
chemistry)in the final product of the cascade sequence (see
also caption, Figure 2).
Reasoning that the nature of the groups (R1)residing on
the C2/C2’ hydroxy groups may make a difference in the
outcome of the anticipated reactions, we proceeded to
construct different monomeric units as starting materials for
the cascade. Scheme 1 summarizes the synthesis of hydro-
quinones 11a–11c featuring a Hauser annulation[6] to con-
struct the requisite tricyclic system. Thus, protection of the
known diacetate 5[7] with MOMCl or TBSCl followed by
desymmetrization using porcine liver esterase (PLE)at pH 8
afforded alcohols 6a[8] or 6b[7] in 95 and 90% yield,
respectively, over the two steps. PCC oxidation under
buffered conditions using NaOAc followed by brief (10 min)
exposure to DBU at 258C furnished the desired enones 7a or
7b in 68 and 67% yield, respectively, over the two steps. The
other partners for the Hauser annulation, nitriles 10a and 10b
were synthesized as shown in Scheme 1. Thus, protection of
the commercially available salicylic acids 8a or 8b with excess
TBSCl followed by treatment with (COCl)2 and a catalytic
amount of DMF in CH2Cl2 at 08C afforded the corresponding
acid chlorides, which were quenched with Me2NH to furnish
Figure 2. Stereoselectivity considerations for the dimerization step of
anthradihydroquinones to modified bisanthraquinones. The shown
enantiomers of the starting anthraquinones correspond to ent-1a, ent-
1b, 2a, and 2b. Should the pathway involving arrangement C be
possible, the opposite enantiomers would have been needed to obtain
natural cytoskyrin A (1a) and graciliformin (1b).
amides 9a or 9b in 85 and 74% yield, respectively, over the
three steps. Ortho-lithiation of amides 9a or 9b using tBuLi
and TMEDA at ꢀ788C and subsequent quenching with
freshly distilled DMF yielded the corresponding aldehydes.
Exposure of the latter compounds to TMSCN, a catalytic
amount of KCN, [18]crown-6, and AcOH afforded the
deprotected nitrile compounds, which were finally treated
with MOMCl and iPr2NEt at 08C to furnish the required
building blocks 10a and 10b in 64 and 50% yield, respec-
tively, over the three steps.
With the two fragments in hand, the stage was now set for
the synthesis of the requisite anthradihydroquinones 11a–
11c. Treatment of nitriles 10a or 10b with LHMDS in THF at
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ever, treatment of purified 4a or 4b (flash
column chromatography on silica gel)with
MnO2 (1.5 wt equiv)and Et 3N (5.0 equiv,
added as soon as 14a or 14b were observed
by thin layer chromatography (TLC), ca. 6 h)
in CH2Cl2 at 458C for 12 h resulted in the
formation of 15a or 15b in 71 and 81% yield,
respectively, through the intermediacy of
fleeting compounds 13a or 13b and 14a or
14b.
Use of carefully purified 11a or 11b
(preparative TLC)enabled the realization of
an impressive seven-step cascade sequence
featuring the transformation of tricyclic mon-
omers 11a or 11b into nonacyclic systems 15a
or 15b in 60 and 50% yield, respectively,
involving a sequence of alternating oxidations
and double Michael reactions as shown in
Scheme 2. The remaining mass was accounted
for by the formation of aromatized monomers
16a or 16b in 40 and 50% yield, respectively.
This cascade required treatment of 11a or 11b
Scheme 1. Reagentsand conditions: a) MOMCl (3.8 equiv), iPr2NEt (3.8 equiv), CH2Cl2,
258C, 1.5 h; TBSCl (3.8 equiv), imid (3.8 equiv), CH2Cl2, 258C, 48 h; b) PLE (1.0 equiv),
buffer pH 8 (0.1m), tBuOH (8% v/v), 258C, 4 h, 95% (6a), 90% (6b) over two steps;[8]
c) PCC (3.0 equiv), NaOAc (3.0 equiv), CH2Cl2, 258C, 12 h; d) DBU (1.0 equiv), CH2Cl2,
258C, 10 min, 68% (7a), 67% (7b) over two steps; e) TBSCl (4.0 equiv), imid
(6.0 equiv), DMF, 258C, 16 h; f) i. (COCl)2 (1.25 equiv), DMF (cat.), CH2Cl2, 08C, 2 h;
ii. Me2NH·HCl (1.0 equiv), Et3N (3.0 equiv), CH2Cl2, 08C, 30 min, 85% (9a), 74% (9b)
over three steps; g) TMEDA (3.0 equiv), tBuLi (3.0 equiv), DMF (3.0 equiv), THF, ꢀ78!
