Synthesis of a C1-C21 subunit of the protein phosphatase inhibitor tautomycin: A formal total synthesis

Article abstract of DOI:10.1021/jo0056951

The synthesis of a C1-C21 subunit of tautomycin is described. The convergent route employs enantioenriched allenylstannane and zinc reagents derived from (S)-3-butyn-2-ol methanesulfonate. These reagents react with appropriate aldehyde segments to yield s

Full text of DOI:10.1021/jo0056951

J . Org. Chem. 2001, 66, 1373-1379
1373
Syn th esis of a C1-C21 Su bu n it of th e P r otein P h osp h a ta se
In h ibitor Ta u tom ycin : A F or m a l Tota l Syn th esis
J ames A. Marshall* and Mathew M. Yanik
Department of Chemistry, McCormick Road, P.O. Box 400319, University of Virginia,
Charlottesville, Virginia 22904
jam5x@virginia.edu
Received October 23, 2000
The synthesis of a C1-C21 subunit of tautomycin is described. The convergent route employs
enantioenriched allenylstannane and zinc reagents derived from (S)-3-butyn-2-ol methanesulfonate.
These reagents react with appropriate aldehyde segments to yield syn and anti adducts with high
diastereoselectivity. The derived lithioalkynes are joined stepwise to a CO equivalent, (MeONMe)2-
CdO, to afford an intermediate ketone which is converted to the core spiroketal moiety of tautomycin
upon acid treatment. Chain elongation by another addition of the aforementioned allenylzinc reagent
to a spiroketal aldehyde proceeds with high diastereoselectivity to install the remaining stereo-
centers. The resulting homopropargylic alcohol adduct is converted to a methyl ketone through
intramolecular hydrosilylation of the alkyne and Tamao oxidation of the derived five-membered
siloxane. This ketone proved identical to an intermediate employed by Chamberlin in a prior total
synthesis of tautomycin.
The antifungal soil metabolite tautomycin has at-
tracted the attention of several groups because of its
structural intricacy and novel biological activity relating
to its selective inhibition of protein-serine/threonine
phosphatase types 1 and 2A.1 To date four total syntheses
have been reported.1a-d These and related syntheses of
tautomycin subunits have mainly relied upon chiral
auxiliary-directed aldol additions and carbohydrate in-
termediates for introduction of the various stereogenic
centers. In recent years we have been developing a
complimentary approach to polyketides such as tauto-
mycin in which chiral enantioenriched allenylmetal
reagents are added to aldehydes, affording homopropar-
gylic alcohols with contiguous OH- and CH3-substituted
stereocenters characteristic of the propionate segments
of these natural products.2 An appealing feature of this
approach is the ability to employ the alkynyl moiety of
these adducts to initiate coupling reactions or for intro-
duction of additional functional features of targeted
intermediates.3 The present report details efforts along
these lines which have led to a convergent and stereo-
selective synthesis of the C1-C21 subunit of tautomycin
previously prepared by Chamberlin and co-workers in
their total synthesis of the natural product.1a
Our synthetic plan is summarized in Figure 1. Accord-
ingly allenylmetal reagents derived from (S)-3-butyn-2-
ol would be used to form C-C bonds at C6/C7 (D), C13/
C14 (C), and C18/C19 (E) with the appropriate stereo-
genicity. The stereocenters at C3 and C15 (A and B)
(1) (a) Sheppeck, J . E., III; Liu, W.; Chamberlin, A. R. J . Org. Chem.
1997, 62, 387 and references cited. (b) Oikawa, M.; Ueno, T.; Oikawa,
H.; Ichihara, A. J . Org. Chem. 1995, 60, 5048. (c) Ichikawa, Y.; Tsuboi,
K.; J iang, Y.; Naganawa, A.; Isobe, M. Tetrahedron 1997, 57, 5123 and
references cited. (d) Shimizu, S.; Nakamura, S.; Nakada, M.; Shibasaki,
M. Tetrahedron 1996, 52, 13363. (e) Nagumo, S.; Arai, T.; Akita, H.
Tetrahedron Lett. 1997, 38, 5165.
F igu r e 1. Synthetic plan for the key tautomycin subunit F .
would originate with commercially available methyl (R)-
and (S)-3-hydroxy-2-methylpropionate.4 The terminal
alkynyl centers at C11 and C9 in the homopropargylic
(2) Marshall, J . A. Chem. Rev. 2000, 100, 3163.
(3) Cf. Marshall, J . A.; J ohns, B. A. J . Org. Chem. 1998, 63, 7885.
(b) Marshall, J . A.; J ohns, B. A. J . Org. Chem. 2000, 65, 1501. (c)
Marshall, J . A.; Yanik, M. M. Tetrahedron Lett. 2000, 41, 4717.
(4) Aldrich Chemical Co., Milwaukee, WI.
10.1021/jo0056951 CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/24/2001

1374 J . Org. Chem., Vol. 66, No. 4, 2001
Marshall and Yanik
Sch em e 1. Syn th esis of th e C11-C18 Su bu n ita
Sch em e 2. Syn th esis of th e C2-C9/10 Su bu n ita
a
(a) (EtO)2POCH2CO2Et, LiCl, DBU, CH3CN (92%); (b) H2/Pd-
C, EtOAc (98%); (c) DIBAL-H (99%); (d) Cl3CC(dNH)OBn, TESOTf
(1 mol %), CH2Cl2 (87%).
adducts C and D would be used to effect nucleophilic
addition to a C10 carbonyl equivalent producing the C2-
C18 chain. Further elaboration of this adduct through
Wittig homologation to introduce C1 and a third allenyl-
metal addition to append C19-C21 would afford inter-
mediate E with the correct configuration at all stereo-
centers. The C20 carbonyl group would be incorporated
by directed hydration of the terminal alkyne produced
in the allenylmetal addition (E f F ).
a
(a) (EtO)2POCH2CO2Et, LiCl, DBU; (b) H2/Pd-C; (c) DIBAL-
H; (d) i. TBSCl, Im; ii. BuLi, CH2O; (e) Et3SiCl, (f) TBSCl, Im; (g)
K2CO3, MeOH; (h) TPAP, NMO.
case the (R)-enantiomer of 2-methyl-3-OTBS propanal
(11) was employed in the Horner-Emmons condensation
to afford the conjugated ester 12 (Scheme 2). Hydrogena-
tion, as before, afforded ester 13 which was reduced to
aldehyde 14, B in our synthetic plan, with DIBAL-H.
