Enantioselective synthesis of the lomaiviticin aglycon full carbon skeleton reveals remarkable remote substituent effects during the dimerization event

Article abstract of DOI:10.1002/chem.201002157

A full carbon skeleton of the natural product lomaiviticin has been synthesized. The approach features anionic annulation reactions to deliver A and B rings of the natural product, and stereoselective oxidative enolate coupling to form the central C2-C2′

Full text of DOI:10.1002/chem.201002157

DOI: 10.1002/chem.201002157
Enantioselective Synthesis of the Lomaiviticin Aglycon Full Carbon Skeleton
Reveals Remarkable Remote Substituent Effects during the Dimerization
Event
Hong Geun Lee, Jae Young Ahn, Amy S. Lee, and Matthew D. Shair*[a]
Lomaiviticin A (1) and lomaiviticin B (2) are novel C2-
symmetric diazobenzofluorene glycoside marine natural
products (Figure 1).[1] Lomaiviticin A (1) potently inhibits
the growth of cultured cancer cell lines (GI50 values ranging
from 0.007 to 72.0 nm), and both 1 and 2 exhibit impressive
growth inhibition activity against Gram-positive bacteria.
Compound 1 causes damage to DNA in vitro. It has been
speculated that a reactive species derived from the diazo-
benzofluorenones of 1 and 2 causes damage to nucleic acids,
leading to the cytotoxic activities of these molecules. Experi-
mental studies have provided support for the formation of
reactive species from diazofluorenone structures.[2] However,
it remains to be determined how the full structures of 1 and
2 react under physiologically relevant conditions and what
cellular components are perturbed by 1 and 2.
The structures of 1 and 2 are unprecedented and striking.
The unusual structures of 1 and 2 pose interesting questions
À
about how they are biosynthesized, especially how the C2
C2’ bond is made, and questions about how to achieve syn-
theses of these molecules. Although a synthesis of 1 or 2 has
not yet been achieved, many approaches to these molecules
have been reported,[3] including our own enantioselective
synthesis of the central (C-D-D’-C’) ring system of 1.[3b]
A
synthesis of the full carbon skeleton of 1 and 2 has not yet
been accomplished. To achieve syntheses of 1 and 2, there
are significant challenges to overcome; the most difficult of
À
À
which is likely formation of the C2 C2’ s bond. The C2 C2’
bond links two highly functionalized “halves” of 1 and 2,
which closely resemble the related natural product kinamy-
cins.[4] The congested environment surrounding the C2 C2’
bond, stereochemical control during bond formation, and
the potential lability of the D and D’ rings render the forma-
tion of this bond extremely challenging. Late-stage dimeri-
À
À
zation and formation of the C2 C2’ bond, in which double-
processing is kept at a minimum, would be the most effi-
À
cient means of synthesizing 1 and 2. Since the C2 C2’ bond
in 1 and 2 is part of a 1,4-diketone (C1-C2-C2’-C1’), a late-
stage oxidative enolate coupling would be the ideal reaction
to construct this bond. However, the high potential for b-
À
elimination of the C3 tertiary carbinol from a C1 C2 eno-
late, coupled with the likely poor stereoselectivity of such an
oxidative enolate coupling reaction, renders this approach
unattractive. To circumvent these obstacles, we developed a
strategy utilizing the oxidative enolate coupling of 7-oxanor-
bornanones to achieve the first enantioselective synthesis of
the central ring system of the aglycon of 1 (Scheme 1, see
black structures in brackets). The 7-oxanorbornanone struc-
ture prevents b-elimination at C3 due to stereoelectronic ef-
fects, and it provides perfect diastereoselectivity during the
Figure 1. Structures of lomaiviticin A and B.
[a] H. G. Lee, J. Y. Ahn, A. S. Lee, Prof. M. D. Shair
Department of Chemistry and Chemical Biology, Harvard University
12 Oxford Street, Cambridge, MA 02138 (USA)
Fax : (+1)617-496-4591
À
formation of the C2 C2’ bond due to double diastereodiffer-
entiation in the dimerization event. Herein we report stereo-
selective coupling of the monomeric units of 1 and 2 leading
to the first synthesis of the full carbon skeleton of the agly-
cons of 1 and 2. During the course of these studies, remark-
E-mail: shair@chemistry.harvard.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201002157.
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COMMUNICATION
Scheme 1. Synthesis plan.
able remote substituent effects during the key dimerization
reaction have been observed, which may further complicate
future syntheses of 1 and 2.
