Total synthesis of cribrostatin IV: Fine-tuning the character of an amide bond by remote control

Article abstract of DOI:10.1021/ja050203t

We report the enantioselective total synthesis of cribrostatin IV (1). Key features of this synthesis involve the convergent coupling of two highly functionalized homochiral components followed by a "lynchpin" Mannich cyclization to establish the pentacyc

Full text of DOI:10.1021/ja050203t

Published on Web 03/10/2005
Total Synthesis of Cribrostatin IV: Fine-Tuning the Character of an Amide
Bond by Remote Control
Collin Chan, Richard Heid, Shengping Zheng, Jinsong Guo, Bishan Zhou, Takeshi Furuuchi, and
Samuel J. Danishefsky*
Department of Chemistry, Columbia UniVersity, HaVemeyer Hall, New York, New York 10027, and
Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute 1275 York AVenue, New York, New York 10021
Received January 12, 2005; E-mail: s-danishefsky@mskcc.org
Scheme 1. Synthetic Strategy for Cribrostatin IV (1)
The piperizinohydroisoquinoline motif (a) appears in a diverse
series of alkaloids, including naphthyridinomycin, the quinocarci-
noids, the saframycins, the reneiramycins, and the ecteinascidins.1
Exemplary of the ecteinascidins is ET-743,2 (b), one of the most
potent cytotoxins known. This drug, whose availability is to a great
extent due to the dominant total synthesis of E. J. Corey and
associates,3 is currently being evaluated at various clinical levels
for the treatment of a range of cancers.
Obviously, conciseness and efficiency would be pivotal for a
total synthesis to service such broader ends. Our plan involved
joining an AB-ring moiety to a putative DEF precursor via
fashioning of an amide bond [see (f)]. In the defining f f g
transformation, C11, ultimately in the form of an aldehyde,
interpolates itself between C3 and N12. This line of reasoning led
us back to genus-type structures [(d) and (e)].
Needless to say, for such a scheme to be implementable in an
organized way, the components to be merged [(d) and (e)] must
be presented as suitably functionalized subunits, whose absolute
configurations correspond, at pertinent stereogenic centers, to
cribrostatin IV (1). Specifically, we elected to couple components
9 and 17. We first describe the syntheses of these configurationally
“matched” compounds using reagent-controlled enantiotopic induc-
tion in catalytic settings. From there, we go on to describe the first
total synthesis of cribrostatin IV (1).
Commercially available 3-methyl-1,2-dimethoxybenzene was
converted to 2 (Scheme 2).10 Regiospecific bromination ortho to
the phenolic group, followed sequentially by methylation and
Baeyer-Villiger-like cleavage of the aldehyde function, provided
a new phenol, in which the hydroxyl group was subsequently
protected as its -TBDPS derivative (see compound 3). Lithiation
of the bromo function was followed by C-acylation with compound
4, which corresponds to the Weinreb amide of -OBn glycolic
acid.11
Entrance to the “chiral pool” was accomplished through reduction
of the benzyl ketone (cf. 5 f 6), following protocols first described
by Noyori and associates.12 Displacement of the hydroxyl group
through the agency of diphenylphosphoryl azide provided 7.13
Reduction of 7, and two-carbon homologation, followed by
regiospecific exposure of the A-ring phenol group, was followed
by its temporary protection in the form of allyl ether 8. Finally,
Bobbitt modified Pomeranz-Fritsch cyclization of 8 gave rise to
9.14 The configurational inhomogeneity of the future C4 at the stage
In 2000, Pettit reported the isolation and structural deduction of
a neoplastic agent, cribrostatin IV (1), from a blue marine sponge,
Cribrochalina, in reef passages in the Republic of Maldives.4
Shortly thereafter, Kubo and colleagues reported a reassignment
of the structure of the semisynthetically derived reneiramycin H,5a
thereby showing it to be the same as 1.5b
Several considerations converged to direct our attentions to a
possible total synthesis of cribrostatin IV (1). While lacking the
propeller-like character of ET-743, 1 is arguably the most func-
tionalized of the traditional pentacyclic-type core alkaloids. Thus,
eVery skeletal carbon atom in 1 appears in oxidized form, with its
A-ring in the quinonoidal oxidation leVel and its E-ring as an ET-
saframycin “hybrid”6 in its core domain. The presence of the
C3-C4 double bond, in the context of the A-ring quinone, serves
as a central connecting element in a formal vinylogous imidic
network.7 Also worthy of note is the hydroquinone E-ring, which
owes its otherwise surprising stability to the presence of the keto
group at C14.8
Not the least intriguing feature of cribrostatin IV (1) is that it is
a potent (low micromolar) cytotoxic agent. While in the context of
saframycins and particularly ET-743, much higher cytotoxicities
are expected and encountered, 1 lacks the characteristic N2-C21
cyanomethinyl or the N2-C21 hydroxymethinyl (i.e., hemiaminal)
motifs [see (c)].1 Pre-C21 iminium ion functionalities had been
presumed to be essential to both in vitro and in vivo activity.9
Because 1 is isolatable in only trace amounts, total synthesis could
well surpass isolation as a means to access quantities of material
suitable for evaluation of biological activity. Thus, a viable synthetic
route to 1 could set into motion a focused discovery program
seeking to optimize between potency, maximum tolerable dose, and
therapeutic index of potential congeners.