Addition of the (M)-allenylzinc reagent, generated in situ
from the mesylate of (S)-3-butyn-2-ol (15), gave rise to
the anti adduct 17 as the major component of an
inseparable 85:15 mixture. This result was expected as
such additions are most diastereoselective (>90:10) with
branched aldehydes.2 The alcohol adduct 17 and its
inseparable diastereomer were converted to the TES
ether 18, corresponding to D, also an inseparable mix-
ture.
Several different approaches were examined for cou-
pling of the C2-C9 and C11-C18 alkynyl subunits 10
and 18 to a C10 carbonyl equivalent. Our preliminary
experiments were conducted with subunits arrived at by
identical routes to those just described with the exception
of protecting groups. In the first of these, cleavage of the
propargylic acetate 20 (obtained through addition of the
allenylzinc reagent, prepared in situ from mesylate 16,
to aldehyde 14 followed by TBS protection of the alcohol
adduct 19), and TPAP oxidation11 of the resulting alcohol
21, afforded aldehyde 22 in high overall yield. Alterna-
tively, alcohol 21 could be prepared through protection
of alcohol 17 (from 15 plus 14) as the TBS ether and
subsequent addition of the lithioalkyne to formaldehyde.
Our synthesis of the C11-C18 segment commenced
with Horner-Emmons condensation of triethylphospho-
noacetate with (S)-2-methyl-3-OTBS propanal (1), readily
obtained from the hydroxy ester precursor upon silyl
ether formation and reduction.5 Use of sodium hydride
as base for this condensation resulted in partial epimer-
ization of the aldehyde, whereas the Masamune-Roush
protocol employing LiCl and DBU gave product of high
ee in excellent yield.6 The choice of ethyl acetate as
solvent for hydrogenation of unsaturated ester 2 over
Pd-C was important. In ethanol complete loss of the TBS
ether occurred. Reduction of the ester and benzylation
of alcohol 4 with benzyl trichloroacetimidate yielded
diether 5.7 Triflic acid, generated in situ by addition of a
small amount of triethylsilyl triflate, proved to be a most
convenient method to catalyze the benzylation reaction.
The acetimidate methodology solved the problem of 1,5
silyl migration which took place when the benzylation
was carried out with NaH and benzyl bromide. Desily-
lation of the TBS ether 5 with TBAF, followed by Swern
oxidation8 of alcohol 6 afforded aldehyde 7, corresponding
to A in our synthetic plan, in near-quantitative yield.9
The first of our three allenylmetal additions was
conducted on this aldehyde with the (M)-allenylstannane
8, obtained from the mesylate of (S)-3-butyn-2-ol by
treatment with Bu3SnLi‚CuBr‚SMe2 in THF (Scheme 1).
The BF3‚OEt2-promoted addition afforded the syn,syn
stereotriad 9 as the major diastereomer of a 94:6 mix-
ture.10 The alcohol was protected as the TES ether 10.
The preparation of the second major coupling fragment,
alkyne D, parallels that outlined above for 10. In this
Addition of the lithium acetylide 23 (prepared along
the lines of 10 in Scheme 1) to aldehyde 22 resulted in
multiple unidentifiable decomposition products. Others
have reported problems associated with acetylide addi-
tions to complex aldehydes.12 We hoped that the use of
the saturated aldehyde in the addition reaction might
minimize side products and decomposition. Unfortu-
nately, hydrogenation of acetate 20 or alcohol 21 with
various Pd or Rh catalysts was accompanied by signifi-
cant hydrogenolysis of the propargylic moiety.
(5) Marshall, J . A.; Perkins, J . F.; Wolf, M. A. J . Org. Chem. 1995,
60, 5556.
(6) Blanchette, M. A.; Choy, W.; Davis, J . T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25,
2183.
(7) Widmar, U. Synthesis 1987, 568.
(8) Mancuso, A. J .; Huang, S.-L.; Swern, D. J . Org. Chem. 1978,
43, 2480.
(9) Alcohol 6 could also be prepared in seven steps from 1,5-
pentanediol, or in four steps from the known 5-benzyloxypentanoic acid
through an Evans oxazolidinone alkylation. See the Supporting
Information for details.
(11) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. J .
Chem. Soc., Chem. Commun. 1987, 1625.
(12) Carreira, E. M.; Du Bois, J . J . Am. Chem. Soc. 1995, 117, 8106
and references cited.
(10) Marshall, J . A.; Wang, X-j. J . Org. Chem. 1992, 57, 1242.

Synthesis of C1-C21 of Tautomycin
J . Org. Chem., Vol. 66, No. 4, 2001 1375
Sch em e 3. In itia l Rou te to a Sp ir ok eta l In ter m ed ia tea
a
(a) i. TPAP, NMO, (85%); ii. H2/Rh-Al2O3, EtOAc (94%); (b) i. PPTs, EtOH; ii. MeOH, HCl (74%).
Sch em e 4. Syn th esis of Keton e 31
Our next option was to attenuate the acetylide reagent
through transmetalation of the lithium acetylide 23 with
anhydrous CeCl3 forming the less basic and highly
nucleophilic cerium acetylide.13 With this reagent addi-
tion to the alkynal 22 proceeded in moderate yield.
Ensuing hydrogenation of the dialkynyl carbinol 24
proceeded without hydrogenolysis but led to a 70:30
mixture of the saturated alcohol and ketone 25 (Scheme
3), the latter arising through a presumed alkyne-allene
isomerization on the catalyst surface. This complication
could be circumvented by switching the order of steps.
