Total synthesis of the serine/threonine-specific protein phosphatase inhibitor tautomycin

Article abstract of DOI:10.1021/jo961633s

A convergent, asymmetric synthesis of the protein phosphatase inhibitor, tautomycin, is described. The natural product was constructed by joining two major fragments of comparable complexity at the C21-C22 bond. Absolute stereochemistry of the C1-C21 ketone originates from (S)-citronellene and (2R,3S)-geraniol epoxide. The anti stereochemical relationships at C6-C7 and C18-C19 were introduced with Duthaler's chiral titanium propionic enolate. Syn stereochemical relationships at C13-C14 and C23-C24 were established using an Evan's oxazolidinone chiral auxiliary. The spiroketal was efficiently constructed via a one-pot double-alkylation-spirocyclization sequence with acetone N,N-dimethylhydrazone serving as the central linchpin. Final coupling of the two halves using a chelation-controlled Mukaiyama aldol addition followed by deprotection yielded synthetic tautomycin that is identical to the natural product.

Full text of DOI:10.1021/jo961633s

J . Org. Chem. 1997, 62, 387-398
387
Tota l Syn th esis of th e Ser in e/Th r eon in e-Sp ecific P r otein
P h osp h a ta se In h ibitor Ta u tom ycin 1
J ames E. Sheppeck, II, Wen Liu, and A. Richard Chamberlin*
Department of Chemistry, University of California, Irvine, California 92717
Received August 22, 1996X
A convergent, asymmetric synthesis of the protein phosphatase inhibitor, tautomycin, is described.
The natural product was constructed by joining two major fragments of comparable complexity at
the C21-C22 bond. Absolute stereochemistry of the C1-C21 ketone originates from (S)-citronellene
and (2R,3S)-geraniol epoxide. The anti stereochemical relationships at C6-C7 and C18-C19 were
introduced with Duthaler’s chiral titanium propionic enolate. Syn stereochemical relationships at
C13-C14 and C23-C24 were established using an Evan’s oxazolidinone chiral auxiliary. The
spiroketal was efficiently constructed via a one-pot double-alkylation-spirocyclization sequence
with acetone N,N-dimethylhydrazone serving as the central linchpin. Final coupling of the two
halves using a chelation-controlled Mukaiyama aldol addition followed by deprotection yielded
synthetic tautomycin that is identical to the natural product.
In tr od u ction
okadaic acid congeners acanthafolicin and the dinophy-
sistoxins.10 Many of these structurally dissimilar inhibi-
tors have been exploited as small molecule probes in
molecular biology11 because they all selectively inhibit
two of the four major types of serine/threonine PPs (PP1
and PP2A over PP2B (calcineurin) and PP2C). Canthari-
din, OA, and thyrsiferyl 23-acetate further exhibit vary-
ing selectivity for PP2A over PP1, whereas the other
inhibitors are essentially equipotent for both phos-
phatases. The specific inhibition of particular PPs is
physiologically important since four endogenous proteins,
DARPP-32,2 inhibitor-1, inhibitor-2, and NIPP-1,12 act to
stringently regulate PP1, and abnormally low levels of
PP activity have been implicated in human cancer13 and
Alzheimer’s disease.14
One of the most pervasive controllers of signal trans-
duction in eukaryotic cells is the reversible phosphory-
lation of serine-, threonine-, and tyrosine-containing
proteins by protein phosphatases (PPs) and protein
kinases (PKs). This molecular “on-off switch” is respon-
sible for regulating such diverse and important processes
as memory, cell growth, neurotransmission, glycogen
metabolism, muscle contraction, and many others.2 Much
of the current knowledge of the serine/threonine-specific
protein phosphatases has disseminated from studies of
their inhibition by a strikingly diverse collection of
natural products known as the okadaic acid class of
inhibitor,3 which is comprised of three structural types:
(1) cyclic peptides such as the microcystins4 and nodu-
larins;5 (2) terpenoids including cantharidin6 and thyr-
siferyl 23-acetate;7 and (3) polyketides such as the
calyculins,8 tautomycin (TM),9 okadaic acid (OA), and the
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and cantharidin are all available from commercial sources.
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X Abstract published in Advance ACS Abstracts, J anuary 1, 1997.
(1) Dedicated to our brilliant colleague and friend, J im D. Bain, who
died March 2, 1995, of leukemia.
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S0022-3263(96)01633-7 CCC: $14.00 © 1997 American Chemical Society

388 J . Org. Chem., Vol. 62, No. 2, 1997
Sheppeck et al.
Sch em e 1
Our interest in the serine/threonine-specific protein
phosphatases stems from their central role in cellular
regulation. The discovery of new selective PP inhibitors
would be of great value in elucidating the physiological
roles of the PPs, and an important component of that
process is an effort to establish the relationship between
structure and inhibition potency/selectivity among these
molecules. We believe that all of these natural products,
whether in part or in whole, are acting as sophisticated
peptidemimetics of phosphorylated DARPP-3215 and that
a combination of molecular design and synthesis prom-
ises to lead to important new selective inhibitors. Among
other targets, we chose tautomycin because it is the only
small molecule that is selective for PP1 over PP2A (albeit
only slightly: IC50 ) 22 and 32 nM, respectively). TM
was discovered in 1987, and its structure was elucidated
in 1993.9a,16 Two groups have reported total syntheses
of TM, and others have published synthetic progress
toward the molecule.17 We have independently developed
a convergent and efficient synthetic route that will allow
us to pursue the goal of discovering PP1-selective inhibi-
tors.
Syn th etic Str a tegy
We envisioned a highly convergent synthesis that
would rely upon efficient coupling reactions of readily
prepared subunits. Since the stereochemistry of TM
resides in clusters separated by unfunctionalized hydro-
carbon regions, asymmetric centers were to be introduced
using more reagent control than substrate-directed reac-
tions. Our antithetic analysis begins with the retroal-
dolization of the C21-C22 and C18-C19 bonds to give
aldehydes 28 and 14 and a central C19-C21 linchpin
that is a formal 2-butanone equivalent (Scheme 1).
Saponification of 28 yields the C1′-C7′ anhydride sub-
unit and the C22-C26 Weinreb amide. This strategy is
akin to that also used by Oikawa’s group for the C18-
C26 segment18 but is markedly different in the construc-
tion of each subunit and the spiroketal. The aldehyde
14 was disconnected to take advantage of a spiroketal
synthesis via sequential alkylations of acetone N,N-
dimethylhydrazones to give the C1-C8 and C12-C18
iodide subunits. Disconnection at C8-C9 also conve-
niently allows for the introduction of the C6-C7 and
C18-C19 stereogenic centers using the same chiral
auxiliary, since both stereochemical features bear the
same absolute and relative stereochemistry.
We planned silyl protection of all potentially labile
functionality throughout the synthesis, anticipating that
a single deprotection step at the end of the synthesis
would directly yield TM. The C1-C2 methyl ketone was
to be carried through as the corresponding alkene, which
would require a selective oxidative cleavage of the C18
alkene in the presence of the C1 alkene after spirocy-
clization. The final coupling of the C1-C21 subunit and
the aldehyde 28 was envisioned as a chelation-controlled
Mukaiyama aldol reaction that should give the requisite
stereochemistry at C22.18
(13) (a) Fujiki, H. Mol. Carcinog. 1992, 5, 91-94. (b) Fujiki, H.;
Suganuma, M. Adv. Cancer Res. 1993, 61, 143-195. (c) Sogawa, K. et
al. Cancer Lett. 1995, 89, 1-6. (d) Li, M.; Makkinje, A.; Damuni, Z.
J . Mol. Biol. 1996, 271, 11059-11062.
(14) (a) Gong, C.-X.; Grundke-Iqbal, I.; Iqbal, K. Neurosci. 1994, 61,
765-772. (b) Gong, C.-X.; Inge, G.-I.; Damuni, Z.; Iqbal, K. FEBS Lett.
1994, 341, 94-98. (c) Gong, C.-X.; Singh, T. J .; Grundke-Iqbal, I.;
Iqbal, K. J . Neurochem. 1994, 62, 803-806. (d) Morishima-Ka-
washima, M.; et al. J . Biol. Chem. 1995, 270, 823-829. (e) Roush, W.
Science 1995, 267, 793-794. (f) Gong, C.-X.; Shaikh, S.; Wang, J .-Z.;
Zaidi, T.; Grundke-Iqbal, I.; Iqbal, K. J . Neurochem. 1995, 65, 732-
738. (g) da Cruz e Silva, E. F.; da Cruz e Silva, A. B.; Zaia, C. T.;
Greengard, P. Mol. Med. 1995, 1, 535-541.
(15) Gauss, C.; Sheppeck, J . E., II; Chamberlin, A. R. Unpublished
results.
(16) (a) Ubukata, M.; Cheng, X.-C.; Isono, K. J . Chem. Soc., Chem.
Commun. 1990, 244-246. (b) Ubukata, M.; Cheng, X.-C.; Isobe, M.;
Isono, K. J . Chem. Soc., Perkin Trans. 1 1993, 617-624.
(17) For Oikawa and Ichihara’s TM total synthesis, see: (a) Oikawa,
M.; Oikawa, H.; Ichihara, A. Tetrahedron Lett. 1993, 30, 4797-4800.
(b) Oikawa, H.; Oikawa, M.; Ueno, T.; Ichihara, A. Tetrahedron Lett.
1994, 35, 4809-4812. (c) Oikawa, M.; Ueno, T.; Oikawa, H.; Ichihara,
A. J . Org. Chem. 1995, 60, 5048-5068. (d) Ueno, T.; Oikawa, M.;
Oikawa, H.; Ichihara, A. Biosci. Biotech. Biochem. 1995, 59, 2104-
2110. For Isobe’s total TM synthesis, see: (e) Ichikawa, Y.; Naganawa,
A.; Isobe, M. Synlett. 1993, 737-738. (f) Ichikawa, Y.; Tsuboi, K.;
Naganawa, A.; Isobe, M. Synlett. 1993, 907-908. (g) Naganawa, A.;
Ichikawa, Y.; Isobe, M. Tetrahedron 1994, 50, 8969-8982. (h) J iang,
Y. M.; Ichikawa, Y.; Isobe, M. Synlett 1995, 3, 285-288. (i) Ichikawa,
Y.; Tsuboi, K.; J iang, Y.; Naganawa, A.; Isobe, M. Tetrahedron Lett.
1995, 36, 7101-7104. (j) J iang, Y.; Isobe, M. Tetrahedron 1996, 52,
2877-2892. For partial TM syntheses, see: (k) Nakamura, S.-i.;
Shibasaki, M. Tetrahedron Lett. 1994, 35, 4145-4148. (l) Maurer, K.
W.; Armstrong, R. W. J . Org. Chem. 1996, 61, 3106-3116.
(18) This strategic coupling was also successfully demonstrated in
Oikawa and Ichihara’s tautomycin synthesis. Also see: (a) Mu-
kaiyama, T.; Banno, K.; Narasaka, K. J . Am. Chem. Soc. 1974, 96,
7503-7509. (b) Mukaiyama, T. Org. React. 1982, 28, 203-331. (c)
Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1984, 23, 556-569. (d)
Reetz, M. Acc. Chem. Res. 1993, 26, 462-468.

Total Synthesis of Tautomycin
Sch em e 2a
J . Org. Chem., Vol. 62, No. 2, 1997 389
primary alcohol into an iodide leaving group23 completed
the C1-C8 subunit 5.
Syn th esis of th e C12-C18 Su bu n it. Our plans for
the synthesis of the C12-C18 subunit required a syn
aldol addition to a chiral R-methyl aldehyde fragment
that contained a second latent aldehyde at C18, and
geraniol epoxide was chosen for this purpose. While this
compound is readily obtained, as described below, the
regioselective reductive opening of the epoxide to give a
1,2-diol initially was problematic. LiAlH4 and DIBAL
give statistical mixtures of the desired 1,2-diol and the
undesired 1,3-diol (from reduction of the epoxide at the
3 and 2 positions of geraniol epoxide, respectively),
although Dai had reported a 7:1 preference for the
desired 1,2-diol isomer using a mixture of Ti(OiPr)4 and
excess LiBH4 in benzene.24 However, we experienced
solubility problems with LiBH4 in benzene while trying
to scale up this reaction, so we sought another reagent
that might also be more selective. After screening a
variety of conditions, we found that 2-3 equiv of NaBH3-
CN in THF with 2-3 equiv of glacial acetic acid smoothly
reduces chiral geraniol epoxide (90-93% ee from Sharp-
less epoxidation)25 at room temperature with >20:1
regioselectivity to form the 1,2-diol 6 in good to excellent
yield.26 Smaller scale reactions (1-2 mmol) consistently
proceed in over 90% isolated yield, whereas larger scale
reactions (50-100 mmol) requires more reagent and
longer reaction times due to competitive destruction of
NaBH3CN by HOAc. This reduction proceeds stereospe-
cifically with inversion (chiral GC) and gives no reaction
without added HOAc. We were surprised to find that
such mild conditions reductively opened the epoxide and
suspect that the reduction may take place with neighbor-
ing-group participation by the primary hydroxyl sub-
stituent. The observation that the TBS ether of geraniol
epoxide is inert under the reaction conditions supports
this contention.
a
Key: (a) m-CPBA, CH2Cl2, 0 °C; (b) H5IO6, Et2O, 0 °C; (c)
Duthaler’s reagent, Et2O, -78 to -20 °C; (d) TBSOTf, 2,6-lutidine,
CH2Cl2, 0 °C to rt; (e) DIBAL, hexanes, -78 °C; (f) Ph3PI2,
imidazole, CH3CN/Et2O, 0 °C to rt.
Resu lts a n d Discu ssion
Syn th esis of th e C1-C8 Su bu n it. The synthesis of
the C1-C8 primary iodide (Scheme 2) begins with the
selective oxidative cleavage of S-citronellene19 via a two-
step procedure published by Ireland.20 After attempting
several types of enantioselective anti aldol additions to
this aldehyde, we settled on the Duthaler reagent21 for
several reasons. This chiral titanium enolate reagent
exhibits excellent enantioselectivity (albeit modest dias-
tereoselectivity) and is also conveniently scaled up.
Addition to the aldehyde 1 consistently gave the desired
anti aldol product, 2, in good yield with 94-96% ee and
approximately 8:1 diastereoselectivity.22 Silylation of the
newly formed hydroxyl substituent, reduction of the aryl
ester with DIBAL, and conversion of the resultant
Next, the diol 6 was cleaved with NaIO4 to give the
corresponding aldehyde, which reacted with the boron
enolate of Evan’s norephedrine-derived chiral auxiliary
in a “matched,” double diastereoselective aldol reaction.27
Oxazolidinone 7 was the major component of two sepa-
rable diastereomeric products, the other one arising from
mismatched aldol addition to the 3-5% of the minor
enantiomeric aldehyde (from geraniol epoxide). Analo-
gous to the C1-C8 subunit, 7 was protected as a TBS
ether and then reduced with LiBH4 with 1 equiv of MeOH
or H2O, but these conditions28 gave unacceptable amounts
of competitive reduction of the carbamate carbonyl. This
problem was circumvented using the standard lithium
benzyloxide transesterification method29 followed by
DIBAL reduction to give primary alcohol 10, which was
(19) Although (S)-citronellene is commercially available from Fluka,
we prepared it from (S)-citronellol using the Chugaev method of
Kocienski and Cernigliaro (J . Org. Chem. 1977, 42, 3622-3624) on a
200 g scale (50% yield). We wish to thank Takasago Ltd. for the
generous gift of (S)-citronellol.
(20) (a) Ireland, R. E. et al. J . Am. Chem. Soc. 1983, 105, 1988-
2006. (b) Ireland, R. E.; Thaisrivongs, S.; Dussualt, P. H. J . Am. Chem.
Soc. 1988, 110, 5768-5779.
(21) (a) Oertle, K.; Beyeler, H.; Duthaler, R. O.; Lottenbach, W.;
Riediker, M.; Steiner, E. Helv. Chim. Acta 1990, 73, 353-358. (b)
Duthaler, R. O.; Herold, P.; Wyler-Helfer, S.; Riediker, M. Helv. Chim.
Acta 1990, 73, 659-673.
(22) The enantiomeric excess was judged by 500 MHz 1H NMR
analysis of the Mosher ester using a racemic control. Dale, J . A.; Dull,
D. L.; Mosher, H. S. J . Org. Chem. 1969, 34, 2543-2549. The relative
and absolute stereochemistry was predicted using the Duthaler
precedent but unambiguously determined using the following reaction
sequence:
(23) (a) Singh, A. K.; Bakshi, R. K.; Corey, E. J . J . Am. Chem. Soc.
1987, 109, 6187-6189. (b) Garegg, P. J .; Samuelsson, B. J . Chem.
Soc., Perkin Trans. 1 1980, 2866-2868.
(24) Dai, L.-X.; Lou, B.-L.; Zang, Y.-Z.; Guo, G.-Z. Tetrahedron Lett.
1986, 27, 4343-4346.
(25) (a) Katsuki, T.; Sharpless, K. B. J . Am. Chem. Soc. 1980, 102,
5974-5976. (b) Gao, Y.; Hanson, R. M.; Klunder, J . M.; Ko, S. Y.;
Masamune, H.; Sharpless, K. B. J . Am. Chem. Soc. 1987, 109, 5765-
5780.
(26) During the course of our synthetic investigations, a paper
appeared describing the reduction of geraniol epoxide with NaCNBH3
and BF3OEt2: Taber, D. F.; Hoaze, J . B. J . Org. Chem. 1994, 59, 4004-
4006.
(27) Evans, D. A.; Bartroli, J . Tetrahedron Lett. 1982, 23, 807-810.
(28) Penning, T. D.; Djuric, S. W.; Haack, R. A.; Kalish, V. J .;
Miyashiro, J . M.; Rowell, B. W.; Yu, S. S. Synth. Commun. 1990, 20,
307-312.
Absolute stereochemistry was determined later in the synthesis by
spectroscopic identity of a derivative of 14 with an authentic tauto-
mycin intermediate degraded from the natural product (see ref 9a,b).

