Total synthesis of zincophorin and its methyl ester

Article abstract of DOI:10.1021/jo0496042

A total synthesis of the naturally occurring ionophore zincophorin has been realized. The route features an intramolecular oxymercuration of a cyclopropanemethanol and a Carroll-Claisen rearrangement for the respective elaboration of the C1-C12 and C13-C25 subunits, which have been assembled by using a highly diastereoselective titanium-mediated aldol condensation.

Full text of DOI:10.1021/jo0496042

Tota l Syn th esis of Zin cop h or in a n d Its Meth yl Ester
Magali Defosseux, Nicolas Blanchard, Christophe Meyer,* and J anine Cossy*
Laboratoire de Chimie Organique, asocie´ au CNRS, ESPCI,
10 rue Vauquelin 75231 Paris Cedex 05 - France
christophe.meyer@espci.fr; janine.cossy@espci.fr
Received March 10, 2004
A total synthesis of the naturally occurring ionophore zincophorin has been realized. The route
features an intramolecular oxymercuration of a cyclopropanemethanol and a Carroll-Claisen
rearrangement for the respective elaboration of the C1-C12 and C13-C25 subunits, which have
been assembled by using a highly diastereoselective titanium-mediated aldol condensation.
In tr od u ction
The useful antiinfectious properties displayed by many
naturally occurring polyoxygenated ionophores have been
explained by their capacities to form lipophilic complexes
with various cations, usually alkaline or alkaline-earth
ones, which affect proton-cation exchange processes
across biological membranes.1,2 In 1984, two independent
reports described the isolation of new monocarboxylic
acid ionophores, griseocholin3 and antibiotic M144255,4
from cultures of strains of Streptomyces griseus. The
structure of griseocholin was first established by exten-
sive NMR experiments,3,5 whereas the three-dimensional
structure of antibiotic M144255, including its absolute
configuration, was ascertained by X-ray diffraction of its
zinc-magnesium salt.4 In fact, these two compounds
turned out to be the same monocarboxylic acid ionophore
1 (Figure 1).4 Of considerable interest from the pharma-
cological perspective was the remarkable affinity exhib-
ited by this ionophore for divalent cations and especially
zinc, on the basis of which it was given the trivial name
zincophorin. Zincophorin and its calcium salt exhibited
broad in vitro antibiotic activities against Gram-positive
bacteria as well as Clostridium welchii.3,4 The ammonium
and sodium salts of zincophorin showed significant
anticoccidal activity against Eimeria tenella in chicken
embryos.3,4 Moreover, the methyl ester of zincophorin 2
was reported to possess antiviral activity with reduced
host cell toxicity compared to the free acid.6,7 Zincophorin
has elicited considerable synthetic interest as the prepa-
ration of elaborated fragments has been reported.8-15
However, only one single total synthesis was accom-
F IGURE 1. Structure of zincophorin and its methyl ester.
plished by Danishefsky et al. in 1988, which highlighted
the potential of Lewis acid promoted cyclocondensation
between silyloxydienes and aldehydes as a route toward
oxygen heterocycles as well as polypropionate units.8
Herein, we report a full account of our studies concern-
ing the total synthesis of zincophorin and its methyl
ester, featuring new approaches toward the preparation
and the coupling of two subunits.
The twenty-five carbon backbone of zincophorin con-
tains a number of interesting structural elements usually
encountered in polypropionates, such as a propionic acid
unit branched at C2 with a trisubstituted tetrahydropy-
ran (C3-C7), alternate methyl and hydroxyl groups (C8-
C13 and C18-C19), one disubstituted double bond (C16-
C17) and a trisubstituted one (C20-C21) both of (E)
configuration, and a remote isolated stereocenter (C22).
We set ourselves the challenging goal of disconnecting
the carbon framework within the characteristic C9-C13
polypropionate-type segment and obtain zincophorin and
its methyl ester from an aldol of type A, by achieving
(8) (a) Danishefsky, S. J .; Selnick, H. G.; Zelle, R. E.; DeNinno, M.
P. J . Am. Chem. Soc. 1988, 110, 4368. (b) Zelle, R. E.; DeNinno, M. P.;
Selnick, H. G.; Danishefsky, S. J . J . Org. Chem. 1986, 51, 5032.
(9) (a) Balestra, M.; Wittman, M. D.; Kallmerten, J . Tetrahedron
Lett. 1988, 29, 6905. (b) Cywin, C. L.; Kallmerten, J . Tetrahedron Lett.
1993, 34, 1103.
(10) Booysen, J . F.; Holzapfel, C. W. Synth. Commun. 1995, 25, 1473.
(11) Burke, S. D.; Ng, R. A.; Morrison, J . A.; Alberti, M. J . J . Org.
Chem. 1998, 63, 3160.
(1) Polyether Antibiotics; Westley, J . W., Ed.; Marcel Dekker: New
York, Vol. 1, 1982; Vol. 2. 1983.
(2) Dobler, M. In Ionophores and their Structures; Wiley: New York,
1981.
(3) Gra¨fe, U.; Schade, W.; Roth, M.; Radics, L.; Incze, M.; Ujszaszy,
K. J . Antibiot. 1984, 37, 836.
(4) Brooks, H. A.; Gardner, D.; Poyser, J . P.; King, T. J . J . Antibiot.
1984, 37, 1501.
(5) Radics, L. J . Chem. Soc., Chem. Commun. 1984, 599.
(6) Gra¨fe, U., Tonew, E., Schade, W., Reinhardt, G., Ha¨rtl, A. Ger.
(East) Patent DD 231 793, 1986.
(7) Tonew, E.; Tonew, M.; Gra¨fe, U.; Zopel, P. Pharmazie 1988, 43,
717.
(12) Marshall, J . A.; Palovich, M. R. J . Org. Chem. 1998, 63, 3701.
(13) (a) Chemler, S. R.; Roush, W. R. J . Org. Chem. 1998, 63, 3800.
(b) Chemler, S. R.; Roush, W. R. J . Org. Chem. 2003, 68, 1319.
(14) Guindon, Y.; Murtagh, L.; Caron, V.; Landry, S. R.; J ung, G.;
Bencheqroun, M.; Faucher, A.-M.; Gue´rin, B. J . Org. Chem. 2001, 66,
5427.
(15) (a) Cossy, J .; Blanchard, N.; Defosseux, M. Meyer, C. Angew.
Chem., Int. Ed. 2002, 41, 2144. (b) Defosseux, M.; Blanchard, N.;
Meyer, C.; Cossy, J . Org. Lett. 2003, 5, 4037.
10.1021/jo0496042 CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/02/2004
4626
J . Org. Chem. 2004, 69, 4626-4647

Total Synthesis of Zincophorin and Its Methyl Ester
SCHEME 1. Retr osyn th etic An a lysis of
Zin cop h or in
heterocycles and especially those encountered in the
structures of naturally occurring ionophores,19,20 the
corresponding reaction with cyclopropane derivatives has
received much less attention in the context of natural
product synthesis. On the basis of literature precedents
and our investigations,18,21,22 it was anticipated that the
electrophilic ring-opening reaction of the three-membered
ring in compound E with mercury(II) salts should occur
regioselectively at the most electron-rich bond, due to the
negative inductive effect of the hydroxyalkyl substituent.
Moreover, concomitant nucleophilic attack of the hy-
droxyl group (at C3) should occur stereoselectively and
should lead to an inversion of configuration at C7.18,21,22
Subsequent reductive demercuration23 would enable the
installation of the methyl group at C8. The absolute
configurations at C2 and C3 in the requisite oxymercu-
ration precursor of type E could be controlled by using a
chiral auxiliary-mediated aldol condensation between an
appropriate chiral enolate and an aldehyde of type F ,
which incorporates three contiguous stereocenters (C6-
C8). On the basis of our previous studies,24 the relative
configuration at C6 could be controlled by achieving a
diastereoselective hydroboration of an isopropenylcyclo-
propane of type H followed by a chain extension sequence
in order to transform the resulting alcohol G to the
aldehyde of type F . Finally, the isopropenylcyclopropane
of type H could be prepared by nucleophilic ring-opening
of the optically enriched cyclopropyl lactone 3 (Scheme
2).25,26 To study the influence of the protecting group in
the intramolecular oxymercuration of the cyclopro-
panemethanol derivative of type E, the use of a tert-
butyldiphenylsilyl ether (P ) TBDPS) and a benzyl group
(P ) Bn) were considered for the alcohol moiety at C9.
The intramolecular enantioselective cyclopropanation
of allyl diazoacetate catalyzed by Doyle’s chiral dirhodium
the diastereoselective reduction of the carbonyl group at
C11 and subsequent deprotection steps. As anti,anti-
methyl-hydroxyl-methyl arrays have been recognized to
be difficult to synthesize,13,16 a plausible disconnection
in the aldol A appeared to be the C12-C13 bond. Due to
the syn relationship between the methyl group at C12
and the hydroxyl group at C13, the construction of the
C12-C13 bond was envisaged by using an aldol conden-
sation between the (Z)-enolate derived from an ethyl
ketone of type B (C1-C12 subunit) and an aldehyde of
type C (C13-C25 subunit). The stereochemical outcome
of the aldol coupling should be exclusively controlled by
the C10 stereocenter present in ethyl ketone B as the
stereogenic centers in the aldehyde C are too remote from
the carbonyl group to exert any influence on the stereo-
selectivity. Therefore, the stereochemical relationship
between the two methyl groups at C10 and C12 in the
aldol A should be syn (Scheme 1).17
(18) (a) Collum, D. B.; Mohamadi, F.; Hallock, J . S. J . Am. Chem.
Soc. 1983, 105, 6882. (b) Landais, Y.; Parra-Rapado, L. Tetrahedron
Lett. 1996, 37, 1209. (c) Barrett, A. G. M.; Tam, W. J . Org. Chem. 1997,
62, 4653.
Having identified the key disconnection in the ret-
rosynthetic analysis of zincophorin, the preparation of
the corresponding C1-C12 and C13-C25 subunits was
examined.
(19) (a) Bartlett, P. A. Olefin Cyclization Processes that Form
Carbon-Heteroatom Bonds In Asymmetric Synthesis; Morrison, J . D.,
Ed.; Academic Press: New York 1983; Vol. 3, pp 411-454. (b) Boivin,
T. L. B. Tetrahedron 1987, 43, 3309. (c) Cardillo, G., Orena, M.
Tetrahedron 1990, 46, 3321. (d) Harmange, J .-C.; Figade`re, B. Tetra-
hedron: Asymmetry 1993, 4, 1711. (e) Bratt, K.; Garavelas, A.;
Perlmutter, P.; Westman, G. J . Org. Chem. 1996, 61, 2109. For related
intramolecular oxymercuration of allenes, see: (f) Walkup, R. D.; Park,
G. J . Am. Chem. Soc. 1990, 112, 1597. (g) Walkup, R. D.; Kim, S. W.
J . Org. Chem. 1994, 59, 3433.
Resu lts a n d Discu ssion
In the retrosynthetic analysis of the C1-C12 subunit
of type B, it was envisaged to install the C9 and C10
stereocenters with the required absolute configurations
by achieving a stereoselective carbon chain extension of
the aldehyde of type D (C1-C9 subunit). The original
key stage of our synthetic plan relied on the construction
of the tetrahydropyran ring by using an intramolecular
oxymercuration reaction of an appropriately substituted
cyclopropanemethanol derivative of type E.18 Whereas
the intramolecular oxymercuration of alkenes or related
compounds has been widely used to synthesize oxygen
(20) Intramolecular oxymercuration of alkenes were used to elabo-
rate some oxygen heterocycles in the total synthesis of antibiotic X-206
((a) Evans, D. A.; Bender, S. L.; Morris, J . J . Am. Chem. Soc. 1988,
110, 2506) and ionomycin: (b) Evans, D. A.; Dow, R. L.; Shih, T. L.;
Takacs, J . M.; Zahler, R. J . Am. Chem. Soc. 1990, 112, 5290.
(21) For some applications of the ring-opening of cyclopropyl-
carbinols with mercury(II) salts, see: Meyer, C.; Blanchard, N.;
Defosseux, M.; Cossy, J . Acc. Chem. Res. 2003, 36, 766.
(22) Collum, D. B.; Still, W. C.; Mohamadi, F. J . Am. Chem. Soc.
1986, 108, 2094.
(23) Kang, S. H.; Lee, J . H.; Lee, S. B. Tetrahedron Lett. 1988, 39,
39 and references therein.
(24) (a) Cossy, J .; Blanchard, N.; Hamel, C.; Meyer, C. J . Org. Chem.
1999, 64, 2608. (b) Cossy, J .; Blanchard, N.; Meyer, C. Synthesis 1999,
1063. (c) Cossy, J .; Blanchard, N.; Meyer, C. Tetrahedron Lett. 1999,
40, 8361.
(16) (a) Hoffmann, R. W. Angew. Chem., Int. Ed. Engl. 1987, 26,
489. (b) Hoffmann, R. W. Synthesis 1994, 629.
(25) Cossy, J .; Blanchard, N.; Meyer, C. Eur. J . Org. Chem. 2001,
339.
(17) (a) Evans, D. A.; Rieger, D. L.; Bilodeau, M. T.; Urpi, F. J . Am.
Chem. Soc. 1991, 113, 1047. (b) Bernardi, A.; Capelli, A. M.; Comotti,
A.; Gennari, C.; Gardner, M.; Goodman, J . M.; Paterson, I. Tetrahedron
1991, 47, 3471. (c) Evans, D. A.; Ng, H. P.; Clark, S.; Rieger, D. L.
Tetrahedron 1992, 48, 2127. (d) Evans, D. A.; Dart, M. J .; Duffy, J . L.;
Rieger, D. L. J . Am. Chem. Soc. 1995, 117, 9073.
(26) (a) Doyle, M. P.; Austin, R. E.; Bailey, A. S.; Dwyer, M. P.;
Dyatkin, A. B.; Kalinin, A. V.; Kwan, M. M. Y.; Liras, S.; Oalmann, C.
J .; Pieters, R. J .; Protopopova, M. N.; Raab, C. E.; Roos, G. H. P.; Zhou,
Q. L.; Martin, S. F. J . Am. Chem. Soc. 1995, 117, 5763. (b) Doyle, M.
P.; Winchester, W. R.; Protopopova, M. N.; Kazala, A. P.; Westrum, L.
J . Org. Synth. 1996, 73, 13.
J . Org. Chem, Vol. 69, No. 14, 2004 4627