Thus oxidation of alcohol 24 with TPAP11 and hydroge-
nation of the dialkynyl ketone afforded the saturated
ketone 25 without incident. Conversion of this ketone to
the spiroketal 26 (R ) DPS) through selective cleavage
of the TBS ethers of ketone 25 could not be achieved.
Treatment of 25 with PPTS in ethanol resulted in only
partial desilylation of these ethers.14 The use of TBAF
for selective cleavage resulted in multiple partially
desilylated products. Finally, with methanolic HCl all
silyl ethers were cleaved leading to the spiroketal diol
26 (R ) H). This diol contains the spiroketal core of
tautomycin, but represents a synthetic dead end for lack
of methodology to differentiate the two primary alcohol
termini. A similar problematic secondary OTBS depro-
tection recently noted in a reported synthesis of disco-
dermolide,3a was solved by substituting the secondary
TBS protecting group to the more labile TES ether.
Accordingly, the foregoing sequence was applied to the
TES-protected homopropargylic ether 10 to afford prop-
argylic alcohol 27 which led to ynal 28 (Scheme 4).
Addition of the cerium acetylide 18(Ce), derived from
alkyne 18, to aldehyde 28 proceeded as expected affording
alcohol 29, which was oxidized with TPAP to ketone 30.
Hydrogenation15 of this diynone to the saturated ketone
31 on the Lindlar catalyst proceeded smoothly, without
concomitant hydrogenolysis of the benzyl group.16
Alcohol 27 could be prepared more convergently through
addition of the allenic stannane 32 to aldehyde 7 (eq 1).
Protection of alcohol 33 as the TES ether 34 and
saponification afforded propargylic alcohol 27 in high
overall yield.
In the course of these studies we developed an im-
proved and economical route to the propargylic alcohol
precursor of stannane 32 based on a procedure for
converting aldehydes to acetylenes recently disclosed by
a group from DuPont.17 Accordingly, lithiodichloromethane
was prepared in situ and added to the TBS ether 35 of
(S)-lactic aldehyde affording the dichloro alcohol inter-
mediate which was converted to tosylate 36 without
isolation (eq 2). Treatment of this tosylate with 3 equiv
of butyllithium and addition of the resulting lithio
acetylide to paraformaldehyde afforded the TBS-protect-
(13) (a) Imamoto, T.; Kusumoto, T.; Tawarayama, Y.; Sugiura, Y.;
Mita, T.; Hatanaka, Y.; Yokoyama, M. J . Org. Chem. 1984, 49, 3904.
(b) Imamoto, T.; Sugiura, Y.; Takiyama, N. Tetrahedron Lett. 1984,
25, 4233. (c) Imamoto, T.; Takiyama, N.; Makamura, K.; Tetrahedron
Lett. 1985, 26, 4763.
(14) Prakash, C.; Saleh, S.; Blair, I. A. Tetrahedron Lett. 1989,
30, 19.
(15) Cook, L. R.; Oinuma, H.; Semones, M. A.; Kishi, Y. J . Am. Chem.
Soc. 1997, 119, 7928.
(16) Pd/CaCO3 poisoned with lead was purchased from Aldrich
Chemical Co.
(17) Wang, Z.; Yin, J .; Campagna, S.; Pesti, J . A.; Fortunak, J . M.
J . Org. Chem. 1999, 64, 6918.

1376 J . Org. Chem., Vol. 66, No. 4, 2001
Marshall and Yanik
Sch em e 5. Alter n a tive Rou te to Keton e 31 th r ou gh Ur ea Cou p lin g
Sch em e 6. Sp ir ok eta l F or m a tion a n d Ch a in
Exten sion
ed (S)-pentynediol derivative 37 in 82% yield. Our
previous synthesis of this material18 utilized the Corey-
Fuchs19 reaction, which is difficult to perform on a large
scale owing to the significant quantity of triphenylphos-
phine oxide byproduct. This improved route to alcohol
37, which is easily amenable to large scale synthesis,
should greatly improve accessibility to chiral allenylmetal
reagents via propargylic alcohols such as 38.10
benzyl ether was removed with lithium naphthalenide
in THF22 affording the known alcohol 48.1b Comparison
1
of the H NMR spectrum and optical rotation with the
reported values confirmed the identity of this material.
Oxidation of alcohol 48 with the Dess-Martin perio-
dinane21 reagent gave rise to aldehyde 49, which yielded
the anti homopropargylic alcohol adduct 50 as an 86:14
mixture of diastereomers upon treatment with the alle-
nylzinc reagent derived in situ from the mesylate of (S)-
3-butyn-2-ol (15) (Scheme 7). At this point it was neces-
sary to effect hydration of the terminal alkyne. This
conversion proved to be one of the more challenging
aspects of the synthesis. Direct hydration of the ho-
mopropargylic alcohol or ester derivatives with mercury
salt catalysis proved ineffective affording mixtures of
decomposition products. The next two alternatives, ex-
amined in model systems, were selective reduction of the
alkyne followed by Wacker oxidation,23 or Cp2ZrCl2-
catalyzed carboalumination24 to be followed by an oxida-
tive cleavage to afford the requisite ketone. Partial
hydrogenation of the terminal alkyne proved problematic
resulting in rapid overreduction to the alkane. This could
be circumvented by hydrozirconation with Cp2ZrHCl25 to
afford the alkene. Standard and modified conditions for
the Wacker oxidation proved to be extremely sluggish;
even with stoichiometric quantities of palladium salts
A second, slightly more efficient route to ketone 31 was
also developed (Scheme 5). This route employs the
N-methoxy-N-methylurea 40 as the C10 carbonyl equiva-
lent.20 Addition of the lithio acetylide 39 afforded the
amide 41. Hydrogenation over Lindlar’s catalyst con-
verted 41 to the saturated amide 42 which yielded ynone
44 upon treatment with the lithio acetylide 43. Acetylide
43 could also be added to the alkynyl amide 41 to afford
the diynone 30, but this procedure again proved prob-
lematic affording multiple decomposition products with
a resulting low yield. Hydrogenation of ynone 44 over a
poisoned Pd catalyst led to ketone 31 in high yield. A
major advantage of this latter route to ketone 31 is the
ability to use readily prepared alkynyllithium reagents
in the coupling sequence.