390 J . Org. Chem., Vol. 62, No. 2, 1997
Sheppeck et al.
Sch em e 3a
to a methyl ketone. Using the same Duthaler reagent
as before (Scheme 2), but with the aldehyde 14 as the
electrophile, gave two inseparable diastereomers (7:1
anti/syn ratio) in 76% combined yield. Attempts to
convert the ester mixture directly into the Weinreb
amides using the standard Me2AlN(Me)OMe conditions31
failed, perhaps due to the extreme steric bulk of the
ortho-substituted aryl ester. Instead, 15 was first sa-
ponified using the original conditions of Heathcock and
Pirrung32 and then coupled to the Weinreb amine using
DCC and HOAt.33 No epimerization of the R-methyl
substituent was observed, and the syn and anti diaster-
eomers were chromatographically separated at this point.
Finally, treatment of the anti isomer with MeLi (3.3
equiv) afforded the â-hydroxy ketone 17 in good overall
yield without the need for hydroxyl protection.34
Syn t h esis of t h e C22-C26 Su b u n it . This simple
subunit was constructed from the methoxyacetyl-substi-
tuted oxazolidinone 18. Following Evan’s precedent,35
the tin enolate of 18 was allowed to react with isobu-
tyraldehyde in the presence of TMEDA to give all four
possible diastereomers (79% yield total) in a ratio of 73:
14:9:4 favoring the desired stereoisomer 19.36 Oxazoli-
dinone 19 was easily separated and then transaminated
in standard fashion31 to give quantitative conversion to
20 (Scheme 5).
a
Key: (a) NaBH3CN, HOAc, THF, rt; (b) NaIO4, Et2O, rt; (c)
(4R,5R)-4-methyl-5-phenyl-N-propionyl-2-oxazolidinone, Bu2BOTf,
TEA, THF, -20 °C; (d) TBSOTf, 2,6-lutidine, CH2Cl2; (e) LiOBn,
THF; 0 °C to rt; (f) DIBAL, CH2Cl2, -78 to 0 °C; (g) Ph3PI2,
imidazole, CH3CN/Et2O, 0 °C to rt.
Syn th esis of th e C1′-C7′ An h yd r id e Su bu n it:
Cou p lin g to 20. Surprisingly, the greatest challenge in
this synthesis of tautomycin proved to be in the construc-
tion of the simple-looking diester subunit 26. Controlling
both the geometry of the alkene and the allylic hydroxyl
stereochemistry with high fidelity prompted us to explore
a number of synthetic avenues. The most direct strategy
that we investigated was the double carbonylation of a
propargylic â-keto or â-hydroxy ester (and protected
variants) using Hoberg’s Ni(CO)2bipy reagent.37 Al-
though this reagent reportedly reacts with internal
alkynes to form a dioxonickelacyclopentane intermediate
that directly gives disubstituted maleic anhydrides when
oxidized with O2, only addition to excess 2-butyne and
diphenylacetylene had been described. We were disap-
pointed to find that under a variety of conditions no
detectable nickelacyclopentane adduct was formed with
our electron-deficient substrates. After unsuccessfully
testing a number of other strategies, we finally settled
on the addition of a mixed methyl cuprate to a sym-
metrical acetylenedicarboxylic ester, followed by trapping
of the intermediate with an electrophile (Scheme 6).38 Not
surprisingly, the use of malonic acid chlorides as the
electrophile quenched the intermediate vinyl cuprate by
depronation of the highly acidic R-proton. Attempts to
transformed into the C12-C18 iodide 11, as before
(Scheme 3).
Con str u ction of th e C1-C18 Su bu n it via in Situ
Dou b le Alk yla t ion . The concise assembly of the
spiroketal-containing subunit was conveniently achieved
using R,R′ sequential alkylations of acetone N,N-dimeth-
ylhydrazone with the previously prepared iodide sub-
units.30 Treatment of lithiated acetone N,N-dimethyl-
hydrazone with the iodide 5, followed by a second
lithiation (n-BuLi) and subsequent treatment with an
equimolar amount of the iodide 11, cleanly afforded the
bis(silyloxy)hydrazone. Aqueous workup and treatment
of the crude reaction product with HF in a mixture of
CH3CN and i-PrOH removed both TBS groups and
induced spiroketalization to give 12 as a single isomer
in 77% overall yield (based on 5) (Scheme 4). The
completion of the synthesis of 14 required selective
oxidative cleavage of the trisubstituted olefin of 12 (a
transformation that is nearly identical to that of citronel-
lene in Scheme 2), which was achieved by reapplying the
Ireland conditions at lower temperature to give a 98%
yield of the desired monoepoxide 13. Oxidative cleavage
of this product gave a disappointingly low yield (53%) of
the aldehyde 14 on a large scale, but the abundant
quantity of 14 that was readily available discouraged
further optimization of this reaction.
(31) (a) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815-
3818. (b) Levin, J . I.; Turos, E.; Weinreb, S. M. Synth. Commun. 1982,
12, 989-993.
(32) Heathcock, C. H.; Pirrung, M. C.; Montgomery, S. H.; Lampe,
J . Tetrahedron 1981, 37, 4087-4095.
Synthesis of the ketone 17 required installation of the
C18-C19 anti stereochemistry and further manipulation
(33) Carpino, L. A. J . Am. Chem. Soc. 1993, 115, 4397-4398.
(34) We observed small (3-5%) amounts of retroaldolization upon
quenching this reaction into a 0 °C solution of 1 N HCl.
(35) (a) Evans, D. A.; Gage, J . R.; Leighton, J . L.; Kim, A. S. J . Org.
Chem. 1992, 57, 1961-1963. For use of a methoxyacetyl-substituted
oxazolidinone in a syn aldol reaction, see: (b) Ku, T. W.; Kondrad, K.
H.; Gleason, J . G. J . Org. Chem. 1989, 54, 3487-3491. (c) Andrus, M.
B.; Schreiber, S. L. J . Am. Chem. Soc. 1993, 115, 10420-10421.
(36) Unambiguous stereochemical assignment of 19 was determined
by X-ray crystallographic analysis of the TBS ether and confirms the
Evan’s precedent.
(29) (a) Evans, D. A. Aldrichim. Acta 1982, 15, 23-32. (b) Evans,
D. A.; Ennis, M. D.; Mathre, D. J . J . Am. Chem. Soc. 1982, 104, 1737-
1739.
(30) (a) Corey, E. J .; Enders, D. Tetrahedron Lett. 1976, 3, 11. (b)
J ung, M. E.; Shaw, T. J . Tetrahedron Lett. 1979, 4149. (c) Evans, D.
A.; Sacks, C. E.; Kleschick, W. A.; Taber, T. R. J . Am. Chem. Soc. 1079,
101, 6789-6791. (d) Enders, D.; Dahmen, W.; Dederichs, E.; Weuster,
P. Synth. Commun. 1985, 13, 1235-1242. (e) Yamashita, M.; Mat-
sumiya, K.; Tanabe, M.; Suemitsu, R. Bull. Chem. Soc. J pn. 1985, 58,
407-408. (f) Reddy, G. B.; Mitra, R. B. Synth. Commun. 1986, 16,
1723-1729. (g) Enders, D.; Dahmen, W.; Dederichs, E.; Gatzweiler,
W.; Weuster, P. Synthesis 1990, 1013-1019. (h) Evans, D. A.; Rieger,
D. L.; J ones, T. K.; Kaldor, S. W. J . Org. Chem. 1990, 55, 6260-6268.
(37) (a) Herrera, A.; Hoberg, H. Synthesis 1981, 831-833. (b)
Herrera, A.; Hoberg, H.; Mynott, R. J . Organomet. Chem. 1981, 222,
331-336.

Total Synthesis of Tautomycin
J . Org. Chem., Vol. 62, No. 2, 1997 391
Sch em e 4a
a
Key: (a) lithioacetone N,N-dimethylhydrazone, THF, -78 °C to rt; then n-BuLi (2.41 M) -78 to 0 °C, then 11, -78 °C to rt; (b) HF
(concd 47%), 6:1 CH3CN/i-PrOH; (c) m-CPBA, CH2Cl2, -20 °C; (d) H5IO6, Et2O, 0 °C; (e) Duthaler’s reagent, Et2O, -78 to -20 °C; (f)
KOH, 1:2 MeOH/H2O; DCC, HOAt, i-Pr2NEt, DMF, 0 °C to rt; (g) MeLi, THF, -78 to -20 °C.
Sch em e 5a
Sch em e 7a
a
Key: (a) Ph2POCl, DMAP, TEA, toluene, 20; (b) DIBAL (4.0
equiv), THF, -78 °C.
geometrical isomers in 83% yield. This synthetic se-
quence was originally carried out using a bis(2-(trimeth-
ylsilyl)ethyl ester) protecting group, but we were forced
to change to a bis-benzyl ester for reasons described
below.
a
Key: (a) Sn(OTf)2, TEA, CH2Cl2, -78 °C, TMEDA, then
i-PrCHO; (b) Me2AlN(Me)OMe, CH2Cl2, -10 °C, then 19.
Sch em e 6a
At this point, we thought that the requisite 3′(R)
stereogenic center might be introduced via a kinetic
resolution of the racemic acid 26 (derived from (()-23)
using the easily-obtained subunit 20 as a “chiral resolving
agent” in the ester-coupling reaction. The racemic acid
(()-26 was synthesized by reducing enone 22 with NaBH4
to give the alcohol (()-23 in 82% yield. Protection of the
hydroxyl substituent as a TES ether, ozonolytic cleavage
of the disubstituted alkene, and subsequent oxidation of
the aldehyde to a carboxylic acid gave (()-26 in 77%
overall yield. With both 20 and (()-26 in hand, the
kinetic resolution was attempted using a mixed phos-
phonic anhydride esterification method (Scheme 7).41 The
reaction proceeded rapidly to give one diastereomer at
50% conversion and could be forced to produce the second
diastereomer only at higher temperature, clearly sug-
gesting that a kinetic resolution might be possible.
Unfortunately, the rapidly formed diastereomer proved
to have the incorrect 3′-stereochemistry, thwarting our
plans. The two diastereomers were easily separated,
however, and both 27a and its C3′ epimer 27b42 were
independently reduced by DIBAL with high chemoselec-
tivity (in preference to the three esters) to give aldehydes
28 and 3′-epi-28, respectively, that ultimately provided
access to both TM itself and 3′-epi-TM.
a
Key: (a) MeCuLiCN, Et2O, -78 °C, then 3-pentenoyl chloride,
-78 to 0 °C; (b) (+)-DIP-Chloride, THF, -20 °C, 3 days, 0 °C, 4 h;
(c) TESCl, TEA, CH2Cl2, 0 °C to rt; (d) O3, CH2Cl2, -78 °C; Ph3P,
-78 °C to rt; (e) NaClO2, 2-methyl-2-butene, t-BuOH/H2O, 0 °C.
prepare the analogous ketenes resulted in polymeric
precipitates, and trapping with malonic anhydride39 also
proved unsuccessful. However, use of the malonic acid
equivalent 3-pentenoyl chloride40 ultimately worked well,
giving the unstable enone 22 as a >20:1 mixture of
(38) (a) Marino, J . P.; Linderman, R. J . J . Org. Chem. 1981, 46,
3696-3702. (b) Marino, J . P.; Linderman, R. J . J . Org. Chem. 1983,
48, 4621-4628. (c) Yamamoto, Y.; Yatagai, H.; Kazuhiro, M. J . Org.
Chem. 1979, 44, 1744-1746. (d) Nishyama, H.; Sasaki, M.; Itoh, K.
1981.
(39) Perrin, C. L.; Arrhenius, T. J . Am. Chem. Soc. 1978, 100, 5249-
5251.
(40) 3-Pentenoyl chloride was synthesized according to the procedure
of Martin and Sanders (Martin, M. M.; Sanders, E. B. J . Am. Chem.
Soc. 1967, 3777-3782) from the commercially available acid (Fluka).
(41) J ackson, A. G.; Kenner, G. W.; Moore, G. A.; Ramage, R.;
Thorpe, W. D. Tetrahedron Lett. 1976, 40, 3627-3630.

