Total synthesis of macbecin I

Article abstract of DOI:10.1002/anie.200800400

(Chemical Presented) Beyond the bounds of biosynthesis: In a step towards the goal of developing a synthetic pathway for the production of collections of complex molecules related to the benzoquinone ansamycin antibiotics, a natural member of this class w

Full text of DOI:10.1002/anie.200800400

Angewandte
Chemie
DOI: 10.1002/anie.200800400
Natural Product Synthesis
Total Synthesis of Macbecin I**
Justin K. Belardi and Glenn C. Micalizio*
Structurally complex natural products continue to serve as
stimuli for the development of synthetic organic chemistry.
While numerous total syntheses of complex targets have been
achieved, a remaining concern in the evolution of organic
chemistry is the efficiency with which such architectures can
be prepared. With the aim of establishing more efficient
pathways to complex targets, we have been developing new
strategies for the cross-coupling of a variety of highly
functionalized p systems. Herein, we describe the application
of one such process as the key step in a concise total synthesis
of macbecin I (Scheme 1), a benzoquinone ansamycin anti-
biotic.
inhibitors of Hsp90.[3] Numerous reports have described
synthetic pathways to access less complex nonnatural benzo-
quinone ansamycins in an effort to optimize their biological
properties.[4] Herein, we describe a total synthesis of macbe-
cin I that proceeds with high step economy[5] with respect to
previous studies in this area[2] and highlights the utility and
mild nature of titanium-mediated cross-coupling reactions
between functionalized alkynes and chiral aldehydes.[6]
Our retrosynthesis for macbecin I relied on a two-step
functionalization of the macrocyclic lactam 1 (Scheme 2), a
process previously described by Baker and Castro.[2a,b] We
The benzoquinone ansamycin antibiotics are a class of
polyketide-derived natural products that display a range of
antitumor, antibacterial, antifungal, and antiprotozoal activ-
ities.[1] Members of this class (Scheme 1) have been targets for
Scheme 1. Representative benzoquinone ansamycin antibiotics.
Scheme 2. Key bond constructions targeted for a synthesis of mac-
becin I. a) nucleophilic addition, b) nucleophilic substitution,
c) propargylation, d) palladium-catalyzed cross-coupling.
synthesis since the early 1980s, with the first total synthesis
appearing in 1989.[2a] Their unique chemical structures, which
have in common a 19-membered macrocyclic lactam that
houses a functionalized quinone, seven stereocenters, and
three stereodefined olefins, have continued to challenge
synthetic chemists for nearly twenty years.[2] Interest in this
class of macrocyclic compounds as potential therapeutics has
risen dramatically since the discovery that they are potent
envisioned that this complex intermediate could be derived
from the coupling of the aniline-containing alkyne 2 with the
stereochemically defined, and likely sensitive, b,g,d,e-unsatu-
rated aldehyde 3. Alkyne 2 should be accessible through three
ꢀ
key C C bond-forming processes (highlighted as a–c),
whereas aldehyde 3 could be prepared by the formation of
ꢀ
a central C C bond (d). We describe herein the application of
this ambitious coupling process to the total synthesis of the
benzoquinone ansamycin macbecin I.
[*] J. K. Belardi, Prof. G. C. Micalizio
Department of Chemistry, Yale University
225 Prospect Street, New Haven, CT 06520-8107 (USA)
Fax: (+1)203-432-6144
The synthesis of alkyne 2 commenced with a Myers
alkylation of the iodide 4,[7] followed by reduction to provide
the primary alcohol 6 (d.r. 9:1) in 70% yield over two steps
(Scheme 3). The oxidation of 6 to the corresponding alde-
hyde, followed by diastereoselective propargylation with the
chiral allenyl stannane 7, afforded the homopropargylic
alcohol 8 in 50% yield over two steps (diastereoselection as
judged prior to purification (d.s.) 4:1).[8] While the diastereo-
E-mail: glenn.micalizio@yale.edu
[**] We gratefully acknowledge financial support of this research by the
American Cancer Society (RSG-06-117-01), the Arnold and Mabel
Beckman Foundation, Boehringer Ingelheim, and Eli Lilly & Co. The
authors also thank Dr. Eric Paulson for assistance with the
spectroscopic characterization of 1 and macbecin I.
Supportinginformation for this article is available on the WWW
under http://www.angewandte.org or from the author.
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iodide 17[11] then delivered enyne 18 in 88% yield.
Lindlar reduction of the alkyne, followed by desilyla-
tion, provided diol 19 in 90% yield. Finally, oxidative
cleavage of the 1,2-diol[12] afforded the desired b,g,d,e-
unsaturated aldehyde 3. This highly sensitive inter-
mediate was used in the subsequent coupling reaction
without purification.
The titanium-mediated coupling of alkyne 2 with
aldehyde 3 proceeded in an efficient manner to afford
a mixture of coupled products in 74% combined yield
(Scheme 5). While chromatographic purification of
this mixture was not possible, Bakerꢀs intermediate 1
was accessed in 44% yield through a two-step process-
ing of this mixture: 1) saponification (LiOH, THF,
MeOH, H2O) and 2) macrocyclization (BOPCl,
iPr2NEt, toluene). During the course of these two
steps, the minor regio- and stereoisomers derived from
the coupling of 2 and 3 were effectively removed. This
process provided a straightforward preparative means
of accessing 1 as a single isomer and completing a
formal total synthesis of macbecin I.
Scheme 3. Preparation of the alkyne couplingpartner 2: a) 5, LDA, THF,