Exposure of ketone 31 to methanolic HCl effected
cleavage of the silyl ethers with ensuing cyclization to
the spiroketal. The spiroketal was obtained in 92% yield
as a roughly 80:14:5:1 mixture (based on the ratios of
the inseparable diastereomeric adducts, 9 (94:6) and 17
(85:15), obtained in the two allenylmetal additions) of
diastereomers favoring 45 (Scheme 6). Through careful
chromatography of the mixture, pure spiroketal 45 could
be obtained in 50% yield. Dess-Martin periodinane
oxidation21 of alcohol 45 and Wittig methylenation of the
derived aldehyde 46 gave the terminal olefin 47. The
(22) Liu, H. J .; Yip, J .; Shia, K. S. Tetrahedron Lett. 1997, 38, 2252.
(23) Smith, A. B., III.; Friestad, G. K.; Barbosa, J .; Bertounesque,
E.; Hull, K. G.; Iwashima, M.; Qiu, U.; Salvatore, B. A.; Spoors, P. G.;
Duan, J . J .-W. J . Am. Chem. Soc. 1999, 121, 10468 and references
cited.
(18) Marshall, J . A.; Xie, S. J . Org. Chem. 1995, 60, 7230.
(19) Corey, E. J .; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769.
(20) Whipple, W. L.; Reich, H. J . J . Org. Chem. 1991, 56, 2911.
(21) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4155.
(24) Van Horn, D. E.; Negishi, E.-I. J . Am. Chem. Soc. 1978, 100,
2252.
(25) Schwartz, J .; Labinger, J . A. Angew. Chem., Int. Ed. Engl. 1976,
15, 333.

Synthesis of C1-C21 of Tautomycin
J . Org. Chem., Vol. 66, No. 4, 2001 1377
Sch em e 7. F in a l Ch a in Exten sion a n d Ter m in a l Alk yn e Hyd r a tion a
a
Dess-Martin periodane.
extended reaction times (>1 week) were necessary.
Attempted carboalumination gave only starting material
and, under more forcing conditions, resulted in decom-
postion products. These problems motivated our search
for mild conditions to effect the desired transformation.
A solution was eventually developed which employed an
intramolecular hydrosilylation-oxidation sequence.26 Ac-
cordingly, the mixture of alcohols 50 was silylated with
(Me2SiH)2NH and the silyl ether 51 was treated with 0.5
mol % of H2PtCl6 in THF affording the cyclic siloxane
52, a labile intermediate that was best oxidized under
Tamao conditions without purification.27 In this way
ketone 53, corresponding to F in our plan, was obtained
in 82% yield as a separable 86:14 mixture of diastereo-
mers.
Exp er im en ta l Section
Gen er a l. Anhydrous THF, diethyl ether, and dichlo-
romethane were purified by pressure filtration through acti-
vated alumina. Proton and carbon NMR spectra were acquired
in CDCl3 at 300 and 75 MHz, respectively, unless otherwise
stated. All aqueous solutions used in the workup procedures
were saturated unless otherwise stated. Bulb-to-bulb distil-
lation temperatures refer to the temperature of the bath.
Concentration in vacuo refers to high vacuum (0.005-0.1
mmHg). Other “concentrations” were effected on a Rotovap
with a water aspirator (ca. 100-20 mmHg). Gas chromatog-
raphy was conducted on Supelco R or â Dex 120 columns.
(3S,4S,5R)-8-Ben zyloxy-3,5-d im eth yl-1-octyn -4-ol (9).
To solution of aldehyde 7 (3.64 g, 17.7 mmol) and allenyl
stannane 8 (7.4 g, 21.4 mmol) in CH2Cl2 (80 mL) at -78 °C
was added BF3‚OEt2 (7.6 mL, 60.0 mmol) dropwise over 2
min.10 After 40 min the reaction was quenched by pouring into
a rapidly stirred solution of NaHCO3 and warmed to room
temperature. The mixture was extracted twice with ether,
dried over MgSO4, and concentrated. Purification by chroma-
tography on silica gel (5% EtOAc/hexanes-20% EtOAc/hex-
anes) afforded 3.94 g (88%) of acetylene 9 as a 94:6 mixture of
inseparable diasteromers. Rf ) 0.50 (30% EtOAc/hexanes); [R]D
It was found that the silylation/hydrosilylation se-
quence required complete removal of residual palladium
carried over from the allenylzinc addition reaction to
prevent exothermic polymer formation. This was achieved
efficiently and inexpensively through conversion of alco-
hol 50 to the acetate, which was then chromatographed
and deacetylated with DIBAL-H. This combination of
steps, which could be effected in near-quantitative yield,
removed all palladium contaminants. Ketone 53 proved
identical to an intermediate prepared by Chamberlin in
his total synthesis of tautomycin.1a
+2.21 (c ) 1.9, CHCl3); IR 3458, 3300, 2942, 2855 cm-1; H
1
NMR δ 0.91 (d, J ) 6.6 Hz, 3H), 1.23 (d, J ) 6.9 Hz, 3H),
1.15-2.02 (m, 6H), 2.07 (d, J ) 2.4 Hz, 1H), 2.57 (m, 1H),
3.41-3.52 (m, 3H), 4.50 (s, 2H), 7.26-7.34 (m, 5H); 13C NMR
δ 12.9, 16.8, 27.2, 30.1, 30.4, 35.0, 70.2, 70.5, 72.9, 77.1, 86.4,
127.5, 127.6, 128.3, 138.5; GC â-Dex, 200 °C, 1 °C ramp, 7.95
(6%), 8.28 (94%). Anal. Calcd for C17H24O2: C, 78.42; H, 9.29;
Found: C, 78.15; H, 9.52.
In summary, the allenylmetal approach compares quite
favorably with previous routes to the dispiroketal subunit
of tautomycin.1 The present synthesis employs readily
available starting materials and takes advantage of
allene chirality to control diastereoselection. Moreover
it is highly convergent and amenable to the preparation
of various analogues and homologues through variations
both in the starting materials and the chiral reagents.