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10.1021/ja050203t CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Scheme 4. Cyclization Leading to Pentacyclic Core 21a
Scheme 2. Synthesis of Coupling Partner 9a
a Key: (a) i. Br2, NaOAc, AcOH; ii. Me2SO4, Bu4NBr, NaOH, CH2Cl2,
76% over two steps; (b) i. mCPBA, CHCl3; ii. HCl, MeOH, 78% over two
steps; (c) TBDPSCl, TEA, DMAP, DMF, 89%; (d) i. n-BuLi, toluene:THF
(9:1), -78 °C; ii. 4, 80% over two steps; (e) (RuCl2)2(p-cymene)2, DMF/
HCO2H/TEA, 40 °C, 94%, 95% ee; (f) DPPA, DBU, toluene:DMF (9:1),
50 °C, 82%, 95% ee; (g) 5% Pd/C, 1 atm H2, EtOAc, 80%; (h) i.
(MeO)2CHCHO, AcOH, NaCNBH3, MgSO4, MeOH; ii. TBAF, THF, 99%
over two steps; (i) allyl bromide, NaH, DMF, 87%; (j) 8.0 M HCl/dioxane,
97%.
a Key: (a) BOPCl, TEA, CH2Cl2, 89%; (b) DDQ, CH2Cl2/buffer (pH
7), 90%; (c) DMP, 2,6-lutidine, CH2Cl2, 84%; (d) HCO2H, 100 °C, 59%;
(e) i. NaBH4, THF/H2O; ii. AcOH, Bu3SnH, (Ph3P)2PdCl2, CH2Cl2,3 98%
over two steps; (f) CSA, benzene, 80 °C, 80%.
Scheme 5. Unsuccessful Route to 1a
Scheme 3. Synthesis of Coupling Partner 17a
a Key: (a) TsCl, Et3N, CH2Cl2, 84%; (b) ICl, AcOH, 96%; (c) MeI,
K2CO3, acetone, 95%; (d) NaOH, EtOH, 90%; (e) (CH2O)n, Et2AlCl,
CH2Cl2, 86%; (f) BnBr, K2CO3, acetone, 85%; (g) PMBCl, NaH, THF:DMF,
99%; (h) TEA, 14,18 Bu4NBr, (o-tolyl)3P, Pd(OAc)2, CH3CN, 87% (Z isomer
only); (i) Rh[(COD)-(S,S)-Et-DuPhos]+TfO-, 100 psi H2, CH2Cl2/MeOH,
93%, 99% ee; (j) LiOH, MeOH/THF/H2O, 93%; (k) MeI, NaH, THF, 82%.
a Key: (a) 5% Pd/C, H2 (1 atm) EtOAc; (b) Fremy salt, KH2PO4, CH3CN/
H2O; (c) SeO2, dioxane, 100 °C; (d) DMP, CH2Cl2; (e) 10% Pd/C, H2 (1
atm), MeOH; (f) air, MeOH.
Compound 22, arising from selective deprotection of the aromatic
benzyl group of 21, was oxidized with Fremy salt to afford
bisquinone 23 (Scheme 5).22 Oxidation of 23 with selenium dioxide
occurred regio- and stereospecifically at C14 to give rise to 24.23
The latter, following exposure to Dess-Martin periodinane (DMP),
gave rise to a relatively stable keto bisquinone. Reduction of the
two quinone rings as well as deprotection of the primary alcohol
at C22 was followed by selective air oxidation of the A-ring
hydroquinone. Clearly, the selectivity in this oxidation arises from
the high-energy character of the E-ring quinone due to the C14
ketone.24 Compound 25, requiring only “angelation” of the primary
alcohol (see C1 hydroxymethyl group), was now in hand.
However, despite extensive efforts, all attempts to accomplish
the requisite esterification failed. Substrate 25 exhibited instability
to a range of mildly basic conditions of the type needed to mediate
the acylation reaction. We attributed the vulnerability of the
substrate to various bases as reflecting its susceptibility to nucleo-
philic attack at C21. This was then followed by cleavage of the
C21-C13 (â-dicarbonyl) bond.25 It was noted that the character of
the C21 carbonyl function in compound 25 was that of a vinylogous
imide. Indeed in such a context, the â-dicarbonyl connectivity of
C14 and C21 could well exhibit high base lability. Our remaining
possibility was to attempt the esterification at an earlier stage, while
the A-ring was in the hydroquinone, rather than in the quinone,
oxidation level. We hoped that this change in oxidation level, though
somewhat remote from the reactive C21 center, could profoundly
alter its character in electronic terms, perhaps allowing for
angelation at C22. Of course, in such a setting, we would be obliged
to conduct significant chemistry with the potentially labile angelate
already in place.
of 9 constitutes an esthetic awkwardness rather than a substantive
complication to the overall synthesis (vide infra).