392 J . Org. Chem., Vol. 62, No. 2, 1997
Sheppeck et al.
Sch em e 8a
a
Key: (a) TMSOTf, TEA, CH2Cl2, 0 °C; (b) 28, TiCl4, CH2Cl2, -78 to -20 °C; (c) HF (5%), CH3CN/H2O, rt; (d) PdCl2, CuCl, O2, DMF,
rt; (e) 5% Pd/C, H2, 9:1 THF/H2O.
An improvement upon the resolution above was later
realized by reduction of ketone 22 with a chiral reducing
agent. With this substrate, stoichiometric amounts of
Corey’s (+)-oxazaborolidine reagent43 gave 25% ee of the
alcohol favoring the (S) enantiomer, the opposite product
predicted by the Corey paradigm (assuming the maleate
is the “large” group). However, reduction of the same
substrate with (+)-DIP-Chloride44 gave 80% ee (Mosher
ester analysis) of the desired (R) enantiomer in 88% yield,
which was taken through the synthetic sequence in
Scheme 6, as before, to give 26. Esterification with 20,
as described above, again gave 27a and its 3′-diastere-
omer, but now in a 9:1 ratio favoring the former.
Cou p lin g of Su bu n its 28 a n d 17: Com p letion of
th e Syn th esis. The coupling of 28 and 17 was originally
planned as the obvious chelation-controlled (anti-Felkin)
Mukaiyama aldol reaction.18 As depicted in Scheme 8,
treatment of 17 with TMSOTf and TEA concommitantly
protected the hydroxyl substituent and formed the silyl
enol ether, which was used without purification. Reac-
tion with 28 occurred cleanly, and the mixture of silyl
ethers was directly subjected to deprotection conditions
(HF, CH3CN/H2O) to afford a single detectable diastere-
omer, 29, in 42% overall yield for three steps (based on
17). Wacker oxidation of the terminal alkene group in
29 gave the methyl ketone 30 without detectable epimer-
ization, which was now poised for the final deprotection.
Our original synthetic design employed silyl protection
throughout the synthesis, anticipating that a single
desilylation step would unmask all of the functionality
in the molecule and leave only the final alkene oxidation.
Unfortunately, complete desilylation of the bis-silyl ester
29b (from bis(2-(trimethylsilyl)ethyl)acetylenedicar-
boxylate)45 under many reaction conditions proved un-
managable due to the robust 2-(trimethylsilyl)ethyl
esters. The commonly used reagent TBAF could remove
these protecting groups, but the basicity associated with
“dry” sources of fluoride-induced acyl migration followed
by â-elimination at C22sa known degradative process
of tautomycin.9b,46 Faced with no obvious alternatives,
we were forced to retrace our steps with the bis-benzyl
ester in place of the bis-TMSE ester (Schemes 6 and 7).45
With this change, we were gratified to find that the bis-
benzyl ester 30a smoothly deprotected under hydro-
genolytic conditions to give a 78% yield of tautomycin
(quantitative based on recovered starting material).
Synthetic tautomycin was spectroscopically and chro-
matographically indistinguishable from an authentic
sample of TM (1H, 13C, IR, HRMS, HPLC coinjection).
Con clu sion s
A highly efficient, modular synthesis of tautomycin has
been completed. Use of the readily available chiral
terpenes citronellene and geraniol epoxide allowed for the
concise assembly of both halves of the spiroketal, which
were coupled in a one-pot double alkylation-spirocy-
clization sequence. J udicious use of Duthaler’s and
Evan’s chiral auxiliaries enabled us to install all of the
remaining stereochemistry of the molecule and prepare
reasonable quantities of late synthetic intermediates. The
overall yield of TM is 1.5%, and the longest linear
sequence is 19 steps starting from geraniol epoxide. Use
of this synthetic route for structure-activity studies of
tautomycin and the mechanistic elucidation of serine/
threonine-specific protein phosphatase inhibition is un-
derway.
Exp er im en ta l Section
Gen er a l P r oced u r es. 1H and 13C NMR spectra were
(42) We predicted that the lower Rf diastereomer, 27a , possessed
the desired stereochemistry at C3′ because it correlated much better
with the 1H NMR spectrum of authentic tautomycin. This prediction
proved to be correct because we have taken the high Rf diastereomer
(27b) through the synthetic sequence to make 3′-epitautomycin that
is spectroscopically distinct from tautomycin itself (1H NMR).
(43) Corey’s oxazaborolidine reagent is reviewed in: Deloux, L.;
Srenbik, M. Chem. Rev. 1993, 93, 763-784.
obtained on 300 and 500 MHz spectrometers. 1H NMR and
(45) Dibenzylacetylene dicarboxylate was prepared from ADA using
the procedure of Radell J .; Brodman, B. W.; Hirshfeld, A.; Bergman,
E. D. J . Phys. Chem. 1965, 69, 928-932. Bis[2-(trimethylsilyl)ethyl]-
acetylene dicarboxylate was prepared using the method of Charlton,
J . L.; Chee, G.; McColeman, H. Can. J . Chem. 1995, 73, 1454-1462.
(46) Sugiyama, Y.; Ohtani, I. I.; Isobe, M.; Takai, A.; Ubukata, M.;
Isono, K. Bioorg. Med. Chem. Lett. 1996, 6, 3-8.
(44) Brown’s DIP-Chloride reagent is reviewed in: Dhar, R. K.
Aldrichim. Acta 1994, 27, 43-51.

Total Synthesis of Tautomycin
J . Org. Chem., Vol. 62, No. 2, 1997 393
13C NMR data are reported in ppm from internal tetrameth-
ylsilane. MS was done in house. Thin-layer chromatography
(TLC) was performed on 0.25 mm precoated silica gel plates
(60 F-254), and silica gel chromatography was performed using
200-400 mesh silica gel. Medium-pressure liquid chroma-
tography (MPLC) was conducted on an SiO2 column (3.7 × 44
cm). Normal-phase preparative HPLC was conducted with a
25 × 100 mm silica cartridge, and reversed-phase preparative
HPLC was conducted with a 25 × 100 mm cartridge. Reversed-
phase analytical HPLC was conducted with a 4.6 × 250 mm
column.
mmol). A solution of 2a (11.58 g, 39.89 mmol) in CH2Cl2 (20
mL) was added via cannula using an additional 30 mL to assist
the transfer, and then the reaction was allowed to warm to
room temperature for 12 h. The mixture was quenched into
5% NaHCO3 (200 mL) and separated and the aqueous layer
extracted with CH2Cl2 (2 × 200 mL). The combined organic
layers were dried with MgSO4, filtered, concentrated in vacuo,
and purified by SiO2 chromatography (11 cm × 16 cm, 5:95
Et2O/hexanes) to give 15.20 g (94%) of a pale yellow oil: 1H
NMR (500 MHz, CDCl3) δ 7.04 (m, 3H), 5.66 (ddd, 1H, J ) 18,
10, 7.5 Hz), 4.95 (br d, 1H, J ) 18 Hz), 4.90 (dd, 1H, J ) 10.5,
2 Hz), 4.14 (dt, 1H, J ) 8, 4 Hz), 2.95 (ddd, 1H, J ) 12, 7.5, 5
Hz), 2.13 (s, 6H), 2.10 (m, 1H), 1.60-1.32 (m, 4H), 1.29 (d,
3H, J ) 7.5 Hz), 1.00 (d, 3H, J ) 6.5 Hz), 0.91 (s, 9H), 0.10 (s,
3H), 0.098 (s, 3H); 13C NMR (125.1 MHz, CDCl3) δ 171.8, 148.2,
144.4, 130.1, 128.5 (3), 125.7, 112.8, 73.3, 45.4, 37.9, 32.7, 30.9,
25.9 (3), 20.2, 18.1, 16.6 (2), 11.3, -4.48, -4.55; IR (thin film)
1757, 1640 cm-1; CI HRMS calcd for C24H41O3Si (M + H)+ m/ z
405.2825, found 405.2841. Anal. Calcd for C24H40O3Si: C,
71.29; H, 9.96. Found: C, 71.2; H, 9.99.
(2R,3S,6S)-3-[(ter t-Bu tyldim eth ylsilyl)oxy]-2,6-dim eth yl-
7-octen ol (4). To a -78 °C solution of 3 (13.30 g, 32.87 mmol)
in hexanes (300 mL) was added neat diisobutylaluminum
hydride (11.70 mL, 65.74 mmol) dropwise over 45 min (pre-
cipitation occurred toward the end of the addition). After the
mixture was stirred for 2.5 h, MeOH (2 mL) was carefully
added and the mixture was allowed to warm to ambient
temperature. Sodium potassium tartrate (132 mL, 0.5 M) was
added, followed by Et2O (70 mL), and the biphasic mixture
was rapidly stirred for 10 h. The crude mixture was extracted
with Et2O (3 × 300 mL), dried with MgSO4, filtered, concen-
trated in vacuo, and chromatographed in two portions by
MPLC (3.7 × 44 cm, 50:50 CH2Cl2/petroleum ether f 50:50
Et2O/hexanes, flow rate 20 mL/min) to give 8.61 g (91%) of a
colorless oil and 100 mg of unreacted starting material: 1H
NMR (500 MHz, CDCl3) δ 5.67 (ddd, 1H, J ) 17.5, 10.5, 7.5
Hz), 4.96 (br d, 1H, J ) 17.5 Hz), 4.93 (br d, 1H, J ) 10.5 Hz),
3.78 (dd, 1H, J ) 11, 3.5 Hz), 3.68 (dt, 1H, J ) 6.5, 4.5 Hz),
3.52 (br dd, 1H, J ) 11, 4.5 Hz), 2.78 (br s, 1H), 2.07 (m, 1H),
1.76 (m, 1H), 1.58 (m, 1H), 1.53 (m, 1H), 1.29 (dd, 1H, J ) 16,
7.5 Hz), 1.25 (app s, 1H), 0.99 (d, 6H, J ) 7 Hz), 0.90 (s, 9H),
0.09 (s, 3H), 0.08 (s, 3H); 13C NMR (125.1 MHz, CDCl3) δ 144.4,
112.9, 77.5, 65.4, 37.9, 37.6, 32.4, 31.6, 25.9 (3), 20.3, 18.0, 14.7,
-4.2, -4.8; IR (thin film) 3357 (br), 1640 cm-1; CI HRMS calcd
for C16H35O2Si (M + H)+ m/ z 287.2407, found 287.2405. Anal.
Calcd for C16H34O2Si: C, 67.07; H, 11.96. Found: C, 67.20;
H, 12.02.
(2R,3S,6S)-1-Iod o-3-[(ter t-Bu tyld im eth ylsilyl)oxy]-2,6-
d im eth yl-7-octen e (5). Imidazole (2.25 g, 33.1 mmol) and
Ph3P (8.67 g, 33.1 mmol) were dissolved into a solution of 4
(8.61 g, 30.0 mmol) in 60 mL of 3:1 Et2O/CH3CN. The mixture
was cooled to 0 °C and treated portionwise with I2 (7.63 g, 30.0
mmol) over 30 min and then allowed to warm to ambient
temperature. This reaction is self-titrating, and 50 mg por-
tions of I2 (150 mg, 0.59 mmol total) were added to the colorless
solution until a faint yellow color persisted indicating comple-
tion (note: the color takes ca. 5 min to fade). The heteroge-
neous solution was concentrated to ca. 15 mL volume in vacuo,
diluted with pentane (20 mL), and filtered through a plug of
freshly prepared activity IV Al2O3 with 10:90 Et2O/pentane
(400 mL) and then 50:50 Et2O/pentane (300 mL) until TLC
(anisaldehyde stain) showed no residual product eluting.
Concentration in vacuo precipitated residual Ph3PO that was
largely removed by decanting, and the diluted product was
filtered through a plug of SiO2 with 10% Et2O/pentane (50 mL)
and concentrated to give 11.11 g of a colorless oil (93%)
contaminated with 538 mg of Ph3PO that did not interfere with
subsequent reactions. An analytical sample was prepared by
SiO2 chromatography (5:95 Et2O/pentane), but the remaining
material was used without further purification: 1H NMR (500
MHz, CDCl3) δ 5.67 (ddd, 1H, J ) 18, 10.5, 7.5 Hz), 4.95 (br d,
1H, J ) 18.5 Hz), 4.92 (dd, 1H, J ) 13, 1.5 Hz), 3.58 (q, 1H, J
) 5 Hz), 3.28 (dd, 1H, J ) 9.5, 4.5 Hz), 3.15 (dd, 1H, J ) 9.5,
7 Hz), 2.06 (m, 1H), 1.67 (m, 1H), 1.41 (m, 2H), 1.33 (m, 2H),
0.99 (d, 3H, J ) 6.5 Hz), 0.96 (d, 3H, J ) 6.5 Hz), 0.89 (s, 9H),
0.08 (s, 3H), 0.06 (s, 3H); 13C NMR (125.1 MHz, CDCl3) δ 144.5,
112.7, 74.8, 39.8, 38.0, 31.1, 30.5, 25.9 (3), 20.1, 18.1, 16.9, 14.0,
2′,6′-Dim eth ylph en yl (2S,3S,6S)-2,6-Dim eth yl-3-h ydr oxy-
7-octen oa te (2). To LDA (86.3 mmol) generated in 380 mL
of Et2O in the standard fashion and cooled to -78 °C was
added a -78 °C-cooled solution of 2′,6′-dimethylphenyl propi-
onate (12.8 g, 72.0 mmol) in Et2O (130 mL) via cannula over
30 min. After 3 h, a solution of chloro(cyclopentadienyl)bis-
(1,2:5,6-di-O-isopropylidene-R-D-glucofuranos-3-O-yl)tita-
nium (1.08 L, 90.0 mmol, 83.3 mM in Et2O) was cooled to -78
°C and transferred to the enolate solution via cannula over
25 min, keeping the internal temperature below -70 °C. The
heterogeneous, deep reddish-brown solution was stirred at -78
°C for 20 h, allowed to warm to -30 °C, and then was kept
between -25 and -30 °C for 5 h before being cooled back to
-78 °C. The transmetalated solution was then treated with
neat (S)-4-methyl-5-hexenal (9.29 g, 82.2 mmol) over 15 min
and stirred for 12 h at -78 °C. The rapidly stirred, bright
yellow, heterogeneous solution was quenched with a 1:1
mixture of THF and 8.1 M NH4Cl (120 mL) all at once and
then allowed to warm to rt for 3 h. The pale yellow suspension
was filtered through Celite with Et2O (200 mL), and the
organic phase was sequentially washed with 1 N HCl (320 mL),
saturated NaHCO3 (125 mL), and brine (100 mL). The
aqueous extracts were combined and back-extracted with
EtOAc (2 × 300 mL), consolidated with the ethereal extracts,
dried with MgSO4, and then filtered and concentrated in vacuo.
Purification by SiO2 chromatography (11 × 17 cm, 70:25:5
EtOAc/CH2Cl2/hexanes f 80:20 EtOAc/hexanes) gave 16.00 g
(77%) of a 6.1:1 mixture of the anti and syn diastereomers.
Purification of the anti isomer was effected by flash chroma-
tography on a LOBAR SiO2 column using 3-5 g loadings (E.
Merck, 3.7 × 44 cm, 10:90 EtOAc/hexanes, flow rate 20 mL/
min). Diastereoselectivity was determined using 1H NMR
analysis (500 MHz, CDCl3) of a crude reaction aliquot by
integration of the C3 methines at 3.75 and 4.01 ppm for the
threo and erythro diastereomers, respectively. Proof of relative
stereochemistry for the presumed (2S,3S,6S) diastereomer was
unambiguously determined from coupling constants of the
acetonide in ref 23. Enantioselectivity for the (2S,3S,6S)
diastereomer was determined by Mosher ester analysis using
commercially available (Fluka) (R)-(-)-R-methoxy-R-(trifluo-
romethyl)phenylacetyl chloride under standard conditions. 1H
NMR analysis (500 MHz, C6D6) gives cleanly resolved methoxy
singlets at 3.47 and 3.44 ppm for the (2S,3S) and (2R,3R)
diastereomers, respectively. (2S,3S,6S) Dia ster eom er 2a :
1
Rf 0.42 (15:85 EtOAc/hexanes); H NMR (500 MHz, CDCl3) δ
7.05 (m, 3H), 5.69 (ddd, 1H, J ) 17.5, 10.5, 7.5 Hz), 4.98 (d,
1H, J ) 16 Hz), 4.93 (d, 1H, J ) 10.5 Hz), 3.75 (m, 1H), 2.83
(dq, 1H, J ) 14.5, 7.5 Hz), 2.67 (br d, 1H, J ) 7.0 Hz), 2.15 (s,
6H), 2.14 (m, superimposed, 1H), 1.70-1.35 (m, 4H), 1.41 (d,
3H, J ) 7.5 Hz), 1.02 (d, 3H, J ) 7.0 Hz); 13C NMR (125.1
MHz, CDCl3) δ 174.0, 147.9, 144.4, 130.0, 128.6 (3), 125.9,
112.9, 73.6, 45.5, 37.9, 32.50, 32.47, 20.2, 16.5, 14.8; IR (thin
film) 3521 (br), 1740, 1639 cm-1; CI HRMS calcd for C18H27O3
(M + H)+ m/ z 291.1961, found 291.1949. Anal. Calcd for
C18H26O3: C, 74.45; H, 9.02. Found: C, 74.12; H, 9.07.
(2R,3S,6S) Dia ster eom er (2b): Rf 0.32 (15:85 EtOAc/
hexanes); 1H NMR (500 MHz, CDCl3) δ 7.03 (m, 3H), 5.68 (m,
1H), 4.97 (dd, 1H, J ) 18.5, 1.5 Hz), 4.93 (dd, 1H, J ) 10.5,
1.0 Hz), 4.01, (ddd, 1H, J ) 11.5, 8.0, 4.0 Hz), 2.81 (dq, 1H, J
) 7.5, 4.0 Hz), 2.67 (br d, 1H, J ) 4.0 Hz), 2.13 (s, 6H), 2.10
(m, superimposed, 1H) 1.6-1.5 (m, 3H), 1.37 (d, 3H, J ) 7.0
Hz), 1.30 (m, 1H), 1.02 (d, 3H, J ) 6.5 Hz).
2′,6′-Dim eth ylp h en yl (2S,3S,6S)-3-[(ter t-Bu tyld im eth -
ylsilyl)oxy]-2,6-d im eth yl-7-octen oa te (3). To a 0 °C solu-
tion of 2,6-lutidine (9.45 mL, 81.1 mmol) in 250 mL of CH2Cl2
was added tert-butyldimethylsilyl triflate (11.2 mL, 48.7