Also demonstrated was an application of the hydrosila-
tion methodology to form â-hydroxy ketones in a complex
substrate. The main drawback to the sequence is the
modest diastereoselectivity of allenylzinc additions to
unbranched aldehydes. However, it should be noted that
the aldol or allylboronate counterparts of the analogous
additions used in previous syntheses of tautomycin
proceed with only slightly higher diastereoselectivity and
(3R,4S,7S)-8-(ter t-Bu tyld im eth ylsilyloxy)-3,7-d im eth yl-
1-octyn -4-ol (17). To a solution of Pd(OAc)2 (165 mg, 0.74
mmol) in THF (150 mL) at -78 °C was added a solution of
PPh3 (194 mg, 0.74 mmol) in THF (5 mL), followed by mesylate
15 (3.00 g, 20.0 mmol), aldehyde 14 (3.40 g, 14.8 mmol), and
diethylzinc (5.42 g, 44.1 mmol). The mixture was warmed to
-20 °C for 20 h, quenched with NH4Cl, extracted with ether,
washed with NaHCO3 and brine, dried over MgSO4, and
concentrated. Purification by chromatography on silica gel (5%
EtOAc/hexanes) afforded 2.95 g (70%) of an orange oil consist-
ing of an inseparable mixture of diastereomeric homopropar-
gylic alcohols 17. The diastereomeric ratio was determined to
be 85:15 by GC analysis. Rf ) 0.33 (10% EtOAc/hexanes); [R]D
1
+3.55 (c ) 5.6, CHCl3); IR 3431, 3311, 2958, 2854 cm-1; H
NMR δ 0.04 (s, 6H), 0.87 (s, 2H), 0.88 (s, 10H), 1.22 (d, J )
6.0 Hz, 3H), 1.3-1.7 (m, 5H), 2.11 (d, J ) 2.7 Hz, 1H) 2.52 (m,
1H), 3.37-3.51 (m, 3H); 13C NMR δ 85.2, 74.4, 70.8, 8.2, 35.7,
32.8, 32.4, 29.2, 25.9, 18.3, 17.5, 16.7, -5.3.; G. C. â-Dex, 150
°C, 1 °C ramp, 9.16 min (85%), 9.62 min (15%). Anal. Calcd
for C16H32O2Si: C, 67.54; H, 11.34; Found C, 67.29; H, 11.33.
Tosyla te 36. A solution of LDA was generated at 0 °C by
dropwise addition of BuLi (2.5 M in hexanes, 16.0 mL, 40.0
mmol) to a solution of diisopropylamine (5.6 mL, 40.0 mmol),
in THF (20 mL). The solution of LDA thus formed was added
dropwise over 30 min to a solution of aldehyde18 35 (5.0 g, 26.6
1a,1b
comparable or lower yields.
(26) (a) Marshall, J . A.; Yanik M. M. J . Org. Chem. 1999, 64, 3798.
(b) Marshall, J . A.; Yanik, M. M. Org. Lett. 2000, 2, 2173.
(27) (a) Tamao, K.; Kumada, M.; Maeda, K. Tetrahedron Lett. 1984,
25, 321. (b) Review: J ones, G. R.; Landais, Y. Tetrahedron 1996, 52,
7599.

1378 J . Org. Chem., Vol. 66, No. 4, 2001
Marshall and Yanik
mmol) and CH2Cl2 (5.13 mL, 80.0 mmol) in THF (50 mL) at
-78 °C. After 30 min the light yellow solution was warmed to
0 °C for 30 min. The color of the solution changed from yellow
to dark brown upon warming. TsCl (5.07 g, 26.6 mmol) was
added in one portion, and the mixture was warmed to room
temperature. After 1 h, the reaction was quenched with water
(3 mL) and stirred for 30 min before dilution with 10% HCl
and separation. The aqueous extracts were back extracted with
ether. The organic extracts were washed with brine, dried over
MgSO4, and concentrated affording 10.5 g (92%) of tosylate
36 as a dark brown oil which was used without further
purification. The diastereomeric ratio was 45:55 based on 1H
NMR analysis. 1H NMR δ 0.08 (s, 6H), 0.09 (s, 6H), 0.88 (s,
18H), 1.24 (d, J ) 6.3 Hz, 3H), 1.29 (d, J ) 6.0 Hz, 3H), 2.44
(s, 6H), 4.04 (dq, J ) 6.0, 7.5 Hz, 1H), 4.34 (dq, J ) 3.3, 6.3
Hz, 1H), 4.70 (dd, J ) 3.3, 6.0 Hz, 1H), 4.74 (dd, J ) 2.1, 7.2
Hz, 1H), 5.81 (d, J ) 6.3 Hz, 1H), 6.00 (d, J ) 2.1 Hz, 1H),
7.31 (d, J ) 8.4 Hz, 4H), 7.82 (dd, J ) 5.4, 8.4 Hz, 4H).
(S) 4-(ter t-Bu t yld im et h ylsilyloxy)-2-p en t yn -1-ol (37).
To a solution of tosylate 36 (10.5 g, 24.5 mmol) in THF (50
mL) at -78 °C was added BuLi (2.5 M in hexanes, 30.0 mL,
75 mmol) dropwise over 10 min followed by warming to 0 °C
for 1 h. The solution was recooled to -78 °C, and paraform-
aldehyde (1.5 g, 50 mmol) was added in one portion, followed
by warming the mixture to room temperature for 3 h. The
reaction was quenched by addition of NH4Cl and brine,
extracted with EtOAc, dried over MgSO4, and concentrated.