Defosseux et al.
SCHEME 2. Retr osyn th etic An a lysis of th e
SCHEME 3 a
C1-C12 Su bu n it
complex Rh2((5R)-MEPY)4 (0.1 mol %) afforded (1S,5R)-
3-oxabicyclo[3.1.0]hexan-2-one 3 (ee g 95%, 91%).26,27 The
cyclopropyl lactone 3 was treated with two equivalents
of methyllithium and the subsequent silylation of the
primary lithium alkoxide was carried out by addition of
a mixture of tert-butyldiphenylsilyl chloride and imida-
zole to afford the silyl ether 4a in excellent yield (90%).
By contrast, the in situ benzylation of the primary
lithium alkoxide with benzyl bromide was extremely
sluggish even in the presence of polar cosolvents (HMPA
or DMSO). Therefore, after ring-opening of the cyclo-
propyl lactone 3 with methyllithium, the reaction mixture
was quenched with 50% aqueous NaOH, and subsequent
benzylation under phase-transfer catalysis afforded the
benzyl ether 4b (89%). The tertiary alcohols 4a and 4b
were then dehydrated by using a large excess of meth-
anesulfonyl chloride and triethylamine in the presence
of a stoichiometric amount of DMAP in dichloromethane
at 0 °C, and the isopropenylcyclopropanes 5a (85%) and
5b (83%) were obtained (Scheme 3).25 To introduce the
new stereocenter at C6, adjacent to the three-membered
ring, the protected alcohols 5a and 5b were hydroborated
with BH3‚THF complex in THF. After a standard oxida-
tive alkaline workup with H2O2/NaOH, the corresponding
primary alcohols 6a (91%) and 6b (91%) were obtained
in a highly diastereoselective fashion (dr > 96/4). The
relative configuration of the newly introduced stereo-
center in compounds 6a and 6b was assigned according
to our previous investigations concerning the diastereo-
selectivity of electrophilic additions to alkenyl-substituted
three-membered rings.24
a
Reagents and conditions: (a) Rh2((5R)-MEPY)4 (0.1 mol %),
CH2Cl2, reflux, addition of allyl diazoacetate over 30 h (91%); (b)
MeLi (2 equiv), THF, 0 °C then TBDPSCl, imidazole, DMF, rt
(90%); (c) MeLi (2 equiv), THF, 0 °C then 50% aq NaOH, toluene,
BnBr, cat. BnNEt3Cl (89%); (d) MeSO2Cl, Et3N, DMAP, CH2Cl2,
0 °C (5a : 85%, 5b: 83%); (e) BH3‚THF, THF, -30 °C to rt then
NaOH, H2O2 (6a and 6b: 91%); (f) PCC, 4 Å molecular sieves,
CH2Cl2 (91%); (g) cat. TPAP, NMO, CH2Cl2/MeCN (9/1), 0 °C; (h)
(EtO)2P(O)CH2COOEt, NaH, THF, (8a : 78% from 6a , 8b: 56%
from 6b); (i) H2, cat. PtO2, EtOAc (9a : 98%, 9b: 95%); (j) Dibal-
H, toluene, -78 °C (10a : 97%, 10b: 90%); (k) (R)-11, c-Hex2BCl,
EtNMe2, Et2O, 0 °C then addition of aldehyde 10a or 10b, -78 to
-23 °C (12a : 83%, 12b: 87%); (l) HF‚Pyr, THF (86%).
7a ,29 whereas the oxidation of the primary alcohol 6b was
carried out with the mild reagent TPAP/NMO30 and the
unstable aldehyde 7b was directly engaged in the next
step. A Horner-Wadsworth-Emmons reaction was used
in order to perform the carbon chain extension of alde-
hydes 7a and 7b and provided the corresponding (E)-R,â-
unsaturated esters 8a (78% from 6a ) and 8b (56% from
6b). The double bond in these compounds was hydroge-
nated over PtO2 in ethyl acetate to give esters 9a (98%)
The preparation of suitable precursors for the elabora-
tion of the oxygen heterocycle by an intramolecular
oxymercuration required the carbon chain extension,28
as well as the introduction of the C2 and C3 stereo-
centers. The oxidation of the primary alcohol 6a could
be efficiently carried out with PCC to afford aldehyde
(28) The hydroboration of 5a and 5b was also carried out with
9-BBN-H, but the homologation of the resulting organoborane 9-BBN-
B-alkyl did not proceed readily in the presence of carbenoid type
reagents such as the potassium enolate of methylbromoacetate or
chloroacetonitrile, according to: (a) Brown, H. C.; Nambu, H.; Rogic,
M. J . Am. Chem. Soc. 1969, 91, 6852. (b) Brown, H. C.; Nambu, H.;
Rogic, M. J . Am. Chem. Soc. 1969, 91, 6854.
(27) The ring-opening of the enantiomerically enriched cyclopropyl
lactone 3 and racemic (()-3 with (S)-phenylethylamine (ee > 99%), in
the presence of 2-hydroxypyridine, afforded a mixture of diastereomeric
amides. Quantification of these diastereomers in both cases by 1H NMR
confirmed an ee value greater than 95% for 3; see: Schotten, T.;
Boland, W.; J aenicke, L. Tetrahedron Lett. 1986, 27, 2349.
(29) Several oxidizing reagents could be used, and none of them
caused epimerization at C6. On a large scale, PCC turned out to be
the most convenient: Corey, E. J .; Suggs, J . W. Tetrahedron Lett. 1975,
2647.
(30) Ley, S. V.; Norman, J .; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639.
4628 J . Org. Chem., Vol. 69, No. 14, 2004