394 J . Org. Chem., Vol. 62, No. 2, 1997
Sheppeck et al.
-4.2, -4.4; CI HRMS calcd for C16H34IOSi (M + H)+ m/ z
397.1425, found 397.1446.
1H, J ) 7.4 Hz), 5.10 (m, 1H), 4.79 (m, 1H), 3.94 (m, 1H), 3.70
(m, 1H), 2.69 (d, 1H, J ) 3.9 Hz), 2.05 (m, 1H), 1.97 (m, 1H),
1.68 (s, 3H), 1.62 (s, 3H), 1.59 (m, 1H), 1.45 (m, 1H), 1.24 (d,
3H, J ) 7.1 Hz), 1.16 (m, 1H), 1.01 (d, 3H, J ) 6.5 Hz), 0.94
(d, 3H, J ) 6.4 Hz), 0.94 (d, 3H, J ) 6.44 Hz); 13C NMR (125,
MHz, CDCl3) δ 177.4, 152.4, 133.2, 131.6, 128.8, 128.7, 125.6,
124.3, 78.8, 75.3, 54.8, 39.9, 35.3, 32.9, 25.7, 25.2, 17.6, 15.0,
14.3, 10.9; IR (thin film) 3498 (br), 1691 cm-1; CI HRMS calcd
for C22H32NO4 (M + H)+ m/ z 374.5046, found 374.2326.
[3-(2R,3S,4R),4R,5R]-3-[[(3-ter t-Bu tyldim eth ylsilyl)oxy]-
2,4,8-t r im et h yl-3-h yd r oxy-1-oxo-7-n on en yl]-4-m et h yl-5-
p h en yl-2-oxa zolid in on e (8). To a solution of alcohol 7 (22.4
g, 60 mmol) in 600 mL of CH2Cl2 at 0 °C were added
2,6-lutidine (9.08 mL, 78 mmol) and, 10 min later, tert-
butyldimethylsilyl trifluoromethanesulfonate (16.5 mL, 72
mmol). After 3 h, the solution was quenched by the addition
of 240 mL of saturated aqueous NaHCO3. The aqueous layer
was reextracted with CH2Cl2 (2 × 600 mL), and the combined
organic extracts were washed with 300 mL of NaHSO4 (0.5
M). The aqueous layer was back-extracted with CH2Cl2 (2 ×
600 mL), and the combined organic extracts were dried over
anhydrous Na2SO4, filtered, and concentrated. The resultant
light yellow oil was purified by SiO2 flash chromatography
(10:1 hexane/EtOAc) to give a colorless oil, 26.8 g, in 92%
yield: 1H NMR (500 MHz, CDCl3) δ 7.44-7.29 (m, 5H), 5.63
(d, 1H, J ) 7.1 Hz), 5.08 (m, 1H), 4.72 (m, 1H), 3.96 (m, 2H),
2.01 (m, 1H), 1.93 (m, 1H), 1.68 (s, 3H), 1.60 (s, 3H), 1.55 (m,
2H), 1.19 (d, 3H, J ) 6.4 Hz), 1.18 (m, 1H), 0.90 (s, 9H), 0.87
(2 d, overlapping, 6H, J ) 7.9, 12.0 Hz), 0.07 (s, 3H), 0.06 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 176.0, 152.5, 133.2, 131.2,
128.7, 125.5, 124.6, 78.7, 77.3, 55.1, 41.5, 38.3, 33.4, 26.1, 25.7,
18.4, 17.7, 14.7, 14.6, 14.1, -3.8, -4.1; IR (thin film) 2958,
2928, 1784, 1698 cm-1; CI HRMS calcd for C28H46NO4Si (M +
H)+ m/ z 488.7686, found 488.3196.
(2S,3R)-3,7-Dim eth yl-6-octen e-1,2-d iol (6). To (2R,3S)-
geraniol epoxide (2.01 g, 11.8 mmol, 91% ee) in THF (25 mL)
at rt was dissolved NaBH3CN (1.84 g, 29.6 mmol), and then
the mixture was treated with glacial acetic acid (3.55 g, 59.2
mmol). After 12 h, another 744 mg of NaBH3CN (11.4 mmol)
and 3.55 g acetic acid (59.2 mmol) were added with vigorous
stirring. After an additional 8 h, the completed reaction was
concentrated in vacuo, diluted with Et2O (40 mL), cooled to 0
°C, and carefully treated with 15% aqueous NaOH (40 mL).
The organic layer was separated, and the aqueous layer was
extracted with Et2O (3 × 80 mL). The organic layers were
combined, washed with brine (20 mL), and dried over MgSO4
(the aqueous layer was very slowly treated with dilute HCl in
the back of the hoodsCAUTION: exotherm and HCN evolu-
tion!). Filtration of the ethereal extracts, concentration in
vacuo, and SiO2 chromatography (radial, 4 mm plate, 25:75
CH3CN/CH2Cl2) gave 1.37 g (67%) of a colorless oil. Chiral
GLC analysis of the unpurified material established the 1,2-
diol/1,3-diol ratio as 50:1 and the ee as 91%sidentical to that
of the starting geraniol epoxide: 1H NMR (500 MHz, CDCl3)
δ 5.08 (t, 1H, 3.63 (dd, 1H, J ) 10.4, 2.1 Hz), 3.55 (m, 1H),
3.52 (t, 1H), 3.36 (s, 2H), 2.02 (m, 1H), 1.96 (m, 1H), 1.68 (s,
3H), 1.60 (s, 3H), 1.55 (m, 1H), 1.45 (m, 1H), 1.17 (m, 1H),
0.91 (d, 3H, J ) 6.8 Hz); 13C (125.1 MHz, CDCl3) δ (TMS) 131.5,
124.3, 75.7, 65.1, 35.3, 33.1, 25.6, 25.5, 17.6, 14.4; IR (thin film)
3364 (br), 822, 830; CI HRMS calcd for C10H21O2 (M + H)+
m/ z 173.1542, found 173.1538; GLC analysis (Cyclodex B 0.25
mm × 30 m), tR (2S,3R) ) 19.99 min, tR (2R,3S) ) 20.35 min,
tR (1,3R)-diol ) 22.88 min, tR (1,3S)-diol ) 23.29 min; 150 °C
isothermal, 15 psi head pressure, H2 22.7 mL/min, He 20.7
mL/min, air 402 mL/min.
[3(2R,3S,4R),4R,5R]-3-(3-Hydr oxy-1-oxo-2,4,8-tr im eth yl-
7-n on en yl)-4-m eth yl-5-p h en yl-2-oxa zolid in on e (7). To
diol 6 (16.3 g, 95 mmol) in 600 mL of CH2Cl2 and 600 mL of
pH 7 phosphate buffer was added 65 g of NaIO4 at room
temperature. The reaction mixture was sealed and vigorously
stirred for 8 h. The aqueous layer was extracted with Et2O (2
× 600 mL), and the combined organic extracts were washed
with 300 mL of saturated NaCl, dried over anhydrous Na2-
SO4, and filtered. The solvent was carefully evaporated on a
rotary evaporator, but not all of it was removed due to the
volatility of the aldehyde. The fragrant oil was used im-
mediately in the following step without further purification.
In a separate reaction vessel, freshly prepared di-n-butylboryl
triflate (30.0 mL, 118.8 mmol) was added over a 5 min period
to a -78 °C solution of (4R,5R)-4-methyl-5-phenyl-N-propionyl-
2-oxazolidinone (25.4 g, 109.3 mmol) in freshly distilled CH2-
Cl2 (150 mL). The solution became heterogeneous, and after
10 min, triethylamine (18.5 mL, 133 mmol) was added drop-
wise over a 15 min period. After 30 min at -78 °C, the dry
ice bath was removed and the mixture was allowed to warm
to 0 °C slowly. The heterogeneous mixture was stirred at this
temperature for 1 h and then recooled to -78 °C. The
aldehyde prepared above was then added in one portion. After
45 min, the reaction was allowed to warm to 0 °C and stirred
at this temperature for 7 h. The reaction was quenched with
pH 7 phosphate buffer (160 mL buffer in 320 mL MeOH) and
then treated with 160 mL of H2O2 (30%) in 530 mL of MeOH
and stirred at 0 °C for 1 h. The organic solvent was removed
in vacuo, 530 mL of 10% aqueous NaHCO3 was added, and
the resultant solution was extracted with CH2Cl2 (3 × 600 mL).
The combined organic extracts were dried over anhydrous
MgSO4, filtered, and concentrated to a light yellow oil that
P h en ylm eth yl (2R,3S,4R)-(3[(ter t-Bu tyld im eth ylsilyl)-
oxy]-2,4,8-tr im eth yl-7-n on en oa te (9). To a 0 °C solution
of benzyl alcohol (11.95 mL, 115.5 mmol) in 55 mL of THF
was added n-BuLi (57.7 mL, 92.4 mmol, 1.6 M in hexane). The
reaction mixture was maintained at 0 °C for 15 min and then
cannulated into a cooled (0 °C) solution of 8 in 55 mL of THF.
The reaction mixture was kept at 0 °C for 3.5 h and then was
quenched by adding 460 mL of H2O. The aqueous layer was
extracted with CH2Cl2 (3 × 460 mL), and the combined organic
extracts were dried over anhydrous Na2SO4, filtered, and
concentrated to obtain a crude colorless oil. The product was
purified by SiO2 flash chromatography (10:1 hexane/EtOAc)
to give 19.49 g of colorless oil in 86% yield: 1H NMR (500 MHz,
CDCl3) δ 7.40-7.30 (m, 5H), 5.11 (s, 3H), 5.07 (m, 1H), 3.87
(dd, 1H, J ) 6.6, 6.4 Hz), 2.67 (m, 1H), 1.99 (m, 1H), 1.89 (m,
1H), 1.69 (s, 3H), 1.60 (s, 3H), 1.46 (m, 1H), 1.19 (d, 3H, J )
7.1 Hz), 0.92 (s, 9H), 0.87 (d, 3H, J ) 6.8 Hz), 0.06 (s, 3H),
0.04 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 175.5, 135.0, 131.3,
128.5, 128.13, 128.10, 124.5, 66.1, 43.5, 38.0, 33.4, 26.0, 25.9,
25.7, 18.3, 17.6, 14.5, 13.7, -4.0, -4.1; IR (thin film) 1735 cm-1
;
CI HRMS calcd for C25H43O3Si (M + H)+ m/ z 419.7052, found
419.2981.
(2R,3S,4R)-3-[(ter t-Bu t yld im et h ylsilyl)oxy]-2,4,8-t r i-
m eth yl-7-n on en ol (10). To a cooled (-78 °C) stirred solution
of benzyl ester 9 in 180 mL of CH2Cl2 was added neat DIBAL
(18.0 mL, 101.6 mmol) dropwise over 15 min. The reaction
temperature was held at -78 °C for 30 min and then allowed
to warm to 0 °C and maintained at this temperature for an
additional 30 min. Excess DIBAL was quenched with 2.5 mL
of MeOH, and the reaction mixture was diluted in 160 mL of
CH2Cl2. A solution of 200 mL of K-Na tartrate (0.5 M) was
added at 0 °C, and the viscous solution was stirred vigorously
for 18 h, whereafter two clear layers had formed. The organic
layer was separated, and the aqueous layer was extracted with
CH2Cl2 (3 × 120 mL). The combined organic extracts were
dried over anhydrous Na2SO4, and the solution was filtered
and concentrated in vacuo. SiO2 flash chromatography (5:1
hexanes/EtOAc) afforded a colorless oil, 14.01 g, 96% yield.
1H NMR (500 MHz, CDCl3) δ 5.07 (m, 1H), 3.61 (m, 2H), 3.45
(m, 1H), 2.20 (br, 1H), 1.92 (m, 1H), 1.67 (s, 3H), 1.60 (s, 3H),
1.60 (m, 1H), 1.45 (m, 1H), 1.15 (m, 1H), 0.91 (d, 3H, J ) 6.8
Hz), 0.84 (d, 3H, J ) 6.8 Hz), 0.07 (s, 3H), 0.05 (s, 3H); 13C
1
was analyzed by H NMR (C6D6) and indicated 100:1 diaste-
reoselectivity. The crude mixture was first purified by SiO2
flash chromatography (7:1 hexane/EtOAc), followed by MPLC
(3.7 × 44 cm, 7:1 hexanes/EtOAc, flow rate 20 mL/min) to give
22.8 g of the desired product as a colorless oil (64% yield for
two steps). (2R)-2,6-Dim eth ylh ep ten a l: 1H NMR (500 MHz,
CDCl3) δ 9.59 (d, 1H, J ) 2.0 Hz), 5.06 (m, 1H), 2.27 (m, 1H),
1.74 (m, 1H), 1.67 (s, 3H), 1.07 (d, 3H, J ) 7.1 Hz); 13C NMR
δ 205.1, 132.6, 123.3, 54.7, 30.6, 25.6, 25.2, 17.6, 13.2; IR
(CHCl3) 1726 cm-1
7: 1H NMR (500 MHz, CDCl3) δ 7.44-7.28 (m, 5H), 5.69 (d,
.

