A Convergent Synthesis of the Macrocyclic Core of Cytotrienins: Application of RCM for Macrocyclization

Article abstract of DOI:10.1021/ol036284k

(Equation presented) The asymmetric synthesis of the fully elaborated macrocyclic core of cytotrienins A-D, potent apoptosis-inducing agents, is described. Synthetic highlights include the construction of the aniline bond using a copper-mediated amidation and the use of a ring-closing metathesis (RCM) reaction to efficiently install the (E,E,E)-triene and simultaneously construct the macrocyclic lactam.

Full text of DOI:10.1021/ol036284k

ORGANIC
LETTERS
2004
Vol. 6, No. 4
525-528
A Convergent Synthesis of the
Macrocyclic Core of Cytotrienins:
Application of RCM for Macrocyclization
Gwilherm Evano, Jennifer V. Schaus, and James S. Panek*
Department of Chemistry and Center for Chemical Methodology and
Library DeVelopment, Boston UniVersity, 590 Commonwealth AVenue,
Boston, Massachusetts 02215
panek@chem.bu.edu
Received November 22, 2003
ABSTRACT
The asymmetric synthesis of the fully elaborated macrocyclic core of cytotrienins A−D, potent apoptosis-inducing agents, is described. Synthetic
highlights include the construction of the aniline bond using a copper-mediated amidation and the use of a ring-closing metathesis (RCM)
reaction to efficiently install the (E,E,E)-triene and simultaneously construct the macrocyclic lactam.
In the last two decades, a series of publications reported the
isolation and structure elucidation of several members of a
new class of ansamycin compounds, including mycotrienins
(or ansatrienins),1 trienomycins,1c,2 and thiazinotrienomycins.3
Common structural features of these compounds include a
(E,E,E)-triene within a 21-membered lactam containing four
stereocenters; functionalized side chains and aromatic cores
differentiate the individual structures and play an important
role in their biological activities. More recently, Osada and
co-workers isolated four new members of this family of
compounds, cytotrienins A-D 1-4 (Scheme 1), obtained
Scheme 1. Cytotrienins A-D
(1) (a) Sugita, M.; Natori, Y.; Sasaki, T.; Furihata, K.; Shimazu, A.; Seto,
H.; Otake, N. J. Antibiot. 1982, 35, 1460-1466. (b) Sugita, M.; Sasaki, T.;
Furihata, K.; Shimazu, A.; Seto, H.; Otake, N. J. Antibiot. 1982, 35, 1467-
1473. (c) Smith, A. B., III; Wood, J. L.; Wong, W.; Gould, A. E.; Rizzo,
C. J.; Barbosa, J.; Funayama, S.; Komiyama, K, Omura, S. J. Am. Chem.
Soc. 1996, 118, 8308-8315.
(2) (a) Funyama, S.; Okada, K.; Komiyama, K.; Umezawa, I. J. Antibiot.
1985, 38, 1107-1109. (b) Funyama, S.; Okada, K.; Iwasaki, K.; Komiyama,
K.; Umezawa, I. J. Antibiot. 1985, 38, 1677-1683. (c) Nomoto, H.;
Katsumata, S.; Takahashi, K.; Funayama, S.; Komiyama, K.; Umezawa,
I.; Ohmura, S. J. Antibiot. 1989, 42, 479-481.
(3) (a) Hosokawa, N.; Naganawa, H.; Inuma, H.; Hamada, M.; Takeuchi,
T.; Kanbe, T.; Hori, M. J. Antibiot. 1995, 48, 471-478. (b) Smith, A. B.,
III; Barbosa, J.; Hosokawa, N.; Naganawa, H.; Takeuchi, T. Tetrahedron
Lett. 1998, 39, 2891-2894.
from the fermentation broth of Streptomyces sp. RK95-74.4
Those new ansamycins possess an unusual aminocyclopro-
pane carboxylic acid side chain, and cytotrienins A and B
were shown to induce apoptosis in human acute promyelotic
10.1021/ol036284k CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/16/2004

leukemia HL-60 cells with an ED50 value of 7.7 nM.5 The
absolute and relative stereochemistry of cytotrienins have
yet to be determined but can be assumed to be identical to
those of mycotrienins due to their structural similarities and
biosynthetic pathway.4a,6
The biological activities and unique structures of these
ansamycins have made them attractive targets for synthesis.