258C, 12 h; h) KCN (0.2 equiv), [18]crown-6 (0.2 equiv), TMSCN (1.4 equiv), CH2Cl2,
258C, 4 h; then AcOH, 12 h; i) MOMCl (1.5 equiv), iPr2NEt (1.2 equiv), CH2Cl2, 08C, 1 h,
64% (10a), 50% (10b) over three steps; j) 10 (1.1 equiv), THF, LHMDS (1.1 equiv),
ꢀ788C; then 7 (1.0 equiv), ꢀ78!08C, 2 h, (submitted directly to the cascade).
MOM=methoxymethyl; TBS=tert-butyldimethylsilyl; PLE=porcine liver esterase;
PCC=pyridinium chlorochromate; DBU=1,8-diazabicyclo[5.4.0]undec-7-ene;
DMF=N,N’-dimethylformamide; TMEDA=tetramethylethylenediamine; THF=tetrahy-
drofuran; TMS=trimethylsilyl; LHMDS=lithium bis(trimethylsilyl)amide.
with MnO2 (1.5 wt equiv)in CH Cl2 (0.35m)
2
for 10 min at 258C, conditions that led to the
formation of 4a or 4b as indicated by TLC,
followed by tenfold dilution with CH2Cl2 and
addition of a further 1.5 wt equiv of MnO2
until the formation of 14a or 14b was com-
plete (6 h). Finally, addition of Et3N
(5.0 equiv)and heating to 45 8C for 6 h fur-
nished 15a or 15b. Exposure of the latter
compounds (15b or 15b)to concentrated HCl
in a mixture of MeOH and THF (20:1)
ꢀ788C, followed by addition of 7a or 7b (ꢀ78!08C)gave
crude anthradihydroquinones 11a–11c, which were directly
subjected to the cytoskyrin cascade[1a] (Scheme 2). We had
already established the facilitating role[1a] of MnO2 and
anticipated that the mild reaction conditions employed for
the cascade coupled with the expected reluctance of the final
compound to lose its alkoxy groups by virtue of Bredtꢀs rule[9]
would enable arrival at compounds 2a and 2b, provided that
the feared elimination/aromatization pathway from the
monomeric anthraquinones did not predominate. Indeed,
exposure of 11a or 11b to MnO2 (1.5 wt equiv)in a
concentrated CH2Cl2 solution (0.35m)at 25 8C for 30 min
resulted in the formation of dimeric compounds 4a or 4b as
single diastereoisomers in 64 and 32% yield, respectively,
through a sequence featuring oxidation to the corresponding
anthraquinone (12a or 12b)and dimerization of its easily
generated, under the reaction conditions, enol form. It was
found that when crude 11a or 11b were used, the cascade was
shutdown at the stage of 4a or 4b. This occurrence was
attributed to an, as yet unknown, impurity[10] carried through
from the Hauser annulation which hindered the oxidation of
4a or 4b to 13a or 13b, impeding the cascade. Prolonged
exposure of the thus-obtained 4a or 4b to MnO2 (12 h)
resulted in quantitative formation of 16a or 16b, presumably
through two successive retro-Michael reactions (see
Scheme 3)followed by elimination and aromatization. How-
resulted in global deprotection, affording (+)-2,2’-epi-cytos-
kyrin A (2a)or ( +)-rugulosin (2b)in 93 and 98% yield,
respectively. The 1H NMR spectrum of (+)-rugulosin (2b)in
[D6]DMSO was identical to that reported in the literature[4c]
for the naturally occurring substance. Besides being antici-
pated on the basis of the above arguments (Figure 2), the
stereochemistry of 2a was firmly established through spec-
1
troscopic analysis. Thus, the H NMR spectrum of synthetic
(+)-2,2’-epi-cytoskyrin A (2a)exhibited doublets for H3/H3 ’
(d = 2.85, J = 4.8 Hz)and H2/H2 ’ (d = 4.49, J = 4.8 Hz), while
in the spectrum reported for naturally occurring cytoskyrin A
(1a)[2] both signals for H3/H3’ (d = 2.85)and H2/H2 ’ (d =
4.00)appear as singlets. If 2a was to have the same stereo-
chemistry as cytoskyrin (1a)at C2/C2 ’, the dihedral angle of
H1/H1’-H2/H2’ and H2/H2’-H3/H3’ would have been 788 and
858, respectively (manual molecular models)[3] and hence the
signals for H3/H3’ and H2/H2’ would have been singlets.
