Synthesis of the entire framework of tartrolon B utilizing a silicon-tethered ring-closing metathesis strategy

Article abstract of DOI:10.1021/ol061952y

A tandem ring-closing metathesis (RCM) of silaketal-tethered dienynes gives rise to bicyclic siloxanes, which upon removal of the silicon tether afford dienediol skeletons with a stereodefined E,Z-1,3-diene motif. The implementation of this methodology ha

Full text of DOI:10.1021/ol061952y

ORGANIC
LETTERS
2006
Vol. 8, No. 23
5219-5222
Synthesis of the Entire Framework of
Tartrolon B Utilizing a Silicon-Tethered
Ring-Closing Metathesis Strategy
Yi Jin Kim and Daesung Lee*
Department of Chemistry, UniVersity of WisconsinsMadison, 1101 UniVersity AVenue,
Madison, Wisconsin 53706
dlee@chem.wisc.edu
Received August 7, 2006
ABSTRACT
A tandem ring-closing metathesis (RCM) of silaketal-tethered dienynes gives rise to bicyclic siloxanes, which upon removal of the silicon
tether afford dienediol skeletons with a stereodefined E,Z-1,3-diene motif. The implementation of this methodology has led to the construction
of the entire C1−C21 linear carbon skeleton of tartrolon B.
Tartrolon B (1), a boron-containing C2-symmetrical mac-
rodiolide, is an ion-carrier antibiotic first isolated in 1994
by Ho¨fle and co-workers from the myxobacterium Sorangium
cellulosum strain So ce678.1 Notably, the fermentation of
this strain may be directed to afford both 1 and tartrolons
A1-A3 (2a-c) (Figure 1), depending on the material of the
fermentation vessel (glassware affords 1, and steel affords
its boron-free counterparts 2a-c as diastereomeric mixtures).
Both are, however, inhibitors of Gram-positive bacteria with
MIC values of 1 µg/mL, which indicates that the presence
of boron is not required for its antibiotic activity.2 In addition
to its promising antibiotic properties, noteworthy structural
features of 1 include the C1-C7 fragment, which is also
found in structurally related boron-core antibiotics such as
boromycin,3 aplasmomycin,4 and borophycin.5 Another promi-
nent structural feature that is of particular interest to our
group is the E/Z-diene moiety at C14-C17.
Figure 1. Tartrolons A and B
stereoselective reduction7,8 of the 1,3-E-ene-yne. In the case
of Mulzer’s total synthesis of tartrolon B, this fragment was
constructed through an alkynyllithium addition to acrolein,
followed by a Johnson-Claisen rearrangement, and the re-
sulting 1,3-E-ene-yne was subjected to the Z-selective Boland
reduction to furnish the desired E/Z-1,3-diene piece.8 To
construct this motif more efficiently, we sought to develop
an alternative method, which incorporates a tandem enyne
ring-closing metathesis (RCM).9 Relying on the unique
capacity of enyne metathesis to form 1,3-dienes and a novel
This particular 1,3-diene motif, commonly found in natural
products, is often constructed via metal-mediated Sonogash-
ira-type alkyne-vinyl halide couplings6 followed by Z-
(1) (a) Schummer, D.; Irschik, H.; Reichenback, H; Ho¨fle, G. Liebigs
Ann. Chem. 1994, 283. (b) Schummer, D.; Schomburg, D.; Irschik, H.;
Reichenbach, H.; Hofle, G. Liebigs Ann. Chem. 1996, 965.
(2) Irschik, H.; Schummer, D.; Gerth, K.; Ho¨fle, G.; Reichenbach, H. J.
Antibiot. 1995, 48, 26.
10.1021/ol061952y CCC: $33.50
© 2006 American Chemical Society
Published on Web 10/19/2006