Thus, several strategies have been used for the key macro-
cyclization step. The initial report by Smith for the synthesis
of (+)-trienomycins A and F utilized a bis-Wittig olefina-
tion.7 The synthesis of (+)-mycotrienin I incorporated a
tandem inter-/intramolecular Stille coupling,8 while (+)-
thiazinotrienomycin E was constructed using macrolactam-
ization.9 Described herein is our approach to the fully
elaborated macrocyclic core of cytotrienins, featuring a ring-
closing metathesis (RCM) reaction for the key macro-
cyclization step.
C16 8 fragments, which would be coupled by alkylation of
the sulfone as previously documented.7-9 The aromatic
fragment 7 could be synthesized using Buchwald’s copper-
mediated amidation11 of 9 with 10 while the C9-C16 frag-
ment would derive from addition of lithium anion 11 onto
aldehyde 12, readily available via Abiko and Masamune’s
anti-aldol methodology.12
The synthesis of the aromatic fragment (Scheme 3) started
with a regioselective bromination of commercially available
Scheme 3. Synthesis of the Aromatic Corea
From a retrosynthetic perspective, we envisioned instal-
lation of the side chain late in the synthesis, thereby
permitting construction of cytotrienins A-D from the
common advanced precursor 5 as depicted in Scheme 2. To
Scheme 2. Retrosynthetic Analysis of Cytotrienins A-D
a Reagents and conditions: (a) Br2, AcONa, AcOH, 89%. (b)
Me2SO4, K2CO3, DMF, 99%. (c) BH3‚THF, THF, quant. (d) PPh3,
CBr4, THF, 96%. (e) PhSO2Na, DMF, 86%.
2-hydroxy-5-methoxybenzaldehyde 13 using standard condi-
tions (Br2, AcONa, AcOH). Methylation of the phenol with
dimethyl sulfate and potassium carbonate followed by
reduction of the aldehyde with BH3‚THF gave benzylic
alcohol 16 in excellent yield (99% over two steps). At this
stage, it was necessary to introduce the sulfone, which was
effected by bromination of the benzylic alcohol with tri-
phenylphosphine and carbon tetrabromide followed by
displacement with sodium benzenesulfinate. This reaction
sequence efficiently completed the synthesis of the first
subunit 9 for the amidation reaction.
The synthesis of the chiral subunit 10, required for this
amidation reaction, is depicted in Scheme 4. Its preparation
began with Jacobsen’s hydrolytic kinetic resolution (HKR)
of racemic epoxide (()-18 employing (S,S)-Co(salen).13 This
reaction provided enantiomerically pure diol 19 in multigram
quantities and high enantiomeric purity. Selective protection
of the primary alcohol of the diol 19 (TBSCl, imidazole,
install the C4-C9 (E,E,E)-triene and simultaneously effect
macrocyclization, we decided to employ a challenging
RCM10 using the bis-1,3-diene 6 as the triene precursor.
Further analysis of 6 suggested that it could be disconnected
at the C16-C17 bond to give the aromatic 7 and the C9-
(8) Masse, C. E.; Yang, M.; Solomon, J.; Panek, J. S. J. Am. Chem.
Soc. 1998, 120, 4123-4134.
(9) Smith, A. B., III; Wan, Z. J. Org. Chem. 2000, 65, 3738-3753.
(10) For recent reviews, see: (a) Fu¨rstner, A. Angew. Chem., Int. Ed.
2000, 39, 3012-3043. (b) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res.
2001, 34, 18-29.
(4) (a) Zhang, H. P.; Kakeya, H.; Osada, H. Tetrahedron Lett. 1997, 38,
1789-1792. (b) Osada, H.; Kakeya, H.; Zhang, H. P.; Kobinata, K. PCT
Int. Appl. WO 9823594, 1998.