Crystals of synthetic rugulosin (2b)obtained by slow
crystallization from acetone containing 1% Et3N over
MeOH vapors yielded to X-ray crystallographic analysis
(see ORTEP drawing,[11] Figure 3), proving unambiguously its
structure and, indirectly, rendering further support for the
assigned structure of (+)-2,2’-epi-cytoskyrin A due to the
striking closeness of the 1H NMR spectra of 2a and 2b.
Having established a viable pathway to 2,2’-epi-cytoskyr-
in A (2a)and rugulosin ( 2b)starting from 11a or 11b,
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Scheme 2. The cytoskyrin cascade: synthesis of (+)-2,2’-epi-cytoskyrin A (2a) and (+)-rugulosin (2b) from anthradihydroquinone 11a or 11b,
respectively. Reagents and conditions: a) MnO2 (1.5 wtequiv), CH2Cl2 (0.35m), 258C, 1 h, 64% (4a), 32% (4b) over five steps; b) MnO2,
(1.5 wtequiv), Et3N (5.0 equiv), CH2Cl2, 25!458C, 12 h, 71% (15a), 81% (15b) over three steps; c) conc. HCl, MeOH, THF, 608C, 12 h, 93%
(2a), 98% (2b); d) MnO2 (1.5 wtequiv), CH2Cl2, 258C, 10 min; then MnO2 (1.5 wtequiv), Et3N (5.0 equiv), 25!458C, 12 h, 60% (15a), 40%
(16a), 50% (15b), 50% (16b).
1
characterized by H NMR spectroscopy (see Table 1). Thus
treatment of 11c with MnO2 (1.5 wt equiv)in a concentrated
CH2Cl2 solution (0.35m)at 25 8C for 30 min resulted in the
slow formation of quinone 12c, dimer 18, product 4c, and
aromatized system 16b. Moreover, compound 18, upon
standing in CDCl3, slowly and quantitatively converted into
4c and 16b (4c/16b ꢁ 1:3, as determined by 1H NMR
spectroscopy). This suggests that compounds 12c, 17, and 18
are in equilibrium with each other and that the rate of
aromatization of 17 to 16b is faster than the second Michael
reaction within dimer 18 that leads to the desired compound
4c. These observations were consistent with a stepwise
mechanism for the cytoskyrin cascade involving two consec-
utive Michael reactions as shown in Figure 3, at least in the
case of the TBS-protected derivative 11c.
Figure 3. ORTEP drawing of rugulosin (2b) derived from X-ray crystal-
lographic studies (O burgundy, C gray, H yellow). The molecule of Et3N
per molecule of 2b is not shown. The crystallographic analysis did not
reveal the absolute stereochemistry of 2b, which was assigned as
shown, on the basis of the absolute stereochemistry of the starting
[1c,4]
material and itspositive optical rotation.
The described chemistry demonstrates the power of
cascade reactions in chemical synthesis[12] and underscores
the applicability of such processes in situations facing seem-
ingly intransigent synthetic challenges. Further applications
of these remarkable cascade reactions to the synthesis of
other natural and designed members of the bisanthraquinone
class should be forthcoming.
respectively, we then proceeded to investigate TBS-anthradi-
hydroquinone 11c as a substrate for the cytoskyrin cascade. It
was reasoned that the sheer bulk of the TBS group as
compared to the smaller MOM moiety was expected to retard
both Michael reactions, an occurrence that could result in the
isolation of some of the postulated intermediates of the
cascade. Scheme 3 summarizes our findings, which indeed
included the isolation of two of the reactive species involved,
quinone 12c and highly labile dimer 18, both of which were
Received: October 17, 2005
Revised: November 2, 2005
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Table 1: Selected physical properties for compounds 2a, 2b, 4c, 12c,
16b, and 18.
2a: Rf =0.53 (benzene/acetone 2:1, oxalic acid impregnated TLC);
1H NMR (500 MHz, [D8]THF): d=14.60 (2H, s), 12.10 (2H, s), 7.19
(2H, d, J=2.3 Hz), 6.79 (2H, d, J=2.3 Hz), 4.49 (2H, d, J=4.8 Hz),
3.92 (6H, s), 3.41 (2H, br), 2.85 ppm (2H, d, J=4.8 Hz); 13C NMR
(125 MHz, [D8]THF): d=194.3, 186.5, 182.5, 167.1, 165.5, 135.2, 111.8,
108.0, 107.4, 107.1, 69.9, 67.9, 59.0, 56.4, 49.4 ppm; HRMS (ESI-TOF):
m/z calcd for C30H21O12 [MꢀH]ꢀ: 573.1038; found: 573.1031.