Total Synthesis of Zincophorin and Its Methyl Ester
SCHEME 4. Ela bor a tion of th e Tetr a h yd r op yr a n
Rin g by a n In tr a m olecu la r Oxym er cu r a tion a
and 9b (95%), respectively. Finally, the reduction of these
two ethyl esters with Dibal-H in toluene at -78 °C
afforded aldehydes 10a (97%) and 10b (90%). The next
step dealt with the introduction of the C2 and C3
stereocenters with the required absolute configurations.
An auxiliary-mediated enantioselective aldol condensa-
tion appeared an attractive option for this purpose since
in aldehydes 10a and 10b the stereogenic centers were
too remote from the carbonyl group to act as efficient
stereochemical control elements. The anti relative con-
figuration of the C2 and C3 stereocenters entailed the
involvment of an (E)-enolate and the methodology de-
veloped by Paterson, based on the use of the boron
enolates generated from chiral ethyl ketones derived from
lactic acids, was selected.31 The required ethyl ketone (R)-
11, prepared in three steps from the commercially
available (R)-isobutyl lactate, was converted to an (E)-
boron enolate by treatment with chlorodicyclohexyl-
borane in the presence of N,N-dimethylethylamine as a
base, and condensation with aldehydes 10a and 10b
afforded the corresponding aldol products 12a (83%) and
12b (87%), respectively, with high diastereoselectivity (dr
> 96/4).31 The hydroxyl group at C9 in compound 12a
was deprotected by treatment with HF‚Pyridine complex
in THF to afford the cyclopropanemethanol 12c (86%)
(Scheme 3).
a
Reagents and conditions: (a) Hg(OCOCF3)2, CH2Cl2, rt then
KBr/H2O; (b) n-Bu3SnH, cat. AIBN, THF/toluene (1/1), rt to
60 °C, then CCl4 and KF/H2O; (c) TBDPSCl, imidazole, DMF, rt
(14a : 93%, 14′a : 6%).
The feasibility of the next crucial transformation,
involving the elaboration of the oxygen heterocycle by an
intramolecular oxymercuration of the three-membered
ring, could then be tested with the three substrates
12a -c. Thus, when the silyl ether 12a was treated with
mercuric trifluoroacetate in dichloromethane,18,21,22 a slow
and incomplete reaction occurred and a complex mixture
of products was generated. As the tert-butyldiphenylsilyl
protecting group may interfere with the oxymercura-
tion,22 the same sequence was applied to the benzyl ether
12b. In this case, the oxymercuration occurred rapidly,
and after treatment of the reaction mixture with a
saturated aqueous solution of KBr, the analysis of the
1H NMR spectrum of the crude material indicated the
plausible formation of two diastereomeric organomercuric
bromides 13b and 13′b (85/15 ratio). With the aim of
minimizing the handling of organomercurials, a reductive
demercuration was directly carried out by using
n-Bu3SnH and a catalytic amount of AIBN32 in THF/
toluene (1/1, rt to 60 °C) followed by destruction of the
excess tin hydride with CCl420 and subsequent washings
with an aqueous solution of KF. Unlike the oxymercu-
ration which had proceeded in virtually quantitative
yield, several byproducts were generated during the
reductive demercuration, and an 85/15 diastereomeric
mixture of tetrahydropyrans 14b and 14′b was isolated
in only 45% yield. Much better results were obtained in
the case of the unprotected cyclopropanemethanol 12c.
Indeed, when this compound was subjected to the oxymer-
curation reaction, a diastereomeric mixture of hetero-
cyclic organomercuric bromides 13c and 13′c was formed
and fortunately in this case, the reductive demercuration
proceeded extremely cleanly to afford a 93/7 diastereo-
meric mixture of the tetrahydropyrans 14c and 14′c in
85% yield. After protection of the primary hydroxyl group
at C9 as a tert-butyldiphenylsilyl ether, the two diaster-
eomers 14a and 14′a were separated by flash chroma-
tography and isolated in 93% and 6% yield respectively
(Scheme 4).
The relative configurations of the heterocyclic com-
1
pounds were assigned by H NMR studies on the basis
of the observed differential nuclear Overhauser effects
(NOE), indicating that 14a and 14′a were epimeric at
C7 and that the major diastereomer 14a exhibited the
required trans stereochemical relationship between H3
and H7 for the synthesis of zincophorin.15a
This result confirmed that whereas the intramolecular
oxymercuration of the cyclopropanes 12b or 12c occurred
with a very high level of regioselectivity, the nucleophilic
attack of the hydroxyl group proceeded predominantly,
but not exclusively, with inversion of configuration at
C7.18,21 Thus, the electrophilic ring-opening reaction
occurred at the more electron-rich bond of the three-
membered ring, which is less subjected to the electron-
withdrawing inductive effect of the hydroxymethyl
substituent.18,21-22 This electrophilic ring-opening could
be accompanied by the synchronous stereoselective anti-
nucleophilic attack of the internal hydroxyl group at C3,
leading to an inversion of configuration at C7 and
affording 13c (or 13b) (eq 1) (Scheme 5). Alternatively,
a nonsynchronous process, wherein cyclopropane bond
breaking and intramolecular nucleophilic attack would
not occur at the same rate and would lead to a carbo-
cationic intermediate, could be invoked in order to explain
the formation of the epimeric compounds 13′c (or 13′b)
at C7 (eq 2) (Scheme 5).33
(31) (a) Paterson, I.; Wallace, D. J .; Velazquez, S. M. Tetrahedron
Lett. 1994, 35, 9083. (b) Paterson, I.; Wallace, D. J .; Cowden, C. J .
Synthesis 1998, 639.
(32) Whitesides, G. M.; San Fillipo, J ., J r. J . Am. Chem. Soc. 1970,
92, 6611.
Therefore, as it had been envisaged in our synthetic
plan, the intramolecular oxymercuration of the nonpro-
J . Org. Chem, Vol. 69, No. 14, 2004 4629

Defosseux et al.
SCHEME 5
SCHEME 6. Syn th esis of th e C1-C9 Su bu n it of
Zin cop h or in a
tected cyclopropanemethanol 12c efficiently enabled the
construction of the trisubstituted tetrahydropyran of
zincophorin in good yield (85%) and with high diastereo-
selectivity (dr ) 93/7) (Scheme 4). Comparatively, the
oxymercuration-reductive demercuration of the cyclo-
propanemethanol protected as a benzyl ether 12b af-
forded the oxygen heterocycle 14b with acceptable dia-
stereoselectivity (dr ) 85/15) but with unsatisfactory
yield (45%). Furthermore, it appeared that the selection
of a tert-butyldiphenylsilyl protecting group rather than
a benzyl group (for the alcohol moiety at C9) from the
beginning of the synthesis of the C1-C9 subunit of
zincophorin resulted in higher yields and product stabili-
ties despite an additional deprotection step before and a
protection step after the key oxymercuration step.
The synthesis of zincophorin was then pursued from
compound 14a in which the hydroxyl group at C9 had
been reprotected as a silyl ether, and the next task was
to remove the chiral auxiliary used in the aldol conden-
sation without epimerization of the stereocenter at C2.
The reduction of both the carbonyl group at C1 and the
benzoate was accomplished by using lithium borohydride
in THF.31 The resulting diol 15 was subjected to an
oxidative cleavage with sodium periodate in methanol to
afford aldehyde 16, which was oxidized to the corre-
sponding carboxylic acid 17.34 These three reactions,
which proceeded cleanly and did not require purification
of the intermediate compounds, provided the carboxylic
acid 17 with an excellent overall yield of 90% from 14a .
Esterification of 17 with trimethylsilyldiazomethane35
gave the methyl ester 18 (85%) and subsequent depro-
tection with HF‚Pyridine afforded the primary alcohol
19 (90%). This latter compound was quantitatively
oxidized by Dess-Martin periodinane (DMP)36 to alde-
hyde 20, which constitutes the C1-C9 subunit of
zincophorin.15a Aldehyde 20 turned out to be stable and
no epimerization occurred at C8, provided that the
remaining traces of pyridine had been properly removed
a
Reagents and conditions: (a) LiBH4, THF, -20 °C to rt; (b)
NaIO4, MeOH/H2O; (c) NaClO2, NaH2PO4, 2-methylbut-2-ene,
t-BuOH/H2O, (90% from 14a ); (d) Me3SiCHdN2, MeOH/C6H6
(85%); (e) HF‚Pyr, THF (90%); (f) DMP, Pyr, CH2Cl2 (100%).
from the crude material. Moreover, this compound could
be also purified by flash chromatography on silica gel
without any epimerization (Scheme 6).
The carbon chain extension of aldehyde 20 could then
be investigated with the aim of synthesizing a C1-C12
subunit precursor of type I but this operation, which
required the installation of two new stereocenters (C9
and C10), was considered to be a challenging task due
to the anti,anti relative configuration of the C8-C10
stereotriad. The use of (E)-enolates, (E)-crotylmetals or
allenylmetals was considered in order to effect the desired
transformation. However, the anti stereochemical rela-
tionship between the methyl group at C8 and the
hydroxyl group at C9 suggested that the addition of the
above-mentioned reagents to aldehyde 20 had to involve
a disfavored anti-Felkin-Anh transition state.13,37,38 To
override the stereochemical bias exerted by the C8
stereocenter in aldehyde 20, the use of chiral nucleophilic
reagents exhibiting high π-facial selectivities had to be
considered in this double-asymmetric condensation pro-
ceeding in the mismatched manifold.39 Although its
influence was anticipated to contribute to a smaller
extent to the stereochemical outcome of nucleophilic
additions to aldehyde 20, it is worth mentioning that,
on the basis of Evan’s model for 1,3-asymmetric induc-
tion, the â-alkoxy-substituted stereocenter (C7) should
reinforce the formation of the anti-Felkin diastereomeric
adduct of type I (anti stereochemical relationship be-
tween both oxygenated moieties at C7 and C9 in the
extended zigzag conformation) (Scheme 7).40
The first chain extension attempt was carried out by
using an aldol condensation, and the methodology de-
veloped by Paterson, based on the use of the boron
(33) Other mechanisms were also discussed in ref 18a in order to
explain the stereoselectivities of mercury(II)-mediated opening of
cyclopropanes by internal nucleophiles. These processes were assumed
to be under kinetic control,18a but this was not verified in the particular
case of substrates 12b and 12c. Indeed, reversibility has already been
observed in case of alkenes, see: Harding, K. E.; Marman, T. H. J .
Org. Chem. 1984, 49, 2838.
(34) Balkrishna, B. S.; Childers, W. E., J r.; Pinnick, H. W. Tetra-
hedron 1981, 37, 2091.
(35) Hashimoto, N.; Aoyama, T.; Shioiri, T. Chem. Pharm. Bull.
1981, 29, 1475.
(37) For a recent review, see: Mengel, A.; Reiser, O. Chem. Rev.
1999, 99, 1191.
(38) Roush, W. R. J . Org. Chem. 1991, 56, 4151 and references
herein.
(39) Masamune, S.; Choy, W.; Petersen, J . S.; Sita, L. R. Angew.
Chem., Int. Ed. Engl. 1985, 24, 1.
(40) (a) Evans, D. A.; Duffy, J . L.; Dart, M. J . Tetrahedron Lett. 1994,
35, 8537. (b) Evans, D. A.; Dart, M. J .; Duffy, J . L.; Yang, M. G.;
Livingston, A. B. J . Am. Chem. Soc. 1995, 117, 6619. (c) Evans, D. A.;
Dart, M. J .; Duffy, J . L.; Yang, M. G. J . Am. Chem. Soc. 1996, 118,
4322.
(36) Dess, D. B.; Martin, J . C. J . Am. Chem. Soc. 1991, 113, 7277.
4630 J . Org. Chem., Vol. 69, No. 14, 2004