(5) Kakeya, H.; Zhang, H. P.; Kobinata, K.; Onose, R.; Onozawa, C.;
Kudo, T.; Osada, H. J. Antibiot. 1997, 50, 370-372.
(6) Zhang, H. P.; Kayeka, H.; Osada, H. Tetrahedron Lett. 1998, 39,
6947-6948.
(7) Smith, A. B., III.; Barbosa, J.; Wong, W.; Wood, J. L. J. Am. Chem.
Soc. 1996, 118, 8316-8328.
(11) Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002,
124, 7421-7428.
(12) (a) Abiko, A.; Liu, J. F.; Masamune, S. J. Am. Chem. Soc. 1997,
119, 2586-2587. (b) Inoue, T.; Liu, J. F.; Buske, D. C.; Abiko, A. J. Org.
Chem. 2002, 67, 5250-5256.
(13) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.; Hansen,
K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. N. J. Am. Chem. Soc.
2002, 124, 1307-1315.
526
Org. Lett., Vol. 6, No. 4, 2004

Scheme 4. Completion of the Aromatic Fragmenta
Scheme 5. Synthesis of the C9-C16 Fragmenta
a Reagents and conditions: (a) (S,S)-Co(salen), AcOH, H2O,
THF, 50% conversion, 47%. (b) TBSCl, imidazole, THF, 0 °C,
96%. (c) Me3OBF4, 4 Å MS, proton sponge, CH2Cl2, 96%. (d) H2,
Pd/C, MeOH, quant. (e) EtOCOCl, Et3N, CH2Cl2, -20 °C then
NH3 gas 91%. (f) 9 (1.0 equiv), 20 mol % CuI, 40 mol % N,N′-
dimethylethylenediamine, K2CO3, toluene, 110 °C, 82%.
a Reagents and conditions: (a) Cy2BOTf, Et3N, CH2Cl2 -78 °C
then CHOCH2CH2OTBS, -78 °C to room temperature, 94%, dr
> 30:1. (b) TBSOTf, 2,6-lutidine, CH2Cl2, 96%. (c) Me(MeO)NH‚
THF) allowed for the methylation of the secondary hydroxyl
group with Meerwein’s reagent in excellent overall yield
(92% over two steps). Subsequent debenzylation of the ester
20 by hydrogenolysis followed by amidation in a two-step,
one-pot procedure via a mixed anhydride provided the
desired amide 10 in good yield.
i
HCl, PrMgCl, THF, -20 to 5 °C, 87%. (d) DibalH, THF, -78
°C. (e) 11, THF, -78 °C, 73% (two steps), dr ) 6.5:1. (f) TIPSOTf,
2,6-lutidine, CH2Cl2, 98%. (g) DDQ, CH2Cl2/H2O (10/1), 0 °C,
94%. (h) I2, PPh3, imidazole, CH2Cl2, 0 °C, 88%.
To undertake the assembly of the aromatic fragment 7, a
copper-mediated amidation between aryl bromide 9 and
amide 10 was investigated. After screening several reaction
conditions,11 it was determined that this coupling was best
effected using 20 mol % CuI, 40 mol % N,N′-dimethyl-
ethylenediamine, and potassium carbonate as a base in
toluene at 110 °C and using a slight excess (1.2 equiv) of
the amide 10. Under these conditions, amidation product 7
was obtained in 84% yield. Moreover, we found that a 1:1
ratio of bromide 9 and amide 10 did not significantly
decrease the yield of this reaction since the aromatic fragment
could be obtained in 82% yield and in multigram quantities.