Total Synthesis of Tautomycin
J . Org. Chem., Vol. 62, No. 2, 1997 395
NMR (125 MHz, CDCl3) δ 131.3, 124.6, 76.7, 66.4, 39.3, 35.9,
34.5, 26.1, 26.0, 25.7, 18.2, 17.6, 15.7, 12.5, -4.1, -4.3: IR
(thin film) 3345 (br) cm-1; CI HRMS calcd for C18H39O2Si (M
+ H)+ m/ z 315.5958, found 315.2728.
6.56 g of 13 and 321 mg of unreacted starting material (98%
yield, 100% based on recovered 12): 1H NMR (500 MHz,
CDCl3) δ 5.70 (m, 1H), 4.96 (br d, 1H, J ) 17 Hz), 4.92 (br d,
1H, J ) 10.5 Hz), 3.30 (m, 1H), 3.16 (m, 1H), 2.71 (t, 1H, J )
6 Hz), 2.11 (m, 1H), 2.04 (m, 1H), 1.85 (m, 1H), 1.70-1.20 (m,
17H), 1.31 (s, 3H), 1.27 (2 s, 3H), 1.00 (app t, 6H), 0.90 (d, 3H,
J ) 7 Hz), 0.81 (d, 3H, J ) 6.5 Hz); CI HRMS calcd for
C25H45O3 (M + H)+ m/ z 393.3368, found 393.3358.
(2R,3S,4R)-3-[(ter t-Bu tyldim eth ylsilyl)oxy]-1-iodo-2,4,8-
tr im eth yl-7-n on en e (11). A 0 °C solution of alcohol 10 (14
g, 44 mmol), PPh3 (12.87 g, 49.06 mmol), and imidazole (3.34
g, 49.06 mmol) in 84 mL of Et2O/CH3CN (3:1) was treated with
iodine (11.32 g, 44 mmol) portionwise. The solution was then
allowed to warm to rt and after 45 min was concentrated in
vacuo. The oil was filtered through basic alumina (activity
IV, hexane/Et2O 9:1), concentrated in vacuo, and then flushed
through a SiO2 plug using 9:1 hexane/Et2O. The solvent was
removed on a rotary evaporator to give 16.75 g of the desired
iodide (93% yield) that was used without further purification:
1H NMR (500 MHz, CDCl3) δ 5.08 (m, 1H), 3.55 (t, 1H, J )
4.0 Hz), 3.27 (dd, 1H, J ) 9.53, 6.0 Hz), 3.08 (dd, 1 H, J )
9.53, 7.0 Hz), 2.01 (m, 1H), 1.95-1.85 (m, 2H), 1.68 (s, 3H),
1.58 (s, 3H), 1.58 (m, overlapping, 1H), 1.45 (m, 1H), 1.0 (d,
3H, J ) 6.8 Hz), 0.90 (s, 9H), 0.88 (s, 3H), 0.07 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ 131.3, 124.6, 77.8, 39.9, 36.6, 33.8,
26.2, 26.1, 26.0, 25.8, 18.4, 17.7, 16.2, 15.5, 14.6, -3.8; IR (thin
Ald eh yd e 14. To a 0 °C solution of 13 in 200 mL of Et2O
was added H5IO6 (4.15 g, 18.2 mmol) portionwise over 20 min,
and then the resulting mixture was allowed to warm to rt.
After 3 h, the reaction mixture was filtered through a SiO2
plug with Et2O, concentrated in vacuo, and chromatographed
on SiO2 using 5:95 EtOAc/hexanes to give 3.09 (53%) of a
colorless oil: 1H NMR (500 MHz, CDCl3) δ 9.80 (s, 1H), 5.72
(ddd, 1H, J ) 17.5, 10.5, 7.5 Hz), 4.96 (br d, 1H, J ) 17.5 Hz),
4.92 (br d, 1H, J ) 10.5 Hz), 3.29 (dd, 1H, J ) 10.5 Hz), 3.14
(br t, 1H, J ) 9.5 Hz), 2.47 (m, 2H), 2.13 (m, 1H), 2.05 (m,
1H), 1.85 (m, 1H), 1.80 (m, 1H), 1.70-1.20 (m, 14H), 1.00 (d,
3H, J ) 6.5 Hz), 0.99 (d, 3H, J ) 8 Hz), 0.91 (d, 3H, J ) 7 Hz),
0.81 (d, 3H, J ) 6.5 Hz); 13C NMR (125.1 MHz, CDCl3) δ 202.5,
144.9, 112.4, 95.7, 74.7, 74.5, 41.0, 37.9, 36.0, 35.0, 34.0, 32.9,
30.9, 30.2, 28.2, 27.5, 26.6, 23.9, 20.1, 18.1, 16.3, 10.8; IR (thin
film) 2928, 2856 cm-1
.
film) 1639 cm-1; [R]22 -57.9 (c ) 1.835, CHCl3); CI HRMS
Sp ir ocyclic Dien e 12. To a -78 °C solution of acetone
N,N-dimethylhydrazone (2.590 g, 25.91 mmol) in 68 mL of
THF was added BuLi (10.8 mL, 2.41 M in hexanes) over 5 min,
and the reaction was warmed in a 0 °C bath for 2 h. The
reaction mixture was cooled back to -78 °C and treated with
neat 5 (10.06 g, 25.40 mmol) via cannula using 4 mL of
additional THF to assist the transfer. The heterogeneous
solution was allowed to warm to rt and became a bright yellow
homogeneous solution after 15 min. TLC after 1 h showed no
remaining 5, so the reaction was cooled to -78 °C, treated with
BuLi (10.8 mL, 2.41 M in hexanes), warmed in a 0 °C bath for
2 h, cooled back to -78 °C, and treated with neat 11 (11.00 g,
25.91 mmol), and the heterogeneous orange mixture was
allowed to warm to rt. After 5 h, the reaction was quenched
into pH 7.2 phosphate buffer (200 mL, 1.0 M), extracted with
Et2O (4 × 200 mL), dried with MgSO4, filtered, concentrated
in vacuo, and transferred to a 200 mL polyethylene bottle using
60 mL of CH3CN and 10 mL of i-PrOH. To the unpurified
material was added concentrated aqueous HF (47%, 1 mL
every 8 h for 3 d), and the reaction vessel was capped and
stirred vigorously. After a total of 72 h, the reaction contents
were cautiously quenched into a stirring mixture of Et2O (200
mL) and saturated aqueous Na2CO3 (600 mL) and separated,
and the aqueous layer was extracted with Et2O (4 × 300 mL).
The combined organic layers were dried with MgSO4, filtered,
concentrated in vacuo, and purified by MPLC (LOBAR, 3.7 ×
44 cm, 5:95 Et2O/hexanes, flow rate 20 mL/min) to give 7.36 g
of 11 (77% total yield based on 5 equivalence): 1H NMR (500
MHz, CDCl3) δ 5.72 (ddd, 1H, J ) 18, 10.5, 7.5 Hz), 5.10 (br t,
1 H, J ) 7 Hz), 4.96 (br d, 1H, J ) 18 Hz), 4.91 (br d, 1H, J )
11 Hz), 3.29 (dd, 1H, J ) 10, 2 Hz), 3.17 (dt, 1H, J ) 7.5, 2
Hz), 2.13 (m, 1H), 2.04 (m, 2H), 1.95 (m, 1H), 1.85 (m, 1H),
1.68 (s, 3H), 1.61 (s, 3H), 1.73-1.35 (m, 12 H), 1.3-1.2 (m,
3H), 1.01 (d, 3H, J ) 6.5 Hz), 0.99 (d, 3H, J ) 6.5 Hz), 0.88 (d,
3H, J ) 7 Hz), 0.82, (d, 3H, J ) 6.5 Hz); 13C NMR (125.1 MHz,
CDCl3) δ 145.0, 131.4, 124.7, 112.4, 95.6, 74.8, 74.6, 37.9, 36.1,
35.1, 34.1, 32.9, 31.8, 30.9, 30.3, 28.3, 27.5, 26.7, 25.7, 24.6,
D
calcd for C22H39O3 (M + H)+ m/ z 351.2900, found 351.2908.
â-Hyd r oxy Keton e 15. To LDA (10.08 mmol) generated
in 43 mL of Et2O in the standard fashion and cooled to -78
°C was added a -78 °C-cooled solution of 2′,6′-dimethylphe-
nylpropionate (1.44 g, 8.08 mmol) in Et2O (15 mL) via cannula
over 15 min, keeping the internal temperature under -70 °C.
After 3 h, a -78 °C solution of chloro(cyclopentadienyl)bis-
(1,2:5,6-di-O-isopropylidene-R-D-glucofuranos-3-O-yl)tita-
nium (120 mL, 10.0 mmol, 83.3 mM was transferred to the
enolate solution via cannula, keeping the internal temperature
below -70 °C. The reaction was stirred at -78 °C for 24 h,
allowed to warm to -30 °C, and then was kept between -20
and -25 °C for 5.5 h before being cooled back to -78 °C. The
reagent was treated with a solution of 14 (2.80 g, 8.00 mmol)
in Et2O (8 mL + 4 mL to assist transfer) and stirred for 12 h
at -78 °C after which the reaction was quenched with a 1:1
mixture of THF and saturated aqueous NH4Cl (32 mL) all at
once and then stirred vigorously for 3 h at 0 °C. The solution
was filtered through a plug of Celite with EtOAc (50 mL), and
the organic phase was sequentially washed with 0.5 N HCl
(100 mL), saturated NaHCO3 (100 mL), and brine (50 mL).
The aqueous extracts were combined and back-extracted with
EtOAc (1 × 200 mL), and the organic extracts were combined,
dried with MgSO4, and then filtered and concentrated in vacuo.
Purification by SiO2 chromatography (8:92 EtOAc/hexanes f
25:75 EtOAc/hexanes) gave 3.23 g of a 7.4:1 anti/syn aldol
product mixture and 590 mg of recovered 14 (76% yield, or
97% based on recovered starting material). An analytical
sample was purified by HPLC (8:92 EtOAc/hexanes, tR 24 min,
5 mL/min), but the two diastereomers were not separated at
this point since they are easier to purify after convertion into
16: Rf 0.31 (15:85 EtOAc/hexanes); 1H NMR (500 MHz, CDCl3)
δ 7.06 (br s, 3H), 5.72 (ddd, 1H, J ) 17.5, 10.5, 7.5 Hz), 4.96
(br d, 1H, J ) 17.5 Hz), 4.91 (br d, 1H, J ) 10.5 Hz), 3.76 (dt,
1H, J ) 7, 3 Hz), 3.31 (dd, 1H, J ) 10, 1.5 Hz), 3.16 (br dt,
1H, J ) 9, 1.5 Hz), 2.87 (dq, 1H, J ) 14, 7 Hz), 2.16 (s, 6H),
2.17-2.00 (m, 2H), 1.88 (m, 1H), 1.8-1.2 (m, 18H), 1.45 (d,
3H, J ) 7.5 Hz), 1.03 (d, 3H, J ) 6.5 Hz), 1.00 (d, 3H, J ) 6.5
Hz), 0.91 (d, 3H, J ) 7 Hz), 0.82, (d, 3H, J ) 6.5 Hz); 13C NMR
(125.1 MHz, CDCl3) δ 174.0, 147.8, 144.9, 130.0, 128.7 (3),
126.0, 112.4, 95.6, 74.7, 73.9, 45.2, 37.9, 36.1, 65.1, 34.8, 32.9,
31.6, 30.9, 30.2, 28.2, 27.7, 27.6 (2), 26.7, 20.1, 18.1, 16.7, 16.5
20.1, 18.1, 17.7, 16.4, 10.8; IR (thin film) 1640 cm-1; [R]21
D
-62.5 (c ) 0.665, CHCl3); CI HRMS calcd for C25H45O2 (M +
H)+ m/ z 377.3419, found 377.3420. Anal. Calcd for
C25H44O2: C, 79.73; H, 11.78. Found: C, 80.02; H, 11.82.
Ep oxid e 13. To a -20 °C solution of 12 (6.62 g, 17.11
mmol) in 200 mL of CH2Cl2 was added m-CPBA (3.55 g, 83.2%
by iodometric titration, actual ) 2.95 g, 17.09 mmol) via a solid
addition funnel over 30 min. After 5.5 h, the cold solution was
filtered through a Buchner funnel, the cake was washed with
0 °C 10:90 Et2O/pentane (150 mL), and the solution was
shaken sequentially with 10% aqueous Na2SO3 (50 mL),
saturated aqueous NaHCO3 (50 mL), and brine (50 mL). The
combined aqueous layers were back-extracted with CH2Cl2 (2
× 50 mL), and the combined organic layers were dried over
Na2SO4, filtered, concentrated in vacuo, and chromatographed
on SiO2 (10:90 Et2O/hexanes f 25:75 Et2O/hexanes) to give
(2), 14.9, 10.9; IR (thin film) 3492 (br), 3070, 1738, 1639 cm-1
;
CI HRMS calcd for C33H52O5 (M)+ m/ z 528.3815, found
528.3827.
Wein r eb Am id e 16. Following the procedure of Heathcock
et al.,32 a 7.4:1 mixture of 15a and 15b (2.49 g, 4.33 mmol)
was dissolved in MeOH (26 mL) and treated with a solution
of KOH (2.43 g, 43.3 mmol) in 1:2 MeOH/H2O (17 mL). After
2 h, the reaction was diluted with Et2O, cooled with dry ice,
and quenched with 1 N HCl (100 mL). The ethereal phase
was separated, and the aqueous phase was extracted with
additional Et2O (4 × 150 mL), dried with MgSO4, filtered,