As stated, our synthesis plan is to perform an oxidative di-
merization of the enolate of 4 to afford 3 (Scheme 1). An
annulation reaction[5] between enone 5 and a known cyano-
lowed us to isolate 7 in 89% yield. Protecting group manip-
ulation of 7 afforded 8. The C5 carbinol of compound 8 was
then oxidized under standard Swern conditions. Surprisingly,
the product was obtained as the chlorinated b-ketoester 9.[7]
The reductive dechlorination of 9 with Zn afforded b-ke-
toester 10, which underwent decarboxylative deallylation[8]
A
4
(see
upon exposure to [PdCl2ACHTUNGTERNNU(G PPh3)2] and nBu3SnH, furnishing
Scheme 3, 12). Enone 5 would be accessible from intermedi-
ate 6, a compound for which we had previously developed
an enantioselective synthesis.[3b] Initially, an anionic annula-
tion reaction on an enone similar to 5, but with C1 at the
ketone oxidation state, was attempted. Unfortunately, the
basic conditions of the annulation were not compatible with
the C1 ketone. Therefore, we were forced to protect the C1
ketone of 6 in its reduced form by treatment with NaBH4
(Scheme 2). Surprisingly, 7 was obtained as the major prod-
uct when the reduction was performed in allyl alcohol sol-
vent. We speculate that transesterification of the oxazolidi-
none chiral auxiliary occurs from the boronate of allyl alco-
hol. Quenching the remaining borohydride with acetone al-
ketone 11 in 85% yield. Finally, a-phenylselenation of the
enolate of 11, followed by oxidation, delivered enone 5.[9]
For the key annulation reaction, we used the cyanophtha-
lide method developed by Kraus[10] (Scheme 3). Addition of
the anion of 12 to enone 5 afforded hydroquinone 13a in
85% yield. The C5 ketone of 13a was protected as a dioxo-
lane.[11] Protection of the two phenols of 14a as their corre-
sponding allyl ethers (compound 15a), followed by reduc-
tive cleavage of the pivaloyl group, and subsequent oxida-
tion at C1 afforded ketone 16a, setting the stage for the key
oxidative enolate coupling.
For synthesis of the C-D-D’-C’ central ring system of 1
and 2, we had developed conditions for the oxidative eno-
late coupling reaction involving deprotonation of the ketone
with LHMDS at À788C, addition of [Cp2FePF6] and warm-
ing to À608C.[12] We then applied these conditions to the ox-
idative dimerization of ketone 16a (Scheme 4). Unfortu-
nately, none of the desired dimer (17a) was formed under
these conditions, and only starting material 16a or decom-
posed material was isolated (Scheme 4).
In light of these disappointing results, we tried to rational-
À
ize why our C D ring system published earlier underwent
À
successful dimerization, but the A D ring system here
failed to dimerize. We speculated that nonbonded interac-
tions may be developing in the transition state, which could
be inhibiting dimerization. Since little is known about the
mechanism of this reaction and the trajectory by which sub-
strates approach each other, we attempted to understand
possible developing nonbonded interactions in the transition
state by studying the ground-state conformations of the de-
sired product (compound 17a).[13] We examined compound
17a (Figure 2) and each of the three staggered conforma-
Scheme 2. Synthesis of enone 5. a) NaBH4, allyl alcohol, À788C, 5 min;
then acetone, 238C, 15 min, 89%; b) PivCl, pyridine, CH2Cl2, 408C, 24 h;
c) TBAF, THF, 238C, 16 h, 91% over two steps; d) DMSO, (COCl)2,
À788C, 30 min; then Et3N, 23 8C, 30 min; e) Zn dust, AcOH, 238C, 2 h,
96% over two steps; f) [PdCl2ACHTNUGTRNE(UGN PPh3)2], nBu3SnH, AcOH, toluene, 08C,
30 min; then 1108C, 30 min, 85%; g) LHMDS, THF, À788C, 30 min;
then PhSeBr, À788C, 5 min; then H2O2, CH2Cl2/THF 1:1, 08C, 4 h, 73%.
Piv=trimethylacetyl, TBAF=tetrabutylammonium fluoride, THF=tet-
rahydrofuran, DMSO=dimethyl sulfoxide, LHMDS=lithium bis(trime-
thylsilyl)amide.
À
À
tions about the C2 C2’ bond, specifically H2 H2’ dihedral
angles of 60, 180, and À608 (see Figure 2). The conformation
À
with a H2 H2’ dihedral angle of 1808 adopted an “n” con-
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13059

M. D. Shair et al.
relevant conformer since the C3 and C3’ ethyl groups were
À
suffering from severe nonbonded interactions. The 608 H2
H2’ dihedral angle conformation also exists in an “n” con-
À
formation, but it does not suffer from the destabilizing C3
C3’ ethyl interactions. However, we did notice potential
nonbonded interactions between the C11 and C11’ allyloxy
À
groups (see dotted arrow). Finally, the À608 H2 H2’ dihe-
dral angle conformation exists in a “z” conformation, which
was also given due to the resemblance to the letter “z” in
shape, and in this conformation nonbonded interactions may
develop between C11 (and C11’) allyloxy groups and the
C3’ (and C3) ethyl groups. Since in both the “n” and “z”
conformations, the C11 (and C11’) allyloxy groups may be
preventing dimerization, we decided to synthesize the tetra-
cyclic dimerization precursor where the C11 allylACTHNUGRTNEUNGoxy group
is replaced with a hydrogen atom (16b, R=H). This forced
us to devise a new annulation strategy to access this struc-
ture from enone 5.