Bulb to bulb distillation (0.05 mmHg, 90 °C) afforded 4.32 g
(82%) of alcohol 37 as a colorless oil with spectral character-
istics matching those previously reported.18
(2S,5S,6R,12S,13S,14R)-2,6,12,14-Tet r a m et h yl-1-(ter t-
bu tyld im eth ylsilyl)oxy-5,13-(tr ieth ylsilyl)oxy-17-ben zy-
loxy-7-h ep ta d ecyn -9-on e (44). A solution of alkyne 18 (2.90
g, 7.00 mmol) in THF (5 mL) was added to a solution of BuLi
(2.0 M in hexanes, 3.05 mL, 6.11 mmol) in THF (20 mL) at
-78 °C. After 15 min the yellow solution was warmed to 0 °C
for 15 min and then recooled to -78 °C. A solution of the amide
42 (2.17 g, 4.70 mmol) in THF (5 mL) was added, and the
reaction mixture was warmed to 0 °C for 1 h, quenched with
NH4Cl, extracted with ether, dried over MgSO4, and concen-
trated. Purification by chromatography on silica gel (2.5%
EtOAc/hexanes-10% EtOAc/hexanes) afforded 809 mg (85%)
of recovered alkyne and 3.38 g (88%) of ynone 44 as a light
yellow oil. Rf ) 0.35 (10% EtOAc/hexanes); IR 2951, 2872, 2208,
1675 cm-1; 1H NMR δ 0.03 (s, 6H), 0.56 (q, J ) 7.5 Hz, 12 H),
0.83-0.90 (m, 9H), 0.89 (s, 9H), 0.93 (t, J ) 8.4 Hz, 18H), 1.19
(d, J ) 6.9 Hz, 3H), 1.25-1.85 (m, 13H), 2.48 (m, 2H), 2.71
(dq, J ) 7.2, 4.5 Hz, 1H), 3.33-3.51 (m, 5H), 3.67 (m, 1H),
4.50 (s, 2H), 7.25-7.35 (m, 5H); 13C NMR δ -5.4, 5.1, 5.6, 6.9,
7.1, 14.8, 14.9, 15.0, 16.5, 18.3, 25.9, 27.8, 28.5, 29.1, 30.6, 31.1,
35.8, 36.1, 36.5, 43.9, 68.3, 70.7, 72.8, 74.3, 79.8, 95.8, 127.4,
127.5, 128.3, 138.6, 188.2.
(2S,5S,6R,12S,13S,14R)-2,6,12,14-Tet r a m et h yl-1-(ter t-
bu tyld im eth ylsilyl)oxy-5,13-(tr ieth ylsilyl)oxy-17-ben zy-
loxyh ep ta d eca n -9-on e (31). A solution of ynone 44 (5.24 g,
6.40 mmol) in EtOAc (250 mL) was purged with argon. To this
solution was added Lindlar’s catalyst (Pd/CaCO3 poisoned with
lead, 8.00 g), and a balloon of hydrogen was affixed. The
resulting suspension was vigorously stirred for 26 h. The
catalyst was separated by filtration through Celite-545, and
the solids were rinsed with ether (250 mL). Concentration
afforded 5.13 g (95%) of saturated ketone 31 as a colorless oil
which was used in the next step without further purification.
An analytical sample was purified by chromatography on silica
gel (5% EtOAc/hexanes). Rf ) 0.35(10% EtOAc/hexanes); [R]D
Ur ea (40) The reported procedure20 was not easily repro-
duced; therefore, a modified procedure was developed. To a
suspension of N,O-dimethylhydroxylamine hydrochloride (2.0
g, 20 mmol), pyridine (2.37 g, 30 mmol), and CH2Cl2 (40 mL)
was added carbonyl diimidazole (1.68 g, 10 mmol). The mixture
was refluxed for 16 h, quenched with 10% HCl, extracted with
ether, washed with brine, dried over MgSO4, and concentrated.
Bulb to bulb distillation (0.05 mmHg, 50 °C) afforded 1.10 g
(70%) of urea 40 as a colorless oil with spectral characteristics
1
+4.16 (c ) 0.4, CHCl3); IR 2951, 2872, 1710 cm-1; H NMR δ
0.04 (s, 6H), 0.59 (m, 12H), 0.81-0.95 (m, 9H), 0.89 (s, 9H),
0.95 (td, J ) 8.1 Hz, 1.8 Hz, 21H), 1.20-1.80 (m, 16H), 2.25-
2.55 (m, 4H), 3.25-3.55 (m, 6H), 4.50 (s, 2H), 7.26-7.35 (m,
5H); 13C NMR δ -5.4, 5.2, 5.5, 6.9, 7.1, 14.5, 14.8, 14.9, 16.6,
25.9, 26.5, 27.8, 28.2, 29.2, 29.9, 30.6, 36.0, 36.2, 36.4, 38.2,
40.9, 41.0, 68.2, 68.4, 70.7, 72.8, 76.5, 79.9, 127.4, 127.6, 128.3,
138.6, 211.3. Anal. Calcd for C46H90O5Si3: C, 68.42; H, 11.23;
Found: C, 68.53; H, 11.32.
1
matching those previously reported. IR 2916, 1666 cm-1; H
NMR δ 3.05 (s, 6H), 3.65 (s, 6H); 13C NMR δ 36.0, 60.5.
(5R,6S,7S)-N-Meth yl,N-m eth oxy-9-ben zyloxy-4,6-d im -
eth yl-5-(tr ieth ylsilyl)oxy-2-n on yn eca r boxa m id e (41). To
a solution of BuLi (2.1 M in hexanes, 5.56 mL, 11.8 mmol) in
THF (20 mL) was added a solution of alkyne 10 (4.0 g, 10.8
mmol), in THF (20 mL) at -78 °C. The pale yellow mixture
was warmed to 0 °C for 10 min and recooled to -78 °C, and
urea 40 (2.0 g, 13.5 mmol) was added. After warming to 0 °C
for 1 h, the mixture was quenched with NH4Cl, extracted with
ether, washed with brine, dried over MgSO4, and concentrated.