ꢀ788C!RT (d.r. 9:1); b) BH3·NH3, LDA, THF; c) Dess–Martin periodinane,
CH2Cl2; d) 7, BF3·OEt2, CH2Cl2, ꢀ788C; e) NaH, MeI, THF; f) BBr3, CH2Cl2,
ꢀ788C; g) (COCl)2, DMSO, Et3N, CH2Cl2; h) 10, nBuLi, Et2O, ꢀ788C!RT, then
addition of the aldehyde at ꢀ788C (d.r. 2:1); i) Dess–Martin periodinane,
CH2Cl2; j) LiAlH4, Et2O (2 steps, 76%, d.r. 1:1); k) NaH, MeI, THF; l) 1,3-
dimethylbarbituric acid, [Pd(PPh3)4], CH2Cl2. Bn=benzyl, DMSO=dimethyl
sulfoxide, LDA=lithium diisopropylamide.
With regard to the selectivity of the metal-medi-
ated coupling of alkyne 2 with aldehyde 3, the desired
isomer 20 was obtained as the major product. The
precise levels of regio- and stereoselectivity could not
be determined by analysis of the spectral data gath-
selectivity of this process was expected to be higher based on
the results of similar processes described by Marshall and co-
workers,[8] we anticipated that an erosion of diastereoselec-
tivity could accompany a partial epimerization of the chiral
allenyl stannane by a process that is known to complicate
their preparation.[8c] In spite of the moderate diastereoselec-
tivity of the double asymmetric propargylation, we were
pleased to obtain the desired alkyne as a single isomer after
standard flash column chromatography, and in only four steps
from iodide 4.
Methylation of the secondary alcohol in 8, followed by
BBr3-promoted debenzylation, provided the primary alcohol
9 in 73% yield. Alcohol 9 was then converted into the
coupling partner 2 by oxidation to the aldehyde, nucleophilic
addition of a preformed aryl lithium reagent derived from
10,[2i] methylation, and deallylation. As observed in a related
bond construction,[2i] nucleophilic addition of the aryl lithium
reagent derived from 10 to the aldehyde derived from 9
proceeded with 2:1 stereoselection. The desired isomer 11
was produced as the major product and easily purified from
Scheme 4. Preparation of the aldehyde couplingpartner 3: a) 15,
[Pd(PPh3)4], InI, HMPA, THF; b) 17, [Pd(PPh3)4], CuI, Et3N; c) Pd on
CaCO3/lead, quinoline, benzene, H2; d) HF·pyridine, pyridine, THF;
e) Pb(OAc)4, EtOAc. Ms=methanesulfonyl, TBS=tert-butyldimethyl-
silyl.
its diastereomer 12 by column chromatography. Furthermore,
the minor diastereomer 12 could be recycled by a two-step
oxidation/reduction sequence to provide additional quantities
of the desired diastereomer 11. Overall, this pathway
provided a relatively concise and scalable route to the
coupling partner 2, which was prepared in 10 linear steps
from iodide 4.
The preparation of aldehyde 3 began with palladium-
catalyzed asymmetric propargylation of the a-silyloxy acet-
aldehyde 14 with alkyne 15[9] to provide the anti homopro-
pargylic alcohol 16 (d.r. 5:1) in 82% yield (Scheme 4).
Sonogashira coupling[10] with the readily available vinyl
ered. However, in a related coupling reaction of alkyne 2 with
an aldehyde that lacked the terminal methyl ester, the desired
regio- and stereoisomer was produced as the major product
with 7:1 regioselectivity and 3:1 diastereoselectivity.[13]
With the macrocyclic lactam 1 in hand, we turned to a
well-established end-game strategy to complete the total
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enable the probing of structure–activity relationships and
production of significant quantities of benzoquinone ansa-
mycin inspired Hsp90 inhibitors unbound by the constraints
of biosynthesis.
Received: January 25, 2008
Published online: April 11, 2008
Keywords: ansamycin antibiotics · cross-coupling·
.
natural products · titanium · total synthesis
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Scheme 5. Fragment coupling and completion of the total synthesis:
a) 2, ClTi(OiPr)3, c-C5H9MgCl, toluene, ꢀ78 to ꢀ308C, then addition of
3 at ꢀ788C as a solution in toluene, ꢀ788C!RT (74% yield of a
mixture of regio- and stereoisomers); b) LiOH, THF, MeOH, H2O;
c) BOPCl, iPr2NEt, toluene; d) Cl3CONCO, CH2Cl2, then K2CO3,
MeOH; e) CAN, H2O, CH3CN. BOPCl=bis(2-oxo-3-oxazolidinyl)phos-
phinic chloride, CAN=ceric ammonium nitrate.
synthesis of the natural product.[2a,b] The conversion of 1 to the
corresponding carbamate followed by the notoriously chal-
lenging oxidation of the aromatic ring to the quinone (CAN,
H2O, CH3CN)[2a,b] completed the total synthesis of macbe-
cin I.
Overall, the use of a titanium-mediated reductive cross-
coupling reaction between a highly functionalized alkyne and
sensitive chiral aldehyde formed the basis of a convergent
total synthesis of macbecin I. The success of this coupling
reaction demonstrates the functional-group compatibility and
mild nature of the process. Furthermore, the ability to couple
2 with 3 directly led to the total synthesis of a benzoquinone
ansamycin antibiotic in only 15 steps from the readily
available iodide 4 (longest linear sequence). The titanium-
mediated reductive cross-coupling reaction used in this total
synthesis is, to our knowledge, among the most complex
examples of such reaction methodology and demonstrates the
great potential of titanium-mediated coupling processes in the
synthesis of complex molecules.[6i–l]
Although the total number of synthetic operations
required to access macbecin I through this route remains
above thirty (from readily available starting materials), this
synthesis represents a significant advance toward the goal of
developing a synthetic pathway for the production of
collections of complex molecules related to the benzoquinone
ansamycins. Such contributions can serve as a foundation to
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Communications
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