Total Synthesis of Zincophorin and Its Methyl Ester
SCHEME 7. Ca r bon Ch a in Exten sion of th e C1-C9
Su bu n it
SCHEME 9. Ad d ition of a Ch ir a l Cr otyltita n iu m
Rea gen t to Ald eh yd e 20
reagents, capable of overriding substrate control in
numerous situations wherein chiral aldehydes have been
used.41 However, when the (E)-chiral crotyltitanium
reagent (R,R)-25 which is known to direct the nucleo-
philic addition to the Si face of aldehydes41 was condensed
with aldehyde 20, a 70/30 mixture of two separable
diastereomeric homoallylic alcohols 26 and 27 was ob-
tained and the major diastereomer 26 was isolated in
52% yield. Both homoallylic alcohols 26 and 27 neces-
sarily exhibit an anti-relationship between the methyl
group at C10 and the hydroxyl group at C9, due to the
involvment of an (E)-crotylmetal reagent. Moreover, the
major diastereomeric homoallylic alcohol 26, which was
anticipated to result from an anti-Felkin addition con-
trolled by the face-selective crotyltitanium complex (R,R)-
25, should possess the required configurations at C8-
C10. The minor diastereomeric homoallylic alcohol 27
would in turn result from a substrate-directed Felkin-
Anh addition process (Scheme 9). These stereochemical
assignments were confirmed by the synthesis of these
diastereomeric homoallylic alcohols according to another
strategy (vide infra).
SCHEME 8. Ad d ition of a Ch ir a l En ola te to
Ald eh yd e 20a
Although the diastereoselectivity was improved in
favor of the diastereomeric homoallylic alcohol 26 having
the requisite anti,anti-relative configuration at C8-C10,
another class of chiral nucleophiles, the allenylzinc
reagents, was tested since these reagents were demon-
strated to undergo highly diastereoselective reagent-
controlled additions to chiral aldehydes. Thus, the chiral
allenylzinc reagent (P)-29 was generated in situ from the
optically enriched propargylic mesylate (R)-28 (cat.
Pd(OAc)2, cat. PPh3, Et2Zn),42 and its addition to aldehyde
20 proceeded in the mismatched manifold to afford a
diastereomeric mixture of three homopropargylic alcohols
30, 31, and 32 in an 80/12/8 ratio. These diastereomers
were separated by flash chromatography and respectively
isolated in 63%, 9%, and 7% yields (combined yield 79%)
(Scheme 10). To unambiguously assign the configuration
of these three diastereomeric homopropargylic alcohols,
the allenylzinc reagent (M)-29 derived from the enantio-
meric propargylic mesylate (S)-28 was also reacted with
aldehyde 20. This reaction, which now proceeded in the
matched manifold, afforded the homopropargylic alcohol
31 as a single diastereomer in 65% isolated yield (Scheme
10).
a
Reagents and conditions: (a) (S)-11, c-Hex2BCl, EtNMe2, Et2O,
0 °C then add 20, -78 to -23 °C; (b) TBSOTf, 2,6-lutidine, CH2Cl2,
-78 °C (41% from 20); (c) SmI2, THF/MeOH, 0 °C (93%).
enolates generated from chiral ethyl ketones (derived
from lactic esters), was selected.31 However, the addition
of the (E)-boron enolate derived from the ethyl ketone
(S)-11 to aldehyde 20 proceeded in an essentially stereo-
random fashion. Indeed, after silylation of the hydroxyl
group at C9, a 50/50 diastereomeric mixture of ketones
21 and 22 was obtained (41%) and subsequent reductive
removal of the benzoyloxy group was achieved by treat-
ment with samarium diiodide in THF/MeOH31 to give an
inseparable 50/50 diastereomeric mixture of ethyl ketones
23 and 24 (93%) (Scheme 8). The relative configuration
of these two diastereomeric ethyl ketones was assigned
by comparison to 23 prepared by another route (vide
infra).
Therefore, aldehyde 20 exhibited an underestimated
propensity to bias the nucleophilic additions into the
Felkin-Anh mode and the facial selectivity displayed by
the chiral enolate derived from ethyl ketone (S)-11 was
not high enough to override the influence of the aldehyde
C8 stereocenter.
Consequently, a more powerful face-selective reagent
had to be chosen, and we next envisaged the addition of
a chiral crotylmetal reagent. The Hafner-Duthaler cro-
tyltitanium reagents bearing a chiral TADDOL ligand
have been demonstrated to be highly face-selective
(41) (a) Hafner, A.; Duthaler, R. O.; Marti, R.; Rihs, G.; Rothe-Streit,
P.; Schwarzenbach, F. J . Am. Chem. Soc. 1992, 114, 2321. (b) Cossy,
J .; BouzBouz, S.; Pradaux, F.; Willis, C.; Bellosta, V. Synlett 2002, 1595.
(c) BouzBouz, S.; Cossy, J . Org. Lett. 2001, 3, 3995.
(42) (a) Marshall, J . A.; Adams, N. D. J . Org. Chem. 1999, 64, 5201.
(b) Marshall, J . A. Chem. Rev. 2000, 100, 3163.
J . Org. Chem, Vol. 69, No. 14, 2004 4631

Defosseux et al.
substituted aldehydes.44 However, the presence of the
bulky trisubstituted tetrahydropyran substituent (C1-
C7) may be responsible for the difficulties of aldehyde
20 to accommodate nucleophilic additions through an
anti-Felkin transition state. The influence of the â-oxy-
genated substituted stereocenter (C7)40 in aldehyde 20
appeared to be negligible or was not able to compensate
the stereochemical bias exerted by the C8 stereocenter
which seemed to be difficult to override completely.45
SCHEME 10. Ad d ition of Ch ir a l Allen ylzin c
Rea gen ts to Ald eh yd e 20a
Though the undesired diasteromeric homopropargylic
alcohols syn,anti-31 and syn,syn-32 accounted for one-
fifth of the total products, the major diastereomeric
homopropargylic alcohol 30 formed during the course of
the allenylzinc addition, which possesses the required
absolute configurations at C9 and C10 for the synthesis
of zincophorin, was nevertheless isolated in acceptable
yield (63%), and partially hydrogenated to the homoallylic
alcohol 26 (93%).
The synthesis of the C1-C12 subunit of zincophorin
was then pursued from the homoallylic alcohol 26, and
the hydroxyl group at C9 was protected as a TBS ether
33 (87%). After dihydroxylation of the double bond and
oxidative cleavage of the 1,2-diol with sodium periodate,
the resulting aldehyde 34 was treated with an excess of
lithium diethylcuprate (prepared from etheral ethyl-
lithium-lithium bromide complex and copper iodide) to
chemoselectively produce a secondary alcohol46 which was
oxidized with Dess-Martin periodinane (DMP)36 to afford
ethyl ketone 23. These latter four steps proceeded
extremely cleanly, and it was not necessary to purify any
of the intermediates. Under these conditions, the ethyl
ketone 23 which constitutes the C1-C12 subunit of
zincophorin was obtained in 68% yield from the silyl
ether 33 (Scheme 12).
a
Reagents and conditions: cat. Pd(OAc)2, cat. PPh3, Et2Zn,
THF, -30 °C.
SCHEME 11 a
The preparation of the C13-C25 subunit, which con-
tains three of the thirteen asymmetric carbons of zinco-
phorin (C18, C19, and C22) as well as two double bonds
of (E) configuration (C16-C17 and C20-C21), was next
examined.
a
Reagents and conditions: H2 (1 atm), cat. Pd/BaSO4, quinoline,
toluene, rt (26: 93%, 27: 48%).
Moreover, partial hydrogenation of the triple bond of
the diastereomeric homopropargylic alcohols 30 and 31
respectively afforded the homoallylic alcohols 26 (93%)
and 27 (48%) (Scheme 11). Since these last two com-
pounds had been previously synthesized by addition of a
chiral (E)-crotyltitanium reagent to aldehyde 20 (Scheme
9), this result demonstrated that alcohols 26, 27, 30, and
31 all shared the same C9-C10 anti relative configura-
tion. Consequently, the C9-C10 relative configuration
in the minor diastereomeric homopropargylic alcohol 32
was necessarily syn. To explain the formation of the
minor diastereomer 31, having a C8-C9 syn relative
configuration, the formation of the enantiomeric alle-
nylzinc reagent (M)-29 has to be considered as a conse-
quence of the racemization of the intermediate allenylpal-
ladium species.43
In our retrosynthetic analysis of the aldehyde of type
C, the formation of the C16-C17 disubstituted (E)-alkene
was envisaged by performing the anti-reduction of the
carbon-carbon triple bond in a disubstituted alkyne of
(44) (a) Marshall, J . A.; Schaaf, G. M. J . Org. Chem. 2001, 66, 7825.
(b) Marshall, J . A.; Bourbeau, M. P. J . Org. Chem. 2002, 67, 2751.
(45) Other face-selective nucleophiles could have been considered
but were not tested. It is also worth indicating that an alternative
retrosynthetic analysis of zincophorin based on a disconnection at the
C9-C10 bond had also been envisaged. However, a model study
revealed
a complete absence of diastereoselectivity in the aldol
condensation of the (E)-boron enolate derived from ethyl ketone 58, a
simplified surrogate for the C10-C25 fragment of zincophorin, with
aldehyde 20.
These results were in agreement with those reported
by Marshall for double-asymmetric nucleophilic additions
of chiral allenylzincs to simple R-methyl-â-alkoxy-
(43) Allenylpalladium complexes have been shown to be configura-
tionally labile, especially in the presence of zerovalent palladium
catalysts, whereas the configurational stability of allenylzinc reagents
has been clearly demonstrated: (a) Poisson, J .-F.; Normant, J .-F. J .
Am. Chem. Soc. 2001, 123, 4639. (b) Poisson, J .-F.; Chemla, F.;
Normant, J .-F. Synlett 2001, 305.
(46) Posner, G. H.; Whitten, C. E.; McFarland, P. E. J . Org. Chem.
1972, 94, 5106.
4632 J . Org. Chem., Vol. 69, No. 14, 2004

Total Synthesis of Zincophorin and Its Methyl Ester
SCHEME 12. Syn th esis of th e C1-C12 Su bu n it of
SCHEME 13. Retr osyn th etic An a lysis of th e
C13-C25 Su bu n it
Zin cop h or in a
a
Reagents and conditions: (a) TBSOTf, 2,6-lutidine, CH2Cl2,
-78 °C (87%); (b) cat. OsO4, NMO, acetone/H2O; (c) NaIO4, THF/
H2O; (d) Et2CuLi [from 2EtLi‚LiBr + CuI, Et2O, -40 °C], Et2O,
-78 °C; (e) DMP, Pyr, CH2Cl2 (68% from 33).
type J . The other assumption was to take advantage of
a [3,3]-sigmatropic rearrangement in order to create the
C20-C21 trisubstituted (E)-alkene and control the ab-
solute configuration of the asymmetric carbon at C22.47,48
Accordingly, subsequent deoxygenation of the carbonyl
group at C24 would then be required in order to obtain
the C13-C25 subunit C. The requisite [3,3]-sigmatropic
rearangement precursor would therefore be an appropri-
ate derivative of the tertiary allylic alcohol of type K.
Since the absolute configuration at C22 would result from
a chirality transfer arising during the [3,3]-sigmatropic
rearrangement, the choice of the configuration of the
tertiary alcohol at C20 as well as the configuration of the
propenyl unit were crucial issues to consider in ad-
vance.47,48 Moreover, the propenyl moiety could be intro-
duced by nucleophilic addition of a vinylmetal derivative
to the corresponding methyl ketone 35. Due to its
excellent coordinating ability, the OMOM protecting
group was chosen for the hydroxyl at C19 so that
nucleophilic additions to the carbonyl group of methyl
ketone 35 may proceed according to the Cram-chelated
model.49 On the basis of literature results concerning the
stereoselectivity of [3,3]-sigmatropic rearrangements in
the acyclic series, this choice entailed the addition of a
propenylmetal of (Z) configuration.47,48
Methyl ketone 35 could be synthesized from the known
homopropargylic alcohol 36 in which the C13-C15 three
carbon unit (R ) (CH2)3OBn) would be introduced by
alkylation of the terminal alkyne moiety and the config-
uration of the two stereocenters C18 and C19 controlled
by the nucleophilic addition of a chiral allenylzinc reagent
to aldehyde 37, easily prepared from L-ethyl lactate
(Scheme 13).50
Protection of the hydroxyl group of L-ethyl lactate as
a tert-butyldimethylsilyl ether gave 38 (85%),51 and
subsequent reduction with Dibal-H in ether at -40 °C
afforded the sensitive aldehyde 37 (100%), which was
directly engaged in the next step. Treatment of this
aldehyde with the chiral allenyl zinc (M)-29, generated
in situ from the propargylic mesylate (S)-28, afforded the
homopropargylic alcohol 36 with high diastereoselectivity
(dr > 96/4, 75%).50 Indeed, this double-asymmetric con-
densation of the chiral allenylzinc (M)-29 proceeded in
the matched manifold with respect to the stereocenter
of aldehyde 37.
The hydroxyl group at C19 was protected as a meth-
oxymethyl ether 39 (88%), and the terminal alkyne was
deprotonated with n-BuLi followed by alkylation of the
resulting lithium acetylide with 1-benzyloxy-3-bromopro-
pane, in the presence of HMPA as a polar cosolvent, to
provide the disubstituted alkyne 40 (92%).52 The silyl
protecting group of the hydroxyl at C20 was removed
with n-Bu4NF in THF, and the resulting secondary
alcohol 41 was directly oxidized with Dess-Martin
periodinane36 in the presence of pyridine to afford methyl
ketone 35 (92% from 40). The addition of (Z)-prop-1-
enylmagnesium bromide, prepared by transmetalation of
the readily available (Z)-prop-1-enyllithium with an
excess of magnesium bromide etherate, to the methyl
ketone 35 afforded a diastereomeric mixture of the
tertiary alcohols 42 and 42′ (93%, 42/42′ ) 9/1) which
were not separated at this stage. The relative configu-
ration of the major diastereomer, depicted as 42, was
(52) A more convergent approach involving the addition of the chiral
allenylzinc, derived from the propargylic mesylate (S)-59 bearing a
disubstituted triple bond, to aldehyde 37 was also investigated.
However, this reaction was not reproducible and afforded at best the
homopropagylic alcohol 60 in 45% yield (dr g 96/4).
(47) Ziegler, F. E. Chem. Rev. 1988, 88, 1423.
(48) Frauenrath, H. In Houben Weyl (Methods of Organic Chemis-
try), Stereoselective Synthesis; Helmchen, G., Hoffmann, R. W., Mulzer,
J ., Schaumann, E., Eds.; Thieme Verlag: Stuttgart, 1995; Vol. E21d,
pp 3301-3756.
(49) Generally, Cram-chelated additions of organometallic reagents
to carbonyl derivatives proceed with substantially higher diastereo-
selectivites compared to the Felkin-Anh mode: Reetz, M. T. Acc.
Chem. Res. 1993, 26, 462.
(50) (a) Marshall, J . A.; Chobanian, H. R. J . Org. Chem. 2000, 65,
8357. (b) Marshall, J . A.; Xie, S. J . Org. Chem. 1995, 60, 7230.
(51) (a) Massad, S. K.; Hawkins, L. D.; Baker, D. C. J . Org. Chem.
1983, 48, 5180. (b) Procopiou, P. A.; Baugh, S. P. D.; Falck, S. S.; Inglis,
G. G. A. J . Org. Chem. 1998, 63, 2342.
J . Org. Chem, Vol. 69, No. 14, 2004 4633