Scheme 3. Synthesis of dimerization precursors 16a and 16b. a) For 13a:
12, LHMDS, HMPA, THF, À788C, 30 min; then 5, 508C, 3 h, 85%; for
13b: 18, LHMDS, THF, À608C, 6 h; then 5, À788C, 10 min, 79%; b) 1,2-
bis(trimethylsilyloxy) ethane, TMSOTf, CH2Cl2, 238C, 48 h, 76% for
14a, 72% for 14b; c) Cs2CO3, allyl bromide, DMF, 238C, 2 h, 87% for
15a, 76% for 15b; d) NaBHEt3, THF, 08C, 4 h; e) TPAP, NMO,
4 ꢁM.S., CH2Cl2, 238C, 2 h, 90% for two steps for 16a, 88% for two
steps for 16b. HMPA=hexamethylphosphoramide, DMF=dimethyl form-
amide, TMSOTf=trimethylsilyl trifluoromethanesulfonate, TPAP=tetra-
propylammonium perruthenate, NMO=4-methylmorpholine-N-oxide.
To construct 16b, where the C11 substituent is a hydrogen
atom, we synthesized Hauser-type sulfoxide annulation part-
ner 18 (Scheme 3).[14] Deprotonation of 18 with LHMDS at
À608C, followed by exposure to enone 5, delivered phenol
13b in 79% yield. It is worth noting that the use of the
phenyl ester of 18, compared to the more commonly used
methyl ester, dramatically enhanced the rate and yield of
the annulation reaction-a finding that may be useful in other
applications of this reaction.[15] Following the process we de-
veloped previously, 13b was converted to dioxolane 14b.
Allyl protection of the phenol to afford 15b, followed by
cleavage of the C1-pivaloyl group, and subsequent oxida-
tion, delivered ketone 16b. With ketone 16b in hand, we
again attempted to perform oxidative enolate coupling
under identical conditions (LHMDS, HMPA, [Cp2FePF6],
À608C, THF). We were gratified to find that oxidative di-
merization of 16b afforded 17b in 80% yield as a single dia-
stereomer (Scheme 5).
Scheme 4. Attempted oxidative dimerization of 16a. a) LHMDS, HMPA,
THF, À788C, 2 h; then [Cp2FePF6], À608C, 72 h, 0%. LHMDS=lithium
bis(trimethylsilyl)amide, [Cp2FePF6]=ferrocenium hexafluorophosphate.
Scheme 5. Oxidative dimerization of 16b. a) LHMDS, HMPA, THF,
À788C, 2 h; then [Cp2FePF6], À608C, 72 h, 80%; b) [PdCl
2ACHTUNGTRENNUNG(PPh3)2],
nBu3SnH, AcOH, CH2Cl2, 08C, 30 min, 90%.
To confirm the relative stereochemistry at C2 and C2’,
and to determine the conformation of dimeric structure 17b,
we set out to obtain an X-ray crystal structure. Fortunately,
we discovered that removal of the allyl groups of 17b af-
forded 19 as a crystalline solid (Scheme 5), which was sub-
jected to X-ray crystallographic analysis to provide the
Figure 2. Postulated steric interactions in the dimeric products.
formation, the name of which is given because the shape of
the conformer resembles that of the letter “n”. This confor-
mer appeared to be very high in energy and unlikely to be a
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Enantioselective Synthesis of the Lomaiviticin Aglycon
COMMUNICATION
structure shown in Figure 3.[16] The crystal structure con-
dihedral angle of 608). The presence of C2 C2’ torsional
strain in 19 and the potential for severe nonbonded interac-
À
À
firmed that the correct C2 C2’ stereochemistry had been es-
tablished and also that the compound can exist in an “n”
conformation.
tions in the crystal structure suggested to us that there may
À
be a measurable barrier to rotation about C2 C2’, resulting
in atropisomerism. Unfortunately, heating to 90 or cooling
1
to À808C did not result in a change in the H NMR spec-
trum of 19, preventing us from determining whether 19 ex-
hibits atropisomerism.