396 J . Org. Chem., Vol. 62, No. 2, 1997
Sheppeck et al.
concentrated to a bright yellow oil in vacuo, and chromato-
graphed on a short SiO2 column (3.5 × 6 cm, 20:80 EtOAc/
hexanes until the 2,6-dimethylphenol eluted, and then 100%
EtOAc). The bright yellow oil was dissolved in DMF (8 mL)
and 1-hydroxy-7-azabenzotriazole (589 mg, 4.33 mmol), N,N-
diisopropylethylamine (1.46 mL, 8.66 mmol) and N,O-dimeth-
ylhydroxylamine hydrochloride were added sequentially, and
the mixture was stirred until it became homogeneous (5 min).
The reaction was cooled to 0 °C and treated with solid
dicyclohexylcarbodiimide (3.13 g, 15.16 mmol) portionwise over
10 min, and the reaction mixture was allowed to warm to rt
after it became homogeneous. After 8.5 h, the heterogeneous
solution was quenched into 400 mL of a 1:1 mixture of Et2O
and saturated aqueous NaHCO3 and separated, and the
ethereal phase was washed with 1 N HCl, filtered through a
glass frit, and dried over MgSO4. The solution was filtered
and concentrated in vacuo, and crude 1H NMR indicated no
detectable epimerization at the 2 position (i.e., the anti/syn
ratio is still exactly 7.4:1). The oil was purified by radial SiO2
chromatography (2 mm plate, 25:75 EtOAc/petroleum ether
f 60:40 EtOAc/petroleum ether) to give 1.59 g of 16a and 215
mg of 16b (89% for two steps): (2R,3S) Dia ster eom er 16a :
1H NMR (500 MHz, CDCl3) δ 5.72 (ddd, 1H, J ) 17.5, 10.5,
7.5 Hz), 4.96 (br d, 1H, J ) 17.5 Hz), 4.91 (br d, 1H, J ) 10.5
Hz), 3.72 (s, 3H), 3.58 (dt, 1H, J ) 9, 4.5 Hz), 3.28 (dd, 1H, J
) 10.5, 2 Hz), 3.21 (br s, 3H), 3.16 (dt, 1H, J ) 9, 1.5 Hz), 2.97
(br m, 1H), 2.12 (m, 1H), 2.03 (m, 1H), 1.86 (m, 1H), 1.72-
1.12 (m, 18H), 1.24 (d, 3H, J ) 7.5 Hz), 1.23 (m, 3H,
superimposed), 1.00 (d, 3H, J ) 6 Hz), 0.89 (d, 3H, J ) 7 Hz),
0.81, (d, 3H, J ) 6.5 Hz); 13C NMR (125.1 MHz, CDCl3) δ 177.4,
144.9, 112.3, 95.5, 74.6, 74.5, 61.5, 39.7, 37.8, 36.0, 34.7, 34.6,
32.8, 32.2, 31.7, 30.8, 30.2, 28.2, 28.0, 27.4, 26.7, 26.6, 20.0,
mixture was treated with TMEDA (3.11 mL, 31.43 mmol)
dropwise and, after 15 min, with freshly distilled, neat
isobutyraldehyde (2.00 mL, 22.0 mmol). The reaction was
stirred for 5 h at -78 °C and then poured into a rapidly stirring
mixture of 400 mL of 1 M NaHSO4 (aq) and 300 mL of CH2-
Cl2. The organic phase was separated, the aqueous phase was
extracted with EtOAc (2 × 300 mL), and the organic phases
were consolidated and washed with saturated aqueous NaH-
CO3. The resulting solution was filtered through a Buchner
filter, washed with brine, and dried over Na2SO4. The desic-
cant was filtered off, and the solution was concentrated in
vacuo to give 6.10 g of crude material that was analyzed by
1H NMR to determine the diastereomeric ratio. Integration
of the methoxy singlets gives a ratio of 73.4 (2R,3R):14.1
(unassigned):9.0 (2R,3S):3.5 (unassigned). The chemical shifts
(500 MHz, CDCl3) are as follows: starting oxazolidinone, 3.521
ppm; (2R,3R)-isomer, 3.415 ppm; (2R,3S)-isomer, 3.372 ppm;
other two isomers, 3.476 ppm, 3.449 ppm. SiO2 chromatog-
raphy on a LOBAR column (E. Merck, 3.7 × 44 cm, 5:95
acetone/CH2Cl2, flow rate 20 mL/min) gave 3.92 g of (2R,3R),
1.41 g of the other diastereomers, and 764 mg of unreacted
starting material (93% conversion). The product solified upon
standing and was recrystallized from a mixture of hot Et2O/
hexanes (2:5). Four crops gave a total of 3.89 g of product
(58%, 68% based on recovered oxazolidinone): 1H NMR (500
MHz, CDCl3) δ 7.36-7.23 (m, 5H), 5.15 (d, 1H, J ) 8.5 Hz),
4.78 (m, 1H), 4.25 (dd, 1 H, J ) 17, 9 Hz), 4.21 (dd, 1H, 9, 3
Hz), 3.62 (dt, 1H, J ) 9, 3 Hz), 3.42 (s, 3H), 3.38 (dd, 1H, J )
13.5, 3.5 Hz), 2.83 (dd, 1H, J ) 13.5, 9.5 Hz), 2.07 (m, 1H),
1.95 (br d, 1H, J ) 9 Hz), 1.00 (d, 3H, J ) 7 Hz), 0.95 (d, 3H,
J ) 7 Hz); 13C NMR (125.1 MHz, CDCl3) δ 173.1, 154.3, 135.0,
129.3(2), 128.9(2), 127.4, 79.5, 77.09, 66.8, 58.1, 55.5, 38.1, 29.7,
18.0, 11.7, 15.1, 10.9; IR (thin film) 3451 (br), 3075, 1640 cm-1
;
19.4, 14.9; IR (KBr) 3493 (br), 3078, 3022, 1775, 1698 cm-1
;
CI HRMS calcd for C27H50NO5 (M + H)+ m/ z 468.3688, found
mp 94-95 °C; [R]22D -102.3 (c ) 2.00, MeOH); CI HRMS calcd
for C17H24NO5 (M + H)+ m/ z 322.1655, found 322.1655. Anal.
Calcd for C17H23NO5: C, 63.54; H, 7.21; N, 4.36. Found: C,
63.77; H, 7.34; N, 4.33.
468.3692.
1
(2S,3S) Dia ster om er 16b: H NMR (500 MHz, CDCl3) δ
5.72 (ddd, 1H, J ) 17.5, 10.5, 7.5 Hz), 4.96 (br d, 1H, J ) 17.5
Hz), 4.91 (br d, 1H, J ) 10.5 Hz), 3.84 (m, 1H), 3.71 (s, 3H),
3.29 (dd, 1H, J ) 9.5, 2 Hz), 3.20 (br s, 3H), 3.16 (dt, 1H, J )
7.5, 1.5 Hz), 2.89 (br d, 1H), 2.13 (m, 1H), 2.03 (m, 1H), 1.85
(m, 1H), 1.70-1.20 (m, 18H), 1.18 (d, 3H, J ) 7 Hz), 1.00 (app
t, 6H, J ) 7 Hz), 0.90 (d, 3H, J ) 7 Hz), 0.82, (d, 3H, J ) 6.5
Hz).
(2R,3R)-2,N-Dim et h oxy-3-h yd r oxy-4,N-d im et h ylp en -
ta n a m id e (20). To a suspension of N,O-dimethylhydroxy-
lamine hydrochloride (2.06 g, 21.08 mmol) in 54 mL of CH2Cl2
cooled to -20 °C was added Me3Al (10.5 mL, 21.08 mmol, 2.0
M) dropwise over 5 min. After another 5 min, the reaction
mixture was allowed to warm to rt for 1 h (it became
homogeneous) and was then cooled back to -20 °C. A solution
of 19 (2.26 g, 7.03 mmol) in 54 mL of CH2Cl2 was added via
addition funnel over 30 min to the above solution and then
stirred between -10 to -15 °C for 4 h and finally at rt for 1 h.
The completed reaction was quenched with 1 N tartaric acid
(54 mL) over 10 min and stirred rapidly for 1 h at rt, the layers
were separated, and the aqueous phase was extracted with
CH2Cl2 (2 × 60 mL). The combined organic layers were dried
over Na2SO4, filtered, concentrated in vacuo, and chromato-
graphed on SiO2 (10:90 acetone/CH2Cl2 f 20:80 acetone/CH2-
Cl2, then EtOAc) to give 1.44 g (100%) of 19: 1H NMR (500
MHz, CDCl3) δ 4.26 (br d, 1H, J ) 5.5 Hz), 3.77 (s, 3H), 3.73
(br s, 1H), 3.38 (s, 3H), 3.26 (br s, 3H), 2.45 (br s, 1H), 1.92
(m, 1H), 0.99 (d, 3H, J ) 7 Hz), 0.95 (d, 3H, J ) 6.5 Hz); 13C
(125.1 MHz, CDCl3) δ 172.4, 77.8, 75.6, 61.4, 57.5, 32.1, 29.7,
19.6, 15.8; IR (KBr) 3440 (br), 1647; mp 44-46 °C; CI HRMS
calcd for C9H20NO4 (M + H)+ m/ z 206.1396, found 206.1384.
Anal. Calcd for C9H19NO4: C, 52.67; H, 9.33; N, 6.82.
Found: C, 52.63; H, 9.36; N, 6.80.
2′-(P h en ylm eth oxy)-(2Z,6E)-4-oxo-2-m eth yl-3-[2′′-[(p h e-
n ylm eth oxy)ca r bon yl]]octa d ien oa te (22). To a suspension
of CuCN (898 mg, 10 mmol) in 40 mL of THF at -40 °C was
added MeLi (7.14 mL, 10 mmol, 1.40 M in Et2O), and after 20
min, the mixture was cooled to -78 °C for 1 h. To this cuprate
solution was added neat 21 (2.94 g, 10 mmol) over 5 min using
2 mL of THF to assist the transfer to immediately produce a
deep orange-red color. After 2 h, t-3-pentenoyl chloride41 (1.3
g, 11 mmol) was added all at once, and the mixture was stirred
for 2 h at -78 °C and then allowed to warm to 0 °C for 15
min. The greenish, heterogeneous solution was quenched with
5.6 mL of water and filtered through a Celite pad with Et2O,
and the filtrate was washed with 150 mL of brine and
separated. The brine was extracted with 300 mL of Et2O, and
â-Hyd r oxy Keton e 17. To a -78 °C solution of 16a (1.115
g, 2.384 mmol) in THF (20 mL) was added MeLi (5.70 mL,
7.98 mmol, 1.40 M in Et2O) dropwise over 15 min, and the
reaction mixture was warmed in a -20 °C bath. After 3 h,
the reaction was quenched into a rapidly stirring, 0 °C mixture
of 1:1 Et2O and 1 N HCl (100 mL) via cannula, the ether layer
was separated, and the aqueous layer was extracted with more
Et2O (3 × 120 mL). The organic phases were combined, dried
over MgSO4, filtered, concentrated in vacuo, and chromato-
graphed on SiO2 (10:90 f 50:50 EtOAc/hexanes gradient) to
give 669 mg of product and 258 mg of unreacted starting
material (66%, 86% based on recovered 16a ): 1H NMR (500
MHz, CDCl3) δ 5.72 (ddd, 1H, J ) 17.5, 10, 7.5 Hz), 4.96 (br d,
1H, J ) 17.5 Hz), 4.91 (br d, 1H, J ) 10.5 Hz), 3.64 (br d, 1H,
J ) 5.5 Hz), 3.29 (dd, 1H, J ) 10, 2 Hz), 3.15 (dt, 1H, J ) 9.5,
1.5 Hz), 2.68 (d, 1H, J ) 6.5 Hz), 2.64 (m, 1H), 2.20 (s, 3H),
2.13 (m, 1H), 2.03 (m, 1H), 1.85 (br m, 1H), 1.7-1.2 (m, 17H),
1.15 (d, 3H, J ) 7 Hz), 1.00 (d, 6H, J ) 7 Hz), 0.89 (d, 3H, J
) 7 Hz), 0.81, (d, 3H, J ) 6.5 Hz); 13C NMR (75 MHz, CDCl3)
δ 214.0, 144.9, 112.3, 95.5, 74.6, 74.0, 51.8, 37.9, 36.0, 35.0,
34.7, 32.9, 31.2, 30.9, 30.2, 29.9, 28.2, 27.6, 27.5, 26.7, 20.1,
18.0, 16.6, 14.0, 10.9; IR (thin film) 3458 (br), 3076, 1711 cm-1
;
CI HRMS calcd for C26H47O4 (M + H)+ m/ z 423.3474, found
423.3499.
[3(2R,3R),4R]-3-(3-Hyd r oxy-2-m eth oxy-4-m eth yl-1-oxo-
p en tyl)-4-(p h en ylm eth yl)-2-oxa zolid in on e (19). Following
the method of Evans et al.,35 a rapidly stirring suspension of
Sn(OTf)2 (13.1 g, 31.43 mmol) in 101 mL of CH2Cl2 was added
triethylamine (4.38 mL, 31.43 mmol) at rt, and after 2 min,
the yellow-brown suspension was cooled to -78 °C. After 15
min, a solution of (R)-(methoxyacetyl)oxazolidinone 18 in 34
mL of CH2Cl2 was added dropwise over 40 min and the
resulting mixture then stirred at -78 °C for 2 h. The reaction