ꢀ
2b: Rf =0.50 (benzene/acetone 4:1, oxalic acid impregnated TLC);
1H NMR (500 MHz, [D6]DMSO): d=14.70 (2H, s), 11.39 (2H, s), 7.46
(2H, s), 7.20 (2H, s), 4.39 (2H, d, J=6.0 Hz), 3.37 (2H, s), 2.78 (2H, d,
J=6.0 Hz), 2.43 ppm (6H, s); 13C NMR (125 MHz, [D8]THF): d=186.0,
184.6, 162.8, 160.4, 148.7, 133.5, 124.7, 121.3, 115.7, 107.6, 70.1ꢀ, 68.0,
59.3, 49.5, 22.0 ppm; HRMS (ESI-TOF): m/z calcd for C30H21O10
[MꢀH]ꢀ: 541.1140; found: 541.1136.
4c: Rf =0.43 (MeOH/CH2Cl2 2:100); 1H NMR (500 MHz, CDCl3):
d=16.28 (1H, s), 14.79 (1H, s), 7.20 (1H, br), 6.81 (1H, br), 6.53 (1H,
br), 6.30 (1H, br), 5.47–5.44 (2H, m), 5.36–5.30 (2H, m), 4.48 (1H, ddd,
J=11.0, 11.0, 4.8 Hz), 4.15 (1H, ddd, J=11.0, 11.0, 4.8 Hz), 3.62 (3H,
s), 3.57 (3H, s), 3.32 (1H, d, J=11.0 Hz), 3.08 (1H, d, J=11.0 Hz), 3.06
(1H, dd, J=17.8, 4.8 Hz), 2.87 (1H, dd, J=17.8, 4.8 Hz), 2.74 (1H, dd,
J=17.8, 11.0 Hz), 2.66 (1H, dd, J=17.8, 11.0 Hz), 2.17 (3H, s), 1.99
(3H, s), 0.98 (9H, s), 0.94 (9H, s), 0.25 (3H, s), 0.20 (3H, s), 0.07 (3H,
s), 0.00 ppm (3H, s).
1
12c: Rf =0.13 (MeOH/CH2Cl2 1:100); H NMR (500 MHz, CDCl3):
d=7.10 (1H, s), 7.00 (1H, s), 5.20 (2H, s), 4.55 (1H, br), 3.63–3.53
(2H, m), 3.52 (3H, s), 2.88–2.81 (1H, m), 2.83–2.79 (1H, m), 2.23 (3H,
s), 0.79 (9H, s), 0.10 (3H, s), 0.07 ppm (3H, s).
1
16b: Rf =0.85 (MeOH/CH2Cl2 5:100); H NMR (500 MHz, CDCl3):
d=13.03 (1H, s), 7.85 (1H, brs, 7.78 (1H, d, J=7.5 Hz), 7.62 (1H, dd,
J=7.5, 8.5 Hz), 7.29 (1H, d, J=8.5 Hz), 7.39 (1H, brs), 5.41 (2H, s),
3.60 (3H, s), 2.51 (3H, s) ppm (3H, s); HRMS (ESI-TOF): m/z calcd for
C17H14O5Na+ [M+Na]+: 321.0733; found: 321.0731.
Scheme 3. Mechanistic investigation of the dimerization cascade (11 c
to 4 c). Reagentsand conditions: a) MnO (1.5 wt equiv), CH2Cl2
2
(0.35 m), 25 8C, 1 h, 20% 4 c; 30% 18; 45% 16 b; 5% 12 c; ratio of
productsdependent on reaction time.
1
18: Rf =0.24 (MeOH/CH2Cl2 2:100); H NMR (500 MHz, CDCl3):
Keywords: anthraquinones · biomimetic synthesis ·
Michael reaction · natural products · total synthesis
d=16.24 (1H, s), 7.59 (1H, s), 7.49 (1H, s), 7.40 (1H, s), 7.34 (1H, s),
5.39–5.37 (2H, m), 5.33–5.31 (2H, m), 4.41–4.40 (1H, m), 4.31–4.29
(1H, m), 4.06–4.05 (1H, m), 3.90–3.89 (1H, m), 3.61 (3H, s), 3.56 (3H,
s), 3.00 (1H, dd, J=5.3, 1.8 Hz), 2.48 (3H, s), 2.46 (3H, s), 2.17–2.13
(2H, m), 2.00 (2H, dd, J=18.5, 3.5 Hz), 0.74 (9H, s), 0.63 (9H, s), 0.13
(3H, s), 0.03 (3H, s), ꢀ0.08 (3H, s), ꢀ0.11 ppm (3H, s).
.
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