Application of tandem ring-closing enyne metathesis: Formal total synthesis of (-)-cochleamycin A

Article abstract of DOI:10.1021/ol900923c

A tandem ring-closing metathesis of a silaketal-based dlenyne substrate proceeded efficiently to provide a bicyclic siloxane, which upon removal of the silicon tether afforded an (E,Z)-1,3-dienediol. Further manipulation of this key functional motif rende

Full text of DOI:10.1021/ol900923c

ORGANIC
LETTERS
2009
Vol. 11, No. 13
2916-2919
Application of Tandem Ring-Closing
Enyne Metathesis: Formal Total
Synthesis of (-)-Cochleamycin A
Sumit Mukherjee and Daesung Lee*
Department of Chemistry, UniVersity of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois 60607
dsunglee@uic.edu
Received April 28, 2009
ABSTRACT
A tandem ring-closing metathesis of a silaketal-based dienyne substrate proceeded efficiently to provide a bicyclic siloxane, which upon
removal of the silicon tether afforded an (E,Z)-1,3-dienediol. Further manipulation of this key functional motif rendered synthesis of the entire
C1-C19 linear skeleton of (-)-cochleamycin A, a late-stage intermediate employed in the previous total synthesis of (+)-cochleamycin A by
Roush and co-workers.
Cochleamycin A was isolated in 1992 by a team headed by
Shindo and Kawai during a screening program for antitumor
antibiotics from a cultured broth of Streptomyces DT136.1
Subsequently, they reported significant antimicrobial activity
against Gram-positive bacteria and cytotoxicity against P388
leukemia cells (IC50 ) 1.6 µg/mL) for cochleamycin A.2 The
relative stereochemistry and the 5,6-fused and 10,6-bridged
tetracyclic core were later revealed by them from exhaustive
NMR studies.3 Not surprisingly, the combination of archi-
tectural complexity and favorable biological activity led to
a number of impressive initital synthetic studies,4 finally
resulting in the first total synthesis and establishment of the
absolute configuration of naturally occurring (+)-cochlea-
mycin A by Tatsuta and co-workers.5 Soon after, Roush and
Dineen also reported their total synthesis of (+)-cochlea-
mycin A.6 These synthetic studies were based on the
proposed biosynthetic pathway of cochleamycins involving
a putative transannular Diels-Alder reaction of (E,Z,E)-
1,6,8-nonatrienes to construct the cochleamycin A skeleton.7
We envisioned that the prowess of enyne metathesis8 to
form 1,3-dienes can be implemented in the synthesis of
(1) Shindo, K.; Kawai, H. J. Antibiot. 1992, 45, 292.
(2) Shindo, K.; Matsuoka, M.; Kawai, H. J. Antibiot. 1996, 49, 241.
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H.; Takao, K.; Tadano, K. Org. Lett. 2001, 3, 3029.
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(7) Shindo, K.; Sakakibara, M; Kawai, H.; Seto, H. J. Antibiot. 1996,
49, 249.
10.1021/ol900923c CCC: $40.75
Published on Web 06/09/2009
 2009 American Chemical Society