Purification by chromatography on silica gel (10-25% EtOAc/
hexanes) afforded 3.60 g (73%) of amide 41 as a light yellow
Sp ir ok eta l 45. To a solution of ketone 44 (5.13 g, 6.08
mmol) in MeOH (60 mL) was added aqueous HCl (12 M, 1.4
mL). After 3 h the reaction was judged complete by TLC
analysis and quenched by the addition of solid NaHCO3 (ca. 2
g). The mixture was concentrated directly and then partioned
between brine and EtOAc, dried over MgSO4, and concen-
trated. Purification by silica gel chromatography (7.5% EtOAc/
hexanes) afforded 1.44 g (50%) of spiroketal 45 as a single
diastereomer and another 1.20 g (42%) as a mixture of
diasteromers. Rf ) 0.44 (25% EtOAc/hexanes); [R]D -76.8 (c )
1
oil. H NMR δ 0.58 (q, J ) 7.8 Hz, 6H), 0.90 (d, J ) 6.9 Hz,
1
0.4, CHCl3); IR 3432, 2925, 2856, 1457 cm-1; H NMR δ 0.81
3H), 0.94 (t, J ) 7.8 Hz, 9H), 1.24 (d, J ) 6.9 Hz, 3H), 1.25-
1.94 (m, 5H), 2.73 (dq, J ) 6.0, 6.9 Hz, 1H), 3.22 (br, 3H), 3.44
(t, J ) 6.6 Hz, 2H), 3.56 (dd, J ) 2.7, 8.4 Hz, 1H), 3.73 (s, 3H),
4.50 (s, 2H), 7.26-7.32 (m, 5H).
(d, J ) 6.6 Hz, 3H), 0.88 (d, J ) 6.0 Hz, 3H), 0.89 (d, J ) 6.6
Hz, 3H), 1.00 (d, J ) 6.6 Hz, 3H), 1.07-1.84 (m, 19H), 1.99
(m, 1H), 3.17 (td, J ) 9.6, 2.4 Hz, 1H), 3.32 (dd, J ) 2.4, 10.2
Hz, 1H), 3.40 (m, 2H), 4.50 (s, 2H), 7.32-7.38 (m, 5H); 13C
NMR δ 10.9, 16.3, 16.4, 18.0, 25.9, 26.7, 27.4, 27.8, 28.2, 29.1,
29.9, 30.2, 33.9, 34.9, 35.7, 36.0, 68.1, 70.8, 73.0, 74.3, 74.5,
95.7, 127.5, 127.7, 128.3, 138.3. Anal. Calcd for C28H46O4: C,
75.29; H, 10.38. Found: C, 75.09; H, 10.54.
(4S,5S,6R)-N-Meth yl,N-m eth oxy-9-ben zyloxy-5-(tr ieth -
ylsilyl)oxy-4,6-d im eth yln on a n eca r boxa m id e (42). To a
solution of amide 41 (5.40 g, 11.8 mmol), in EtOAc (120 mL)
was added Lindlar’s catalyst (Pd/CaCO3/Pb, Aldrich, 5.0 g). A
balloon of hydrogen was affixed, and the mixture was vigor-
ously stirred for 22 h and then filtered through Celite-545,
washing with additional ether. Concentration afforded 5.30 g
(96%) of saturated amide 42 as a clear colorless oil. Rf ) 0.22
(25% EtOAc/hexanes); [R]D -1.11 (c ) 2.15, CHCl3); IR 2960,
2872, 1675 cm-1; 1H NMR δ 0.57 (q, J ) 8.1 Hz, 6H), 0.85 (dd,
J ) 6.6, 3.3 Hz, 6H), 0.93 (t, J ) 8.1 Hz, 9H), 1.15-1.85 (m,
8H), 2.31 (m, 2H), 3.17 (s, 3H), 3.35 (t, J ) 4.5 Hz, 1H), 3.43
(t, J ) 6.6 Hz, 2H), 3.67 (s, 3H), 4.50 (s, 2H), 7.25-7.35 (m,
5H); 13C NMR δ 5.5, 7.0, 14.8, 14.9, 27.8, 29.0, 29.8, 30.1, 30.6,
36.4, 61.1, 70.7, 70.9, 72.8, 80.0, 127.3, 127.5, 128.2, 138.6.
Anal. Calcd for C26H47NO4Si: C, 67.05; H, 10.17; Found: C,
67.01; H, 10.27.
Alcoh ol 50. To a solution of Pd(OAc)2 (8.0 mg, 0.035 mmol),
in THF (15 mL) at -78 °C was added PPh3 (9.2 mg, 0.035
mmol) in THF (0.35 mL). A solution of mesylate 15 (212 mg,
1.43 mmol) in THF (1 mL) was added followed by aldehyde
49 (250 mg, 0.71 mmol) in THF (1 mL) and finally Et2Zn (1.0
M in hexanes, 2.10 mL, 2.10 mmol). The mixture was warmed
to -20 °C. After 25 h the mixture was quenched with 10%
HCl, extracted with ether, washed with brine, dried over
MgSO4, and concentrated. Purification by chromatography on
silica gel (5% EtOAc/hexanes) afforded 236 mg (82%) of
homopropargylic alcohol 50 as a yellow oil. Rf ) 0.50 (20%
EtOAc/hexanes); [R]D -36.8 (c ) 4.00, CHCl3); IR 3458, 3318,

Synthesis of C1-C21 of Tautomycin
J . Org. Chem., Vol. 66, No. 4, 2001 1379
2951, 2872 cm-1; 1H NMR δ 0.80 (d, J ) 6.3 Hz, 3H), 0.88 (d,
J ) 6.9 Hz, 3H), 0.99 (m, 6H), 1.24 (d, J ) 7.2 Hz, 3H), 1.18-
1.75 (m, 18H), 1.85 (m, 1H), 1.95-2.25 (m, 2H), 2.13 (d, J )
2.4 Hz, 1H), 2.54 (ddq, J ) 2.4, 4.5, 7.2 Hz, 1H), 3.15 (t, J )
9.3 Hz, 1H), 3.29 (d, J ) 9.9 Hz, 1H), 3.36 (m, 1H), 4.89 (dd,
J ) 1.7, 9.9 Hz, 1H), 4.93 (dd, J ) 1.7, 17.4 Hz, 1H), 5.63 (ddd,
J ) 7.2, 9.9, 17.4 Hz, 1H). Anal. Calcd for C26H44O3: C, 77.18;
H, 10.96; Found C, 77.00; H, 11.05.