Total Synthesis of Tautomycin
J . Org. Chem., Vol. 62, No. 2, 1997 397
the combined organic layers were dried over MgSO4, filtered,
concentrated in vacuo, and chromatographed on SiO2 (10:90
EtOAc/hexanes) to give 3.25 g (83% yield) of a pale yellow oil
as a single detectable geometrical isomer. This material is
semistable and should be reduced the day it is prepared: 1H
NMR (500 MHz, CDCl3) δ 7.25 (m, 10H), 5.46 (m, 2H), 5.01
(s, 4H), 3.26 (m, 2H), 2.03 (s, 3H), 1.65 (d, 2H, J ) 3.5 Hz); IR
(thin film) 3033, 1731, 1704, 1643 cm-1; CI HRMS calcd for
C24H25O5 (M + H)+ m/ z 393.1702, found 393.1694.
(2Z,4R)-4-[(Tr iet h ylsilyl)oxy]-2-m et h yl-3-[1′′-(p h en yl-
m eth oxy)ca r bon yl]h exen ed ioic Acid , 1′-P h en ylm eth yl
Ester (26). To a rt solution of 25 (782 mg, 1.56 mmol) and
2-methyl-2-butene (709 µL, 6.69 mmol) in 3:1 t-BuOH/H2O (17
mL) were added NaHPO4‚H2O (228 mg, 1.65 mmol) and then
NaClO2 (427 g, 4.72 mmol) all at once to give a yellow solution
that faded to colorless after 10 min. After 0.5 h, the reaction
was diluted with brine (100 mL) and extracted with EtOAc (3
× 150 mL), and the combined organic extracts were dried over
MgSO4, filtered, and concentrated in vacuo. The crude oil was
chromatographed on SiO2 (50:50 EtOAc/hexanes f 100%
EtOAc) to give 778 mg (96%) of a colorless oil: 1H NMR (500
MHz, CDCl3) δ 7.25 (m, 10H), 5.14 (dd, 1H, J ) 9.0, 4.0 Hz),
5.08 (d, 1H, J ) 12.0 Hz), 5.02 (d, 1H, J ) 12.0 Hz), 5.01 (d,
1H, J ) 12.0 Hz), 4.95 (d, 1H, J ) 12.0 Hz), 2.99 (dd, 1H, J )
16.0, 9.0 Hz), 2.67 (dd, 1H, J ) 16.0, 4.0 Hz), 2.02 (s, 3H),
0.87 (t, 9H, J ) 8.0 Hz), 0.55 (q, 6H, J ) 8.0 Hz); 13C NMR
(125 MHz, CDCl3) δ 176.5, 167.3, 166.9, 142.5, 135.4, 135.2,
129.9, 128.5 (2), 128.4 (3), 128.3 (3), 128.1 (2), 67.3, 67.2, 66.9,
41.8, 14.8, 6.6 (3), 4.4 (3); IR (thin film) 3500-2600 br, 3034,
1714, 1644 cm-1; CI HRMS calcd for C28H37O7Si (M + H)+ m/ z
513.2308, found 513.2321.
(2R,3R,3′R)-Tr iester 27a . To 26 (550 mg, 1.07 mmol) in
4 mL of toluene was added 450 µL of triethylamine (3.2 mmol)
and then diphenylphosphoryl chloride (230 µL, 1.18 mmol) over
10 min at rt. The bright yellow, heterogeneous solution was
stirred at rt for 2 h, and then a mixture of 20 (242 mg, 1.18
mmol) and DMAP (20 mg, 0.16 mmol) in 1 mL of toluene was
transferred with a cannula over 1 min (1 mL used to assist
the transfer). The yellow mixture was stirred at rt for 13 h.
The reaction was quenched into saturated aqueous NaHCO3
and Et2O and separated, and the aqueous layer was extracted
with additional Et2O (3 × 80 mL). The combined organic
phases were dried over MgSO4, filtered, concentrated in vacuo,
and chromatographed on SiO2 (40:60 EtOAc/hexanes f 50:50
EtOAc/hexanes) to give 540 mg (72%) of a pale yellow oil
comprising an exactly 1:1 ratio of diastereomers. The two
diastereomers were easily purified by HPLC (35:65 EtOAc/
hexanes, 5 mL/min, tR 27a : 13.5 min, tR 27b: 18.2 min). The
low Rf diastereomer was established as having the desired (R)
absolute stereochemistry at the 3′ position.41 3′(R) Dia ste-
r eom er 27a : Rf 0.49 (50% EtOAc/hexanes); 1H NMR (500
MHz, CDCl3) δ 7.30 (m, 10H), 5.17 (dd, 1H, J ) 8.5, 3.5 Hz),
5.12 (br m, 1H), 5.08 (d, 1H, J ) 12.5 Hz), 5.06 (d, 1H, J )
12.5 Hz), 5.01 (d, 1H, J ) 12.5 Hz), 4.95 (d, 1H, J ) 12.5 Hz),
4.26 (br d, 1H, J ) 4.5 Hz), 3.65 (s, 3H), 3.33 (s, 3H), 3.11 (br
s, 3H), 2.92 (dd, 1H, J ) 17.0, 8.5 Hz), 2.60 (dd, 1H, J ) 17.0,
3.5 Hz), 2.15 (m, 1H), 2.01 (s, 3H), 0.94 (t, 6H, J ) 7.5 Hz),
0.86 (t, 9H, J ) 8.0 Hz), 0.53 (q, 6H, J ) 7.5 Hz); 13C NMR (75
MHz, CDCl3) δ 171.2, 169.6, 167.4, 167.0, 143.0, 135.4, 135.2,
129.4, 128.5 (3), 128.3 (5), 128.0 (2), 77.2, 76.4, 67.1, 66.9, 66.8,
61.3, 57.8, 41.5, 32.4, 28.6, 19.3, 16.4, 14.8, 6.6 (3), 4.4 (3); IR
(thin film) 3034, 1738, 1732, 1674 cm-1; FAB HRMS calcd for
C37H54NO10Si (M + H)+ m/ z 700.3517, found 700.3521.
3′(S) Dia ster eom er 27b: Rf 0.55 (50% EtOAc/hexanes); 1H
NMR (500 MHz, CDCl3) δ 7.30 (m, 10H), 5.16 (t, 1H, J ) 6.6
Hz), 5.09 (overlapping, 1H), 5.06 (d, 1H, J ) 12.5 Hz), 4.99 (d,
1H, J ) 12.5 Hz), 4.96 (d, 1H, J ) 12.5 Hz), 4.95 (d, 1H, J )
12.5 Hz), 4.30 (br dd, 1H, J ) 3.5, 1.5 Hz), 3.69 (s, 3H), 3.34
(s, 3H), 3.18 (br s, 3H), 2.87 (dd, 1H, J ) 16.5, 6.0 Hz), 2.83
(dd, 1H, J ) 16.5, 6.6 Hz), 2.11 (m, 1H), 2.02 (s, 3H), 0.88 (t,
9H, J ) 8.0 Hz), 0.85 (overlapping, 6H), 0.57 (q, 6H, J ) 7.5
Hz); 13C NMR (125 MHz, CDCl3) δ 171.1, 169.4, 167.5, 167.0,
142.3, 135.5, 135.3, 130.2, 128.5 (3), 128.32 (5), 128.26 (2), 77.7,
76.5, 67.0, 66.8 (2), 61.4, 58.0, 41.7, 32.4, 28.7, 19.3, 16.5, 15.1,
6.7 (3), 4.4 (3); IR (thin film) 3034, 1732, 1679 cm-1; FAB
HRMS calcd for C37H54NO10Si (M + H)+ m/ z 700.3517, found
700.3522.
1′-(P h en ylm et h yl)-(2Z,4R,6E)-4-h yd r oxy-2-m et h yl-3-
[1′′-(p h en ylm eth oxy)ca r bon yl]octa d ien oa te (23). To a
-20 °C solution of 22 (1.6 g, 4 mmol) in 8 mL of THF was
added a solution of (+)-DIP-Chloride (1.92 g, 6 mmol, Aldrich).
The reaction was stirred for 3 days at -18 °C and then allowed
to warm to 0 °C for 4 h. The reaction mixture was poured
into a 0 °C mixture of H2O2 (0.5 mL, 30%) and MeOH (10 mL).
After the mixture was stirred for 2 h, the solvents were
removed in vacuo, the aqueous layer was extracted with ether
(3 × 30 mL), and the combined ethereal extracts were washed
with brine (20 mL) and then dried over Na2SO4, filtered, and
concentrated in vacuo. The crude oil was purified by radial
SiO2 chromatography (2 mm plate, 12:88 f 25:75 EtOAc/
hexanes) to give 1.4 g of a colorless oil (88% yield). The
enantioselectivity of the reduction was determined to be 80%
ee using standard Mosher ester analysis22 with a racemic
control: 1H NMR (500 MHz, CDCl3) δ 7.32 (m, 10H), 5.55 (m,
1H), 5.42 (m, 1H), 5.03 (s, 4H), 4.57 (dt, 1H, J ) 8.5, 6.0 Hz),
2.50 (d, 1H, J ) 6.5), 2.46 (overlapping, 1H), 2.33 (ddd, 1H, J
) 10.5, 6.0, 5.0 Hz), 1.96 (s, 3H), 1.66 (dd, 3H, J ) 6.5, 0.5
Hz); 13C NMR (125.1 MHz, CDCl3) δ 167.46, 167.37, 141.4,
135.3, 131.1, 129.7 (2), 128.5 (4), 128.3, 125.8 (2), 69.7, 67.1
(2), 39.2, 18.0, 15.0; IR (thin film) 3499 (br), 3032, 1714, 1643
cm-1; CI HRMS calcd for C24H27O5 (M + H)+ m/ z 395.1858,
found 395.1866.
1′-(P h en ylm et h yl)-(2E,4R,6E)-4[(t r iet h ylsilyl)oxy]-2-
m eth yl-3-[1′′-(ph en ylm eth oxy)car bon yl]octadien oate (24).
To a 0 °C solution of 23 (1.283 g, 3.22 mmol) in 15 mL of CH2-
Cl2 was added triethylamine (0.90 mL, 6.44 mmol), 20 mg of
DMAP, and then chlorotriethylsilane (3.44 mL, 15.2 mL).
After 2 h, the reaction was quenched into saturated NaHCO3
and extracted with CH2Cl2 (3 × 100 mL), and the combined
organic layers were dried with MgSO4, filtered, and concen-
trated under reduced pressure. The crude, purple oil was
purified by flash SiO2 chromatography (10:90 EtOAc/hexanes)
to give 1.62 g (99% yield) of a pale yellow oil: 1H NMR (300
MHz, CDCl3) δ 7.25 (m, 10H), 5.47 (ddd, 1H, J ) 15.3, 12.3,
6.3 Hz), 5.41 (m, 1H), 5.09 (d, 1H, J ) 12.6 Hz), 5.03 (d, 1H,
J ) 12.3 Hz), 5.00 (d, 1H, J ) 12.3 Hz), 4.92 (d, 1H, J ) 12.6
Hz), 4.57 (dd, 1H, J ) 7.8, 6.0 Hz), 2.50 (m, 1H), 2.36 (m, 1H),
1.94 (s, 3H), 1.62 (dd, 3H, J ) 5.8, 0.8 Hz), 0.89 (t, 9H, J ) 7.8
Hz), 0.52 (q, 6H, J ) 7.8 Hz); 13C NMR (125.1 MHz, CDCl33)
δ 167.4 (2), 144.8, 135.7, 135.5, 128.4 (3), 128.3 (3), 128.2 (3),
127.9 (2), 126.8 (2), 71.4, 67.0, 66.6, 40.2, 17.9, 14.8, 6.6 (3),
4.6 (3); IR (thin film) 3032, 1641 cm-1; CI HRMS calcd for
C30H41O5Si (M + H)+ m/ z 509.2723, found 509.2716.
1′-(P h en ylm eth yl) (2Z,4R)-4-[(Tr ieth ylsilyl)oxy]-2-m eth -
yl-6-oxo-3-[(p h en ylm eth yl)oxy]ca r bon yl]h exen oa te (25).
To a rapidly stirring, -78 °C solution of 23 (1.09 g, 2.15 mmol)
in 20 mL of CH2Cl2 was bubbled O3 portionwise, and the
reaction was followed by TLC for the disappearance of starting
material. The reaction was purged with N2 for 10 min and
then treated with Ph3P (562 mg, 2.15 mmol) in 5 mL of CH2-
Cl2 and allowed to warm to rt. After 1 h, the reaction mixture
was concentrated on a rotary evaporator and loaded directly
on a SiO2 column (9 × 11 cm, 15:85 EtOAc/hexanes f 25:75
EtOAc/hexanes) to give 855 mg (80%) of a colorless oil
(lachrymatory!): 1H NMR (500 MHz, CDCl3) δ 9.75 (s, 1H),
7.32 (m, 10H), 5.21 (dd, 1H, J ) 8.0, 4.0 Hz), 5.07 (d, 1H, J )
12.5 Hz), 5.03 (d, 1H, J ) 12.5 Hz), 5.01 (d, 1H, J ) 12.5 Hz),
4.97 (d, 1H, J ) 12.5 Hz), 3.12 (2 dd, 1H, J ) 17.0, 8.0 Hz),
2.73 (dd, 1H, J ) 17.0, 4.0 Hz), 2.01 (s, 3H), 0.87 (t, 9H, J )
8.0 Hz), 0.55 (q, 6H, J ) 8.0 Hz); 13C NMR (125 MHz, CDCl3)
δ 200.0, 167.2, 166.9, 142.7, 135.3, 135.2, 129.5, 128.5 (3), 128.3
(6), 128.1, 67.2, 66.9, 65.6, 50.3, 14.7, 6.6 (3), 4.4 (3); IR (thin
film) 3034, 1728, 1644 cm-1; CI HRMS calcd for C28H35O6Si
(M - H)+ m/ z 495.2159, found 495.2162.
Ald eh yd e 28. To a -78 °C solution of 27a (160 mg, 0.230
mmol) in 8 mL of THF was added DIBAL (610 µL, 0.91 mmol,
1.5 M in toluene) dropwise over 5 min. After 4 h, the reaction
was quenched with 400 µL of acetone and then AcOH (2 equiv,
0.36 mmol). The reaction was warmed to 0 °C and transferred
using a cannula into a rapidly stirring mixture of 1:1 Et2O/
0.5 N tartaric acid. After 20 min, the crude mixture was
extracted with Et2O (3 × 80 mL), and the combined organics