Defosseux et al.
SCHEME 14 a
SCHEME 15. Ca r r oll-Cla isen Rea r r a n gem en t of
43a
a
Reagents and conditions: (a) diketene, cat. DMAP, THF, rt
(43: 88%, 43′: 8%); (b) adsorption on Al2O3, 60 °C (44: 4-10%;
45 + 46: 64-72%).
a
reaction conditions relying on the formation of the
â-ketoester dianion (LDA (2.5-3 equiv), THF, reflux)55-57
only led to traces of the desired product and instead the
conjugated diene 44, presumably resulting from an
intramolecular elimination of acetoacetate, was obtained
in 20% yield. Similarly, the use of a Pd(0) catalytic system
(cat. Pd(OAc)2, NaH, t-BuOH, reflux) led only to traces
of the diene 44 resulting from â-hydride elimination from
the intermediate π-allylic Pd(0) complex.58
Fortunately, it was found that the adsorption of the
tertiary allylic acetoacetate 43 on neutral alumina,
followed by heating the resulting dry powder overnight
at 60 °C was successful at promoting the Carroll-Claisen
rearrangement.59 Under these conditions, the two iso-
meric methyl ketones 45 and 46 were obtained in
satisfactory yield (64-72%, depending on the reaction
scale) and the stereoselectivity was high (45/46 ) 96/4).
It is noteworthy that the intramolecular elimination
reaction of the â-ketoester 43 leading to the conjugated
diene 44 (4-10%) was not a serious competing side
reaction under these conditions (Scheme 15).
Reagents and conditions: (a) TBSCl, imidazole, THF (85%);
(b) Dibal-H, Et2O, -40 °C (100%); (c) (S)-28, cat. Pd(OAc)2, cat.
PPh3, Et2Zn, THF, -20 °C (75%); (d) MOMCl, i-Pr2NEt, CH2Cl2
(88%); (e) n-BuLi, THF, -78 °C then BnO(CH2)3Br, HMPA, -78
°C to rt (92%); (f) n-Bu4NF, THF; (g) DMP, Pyr, CH2Cl2 (92% from
40); (h) ((Z)-prop-1-enyl)MgBr [from ((Z)-prop-1-enyl)Li and
MgBr2‚OEt2, THF/Et2O, 0 °C to rt], -78 °C (93%).
reasonably attributed on the basis of the Cram-chelate
model, due to the presence of the coordinating OMOM
group at the R-position of the carbonyl group (Scheme
14).49
The next crucial step in the synthesis of the C13-C25
fragment involved the [3,3]-sigmatropic rearrangement
of an approppriate substituted vinylic ether derived from
the tertiary alcohol 42. This suitable vinyl ether deriva-
tive has to be generated under sufficiently mild conditions
due to the propensity of tertiary alcohols to dehydrate
under acidic or thermal conditions.47,48 Since ketene silyl
acetals can be generated under mild conditions, the most
attractive option was to acetylate the tertiary allylic
alcohol 42 in order to perform a subsequent Ireland-
Claisen rearrangement.47,48 However all attempts to
acetylate the tertiary alcohols 42/42′ under a variety of
conditions failed.53 By contrast, the diastereomeric mix-
ture of the tertiary alcohols 42 and 42′ (9/1 ratio)
smoothly reacted with diketene in the presence of a
catalytic amount of DMAP to afford the tertiary aceto-
acetates 43 and 43′ (9/1 ratio). The major diastereomer
43 was easily separated from the corresponding epimeric
acetoacetate at C20 43′ by flash chromatography and
isolated in 88% yield. This successful derivatization of
the tertiary alcohol 42 in the form of the â-ketoester 43
led us to rely on a Carroll-Claisen rearrangement.54
Initial attempts to perform the Carroll rearrangement
of the â-ketoester 43 met with little success. Rearrange-
ment under thermal conditions (xylenes, reflux) afforded
an intractable mixture of products, whereas milder
The two stereoisomeric ketones 45 and 46 were sepa-
rated by flash chromatography. The (E)- and (Z)- config-
uration of the double bond in ketones 45 and 46 respec-
tively, was deduced from the examination of the chemical
shifts of C19 and the vinylic methyl group (C27) by 13C
NMR.60 The relative configuration at C22 was first
assigned on the basis of the well-known propensity of
(55) Wilson, S. R.; Price, M. F. J . Org. Chem. 1984, 49, 722.
(56) (a) Gilbert, J . C.; Kelly, T. A. Tetrahedron 1988, 44, 7587. (b)
Snider, B. B.; Beal, R. B. J . Org. Chem. 1988, 53, 4508. (c) Echavarren,
A. M.; de Mendoza, J .; Prados, P.; Zapata, A. Tetrahedron Lett. 1991,
32, 6421. (d) Ouvrard, N.; Rodriguez, J .; Santelli, M. Tetrahedron Lett.
1993, 34, 1149. (e) Genus, J . F.; Peters, D. D.; Ding, J .-F.; Bryson, T.
A. Synlett 1994, 209. (g) Hatcher, M. A.; Posner, G. H. Tetrahedron
Lett. 2002, 43, 5009.
(57) For an asymmetric version of the Carroll-Claisen rearrange-
ment, see: Enders, D.; Knopp, M.; Runsink, J .; Raabe, G. Angew.
Chem, Int. Ed. Engl. 1995, 34, 2278.
(58) Tsuji, J .; Yamada, T.; Minami, I.; Yuhara, M.; Nisar, M.;
Shimizu, I. J . Org. Chem. 1987, 52, 2988.
(59) Pogrebnoi, S. I.; Kalyan, Y. B.; Krimer, M. Z.; Smit, W. A.
Tetrahedron Lett. 1987, 28, 4893.
(60) Kalinowski, H.-O.; Berger, S.; Braun, S. In Carbon-13 NMR
Spectroscopy; J . Wiley & Sons: New York, 1988: The γ-gauche effect
exerted by the cis-olefinic substituent (C22-C25) resulted in an upfield
shift of the C27 methyl group in the (E)-isomer 45, whereas this upfield
shift was conversely observed for C19 in the (Z)-isomer 46.
(53) The use of acetic anhydride in the presence of nucleophilic
catalysts such as DMAP turned out to be inefficient since no reaction
was observed at rt, whereas moderate heating of the reaction mixture
resulted in extensive degradation. Moreover, conditions involving Lewis
acids induced the removal of the MOM protecting group and the
formation of numerous side products.
(54) (a) Carroll, M. F. J . Chem. Soc. 1940, 704. (b) Carroll, M. F. J .
Chem. Soc. 1940, 1266. (c) Carroll, M. F. J . Chem. Soc. 1941, 507.
4634 J . Org. Chem., Vol. 69, No. 14, 2004