complete by TLC analysis, and solid Na2S2O3 was added
gradually (Ca u tion : High ly exoth er m ic, in d u ction pe-
r iod ). The mixture was diluted with EtOAc, washed with
brine, dried over MgSO4, concentrated, and purified by chro-
matography on silica gel (15% EtOAc/hexanes) affording 41
mg (82%) of ketone 53 as a colorless oil composed of an 86:14
mixture of diastereomers. Separation was achieved by careful
chromatography on silica gel (2.5%-5% EtOAc/hexanes), with
the anti diastereomer eluting second, affording 26 mg (52%)
of ketone 53 as a 98:2 mixture of diastereomers as judged by
1H NMR analysis. Spectral charateristics matched those
previously reported.1a Rf ) 0.33 (20% EtOAc/hexanes); [R]D
Dim eth ylsilyl Eth er 51. A 0.5-mL conical vial was charged
with alcohol 50 (50 mg, 0.12 mmol), a stirbar, and tetrameth-
yldisilazane (0.200 mL, 1.15 mmol). The mixture was heated
to 75 °C for 4 h and then cooled to room temperature. Excess
silazane was removed in vacuo at 55 °C overnight to afford
silyl ether 51 as a colorless, highly viscous oil, that was used
in the next step without further purification. IR 3309, 2968,
1
-63.1 (c ) 1.50, CDCl3); IR 3458, 2933, 2872, 1710 cm-1; H
NMR δ 0.80 (d, J ) 6.3 Hz, 3H), 0.88 (d, J ) 6.9 Hz, 3H), 0.99
(d, J ) 6.6 Hz, 6H), 1.14 (d, J ) 7.2 Hz, 3H), 1.20-1.74 (m,
17H), 1.96-2.21 (m, 2H), 2.20 (s, 3H), 2.63 (dq, J ) 7.2, 6.9
Hz, 1H), 3.12 (t, J ) 7.2 Hz, 1H), 3.27 (d, J ) 10.2 Hz, 1H),
3.63 (m, 1H), 4.88 (d, J ) 9.9 Hz, 1H), 4.92 (d, J ) 17.2 Hz,
1H), 5.65 (ddd, J ) 7.5, 9.9, 17.2 Hz, 1H); 13C NMR δ 10.9,
14.1, 16.6, 18.0, 20.1, 26.7, 27.5, 27.6, 28.2, 29.7, 29.9, 30.2,
30.9, 31.3, 32.9, 34.7, 35.1, 36.1, 37.9, 51.8, 74.0, 74.6, 95.6,
112.3, 145.0, 214.1. Anal. Calcd for C26H46O4; C, 73.89; H,
10.97; Found C, 73.73; H, 11.03.
1
2872, 2121 cm-1; H NMR δ 0.22 (s, 6H), 0.80 (d, J ) 6.6 Hz,
3H), 0.88 (d, J ) 6.6 Hz, 3H), 1.00 (m, 6H), 1.17 (d, J ) 7.2
Hz, 3H), 1.18-1.90 (m, 18 H), 2.0-2.25 (m, 2H), 2.07 (d, J )
2.7 Hz, 1H), 2.56 (m, 1H), 3.16 (t, J ) 9.3 Hz, 1H), 3.28 (d, J
) 10.2 Hz, 1H), 3.54 (m, 1H), 4.68 (septet, J ) 3.0 Hz, 1H),
4.90 (dd, J ) 1.6, 9.6 Hz, 1H), 4.92 (dd, J ) 1.6, 17.2 Hz, 1H),
5.65 (ddd, J ) 7.2, 9.6, 17.2, Hz, 1H).
Cyclic Siloxa n e 52. The residue from the previous step
was dissolved in THF (0.24 mL) and H2PtCl6 (0.057 M in THF,
10 µL, 0.57 µmol) was added. The yellow solution was heated
to 60 °C. After 6 h the hydrosilation was judged complete by
IR analysis (Si-H, 2121 cm-1). The mixture was diluted with
ether (0.25 mL), filtered through Celite-545, washing with
additional ether, and concentrated to afford cyclic siloxane 52
as a yellow oil that was used without purification. IR 2942,
Ack n ow led gm en t. This study was supported with
funding from the National Science Foundation (Re-
search Grant CHE-9901319). We thank Professor Cham-
berlin and Professor Ichihara for providing 1H NMR
spectra for compounds 48 and 53.
1
2864 cm-1; H NMR δ 0.22 (s, 6H), 0.80 (d, J ) 6.6 Hz, 3H),
0.89 (d, J ) 6.9 Hz, 3H), 0.98 (d, J ) 6.9 Hz, 6H), 1.04 (d, J )
6.6 Hz, 3H), 1.15-2.40 (m, 21H), 3.18 (t, J ) 9.3 Hz, 1H), 3.30
(d, J ) 10.2 Hz, 1H), 3.48 (m, 1H), 4.89 (dd J ) 1.7, 9.9 Hz,
1H), 4.92 (dd, J ) 1.7, 16.2 Hz, 1H), 5.41 (t, J ) 2.1 Hz, 1H),
5.62 (t, J ) 2.1 Hz, 1H), 5.68 (ddd, J ) 7.5, 9.9, 16.2 Hz, 1H).
Keton e 53. To a solution of the cyclic siloxane 52 (ca. 0.12
mmol) in THF (0.50 mL) and MeOH (1.0 mL) were added KF
(35 mg, 0.60 mmol), KHCO3 (60 mg, 0.60 mmol), and 30% H2O2
(1.0 mL, ca. 8.8 mmol). After 2 h the oxidation was judged
Su p p or tin g In for m a tion Ava ila ble: Characterization
data and experimental procedures for 2-7, 10, 14, 18, 20-
25, 25a , 25b, 26-30, 33, 46-49, 50-OAc, alternative synthesis
of 6; 1H NMR spectra of 5, 7, 20-25, 25a , 25b, 26, 28, 33, 41,
48-50, 50-OAc, 53, comparison spectra for 48 and 53, and a
13C spectrum for 53. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O0056951