398 J . Org. Chem., Vol. 62, No. 2, 1997
Sheppeck et al.
phases were dried over MgSO4 and filtered. The filtrate was
concentrated in vacuo and chromatographed on SiO2 (1.5 ×
13 cm, 25:75 EtOAc/hexanes f 50:50) to give 124 mg of 28
and 35 mg of recovered 27a (84%): 1H NMR (500 MHz, CDCl3)
δ 9.55 (d, 1H, J ) 2.0 Hz), 7.30 (m, 10H), 5.16 (dd, 1H, J )
8.5, 4.0 Hz), 5.08 (d, 1H, J ) 12.0 Hz), 5.04 (d, 1H, J ) 12.5
Hz), 5.00 (d, 1H, J ) 12.0 Hz), 5.00 (overlapping, 1H), 4.93 (d,
1H, J ) 12.5 Hz), 3.58 (dd, 1H, J ) 4.0, 2.0 Hz), 3.39 (s, 3H),
2.96 (dd, 1H, J ) 16.2, 8.5 Hz), 2.68 (dd, 1H, J ) 16.2, 4.0
Hz), 2.03 (m, overlapping, 1H), 2.02 (s, 3H), 0.91 (t, 6H, J )
balloon of O2 for 22 h, after which it was filtered through Celite
with EtOAc, diluted with Et2O, and washed with brine. The
aqueous layer was back-extracted twice with Et2O, and the
combined organic extracts were dried over MgSO4. After being
filtered and concentrated in vacuo, the crude oil was purified
by SiO2 chromatography (1.2 × 15 cm, 40:60 EtOAc/hexanes)
to give 17.2 mg (96% yield) of a colorless oil: 1H NMR (500
MHz, CDCl3) δ 7.30 (m, 10H), 5.15 (ddd, 1H, J ) 7.5, 4.5, 3.0
Hz), 5.07 (d, 1H, J ) 12.0 Hz), 5.04 (d, 1H, J ) 12.0 Hz), 5.03
(d, 1H, J ) 12.0 Hz), 4.99 (d, 1H, J ) 12.0 Hz), 4.29 (br m,
1H), 3.72 (d, 1H, J ) 5.0 Hz), 3.69 (dt, 1H, J ) 8.0, 5.0 Hz),
3.44 (s, 3H), 3.26 (m, 2H), 3.16 (dt, 1H, J ) 10.0, 1.5 Hz), 3.05-
2.95 (m, 2H), 2.70-2.50 (m, 6H), 2.15 (s, 3H), 2.11 (m, 1H),
2.01 (s, 3H), 2.00 (m, overlapping, 1H), 1.85 (br m, 1H), 1.70-
1.20 (m, 18 H), 1.09 (t, 6H, J ) 6.5 Hz), 1.00 (d, 3H, J ) 6.5
Hz), 0.95 (d, 3H, J ) 6.5 Hz), 0.94 (d, 3H, J ) 6.5 Hz), 0.88 (d,
3H, J ) 7.0 Hz), 0.80 (d, 3H, J ) 6.5 Hz); 13C NMR (125 MHz,
CDCl3) δ 214.8, 213.0, 170.5, 167.2, 135.2, 131.5, 128.4 (7),
128.33 (3), 128.26 (2), 95.6, 80.8, 76.3, 74.8, 74.2, 74.1, 67.2,
66.4, 66.2, 59.3, 52.5, 47.3, 45.5 (2), 40.7, 36.0, 34.8 (2), 31.4,
30.6, 30.2, 29.0, 28.5, 28.2, 28.1, 27.6, 27.4, 26.7, 19.6, 18.0,
17.5 (2), 16.7, 16.2, 15.0, 13.7, 11.0; IR (thin film) 3454, 1728,
1714, 1644 cm-1; FAB HRMS calcd for C55H81O14 (M + H)+
m/ z 965.5626, found 965.5622.
Ta u tom ycin . To a solution of 30 (10.7 mg, 11 µmol) in 2
mL of THF and 200 µL of H2O was added 3 mg of Pd (5% on
C). H2 was added to the solution via a balloon through a 20
gauge needle for a total of 5 min while intermittently monitor-
ing the reaction by TLC. After this time, the reaction contents
were passed through a plug of Celite with Et2O, concentrated,
and purified by reversed-phase HPLC (C18 column, 5 mL/min
of 70:30 CH3CN/10 mM AcOH, tR ) 19.6, 20.3 min) to give 7.0
mg of tautomycin and 1.9 mg of unreacted starting material
after lyophilization (82% yield, 100% based on recovered 30).
Chemical correlation of authentic TM (CalBiochem) and
synthetic TM was performed by analytical HPLC (C18 column,
1 mL/min of 70:30 CH3CN/10 mM AcOH, tR ) 16.2 min for
each sample and tR ) 16.1 min for a coinjection of the mixed
sample): 1H NMR (500 MHz, CDCl3) δ 5.22 (br d, 1H, J ) 9.5
Hz), 5.10 (t, 1H, J ) 6.0 Hz), 4.57 (br m, 1H), 4.36 (br m, 1H),
3.71 (m, 1H), 3.45 (s, 3H), 3.27 (dt, 2H, J ) 8.0, 2.0 Hz), 3.16
(dt, 2H, J ) 9.5, 2.0 Hz), 2.99 (dd, 1H, J ) 17.5, 8.5 Hz), 2.93
(dd, 1H, J ) 16.0, 3.0 Hz), 2.77 (dd, 1H, J ) 16.5, 10.0 Hz),
2.68 (dd, 1H, J ) 13.0, 5.0 Hz), 2.67 (dd, overlapping, 1H, J )
7.0, 1.5 Hz), 2.53 (m, 1H), 2.45 (m, 1H), 2.28 (s, 3H), 2.15 (s,
3H), 2.12 (m, 1H), 2.01 (tt, 1H, J ) 13.5, 4.5 Hz), 1.84 (m, 1H),
1.70-1.20 (m, 20 H), 1.12 (app t, 6H, J ) 7.5 Hz), 1.00 (d, 3H,
J ) 7.0 Hz), 0.98 (d, 3H, J ) 6.5 Hz), 0.97 (d, 3H, J ) 7.5 Hz),
0.89 (d, 3H, J ) 7.0 Hz), 0.80 (d, 3H, J ) 6.5 Hz); 13C NMR
(125 MHz, CDCl3) δ 215.5, 213.2, 169.5, 165.8, 164.9, 143.0,
142.1, 95.7, 80.6, 76.4, 74.8, 74.31, 74.28, 66.4, 63.9, 59.1, 52.3,
47.3, 45.8, 41.0, 36.0, 34.9, 34.8, 31.4, 30.7, 30.2, 29.1, 28.7,
28.2, 28.1, 27.6, 27.4, 26.8, 19.4, 18.0, 16.7, 16.3, 13.8, 11.0,
10.2; IR (thin film) 3439, 2924, 2851, 1832, 1767, 1739, 1711
cm-1; FAB HRMS calcd for C55H81O14 (M + H)+ m/ z 965.5626,
found 965.5622. Synthetic tautomycin was spectroscopically
indistinguishable from authentic TM spectra kindly provided
to us by Dr. Ubukata.
6.0 Hz), 0.87 (t, 9H, J ) 8.0 Hz), 0.54 (q, 6H, J ) 8.0 Hz); 13
C
NMR (125 MHz, CDCl3) δ 201.6, 170.3, 167.4, 166.9, 142.6,
135.5, 135.3, 129.8, 128.4 (3), 128.3 (5), 128.0 (2), 85.2, 77.2,
67.0, 66.9, 67.2, 58.7, 41.7, 28.2, 19.1, 17.8, 14.9, 6.7 (3), 4.5
(3); IR (thin film) 3034, 1737, 1644 cm-1; FAB HRMS calcd
for C35H49O9Si (M + Na)+ m/ z 663.2964, found 663.2964.
Diben zyla lk en e 29. Analogous to Oikawa’s procedure,17c
to a solution of 17 (41 mg, 97 µmol) in 2 mL of CH2Cl2 at 0 °C
was added trimethylsilyl triflate (90 µL, 0.47 mmol) over 5
min. The reaction mixture was stirred for 4 h and then
transferred into a 1:4 mixture of saturated aqueous NaHCO3
and CH2Cl2. The organic phase was separated, the aqueous
phase was extracted with CH2Cl2 (2 × 50 mL), and the
combined organic extracts were dried over Na2SO4, filtered,
and concentrated in vacuo. Crude NMR indicated clean
formation of both the silyl enol ether and the C18-(trimeth-
ylsilyl)oxy ether, and this material was used without further
purification. In another reaction vessel, a solution of 28 (52
mg, 81 µM) in 2 mL of CH2Cl2 was cooled to -78 °C and treated
with a -78 °C solution of TiCl4 (122 µL, 0.12 mmol, 1.0 M in
toluene). After 3 min, a dry solution of the crude silyl enol
ether in 1 mL of CH2Cl2 was transferred via cannula to the
reaction. After 30 min at -78 °C, the reaction was warmed
in a -20 °C bath for 3 h and then transferred by cannula into
a mixture of CH2Cl2 and pH 7.0 phosphate buffer. The layers
were separated, and the aqueous phase was extracted three
times with CH2Cl2 and twice with EtOAc. The combined
organic layers were dried over MgSO4, filtered, concentrated
in vacuo, and chromatographed on a SiO2 column (13 cm ×
12 mm, 25:75 EtOAc/hexanes f 50:50 EtOAc/hexanes) to give
25 mg of the low Rf product. The higher eluting compounds
were all combined, concentrated, diluted with 1.5 mL of CH3-
CN, and treated with 200 µL of dilute HF (9:1 H2O/47% HF).
After 5 h at rt, the reaction was worked up by extraction from
brine with Et2O. Purification as before yielded another 8.7
mg of product for a total of 33.7 mg of 29 and 14.1 mg of 17
(44% yield, 56% based on recovered starting material). C18-
TMS 17 silyl enol ether: 1H NMR (500 MHz, CDCl3) δ 5.72
(ddd, 1H, J ) 17.5, 10.5, 7.0 Hz), 5.65 (br d, 1H, J ) 17.5 Hz),
4.92 (br d, 1H, J ) 10 Hz), 4.07 (s, 1H), 4.04 (s, 3H), 3.74 (dt,
1H, J ) 8.0, 1.5 Hz), 3.28 (dd, 1H, J ) 10, 1.5 Hz), 3.16 (dt,
1H, J ) 8, 1.5 Hz), 2.24 (qn, 1H, J ) 7 Hz), 2.12 (m, 1H), 2.04
(m, 1H), 1.83 (m, 1H), 1.70-1.10 (m, 18H), 0.98 (d, 3H), 0.96
(d, 3H), 0.88 (d, 3H), 0.81 (d, 3H), 0.21 (s, 9H), 0.12 (s, 9H).
1
29: H NMR (500 MHz, CDCl3) δ 7.30 (m, 10H), 5.72 (ddd,
1H, J ) 17.5, 10.5, 7.5 Hz), 5.14 (dd, 1H, J ) 7.0, 4.0 Hz),
5.08-5.01 (m, 4H), 4.96 (d, 1H, J ) 17.5 Hz), 4.91 (d, 1H, J )
10.5 Hz), 4.28 (br d, 1H, J ) 2.0 Hz), 3.73 (d, 1H, J ) 4.5 Hz),
3.69 (br s, 1H), 3.44 (s, 3H), 3.29 (dd, 1H, J ) 10.5, 2.0 Hz),
3.25 (dd, 1H, J ) 6.5, 2.0 Hz), 3.15 (br t, 1H, J ) 10.0 Hz),
3.04 (br t, 1H, J ) 2.0 Hz), 2.98 (m, 2H), 2.62 (m, 4H), 2.15-
2.00 (m, 4H), 2.00 (s, 3H), 1.84 (m, 1H), 1.70-1.20 (m, 17H),
1.10 (d, 3H, J ) 7.5 Hz), 0.99 (d, 6H, J ) 7.0 Hz), 0.95 (d, 6H,
J ) 6.5 Hz), 0.88 (d, 3H, J ) 7.0 Hz), 0.81 (d, 3H, J ) 6.5 Hz);
13C NMR (125 MHz, CDCl3) δ 214.8, 170.5, 167.2, 167.0, 145.0,
140.0, 135.2, 131.5, 128.5 (2), 128.46 (4), 128.36 (3), 128.30
(2), 112.4, 95.6, 80.7, 76.5, 76.3, 74.6, 74.0, 67.2, 66.4, 66.2,
59.3, 52.6, 45.5, 40.7, 37.9, 36.0, 35.0, 34.7, 32.9, 31.2, 30.9,
30.2, 28.5 (2), 28.2, 27.5, 27.3, 26.7, 20.1, 19.6, 18.1, 17.4, 16.7,
15.0, 13.7, 11.0; IR (thin film) 3451, 3033, 1728, 1713, 1641
cm-1; FAB HRMS calcd for C55H81O13 (M + H)+ m/ z 949.5677,
found 949.5698.
Ack n ow led gm en t. We are grateful to the Depart-
ment of Education for fellowship support of J .E.S. under
the GAANN Program (Grant No. P-200A10156) and to
the NIH for partial support (Grant No. NS27600). We
also wish to thank J ohn Greaves (UCI) for FAB HRMS,
J oe Ziller (UCI) for X-ray crystallographic analysis of
19 TBS ether, and Dr. Ubukata (RIKEN) for spectra of
tautomycin and its degradation products.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
2b, 5-15, 16a ,b, 17, 22-26, 27a ,b, and 28-30 and a com-
parison of authentic and synthetic tautomycin (27 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
Ta u tom ycin , Bis(ben zyl ester ) 30. To a solution of 29
(17.7 mg, 19 µmol) in a mixture of 1 mL of THF and 1 mL of
DMF (10% water) were added PdCl2 (6.6 mg, 37 µmol) and
CuCl (20 mg, 0.21 mmol) at rt. The reaction was put under a
J O961633S