The synthesis of the C9-C16 fragment is outlined in
Scheme 5. anti-Aldol condensation of 2112 with tert-
butyldimethylsilyloxypropionaldehyde furnished aldol adduct
22 as a single diastereoisomer (94% yield). Protection of
the resulting alcohol as a TBS ether (TBSOTf, 2,6-lutidine,
CH2Cl2) followed by removal of the chiral auxiliary afforded
the Weinreb amide 23. This last step proved to be quite
challenging and required harsh conditions: while most
common methods14 failed to efficiently cleave the bulky
auxiliary, we found after considerable experimentation that
exposure of 22 to 10 equiv of Me(MeO)NMgCl15 from -20
to 5 °C gave the desired amide 23 in 87% yield. Conversion
of amide 23 to C9-C16 fragment 8 entailed installation of
the C13 stereocenter and the trisubstituted (Z)-olefin. To this
end, amide 23 was reduced to aldehyde 12 using DibalH in
THF. Subsequent treatment of 12 at -78 °C with vinyl-
lithium 11 provided the secondary alcohol 24 with a good
overall yield (73% over two steps) and reasonable selectivity
(Felkin:anti-Felkin ) 6.5:1). The stereochemical outcome
of this reaction can be rationalized using a Felkin-Ahn
model, and the stereochemistry at C13 was unambiguously
assigned using 13C NMR chemical shift analysis of the
acetonide derived from the 1,3-diol.16 The completion of 8
was effected by protection of the emerged alcohol as its
triisopropylsilyl ether, DDQ deprotection of the PMB ether,
and conversion of the allylic alcohol to the iodide using a
buffered solution of triphenylphosphine and iodine, which
afforded the C9-C16 fragment 8 in 81% yield over the last
three steps.
As previously reported,7-9 union of fragments 7 and 8 was
effected by alkylation of the sulfone 7 with the iodide 8
(Scheme 6). Deprotonation of the latter with LiHMDS in
THF at -78 °C followed by addition of 8 gave a coupling
product, which was subjected to treatment with sodium
mercury amalgam in buffered methanol, providing the
desulfonylated intermediate 25.
At this stage, we initiated the construction of the key (E,E)-
bis-1,3-diene for macrocyclization by RCM. To prevent any
complications due to cyclization of the amide to an N-
acylhemiaminal in a subsequent step, the amide was protected
as a 2,2,2-trichloroethylaminal, as previously discussed by
(14) (a) Levin, J. I.; Turos, E.; Weinreb, S. M. Synth. Commun. 1982,
12, 989-993. (b) Shimizu, T.; Osako, K.; Nakata, T. Tetrahedron Lett.
1997, 38, 2685-2688. (c) Huang, P. Q.; Zheng, X.; Deng, X. M.
Tetrahedron Lett. 2001, 42, 9039-9041.
(15) Williams, J. M.; Jobson, R. B.; Yasuda, N.; Marchesini, G.; Dolling,
U. H.; Grabowski, E. J. J. Tetrahedron Lett. 1995, 36, 5461-5464.
(16) Evans, D. A.; Rieger, D. L.; Gage, J. R. Tetrahedron Lett. 1990,
31, 7099-7100.
Org. Lett., Vol. 6, No. 4, 2004
527

Scheme 6. Fragment Coupling: Installation of the
Scheme 7. RCM Studies: Effect of Catalyst on
Bis-1,3-dienea
Macrocyclizationa
a Reagents and conditions: (a) 10 mol % 29, CH2Cl2, reflux,
47%. (b) 2 × 10 mol % 31, CH2Cl2, reflux, 73% (83% based on
recovered 6).
a Reagents and conditions: (a) LiHMDS (2.2 equiv), -78 °C
then 8, -78 to -30 °C, 73%. (b) Na(Hg), Na2HPO4, MeOH, -20
°C, 96%. (c) KH, THF, 0 °C then ClCH2OCH2CCl3, rt, 95%. (d)
HF‚pyr, pyr, THF, 0 °C, 91%. (e) pyr‚SO3, Et3N, DMSO, 91%. (f)
(i) 27, BF3‚OEt2, CH2Cl2, -78 to -50 °C; (ii) tBuOK, THF, 61%
(two steps). (g) Na(Hg), Na2HPO4, MeOH, -20 °C, 75%.
ably resulting from an unusual initiation of the RCM at the
internal bond of one of the 1,3-dienes (Scheme 7).22 To
overcome this problem and initiate the RCM at one of the
terminal olefins, 6 was exposed to the less reactive catalyst
31 in refluxing dichloromethane. Use of these conditions
afforded the expected (E,E,E)-triene 523 with excellent
selectivity and yield.