cochleamycin A if we can effectively control the E/Z
stereochemistry of 1,3-diene. Previously, we reported on a
tandem dienyne ring-closing metathesis (RCM) of alkynyl
silaketals to generate bicyclic siloxanes9 in the presence of
Grubbs NHC-ruthenium catalyst.10 Removal of the silicon
tether through protodesilylation allowed for the generation
of stereochemically defined 1,4-substituted (E,Z)-1,3-dienes.
The group selectivity (ring closure from right to left vs that
from left to right) in tandem RCM to obtain only the desired
regioisomer would be achieved by differential substitution
on the alkene as demonstrated in the construction of the
carbon framework of tatrolon B.11 Herein, we report a formal
total synthesis of (-)-cochleamycin A by intercepting the
Roush advanced synthetic intermediate.
(triethylsilyl)acetylide,14 which afforded the known 3-trieth-
ylsilylpropynal15 in 78% yield (Scheme 2). This aldehyde
Scheme 2
Scheme 1. Retrosynthetic Analysis for (-)-Cochleamycin A
was then subjected to double Michael addition of 1,3-
propanedithiol in the presence of basic alumina to give
dithiane aldehyde 8 in 85% yield.16 Asymmetric allylation
utilizing the pseudoephedrine-derived strained silacycle 9
developed by Leighton and co-workers afforded homoallylic
alcohol 10 in 74% yield and 77% enantiomeric excess (ee).17
Many other conventional aymmetric allylation protocols
including Brown’s allylation,18 Roush allylation,19 Keck
(12) For tandem enyne RCM, see: (a) Grimm, J. B.; Otte, R. D.; Lee,
D. J. Organomet. Chem. 2005, 690, 5508. (b) Boyer, F.-D.; Hanna, I.;
Ricard, L. Org. Lett. 2004, 6, 1817. (c) Hoye, T. R.; Jeffrey, C. S.;
Tennakoon, M. A.; Wang, J.; Zhao, H. J. Am. Chem. Soc. 2004, 126, 10210.
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Grebe, T. P. Org. Lett. 2002, 4, 2417. (e) Boyer, F.-D.; Hanna, I.; Ricard,
L. Org. Lett. 2001, 3, 3095. (f) Timmer, M. S. M.; Ovaa, H.; Filippov,
D. V.; van der Marel, G. A.; van Boom, J. H. Tetrahedron Lett. 2001, 42,
8231. (g) Choi, T. L.; Grubbs, R. H. Chem. Commun. 2001, 2648. (h)
Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H. J. Am. Chem.
Soc. 2000, 122, 3783. (i) Kim, S. H.; Zuercher, W. J.; Bowden, N. B.;
Grubbs, R. H. J. Org. Chem. 1996, 61, 1073. (j) Kim, S. H.; Bowden, N.;
Grubbs, R. H. J. Am. Chem. Soc. 1994, 116, 10801. (k) Middleton, M. D.;
Peppers, B. P.; Diver, S. T. Tetrahedron 2006, 62, 10528. (l) Krishna, P. R.;
Narasingam, M. Tetrahedron Lett. 2007, 48, 8721. (m) Kim, B. G.; Snapper,
M. L. J. Am. Chem. Soc. 2006, 128, 52.
As shown in the retrosynthetic analysis in Scheme 1,
ꢀ-keto ester 2, an advanced intermediate employed in the
Roush total synthesis of (+)-cochleamycin A,6 would be
derived from dienediol precursor 3. The tandem RCM12 of
silaketal 4 followed by desilylation would deliver dienediol
3. Silaketal 4 could be obtained from the base-catalyzed
stepwise alcoholysis of cyclopentyltrialkynylsilane 6 with
alcohols 5 and 7. The key intermediate 5 was prepared by
utilizing the anion relay chemistry developed by Smith and
co-workers.13 A general route to a precursor of 5 was
developed starting with the formylation of the lithium
(13) (a) Smith, A. B.; Xian, M. J. Am. Chem. Soc. 2006, 128, 66. (b)
Smith, A. B.; Adams, C. M. Acc. Chem. Res. 2004, 37, 365. (c) Smith,
A. B.; Boldi, A. M. J. Am. Chem. Soc. 1997, 119, 6925. (d) Smith, A. B.;
Wuest, W. M. Chem. Commun. 2008, 45, 5883. (e) Smith, A. B.; Kim,
D.-S. Org. Lett. 2007, 9, 3311.
(14) Journet, M.; Cai, D; DiMichele, L. M.; Larsen, R. D. Tetrahedron
Lett. 1998, 39, 6427.
(15) Bonazzi, S.; Gu¨ttinger, S.; Zemp, I.; Kutay, U.; Gademann, K.
Angew. Chem., Int. Ed. 2007, 46, 8707.
(16) For syntheses of 1,3-dithianes by double conjugate addition, see:
(a) Ranu, B. C.; Bhar, S.; Chakraborti, R J. Org. Chem. 1992, 57, 7349.
(b) Gaunt, M. J.; Sneddon, H. F.; Hewitt, P. R.; Orsini, P.; Hook, D. F.;
Ley, S. L. Org. Biomol. Chem. 2003, 1, 15. (c) Xu, C.; Bartley, J. K.;
Enache, D. I.; Knight, D. W.; Lunn, M.; Lok, M.; Hutchings, G. J.
Tetrahedron Lett. 2008, 49, 2454. (d) Kuroda, H.; Tomiro, I.; Endo, T.
Synth. Commun. 1996, 26, 1539.
(8) For review on enyne metathesis, see: (a) Giessert, A. J.; Diver, S. T.
Chem. ReV. 2004, 104, 1317. (b) Poulsen, C. S.; Madsen, R. Synthesis 2003,
1. (c) Mori, M. Top. Organomet. Chem. 1998, 1, 133. (d) Mori, M. In
Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH: Weinheim, 2003;
Vol. 2, pp 176-204.
(9) Grimm, J. B.; Otte, R. D.; Lee, D. J. Organomet. Chem. 2005, 690,
5508.
(17) Kinnaird, J. W. A.; Ng, P. Y.; Kubota, K.; Wang, X.; Leighton,
J. L. J. Am. Chem. Soc. 2002, 124, 7920.
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(18) Racherla, U. S.; Brown, H. C. J. Org. Chem. 1991, 56, 401.
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Org. Lett., Vol. 11, No. 13, 2009
2917