Total Synthesis of Zincophorin and Its Methyl Ester
SCHEME 16. Ster eoselectivity of th e
Ca r r oll-Cla isen Rea r r a n gem en t of 43
SCHEME 17. Syn th esis of th e C13-C25 Su bu n it of
Zin cop h or in a
[3,3]-sigmatropic rearrangements to proceed (in the acy-
clic series) through a chairlike transition state.47,48 Two
conformers could be distinguished in which either the
branched C19-C13 chain or the methyl group may
occupy an axial position. Since there was an appreciable
difference of steric bulk between both substituents, the
branched chain at C20 was expected to preferentially
occupy the less congested equatorial position, and the
rearrangement would lead to the major methyl ketone
45 having a double bond of (E)-configuration and a C22
stereocenter of (R)-configuration. Conversely, rearrange-
ment of the alternative conformer would lead to the
minor stereoisomer 46 having a double bond of (Z)-
configuration and an (S) configuration at C22 (Scheme
16).61
The synthesis of the C13-C25 fragment was then
pursued from the γ,δ-unsaturated ketone 45, which was
reduced with Dibal-H in ether at -78 °C to afford the
secondary alcohol 47 (55/45 diasteromeric mixture, 98%).
This alcohol was converted to the corresponding mesylate
48 which was reduced with lithium aluminum hydride
in refluxing THF to afford the C24 deoxygenated product
49 (88% yield from 47) (Scheme 17).62,63 Having removed
the carbonyl group at C24, the next crucial step in the
elaboration of the C13-C25 subunit of zincophorin was
the stereoselective reduction of the triple bond in order
to elaborate the C16-C17 disubstituted double bond of
(E)-configuration. However, in compound 49, the second-
ary alcohol moiety at C19 was protected as a methoxy-
methyl ether and its deprotection at a later stage in the
synthesis of zincophorin turned out to be a difficult
task.64,65
a
Reagents and conditions: (a) DIBAL-H, Et2O, -78 °C (98%);
(b) MsCl, i-Pr2NEt, CH2Cl2, 0 °C; (c) LiAlH4, THF, reflux (88%
from 47); (d) p-TsOH, MeOH, rt (85%); (e) LiAlH4, THF, reflux
(61%); (f) TBSOTf, 2,6-lutidine, CH2Cl2, -78 °C; (g) Li, NH3 (l),
THF/t-BuOH (75% from 51); (h) DMP, Pyr, CH2Cl2 (86%).
tuted alkyne 49 was first investigated. Thus, the second-
ary alcohol moiety in compound 49 was slowly but
efficiently deprotected by treatment with a stoichiometric
amount of p-toluenesulfonic acid in methanol at room
temperature for 4 days to afford the corresponding
homopropargylic alcohol 50 (85%). As the dissolving
metal reduction of the triple bond failed after protection
of the secondary alcohol at C19 in compound 50 as a tert-
butyldimethylsilyl ether,66,67 it was decided to take
advantage of the presence of the free hydroxyl group at
(64) There are several literature reports dealing with the difficulties
associated with the removal of the MOM protecting group in the case
of highly functionalized substrates; see: (a) Kocienski, P. J . Protecting
Groups; Georg Thieme Verlag: New York, 1994. (b) Greene, T. W.;
Wuts, P. G. M. Protective Groups in Organic Synthesis; J . Wiley &
Sons: New York, 1999.
(65) The synthesis of the C13-C25 subunit aldehyde 61 having the
hydroxyl group at C19 protected as a MOM ether was first completed
from 49. Although its subsequent aldol coupling with ethyl ketone 23
was successful, it turned out impossible to remove the MOM group
later in the synthesis with decent chemical yield (key: (a) Li, NH3 (l),
THF/t-BuOH (4:1), -33 °C (75%); (b) DMP, Pyr, CH2Cl2 (82%)).
With the aim of replacing the MOM protecting group
at C19 by a TBS group, the deprotection of the disubsti-
(61) The validity of this stereochemical assignment was confirmed
a simpler model substrate: Medana, S.; Meyer, C.; Cossy, J .
(66) The protecting group of the homopropargylic hydroxyl at C19
seemed to have a marked influence on the dissolving-metal reduction
of the triple bond. The reduction of the alkyne 49 having a MOM
protecting group efficiently occurred albeit slowly.65 When the MOM
group was replaced by a TBS group, the triple bond failed to be reduced
in the corresponding substrate and only the debenzylation of the
hydroxyl group at C13 was observed. By contrast, compound 50 having
the alcohol moiety unprotected at C19 underwent both reactions at a
rapid rate and overreduction of the triple bond to the corresponding
alkane was also observed. The different solubilities of these compounds
in liquid ammonia may be in part responsible for these differences.67
(67) Brandsma, L.; Nieuwenhuizen, W. F.; Zwikker, J . W.; Ma¨eorg,
U. Eur. J . Org. Chem. 1999, 775, and references therein.
on
Unpublished results. See the Supporting Information for details.
(62) This two-step sequence was preferred compared to a one-pot
procedure involving the formation of the tosylhydrazone derived from
methyl ketone 45 followed by in situ reduction with sodium cyanoboro-
hydride, which afforded the corresponding deoxygenated product 49
in only 16% isolated yield: Hutchins, R. O.; Maryanoff, B. E.; Molewski,
C. A. J . Am. Chem. Soc. 1971, 93, 1793.
(63) A radical deoxygenation (n-Bu3SnH, cat. AIBN, toluene, reflux)
of the thiocarbonate derived from the secondary alcohol 47 (PhOC(S)-
Cl, pyridine, 1,2-dichloroethane, reflux) was also satisfactory and
afforded the C24 deoxygenated product 49 in 76% yield.
J . Org. Chem, Vol. 69, No. 14, 2004 4635

Defosseux et al.
SCHEME 18. Tota l Syn th esis of Zin cop h or in a n d
Its Meth yl Ester a
the homopropargylic position and reduce the triple bond
by using lithium aluminum hydride. Indeed, the second-
ary alcohol 50 was slowly but efficiently hydroaluminated
with LiAlH4 in refluxing THF and the (E)-homoallylic
alcohol 51 was obtained in 61% unoptimized yield.
Protection of the hydroxyl group at C19 as a tert-
butyldimethylsilyl ether afforded compound 52, which
was subjected to a Birch reduction at -78 °C. The
resulting primary alcohol 53 (75% from 51) was then
oxidized with Dess-Martin periodinane (DMP)36 to afford
aldehyde 54 (86%), which constitutes the C13-C25
subunit of zincophorin having the secondary alcohol
moiety at C19 protected as a tert-butyldimethylsilyl ether
(Scheme 17).
Having synthesized ethyl ketone 23 (C1-C12 subunit)
and aldehyde 54 (C13-C25 subunit), their coupling was
examined by using an aldol reaction, in agreement with
our retrosynthetic analysis (Scheme 4).
Due to the C12-C13 syn relative configuration, it was
necessary to achieve the addition of a (Z)-enolate derived
from ethyl ketone 23 to aldehyde 54. Thus, the (Z)-
titanium enolate 55 derived from ethyl ketone 23 was
generated by treatment with titanium tetrachloride and
Hu¨nig’s base in dichloromethane at -78 °C.17 Reaction
with aldehyde 54 afforded the corresponding aldol 56
(70%) with high diastereoselectivity (dr > 96/4, single
1
diastereomer detected by H NMR). As mentioned previ-
ously, there were detailed literature precedents on these
aldol reactions supporting the indicated stereochemical
outcome (syn relationship between the methyl groups at
C10 and C12) (Scheme 18).17 The completion of the total
synthesis of zincophorin methyl ester 2 was then inves-
tigated. The diastereoselective reduction of the carbonyl
group at C11 was efficiently and simply carried out by
using sodium borohydride in methanol68 and the corre-
sponding diol 57 was directly treated with HF‚Pyridine
in THF in order to deprotect both alcohol functionalities
at C9 and C19. Under these conditions, zincophorin
methyl ester 2 was obtained in 66% yield from the aldol
56 (Scheme 18).
The analytical and spectroscopic data of zincophorin
methyl ester 2 thus obtained, including Rf in two solvent
systems,6 IR6,8 and 1H NMR spectra8 as well as the optical
rotation ([R]D +21.3 (c 0.4, CHCl3)), were in perfect
agreement with those previously reported in the litera-
ture ([R]D +22.4 (c 0.89, CHCl3),8 authentic sample: [R]D
+20.9 (c 2.0, CHCl3)1,6).
a
Reagents and conditions: (a) TiCl4, i-Pr2NEt, CH2Cl2, -78 °C;
(b) addition of aldehyde 54, -78 °C, 2 h, (70%, dr > 96/4); (c)
NaBH4, MeOH, 0 °C; (d) HF‚Pyr, THF, rt, (66% from 56); (e) LiOH,
H2O/MeOH/THF (1/1/2), 50 °C (see text).
the magnesium salt of zincophorin.3-5 Treatment of an
etheral solution of this salt with an aqueous solution of
the disodium salt of EDTA afforded an amorphous solid
which was analyzed by 1H and 13C NMR. Despite the
presence of traces of structurally unrelated impurities,
presumably from organic solvents due to the repeated
manipulations of this sample on such scale (8 mg), the
spectra of this material were unambiguously in perfect
agreement with the literature data reported for zinco-
phorin free acid 1.3-5 However, we do not wish to indicate
an accurate yield value for this last step.
In the previously reported total synthesis by Danishef-
sky, zincophorin was obtained from its methyl ester by
saponification. However, due to the difficulties associated
with its purification, zincophorin was esterified by treat-
ment with etheral diazomethane and converted to the
methyl ester 2.8
We have therefore completed the second total synthesis
of zincophorin methyl ester (and zincophorin) according
to a convergent strategy involving the coupling of the
C1-C12 and C13-C25 subunits by using a highly
diastereoselective titanium-mediated aldol condensation.
The synthesis of the C1-C12 fragment, which was
accomplished in 25 steps from allyl diazoacetate with an
overall yield of 6%, illustrated the synthetic potential of
an intramolecular oxymercuration of a cyclopropanemeth-
anol derivative for the elaboration of the trisubstituted
tetrahydropyran. The preparation of the C13-C25 sub-
We therefore attempted to carry out the saponification
of zincophorin methyl ester 2 with aqueous lithium
hydroxide in THF/methanol at 50 °C. Although this
reaction proceeded cleanly, attempts to purify zinco-
phorin by chromatography on silica gel led to an unde-
termined metal-salt of zincophorin, whose 1H NMR
spectrum favorably compared with the one recorded for
(68) The stereochemical outcome of the reduction of the carbonyl
group at C11 in aldol 56 was investigated with simpler model
substrates. See the Supporting Information for details.
4636 J . Org. Chem., Vol. 69, No. 14, 2004