stereochemical control in tandem RCM of dienynes,10 we
envisioned that a silaketal such as 4 would undergo group-
selective RCM to furnish bicyclic siloxane 5, which upon
simple protodesilylation can furnish 6 (Scheme 1). Gratify-
Because the two-step transformation shown in Scheme 1
could be broadly applicable to the synthesis of related
structural motifs, we developed a strategy to synthesize the
C1-C21 linear chain of tartrolon B. The preparation of
ketone 13 began with asymmetric crotylation12 of aldehyde
7 to yield the syn-crotyl adduct, directly followed by PMB-
ether formation to afford 8 (41% over two steps, Scheme
2). This intermediate was then subjected to hydroboration
Scheme 1
Scheme 2
ingly, the treatment of 4 with a catalytic amount of catalyst
3,11 followed by desilylation, provided a single isomeric
dienediol product 6, a structural equivalent to the C11-C20
fragment of tartrolon B, in good yield. Herein, we report a
unique approach for the synthesis of the entire carbon
framework of tartrolon B based on the enyne RCM strategy.
(3) (a) Hu¨ter, R.; Keller-Schierlein, W.; Knu¨sel, F.; Prelog, V.; Rodgers,
G. C.; Suter, P.; Vogel, G.; Za¨hner, H. J. Antibiot. 1967, 20, 1533. (b)
Dunitz, J. D.; Hawley, D. M.; Miklos, D.; White, D. N. J.; Berlin, Y.;
Marusic, R.; Prelog, V. HelV. Chim. Acta 1971, 54, 1709. For total synthesis,
see: (c) White, J. D.; Avery, M. A.; Choudhry, S. C.; Dhingra, O. P.; Gray,
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followed by Swern oxidation to give aldehyde 9 in excellent
yields. Homologation of the aldehyde under typical condi-
tions gave rise to the methyl enol ether 10 as a mixture of
E/Z-isomers (1.5:1 E/Z, 80%). After trying several different
conditions to convert 10 to the corresponding aldehyde, we
chose a two-step protocol using NBS followed by Zn/AcOH,
which turned out to be the best conditions to give the desired
aldehyde (87%). This aldehyde was then subjected to another
asymmetric crotylation12 to generate anti-crotyl adduct 11
in 57% yield. The resulting alcohol was then protected as
its MOM-ether (75%) and subjected to Wacker oxidation13
to give the desired methyl ketone 13 in 71% yield.
The synthesis of 13 set the aldol addition to 4-pentenal to
establish the C11 stereocenter and the terminal alkene moiety
for the projected tandem dienyne RCM. On the basis of
known examples of substrate-controlled aldol reaction using
R-methyl- or â-alkoxy-substituted methyl ketones,14 we
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Germany, 2003; Vol. 2, pp 176-204.
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Lee, D. J. Organomet. Chem. 2005, 690, 5508. (b) Boyer, F.-D.; Hanna,
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Tennakoon, M. A.; Wang, J.; Zhao, H. J. Am. Chem. Soc. 2004, 126, 10210.
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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.;
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128, 9433. (b) Evans, D. A.; Coˆte´, B.; Coleman, P. J.; Connell, B. T. J.
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Table 1. Selectivity in Methyl Ketone Aldol Reactions
pursued an enol borinate addition to 4-pentenal using (-)-
chlorodiisopinocampheylborane (Table 1). Notably, in Mulz-
er’s evaluation of this chiral boron-mediated aldol chemistry
on related systems,8a the asymmetric induction was substrate-
controlled rather than reagent-controlled (the chiral Ipc’s on
boron did not influence the absolute sense of chirality of
the product). â-Alkoxy-substituted methyl ketones have been
shown to yield 1,5-anti aldol adducts in many reported cases,
although in varying degrees with respect to the overall sense
of asymmetric induction depending on the nature of the
substrate and the conditions used.8a,14,15 Because the chirality
of the reagent was not crucial to the asymmetric induction,
we arbitrarily chose (-)-DIPCl to generate the enol borinate
from various ketones (Table 1, entries 1-3). Unfortunately,
the stereochemical outcome turned out to be less predictable
in these cases, providing aldol products 16-18 all in nearly
a 1:1 mixture of the two epimers at C11. On the basis of
literature precedence, substrates containing the tetrahydro-
pyran moiety (14)8a,14f or the TBS-ether (15)15 as the â-alkoxy
substituent should have favored formation of the 1,5-anti
aldol adduct.
able. Furthermore, a change in reaction temperature from
-10 °C to -20 °C significantly affects the stereoselectivity,
as noted in the final product distribution.
Upon establishing improved conditions for the aldol
reaction, we continued to pursue the proposed route to
investigate the key RCM step. Initially, we envisioned that
aldol product 18 could be directly used for the silaketal
formation utilizing conditions developed in our laboratory
(1 equiv of silyl ether 21,16 with 10 mol % of NaH in
hexanes).17 To our disappointment however, under such basic
conditions the transient silaketal underwent rapid elimination
to afford the R,â-unsaturated ketone. Thus, we had to revise
our plan to mask the ketone functionality in â-hydroxy ketone
18 prior to silaketal formation to avoid the elimination
problem. â-Hydroxy ketone 18 was therefore subjected to
Evans-Tishchenko18 conditions to afford the â-acetoxy
alcohol 19 in 99% yield (Scheme 3). The C9 hydroxyl group
Scheme 3
At this point, we set out to investigate further the
conditions that might improve the selectivity of the aldol
reaction. We thus lowered the reaction temperature from -10
°C to -20 °C and changed the (-)-DIPCl to (+)-DIPCl
(Table 1, entries 4 and 5). To our pleasant surprise, both
factors turned out to be important, giving much higher (6:1)
selectivity for the aldol product 18. These findings indicate
that although switching the chirality of the diisopinocam-
pheylborane does not change the absolute sense of the
asymmetric induction, the degree in which it allows the
favored diastereomer to be formed over the other is consider-
(15) Schmidt, D. R.; Park, P. K.; Leighton, J. L. Org. Lett. 2003, 5,
3535.
Org. Lett., Vol. 8, No. 23, 2006
5221