In conclusion, we have described a convergent synthesis
of the highly functionalized macrocyclic core of the cyto-
trienins. Synthetic highlights include an efficient synthesis
of the aromatic fragment through the use of a copper-
mediated amidation reaction, a modified Peterson olefination
to install the bis-1,3-diene, and a macrocyclization by RCM
to complete the assembly of the carbon framework of
cytotrienins. Studies toward the completion of cytotrienins
A-D are underway and will be reported in due course.
Smith and co-workers in their synthesis of trienomycins.7
Thus, treatment of 25 with potassium hydride and chloro-
methyl 2,2,2-trichloroethyl ether in THF gave the protected
amide as a mixture of atropoisomers at the C22-N aniline
bond (Scheme 6). Selective deprotection of the two primary
TBS ethers using a buffered solution of HF‚pyridine,
followed by a double Parikh-Doering oxidation, afforded
the bis-aldehyde 26.
Transformation of this bis-aldehyde 26 to the bis-1,3-diene
28 (Scheme 6) turned out to be unexpectedly difficult. After
considerable experimentation with conventional procedures
using phosphorus-based olefination reagents, we eventually
turned to an under-utilized reaction previously reported by
Yamamoto17 and modified by Keck.18 Following this pro-
cedure, bis-aldehyde 26 was reacted with allyltin 27 in the
presence of BF3‚OEt2 to give a complex diastereoisomeric
and atropoisomeric mixture of R-hydroxysilanes. Exposure
of this mixture to catalytic potassium tert-butoxide in THF
resulted in the formation of the Peterson elimination product
28 (Scheme 6).19 Finally, deprotection of the amide with
sodium mercury amalgam in buffered methanol provided the
free amide 6 in 75% yield.
Acknowledgment. We are grateful to the NIH-NCI, NIH-
GMS (CA56304) for funding and to Johnson & Johnson,
Merck Co., Novartis, and Pfizer for financial support. J.V.S.
is a recipient of a Division of Organic Chemistry Graduate
Fellowship sponsored by Wyeth-Ayerst.
Supporting Information Available: Experimental pro-
cedures and characterization. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL036284K
(20) (a) For construction of a conjugated, macrocyclic (E,Z,Z)-triene using
RCM, see: Wang, X.; Porco, J. A., Jr. J. Am. Chem. Soc. 2003, 125, 6040-
6041. (b) For an attempt to construct a conjugated, macrocyclic triene using
RCM, see: Wagner, J.; Cabrejas, L. M. M.; Grossmith, C. E.; Papageorgiou,
C.; Senia, F.; Wagner, D.; France, J.; Nolan, S. P. J. Org. Chem. 2000, 65,
9255-9260.
This set the stage for the crucial macrocyclization and
formation of the (E,E,E)-triene by RCM.20 Reaction of 6 with
ruthenium catalyst 29 unexpectedly gave diene 30,21 presum-
(17) Yamamoto, Y.; Saito, Y.; Maruyama, K. J. Organomet. Chem. 1985,
292, 311-318.
(21) The (E,E) stereochemistry of the diene 30 was assigned on the basis
of the coupling constants.
(18) Keck, G. E.; Romer, D. R. J. Org. Chem. 1993, 58, 6083-6089.
(19) The (E,E) stereochemistry of 28 was demonstrated by correlation
with the product obtained from bis-aldehyde 26 using the following
sequence: (i) Ph3PdCHCO2Et, CH2Cl2, (ii) DibalH, THF, (iii) Swern
(22) For a precedent of formation of a diene starting from a bis-1,3-
diene by RCM, see ref 20a.
(23) The (E,E,E) stereochemistry of the triene 5 was assigned on the
basis of the coupling constants between the two protons of the newly created
olefin.
n
oxidation, (iv) Ph3P+CH3Br-, BuLi, THF.
528
Org. Lett., Vol. 6, No. 4, 2004