Total Synthesis of Zincophorin and Its Methyl Ester
aqueous solution of NaOH (80 mL) and diluted with toluene
(80 mL) and CH2Cl2 (15 mL). To the resulting mixture were
successively added benzyltriethylammonium chloride (500 mg,
2.20 mmol, 0.14 equiv) and benzyl bromide (2.40 mL, 20.1
mmol, 1.3 equiv), and after 20 h at rt, the reaction mixture
was cooled to 0 °C, diluted with water (60 mL), and extracted
with ether. The combined organic extracts were dried over
MgSO4, filtered, and concentrated under reduced pressure. The
crude material was purified by flash chromatography (petro-
leum ether/EtOAc gradient 93/7 to 80/20) to give 3.0 g (89%)
of 4b as a colorless oil: [R]20D ) +43.9 (c 1.4, CHCl3); IR (film)
3420, 1245, 1195, 1175, 1160, 1065, 1025, 950, 920, 835, 745,
700 cm-1; 1H NMR δ 7.35-7.26 (m, 5H), 4.57 (d, J ) 11.8 Hz,
1H), 4.49 (d, J ) 11.8 Hz, 1H), 3.95 (dd, J ) 10.3 and 6.4 Hz,
1H), 3.56 (dd, J ) 10.3 and 8.8 Hz, 1H), 2.76 (br s, 1H, OH),
1.37 (s, 3H), 1.20 (m, 1H), 1.19 (s, 3H), 1.06 (m, 1H), 0.75 (m,
1H), 0.48 (m, 1H); 13C NMR δ 137.7 (s), 128.4 (d, 2C), 127.9
(d, 2C), 127.7 (d), 72.7 (t), 70.5 (t), 69.4 (s), 31.3 (q), 30.0 (q),
27.7 (d), 16.1 (d), 7.5 (t); MS-EI m/z (relative intensity) 206
(M - Me+, 0.1), 111 (M-H2O-Bn+, 11), 96 (12), 92 (10), 91
(100). Anal. Calcd for C14H20O2: C, 76.33; H, 9.15. Found: C,
76.16; H, 9.35.
F IGURE 2.
unit was achieved in 18 steps from L-ethyl lactate with
an overall yield of 7% and relied on a stereoselective
Carroll-Claisen rearrangement of a tertiary allylic ac-
etoacetate. This strategy, which entailed the inter-
mediacy of a compound functionalized at C24 by a
carbonyl group, should be also particularly well-suited
for the total synthesis of antibitiotic CP-78,545. This
natural ionophore is the C24-C25-dehydro analogue of
zincophorin which was isolated by Pfizer from modified
strains of Streptomyces (Figure 2).69
Exp er im en ta l Section
(1S,2R)-2-{[(ter t-Bu tyld ip h en ylsilyl)oxy]m eth yl}-1-iso-
p r op en ylcyclop r op a n e (5a ). To a solution of 4a (4.15 g, 11.3
mmol) in CH2Cl2 (200 mL) were added Et3N (24 mL, 0.17 mol,
15 equiv) and DMAP (1.53 g, 12.5 mmol, 1.1 equiv). The
resulting mixture was cooled to 0 °C, and MsCl (9.0 mL, 0.12
mmol, 10 equiv) was added dropwise. After 5 h at 0 °C, the
reaction mixture was hydrolyzed with a saturated aqueous
solution of NH4Cl and extracted with ether. The combined
extracts were washed with brine, dried over MgSO4, filtered,
and concentrated under reduced pressure. The crude material
was purified by flash chromatography (petroleum ether/EtOAc
Syn t h esis of t h e C1-C12 Su b u n it of Zin cop h or in .
(1S,5R)-3-Oxa bicyclo[3.1.0]h exa n -2-on e (3).26 To a solution
of Doyle’s catalyst Rh2((5R)-MEPY)4 (56 mg, 0.061 mmol, 0.001
equiv) in refluxing CH2Cl2 (150 mL) was added, over a period
of 30 h, a solution of allyl diazoacetate (7.38 g, 58.5 mmol) in
CH2Cl2 (350 mL). The solvent was removed by distillation at
atmospheric pressure, and the crude material was purified by
flash chromatography (pentane/Et2O gradient 50/50 to 30/70)
to give 5.23 g (91%) of 3 as a pale yellow oil: [R]20 -65.0 (c
D
1.00, CHCl3) ([R]20 ) +60.2 (c 1.01, CHCl3) for the (1R,5S)
D
enantiomer26); IR (neat) 3080, 1770, 1180, 1035, 995, 980, 950,
95/5) to give 3.37 g (85%) of 5a as a colorless oil: [R]20 +10.7
D
1
930 cm-1; H NMR δ 4.36 (dd, J ) 9.4 and 4.8 Hz, 1H), 4.23
(c 1.0, CHCl3); IR (film) 3070, 1645, 1110, 1065, 820, 740, 720,
(d, J ) 9.4 Hz, 1H), 2.25 (m, 1H), 2.07 (m, 1H), 1.28 (m, 1H),
0.88 (m, 1H); 13C NMR δ 176.4 (s), 69.4 (t), 17.5 (d), 17.3 (d),
12.2 (t); MS-EI m/z (relative intensity) 98 (M+•, 100), 70 (40),
68 (73), 55 (35), 53 (20).
1
700 cm-1; H NMR δ 7.71-7.65 (m, 4H), 7.40-7.33 (m, 6H),
4.79 (br s, 1H), 4.51 (br s, 1H), 3.64 (dd, J ) 10.9 and 5.5 Hz,
1H), 3.41 (dd, J ) 10.9 and 8.9 Hz, 1H), 1.90 (s, 3H), 1.48 (m,
1H), 1.28 (m, 1H), 1.05 (s, 9H), 0.63 (m, 1H), 0.36 (m, 1H); 13
C
2-((1S,2R)-2-{[(ter t-Bu t yld ip h en ylsilyl)oxy]m et h yl}-
cyclop r op yl)p r op a n -2-ol (4a ). To a solution of methyl-
lithium (28 mL, 1.4 M in Et2O, 39 mmol, 3.9 equiv) in THF
(60 mL) at 0 °C was added dropwise a solution of 3 (1.0 g, 10
mmol) in THF (5 mL). After 30 min, a solution of tert-
butylchlorodiphenylsilane (3.4 mL, 13 mmol, 1.3 equiv) and
imidazole (1.8 g, 27 mmol, 2.7 equiv) in DMF (5 mL) was added
dropwise, and 1 h later, the reaction mixture was hydrolyzed
with a saturated aqueous solution of NH4Cl and extracted with
petroleum ether/CH2Cl2 (9/1). The combined extracts were
washed with brine, dried over MgSO4, filtered, and concen-
trated under reduced pressure. The crude material was
purified by flash chromatography (petroleum ether/CH2Cl2 90/
10) to afford 3.4 g (90%) of 4a as a colorless oil: [R]20D ) +15.2
(c 2.1, CHCl3); IR (film) 3430, 3060, 1110, 1065, 1045, 820,
NMR δ 142.9 (s), 135.6 (d, 4C), 134.1 (s, 2C), 129.4 (d, 2C),
127.5 (d, 4C), 110.4 (t), 63.2 (t), 26.8 (q, 3C), 24.3 (q), 22.9 (d),
19.7 (d), 19.2 (s), 6.5 (t); MS-EI m/z (relative intensity) 350
(M+•, 1), 293 (M - t-Bu+, 73), 251 (60), 237 (45), 225 (50), 199
(100), 183 (44). Anal. Calcd for C23H30OSi: C, 78.80; H, 8.63.
Found: C, 78.82; H, 8.65.
(1S,2R)-2-[(Ben zyloxy)m eth yl]-1-isop r op en ylcyclop r o-
p a n e (5b). This compound was synthesized from 4b (7.41 g,
33.7 mmol) according to the procedure described for prepara-
tion of 5a from 4a . Purification by flash chromatography
(petroleum ether/EtOAc 95/5) afforded 5.68 g (83%) of 5b as a
colorless oil: [R]20 +34.3 (c 1.1, CHCl3); IR (film) 3050, 1640,
D
1075, 1025, 885, 735, 695 cm-1; 1H NMR δ 7.37-7.28 (m, 5H),
4.85 (apparent br s, 1H), 4.63 (s, 1H), 4.53 (d, J ) 12.2 Hz,
1H), 4.48 (d, J ) 12.2 Hz, 1H), 3.45 (dd, J ) 9.9 and 6.3 Hz,
1H), 3.30 (dd, J ) 9.9 and 8.1 Hz, 1H), 1.89 (s, 3H), 1.56 (m,
1H), 1.40 (m, 1H), 0.81 (m, 1H), 0.56 (m, 1H); 13C NMR δ 142.7
(s), 138.6 (s), 128.2 (d, 2C), 127.7 (d, 2C), 127.4 (d), 110.7 (t),
72.8 (t), 69.5 (t), 24.0 (q), 22.6 (d), 17.0 (d), 7.1 (t); MS-EI m/z
(relative intensity) 202 (M+•, 0.01), 111 (M - Bn+, 8), 93 (7),
92 (9), 91 (100), 81 (6), 79 (6), 77 (5), 65 (8), 55 (8). Anal. Calcd
for C14H18O: C, 83.12; H, 8.97. Found: C, 83.04; H, 9.09.
1
785, 740, 700 cm-1; H NMR δ 7.74-7.68 (m, 4H), 7.42-7.34
(m, 6H), 4.12 (dd, J ) 11.6 and 6.0 Hz, 1H), 3.69 (dd, J ) 11.6
and 9.8 Hz, 1H), 3.19 (s, 1H, OH), 1.47 (s, 3H), 1.26 (s, 3H),
1.24-1.06 (m, 2H), 1.06 (s, 9H), 0.65 (m, 1H), 0.39 (m, 1H);
13C NMR δ 135.5 (d, 2C), 134.8 (d, 2C), 133.2 (s), 133.1 (s),
129.7 (d), 129.4 (d), 127.7 (d, 2C), 127.6 (d, 2C), 69.6 (s), 64.9
(t), 31.8 (q), 29.7 (q), 27.9 (d), 26.7 (q, 3C), 19.0 (s), 18.5 (d),
7.5 (t); MS-EI m/z (relative intensity) 353 (M - Me+, 1), 311
(M - t-Bu+, 5), 199 (100), 139 (26), 95 (21), 69 (76). Anal. Calcd
for C23H32O2Si: C, 74.95; H, 8.75. Found: C, 75.03; H, 8.71.
2-{(1S,2R)-2-[(Ben zyloxy)m eth yl]cyclop r op yl}p r op a n -
2-ol (4b). To a solution of methyllithium (28 mL, 1.4 M in
Et2O, 39 mmol, 2.6 equiv) in THF (60 mL) at 0 °C was added
dropwise a solution of 3 (1.50 g, 15.3 mmol) in THF (15 mL).
After 30 min, the reaction mixture was hydrolyzed with a 50%
(2R)-2-((1R,2R)-2-{[(ter t-Bu tyldiph en ylsilyl)oxy]m eth yl}-
cyclop r op yl)p r op a n -1-ol (6a ). To a solution of 5a (971 mg,
2.77 mmol) in THF (5 mL) at -30 °C was added dropwise a
solution of BH3‚THF (7.0 mL, 1 M in THF, 7.0 mmol, 2.5
equiv). After 30 min at -30 °C and 2 h at rt, the reaction
mixture was cooled to 0 °C and a 3 M aqueous NaOH solution
(3 mL) and a 30% aqueous solution of H2O2 (3 mL) were
successively added dropwise. After 3 h at rt, the resulting
mixture was extracted with ether, and the combined extracts
were washed with brine, dried over MgSO4, filtered, and
concentrated under reduced pressure. The crude material was
(69) Dirlam, J . P.; Belton, A. M.; Chang, S. P.; Cullen, W. P.; Huang,
L. H.; Kojima, Y.; Maeda, H.; Nishiyama, S.; Oscarson, J . R.; Sakak-
ibara, T. J . Antibiot. 1989, 42, 1213.
J . Org. Chem, Vol. 69, No. 14, 2004 4637