was then protected as its MOM-ether, and the acetoxy group
was removed to reveal the required C11-hydroxyl group in
20 (84% for each step).
As expected, alcohol 20 reacted smoothly with silyl ether
21 to give desired silaketal 22 in 58% yield as a mixture of
two diastereomers, which is the consequence of creating an
additional stereogenic center at the silicon (Scheme 4).
at the most accessible terminal alkene, where the first enyne
ring closure should generate a seven-membered ring followed
by an eight-membered ring closure to furnish bicycle 23.
When 22 was subjected to typical RCM conditions with
catalyst 3 (8 mol %), the desired bicyclic siloxane 23 was
obtained in 89% yield. Removal of the silicon tether was
achieved simply upon treatment with TBAF, affording 24
(60%), which contains the entire C1-C21 carbon framework
of the monomeric seco-acid of tartrolon B.
In summary, we have demonstrated that a temporary
silicon-tethered tandem RCM can be utilized effectively to
construct the C11-C21 E/Z-1,3-diene-containing fragment
of tartrolon B. This fully functionalized C1-C21 diol, 24,
is envisioned to undergo a few protecting group and oxidation
state maneuvers to generate the monomeric seco-acid ap-
propriate for a final dimerization and introduction of the
boron core to deliver the total synthesis of tartrolon B. Efforts
toward these final stages of a total synthesis of tartrolons
are currently under progress, and a full account of the total
synthesis will be reported in due course.
Scheme 4
Acknowledgment. We thank the NIH (CA106673) and
the Sloan Foundation for financial support of this work as
well as the NSF and NIH for NMR and mass spectrometry
instrumentation.
Supporting Information Available: Experimental pro-
cedures and characterization information of representative
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Silaketal 22 was designed such that the ring closure can occur
in a group-selective fashion;19 catalyst initiation should occur
OL061952Y
(17) Grimm, J. B.; Lee, D. J. Org. Chem. 2004, 69, 8967.
(18) Evans, D. A.; Hoveyda, A. H. J. Am. Chem. Soc. 1990, 112, 6447.
(19) Maifeld, S. V.; Lee, D. Chem.-Eur. J. 2005, 11, 6118.
(16) For the preparation of silyl ether 21, see Supporting Information.
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