To reach the configurationally matched coupling partner 17, we
started with the commercially available 3-methylcatechol (10)
(Scheme 3). Temporary protection of the less hindered phenol as
its tosylate derivative was followed by regiospecific iodination. The
iodo compound was converted, as shown, to 11, which following
ortho-hydroxymethylation, afforded 12.15
To enable orderly progress, it would be helpful to differentiate
the protecting patterns on the phenolic hydroxyl versus the benzylic
alcohol, corresponding to the future C11 aldehyde. Fortunately, it
proved possible to define conditions leading to clean benzylation
of the phenolic group. This reaction was, in turn, followed by para-
methoxybenzylation of the benzylic alcohol, giving rise to com-
pound 13. The latter served admirably as a substrate in a Jeffery-
Heck coupling reaction, thus affording compound 15 as the only
isomer.16 Reduction of the double bond with enantiotopic control,
in the manner indicated, afforded 16 in good yield.17 Simple
hydrolysis of the methyl ester and N-methylation gave rise to
coupling partner 17.
Amidation of the carboxylic acid of 17 with secondary amine 9
gave rise to 18 (Scheme 4).19 Oxidative deprotection of the PMB
group, followed by simultaneous oxidation of the primary and
secondary alcohols, afforded the key seco-substrate 19.20 The stage
was set for the critical intramolecular lynchpin-like Mannich
reaction. In the event, cleavage of the Boc function of 19 set into
motion a predictable sequence culminating in the desired product,
20, in good yield.21 From this intermediate, we were able to gain
access to 21 in short order.
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C O M M U N I C A T I O N S
Scheme 6. Completion of Synthesis of Cribrostatin IV (1)a
on key intermediates (PDF). This material is available free of charge
via the Internet at http://pubs.acs.org.
References
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dioxane, 100 °C, 87%; (e) DMP, CH2Cl2; (f) 10% Pd/C, H2 (1 atm), MeOH,
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In the event, compound 26, prepared from compound 21, was
oxidized to 27, and the latter converted to 28 according to the
procedures described above (Scheme 6). Upon treatment of 28 with
acyl chloride 29,26 angelation occurred uneventfully. Compound
30 was obtained following TBS deprotection. The angelated
intermediate, 30, was converted to cribrostatin IV (1) through a
series of straightforward manipulations of rings A and E.8 The
selective air oxidation of the ring A hydroquinone in the last step
follows, as above (see 24 f 25), from the high-energy character
of an E-ring quinone flanked by a ketone.24 The spectroscopic
properties of synthetic 1 were in complete accord with those of
natural cribrostatin IV (1).4
In summary, an enantioselective synthesis of cribrostatin IV (1)
has been accomplished through a convergent coupling of two
extremely functionalized, matched enantiopure compounds, a
“lynchpin Mannich” cyclization to establish the pentacyclic core,
a selective angelation strategy, and the use of the C14 keto function
to distinguish between two hydroquinone-quinone oxidation resting
states in rings A and E. A key feature of the synthesis described
above was the ability to modulate the character of N2 and,
accordingly, C21 by varying the oxidation state of ring A. It is well
within reason that this concept27 could find further application in
fine-tuning SAR profiles of prospective drug candidates in this
series. Studies of the SAR profiles of analogues of cribrostatin IV
(1) by synthesis or by diverted total synthesis28 are underway.
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nine gave lower yields due to polymerization. Accordingly, precursor 14
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(21) In our previous demonstration of this type of reaction (see ref 19b), a syn
relationship was established between C3 and C11. In the case of 19 f 20,
the relationship is anti. We note that, to the best of our knowledge,
compound 20 is the first example of a C3-C11 anti structure in the
saframycin-like backbone series. It is now recognized that the C3-C11
anti vs syn relationship is governed by the relative configurations at C1
and C13. In the matched series, as shown in 19, we obtain anti product.
With C1 as shown, and C13 in the D-amino acid configuration, the C3-
C11 relationship emerges syn. A full account of this remote control element
will be provided shortly.
(22) Zimmer, H.; Lankin, D. C.; Horgan, S. W. Chem. ReV. 1971, 71, 229.
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(25) The range of products arising from the unraveling of the amidic
â-dicarbonyl system has not been fully sorted out. However, we have
support for C13-C21 bond cleavage in some products.
Acknowledgment. This paper is dedicated to the memory of
Professor Louis Fieser, who explicated the notion of high-energy
quinones to one of the authors in 1959 (see ref 24). The authors
wish to thank Professor G. Pettit for a sample of natural cribrostatin
IV, which was used for comparison to the synthesized material.
This work was supported by the National Institutes of Health (Grant
HL 25848) and by Pharmamar Corporation of Madrid, Spain. R.H.
is grateful for financial support from Merck.
(26) Beeby, P. J. Tetrahedron Lett. 1977, 18, 3379.
(27) The notion of the reductive unveiling of drug-like activity from bioacti-
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Am. Chem. Soc. 2004, 126, 1038.
Supporting Information Available: Experimental procedures, 1H
and 13C spectra, optical rotations, HRMS, and additional information
JA050203T
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