allylation,20 or Loh’s indium mediated allylation21 failed to
provide acceptable yields or enatiomeric excess. We suppose
this should be caused by possible chelation of the dithiane
moiety to the allylating agents disabling the complexation
of the aldehyde. The lithium alkoxide generated from alcohol
10 with butyllithium induced a solvent (HMPA)-controlled
1,4-Brook rearrangement to provide intermediate dithiane
anion 11, which was reacted with the diethyl acetal bro-
moacetaldehyde to afford triethylsilyl ether 12.13 Removal
of the silyl group with TBAF afforded alcohol 5 in 64%
yield over two steps.
in the presence of a catalytic amount (10 mol %) of NaH in
hexanes,24 affording silyl ether 15 in 81% yield (Scheme
4). The reaction proceeded to completion in 15-20 min at
room temperature with 1 equiv of 6, and formation of the
symmetrical silaketal was not observed. Subsequent coupling
of silyl ether 15 with alcohol 7 required higher reaction
temperature (60 °C, toluene) to provide the desired silaketal
4 in 68% yield as a mixture of diastereomers originating
from the newly created stereocenter at the silicon. Formation
of a symmetrical silaketal by double addition of 7 was also
observed, which could not be suppressed even with 1.5 equiv
of 15. Silaketal 4 was designed such that the ring closure
can occur in a group-selective manner25 by initiaing the RCM
at the most accessible terminal alkene. Treatment of the
bicyclic siloxane RCM product with TBAF in THF under
reflux provided dienediol 3 in 61% yield over two steps.
Varying amounts of a prematurely terminated monocyclic
siloxane, obtained via an RCM from the monosubstituted
olefin, was also isolated from the RCM-desilylation reaction
sequence. Longer reaction times or higher loading of catalyst
did not reduce the formation of this monocylic siloxane.
With dienediol 3 in hand, we proceeded to the synthesis
of ꢀ-keto ester 2 as shown in Scheme 5. Removal of the
dithane using an excess amount of iodomethane in aqueous
The synthesis of another key building block 7 began with
the asymmetric (E)-crotylboration22 of trans-crotonaldehyde,
providing known allyl alcohol 1323 in 54% yield with 15:1
anti/syn selectivity and 95% ee (Scheme 3). TBS-protection
Scheme 3
26
°
acetone at 60-65 C provided ketone 16 in 79% yield.
The diastereoselective carbonyl reduction of 16, according
to Paterson’s procedure,27 gave syn-1,3-diol 17 in 76% yield,
which was then converted to tri-TBS ether 18 in 73% yield.
Reduction of the pivaloate in 18 with DIBAL-H gave alcohol
19 in quantitative yield. Oxidation of primary alcohol 19 by
using the Parikh-Doering protocol28 gave the corresponding
aldehyde, which was subjected to Horner-Wadsworth-
Emmons olefination29 to give ester 20 in 90% yield for the
two steps. Again, reduction of ester 20 with DIBAL-H in
85% yield followed by carbonate protection of the resulting
allylic alcohol 21 afforded carbonate 22 in 96% yield.
Removal of the acetal group with p-TsOH in acetone gave
the corresponding aldehyde, which was converted to the
ꢀ-keto ester 23 (79% over two steps) by subjecting it to ethyl
diazoacetate in the presence of catalytic amount (10 mol %)
of SnCl2 according to Roskamp’s procedure.30 Finally, we
attempted to remove the carbonate group in the presence of
2% K2CO3 in methanol to obtain the Roush intermediate 2.
However, methyl ꢀ-keto ester 24 was isolated in 82% yield
instead of the corresponding ethyl ester 2, due to a
concomitant transesterification. The subtle difference between
ethyl and methyl ꢀ-keto esters 2 and 24 is inconsequential
for the remaining transformations toward a total synthesis
of the hydroxyl group and regioselective hydroboration-
oxidation gave the silyl ether 14 in 63% yield over two steps.
Pivalation of the resulting primary hydroxyl group proceeded
in 77% yield. This was followed by cleavage of the TBS
ether to furnish alcohol 7 in 78% yield.
With all the required building blocks for silaketal 4
in hand, we first silylated alcohol 5 with trialkynylsilane 6
Scheme 4
(20) Keck, G. E.; Tarbet, K. H.; Geraci, L. E. J. Am. Chem. Soc. 1993,
115, 8467.
(21) Teo, Y.-C.; Tan, K.-T.; Loh, T.-P. Chem. Commun. 2005, 1318.
(22) Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 5919.
(23) Mandal, A. K.; Schneekloth, J. S., Jr.; Kuramochi, K.; Crews, C. M.
Org. Lett. 2006, 8, 427.
(24) Grimm, J. B.; Lee, D. J. Org. Chem. 2004, 69, 8967.
(25) Maifield, S. V.; Lee, D. Chem.sEur. J. 2005, 11, 6118.
(26) Fetizon, M.; Jurion, M. J. Chem. Soc., Chem. Commun. 1972, 382.
(27) Paterson, I.; Perkins, M. V. Tetrahedron Lett. 1992, 33, 8241.
(28) Parikh, J. R.; Doering, W. v. E. J. Am. Chem. Soc. 1967, 89, 5505.
(29) Wadsworth, W. S., Jr.; Emmons, W. D. J. Am. Chem. Soc. 1961,
83, 1733.
(30) Holmquist, C. R.; Roskamp, E. J. J. Org. Chem. 1989, 54, 3258.
2918
Org. Lett., Vol. 11, No. 13, 2009