In summary, we report the first synthesis of the full
carbon skeleton of the lomaiviticin aglycon. An important
aspect of this study was demonstrating that the oxidative
enolate coupling strategy we reported earlier can be applied
to the full monomeric units of the lomaiviticins to assemble
the full carbon skeleton, again with complete stereochemical
À
control in the formation of the C2 C2’ bond. During the
course of these studies, we have discovered that remote
oxygen substituents at C11 (and C11’), surprisingly, have
dramatic effects on the success of the oxidative dimeriza-
tion. It is interesting to speculate whether our observation
that dimerization to form the lomaiviticin aglycon skeleton
requires hydrogen atoms at C11 and C11’ extends to other
dimerization strategies or even to the biosynthesis of 1 and
2. It may be that a biosynthetic dimerization also occurs
with hydrogen at C11 and C11’ and that late stage oxidation
leads to the lomaiviticins. An X-ray crystal structure of the
lomaiviticin aglycon skeleton revealed that a nonbonded in-
Figure 3. X-ray crystal structure of 19.
Closer inspection of the X-ray crystal structure revealed
that the C11 hydrogen atom is in close proximity to the C1’
ketone oxygen atom (and conversely the C11’ hydrogen and
C1 ketone oxygen; see Figure 4). In fact, the interatomic
distance between H11 and O1’ (and H11’ and O1) is only
0.29 ꢁ greater than the sum of their van der Waals radii.
This close contact between the C11 substituent and O1’ (as
well as C11’ and O1) may explain why the first attempted
oxidative dimerization with a C11 allyloxy group failed. If,
as in our first attempted dimerization, C11 bears an oxygen
atom, its greater van der Waals radii of 1.52 ꢁ would have
suffered a nonbonded interaction with O1’. Interestingly, al-
though our analysis of ground-state conformations led us to
convert C11 from an oxygen substituent to hydrogen, we
were surprised to find that it may be a steric clash between
C11 substituent and O1’ that may be preventing dimeriza-
tion.
À
teraction between substituents at C11 and O1’ (and C11’
O1) may be suppressing oxidative dimerization when the
C11 substituent is larger than hydrogen. In addition, the lo-
maiviticin aglycon skeleton exists (or at least crystallizes) in
an unusual “n” conformation with significant torsional strain
À
around the C2 C2’ s bond. The lomaiviticins are challeng-
ing synthesis targets and the advances reported herein are
important steps in eventually achieving their syntheses.
Experimental Section
Oxidative dimerization of 16b: A two neck flask charged with a solid ad-
dition adaptor with ferrocenium hexafluorophosphate (2.32 g, 7.00 mmol,
5.00 equiv) in it was flame dried and charged with argon. Then the flask
was charged with THF (8 mL), HMDS (0.502 mL, 2.38 mmol,
1.70 equiv), 2.29m nBuLi solution in hexane (1.04 mL, 2.38 mmol,
1.70 equiv) and HMPA (0.487 mL, 2.80 mmol, 2.00 equiv) at À788C, suc-
cessively. 40 min later a solution of ketone 16b (830 mg, 1.40 mmol,
1.00 equiv) in 10 mL of THF (plus 2ꢂ1 mL rinse) was cannulated to the
LHMDS/HMPA solution to give a pale yellow solution. 2 h later, ferroce-
nium hexafluorophosphate was added to the reaction system from the
solid addition adaptor. The originally formed deep blue suspension
turned yellowish green in 30 min. The reaction mixture was stirred at
À608C for 3 d. The reaction mixture was quenched with a saturated solu-
tion of NH4Cl and warmed to room temperature. The aqueous phase was
extracted with dichloromethane (3ꢂ20 mL) and the combined organic
phase was dried with anhydrous Na2SO4. The crude product was purified
by flash column chromatography (EtOAc/hexane 1:1 to 1.5:1) to give
dimer 17b (665 mg, 1.12 mmol, 80%) as a pale yellow solid.
Further examination of the X-ray crystal structure of 19
À
revealed unusual torsional strain in the C2 C2’ bond, with a
C1-C2-C2’-C1’ dihedral angle of 298 (compared to a desired
Figure 4. Interatomic distance of C11 hydrogen and C1’ oxygen.
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M. D. Shair et al.
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Acknowledgements
Financial support for this project was provided by a grant from the NIH
(CA125240). A.S.L. acknowledges financial support from an NDSEG fel-
lowship. H.L. and J.A. acknowledge Sanofi-Aventis and Eli Lilly, respec-
tively, for graduate fellowships. Shao-Liang Zheng is acknowledged for
X-ray crystallographic analysis.
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Keywords: annulation
products · remote steric effect · total synthesis
·
antitumor agents
·
natural
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Received: July 28, 2010
Published online: October 26, 2010
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Chem. Eur. J. 2010, 16, 13058 – 13062