Scheme 5. Elaboration of Intermediates and the Completion of a Formal Total Synthesis of (-)-Cochleamycin A
of cochleamycin A. Nevertheless, we decided to synthesize
ethyl ester 2 to directly compare its spectroscopic data to
that reported by Roush. The carbonate deprotection was
attempted again using K2CO3 in ethanol. The reaction was
much slower than in methanol and thus required longer
reaction time or higher temperature. This led to significant
of 2 were in good agreement with that reported by Roush,
except for the opposite sign in optical rotation.6
In conclusion, we have achieved a formal total synthesis
of (-)-cochleamycin A. The key feature of the synthesis is
to form a silaketal from two alkenyl alcohols and trialkynyl
silane followed by tandem enyne RCM to establish the (E,Z)-
1,3-diene moiety required for a Diels-Alder reaction. Further
development and application of this silaketal-based enyne
RCM will be reported in due course.
1
decomposition as evident from the H NMR of the isolated
crude products. Other stronger bases such as sodium ethoxide
reduced the overall reaction time, but increased amounts of
unidentified byproducts were generated. Trimethyltin hy-
droxide mediated hydrolysis of methyl ester according to
Nicolaou’s procedure31 resulted in deesterification-
decarboxylation of the ꢀ-keto ester moiety. However, ethyl
ester 2 could be isolated in fairly high purity (∼90%) by
stopping the reaction at low conversion (30-40%) of 24 with
K2CO3 in ethanol. The 1H and 13C NMR and optical rotation
Acknowledgment. We thank the NIH (CA106673) for
financial support of this work.
Supporting Information Available: General procedures
and characterization data of new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(31) Nicolaou, K. C.; Estrada, A. A.; Zak, M.; Lee, S. H.; Safina, B. S.
Angew. Chem., Int. Ed. 2005, 44, 1378.
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