Defosseux et al.
purified by flash chromatography (pertroleum ether/EtOAc 93/
7) to give 927 mg (91%) of 6a as a colorless oil: [R]20D +26.5 (c
1.2, CHCl3); IR (film) 3450, 3060, 1110, 1080, 1040, 820, 740,
equiv). After 45 min at rt, the reaction mixture was concen-
trated under reduced pressure and the residue was filtered
through silca gel (CH2Cl2/EtOAc 50/50). The filtrate was
evaporated under reduced pressure and the sensitive aldehyde
7b was directly engaged in the next step without further
purification. To a suspension of NaH (788 mg, 60% dispersion
in mineral oil, 19.7 mmol, 1.5 equiv) in THF (60 mL) was added
dropwise triethyl phosphonoacetate (3.90 mL, 19.7 mmol, 1.5
equiv). The reaction mixture was cooled to 0 °C and a solution
of aldehyde 7b in THF (2 mL) was added dropwise. After 50
1
710, 700 cm-1; H NMR δ 7.75-7.68 (m, 4H), 7.44-7.34 (m,
6H), 3.99 (dd, J ) 11.2 and 4.6 Hz, 1H), 3.68 (dd, J ) 10.4
and 4.5 Hz, 1H), 3.68 (br s, 1H, OH), 3.53 (dd, J ) 10.4 and
9.1 Hz, 1H), 3.32 (dd apparent t, J ) 11.2 Hz, 1H), 1.39 (m,
1H), 1.22 (m, 1H), 1.07 (s, 9H), 0.98 (d, J ) 6.7 Hz, 3H), 0.69
(m, 1H), 0.56 (m, 1H), -0.25 (m, 1H); 13C NMR δ 135.6 (d,
2C), 135.5 (d, 2C), 133.0 (s, 2C), 129.7 (d, 2C), 127.7 (d, 4C),
69.0 (t), 64.6 (t), 35.2 (d), 26.6 (q, 3C), 21.3 (d), 18.9 (s), 18.6
(d), 17.8 (q), 5.7 (t); MS-EI m/z (relative intensity) 311 (M -
t-Bu+, 28), 281 (16), 200 (19), 199 (100). Anal. Calcd for
C23H32O2Si: C, 74.95; H, 8.75. Found: C, 75.13; H, 8.73.
(2R)-2-{(1R,2R)-2-[(Ben zyloxy)m et h yl]cyclop r op yl}-
p r op a n ol (6b). This compound was synthesized from 5b (1.50
g, 7.42 mmol) according to the procedure described for the
preparation of 6a from 5a . Purification by flash chromatog-
raphy (petroleum ether/EtOAc gradient 90/10 to 70/30) af-
forded 1.49 g (91%) of 6b as a colorless oil: [R]20D +72.3 (c 1.0,
CHCl3); IR (film) 3400, 3060, 1090, 1070, 1040, 1030, 750, 740,
700 cm-1; 1H RMN δ 7.37-7.27 (m, 5H), 4.54 (s, 2H), 3.86 (dd,
J ) 10.3 and 4.8 Hz, 1H), 3.79 (t, J ) 5.1 Hz, 1H, OH), 3.61
(ddd, J ) 10.7, 6.3 and 4.4 Hz, 1H), 3.44 (m, 1H), 3.12 (dd
apparent t, J ) 10.3 Hz, 1H), 1.37-1.21 (m, 2H), 0.97 (d, J )
6.6 Hz, 3H), 0.75-0.62 (m, 2H), -0.11 (m, 1H); 13C NMR δ
154.6 (s), 128.4 (d, 2C), 128.0 (d, 2C), 127.8 (d), 73.0 (t), 70.5
(t), 69.1 (t), 35.2 (d), 21.3 (d), 17.9 (q), 16.3 (d), 6.3 (t); MS-EI
m/z (relative intensity) 220 (M+•, 0.02), 107 (12), 92 (16), 91
(100), 81 (11). Anal. Calcd for C14H20O2: C, 76.33; H, 9.15.
Found: C, 76.14; H, 9.37.
min at rt, the reaction mixture was hydrolyzed with
a
saturated aqueous solution of NH4Cl and extracted with ether
(3 × 20 mL) and EtOAc (2 × 30 mL). The combined extracts
were washed with brine, dried over MgSO4, filtered and
concentrated under reduced pressure. The crude material was
purified by flash chromatography (petroleum ether/EtOAc 90/
10) to afford 2.00 g (56% from 6b) of 8b as a colorless oil: [R]20
D
-113.7 (c 1.1, CHCl3); IR (film) 1725, 1715, 1650, 1285, 1270,
1
1185, 1090, 1075, 1030, 745, 700 cm-1; H NMR δ 7.36-7.24
(m, 5H), 7.10 (dd, J ) 15.8 and 6.3 Hz, 1H), 5.86 (dd, J ) 15.8
and 1.5 Hz, 1H), 4.51 (s, 2H), 4.19 (q, J ) 7.2 Hz, 2H), 3.53
(dd, J ) 10.1 and 7.2 Hz, 1H), 3.44 (dd, J ) 10.1 and 7.2 Hz,
1H), 1.86 (m, 1H), 1.29 (t, J ) 7.2 Hz, 3H), 1.28 (m, 1H), 1.18
(d, J ) 6.6 Hz, 3H), 0.87-0.75 (m, 2H), 0.12 (m, 1H); 13C NMR
δ 166.9 (s), 153.5 (d), 138.4 (s), 128.3 (d, 2C), 127.7 (d, 2C),
127.5 (d), 119.3 (d), 72.7 (t), 70.1 (t), 60.1 (t), 36.0 (d), 21.5 (d),
19.7 (q), 16.1 (d), 14.2 (q), 8.8 (t); MS-EI m/z (relative intensity)
243 (M - OEt+, 0.2), 197 (M - Bn+, 3), 188 (4), 141 (10), 108
(10), 107 (14), 92 (11), 91 (100), 79 (10). Anal. Calcd for
C
18H24O3: C, 74.97; H, 8.39. Found: C, 74.92; H, 8.56.
Eth yl (4S)-4-((1R,2R)-2-{[(ter t-Bu tyld ip h en ylsilyl)oxy]-
m eth yl}cyclop r op yl)p en ta n oa te (9a ). To a solution of 8a
(2.20 g, 5.04 mmol) in EtOAc (30 mL) was added PtO2 (70 mg,
0.31 mmol, 0.06 equiv), and the resulting mixture was stirred
under an atmosphere of hydrogen. After 6 h, the reaction
mixture was filtered through Celite, and the filtrate was
evaporated under reduced pressure. The residue was purified
by flash chromatography (petroleum ether/EtOAc 93/7) to give
2.15 g (97%) of 9a as a colorless oil: [R]20D -16.6 (c 1.1, CHCl3);
IR (film) 3060, 1735, 1590, 1260, 1175, 1105, 1065, 820, 790,
745, 710, 700, 690 cm-1; 1H NMR δ 7.75-7.69 (m, 4H), 7.48-
7.37 (m, 6H), 4.10 (q, J ) 7.0 Hz, 2H), 3.74 (dd, J ) 11.1 and
6.3 Hz, 1H), 3.64 (dd, J ) 11.1 and 7.9 Hz, 1H), 2.43-2.27 (m,
2H), 1.98 (m, 1H), 1.66 (m, 1H), 1.23 (t, J ) 7.2 Hz, 3H), 1.20-
0.98 (m, 5H), 1.08 (s, 9H), 0.73-0.57 (m, 2H), -0.14 (m, 1H);
13C NMR δ 174.0 (s), 135.6 (d, 2C), 135.5 (d, 2C), 134.0 (s, 2C),
129.5 (d, 2C), 127.6 (d, 2C), 127.5 (d, 2C), 64.1 (t), 60.0 (t),
32.3 (t), 32.2 (t+d,2C), 26.8 (q, 3C), 23.7 (d), 19.9 (q), 19.1 (s),
18.9 (d), 14.2 (q), 7.8 (t); MS-EI m/z (relative intensity) 382
(M - i-C4H8+•, 27), 381 (M - t-Bu+, 88), 227 (20), 199 (100),
197 (23), 183 (34), 181 (22), 139 (36), 135 (27), 95 (15), 77 (11),
55 (10). Anal. Calcd for C27H38O3Si: C, 73.93; H, 8.73. Found:
C, 73.51; H, 9.03.
Eth yl (E),(4R)-4-((1R,2R)-2-{[(ter t-bu tyld ip h en ylsilyl)-
oxy]m eth yl}cyclop r op yl)p en t-2-en oa te (8a ). To a solution
of 6a (11.6 g, 31.6 mmol) in CH2Cl2 (500 mL) at rt, were
successively added 4 Å powdered molecular sieves (28 g) and
PCC (14.5 g, 67.2 mmol, 2.1 equiv). After 1.5 h at rt, the
reaction mixture was diluted with ether and filtered through
silica gel (ether). The filtrate was evaporated under reduced
pressure and the crude aldehyde 7a , was directly engaged in
the next step without further purification. To a suspension of
NaH (1.57 g, 60% dispersion in mineral oil, 39.2 mmol, 1.2
equiv) in THF (200 mL) at 0 °C, was added dropwise trieth-
ylphosphonoacetate (8.9 mL, 45 mmol, 1.4 equiv). After 20 min
at rt, the reaction mixture was cooled to 0 °C and a solution
of 7a in THF (10 mL) was added dropwise. After 1 h at rt, the
reaction mixture was hydrolyzed with a saturated aqueous
solution of NH4Cl and extracted with ether. The combined
extracts were washed with brine, dried over MgSO4, filtered,
and concentrated under reduced pressure. The crude material
was purified by flash chromatography (petroleum ether/Et2O
93/7) to give 10.7 g (78% from 6a ) of 8a as a colorless oil: [R]20
D
-65.8 (c 1.1, CHCl3); IR (film) 3060, 1725, 1715, 1650, 1265,
1245, 1185, 1165, 825, 795, 745, 710, 700, 690 cm-1; 1H NMR
δ 7.73-7.66 (m, 4H), 7.47-7.35 (m, 6H), 7.15 (dd, J ) 15.8
and 5.9 Hz, 1H), 5.88 (dd, J ) 15.8 and 1.8 Hz, 1H), 4.18 (q,
J ) 7.1 Hz, 2H), 3.71 (dd, J ) 11.0 and 6.3 Hz, 1H), 3.64 (dd,
J ) 11.0 and 7.7 Hz, 1H), 1.88 (m, 1H), 1.28 (t, J ) 7.1 Hz,
3H), 1.21 (m, 1H), 1.16 (d, J ) 6.6 Hz, 3H), 1.06 (s, 9H), 0.85-
0.65 (m, 2H), -0.01 (m, 1H); 13C NMR δ 167.0 (s), 153.7 (d),
135.6 (d, 2C), 135.5 (d, 2C), 133.9 (s), 133.8 (s), 129.5 (d, 2C),
127.6 (d, 2C), 127.5 (d, 2C), 119.4 (d), 63.7 (t), 60.0 (t), 35.5
(d), 26.8 (q, 3C), 21.8 (d), 19.7 (q), 19.1 (s), 18.7 (d), 14.3 (q),
7.9 (t); MS-EI m/z (relative intensity) 380 (M - i-C4H8+•, 25),
379 (M - t-Bu+, 83), 227 (50), 199 (100), 197 (23), 183 (59),
181 (26), 139 (15), 135 (47), 107 (28), 105 (18), 91 (16), 79 (23),
77 (15). Anal. Calcd for C27H36O3Si: C, 74.27; H, 8.31. Found:
C, 73.89; H, 8.72.
Eth yl (4S)-4-{(1R,2R)-2-[(Ben zyloxy)m eth yl]cyclop r op -
yl}p en ta n oa te (9b). This compound was synthesized from
8b (1.55 g, 5.38 mmol) according to the procedure described
for the preparation of 9a from 8a . Purification by flash
chromatography (petroleum ether/EtOAc 90/10) afforded 1.49
g (95%) of 9b as a colorless oil: [R]20 -17.2 (c 1.0, CHCl3); IR
D
(film) 1730, 1260, 1180, 1090, 1030, 750, 740, 700 cm-1 1H
;
NMR δ 7.35-7.24 (m, 5H), 4.55 (d, J ) 12.0 Hz, 1H), 4.50 (d,
J ) 12.0 Hz, 1H), 4.10 (q, J ) 7.2 Hz, 2H), 3.51 (dd, J ) 10.1
and 7.5 Hz, 1H), 3.43 (dd, J ) 10.1 and 7.2 Hz, 1H), 2.41-
2.22 (m, 2H), 1.88 (m, 1H), 1.57 (m, 1H), 1.24 (t, J ) 7.2 Hz,
3H), 1.21 (m, 1H), 1.00 (br s, 3H), 1.05-0.95 (m, 1H), 0.77-
0.63 (m, 2H), -0.03 (m, 1H); 13C NMR δ 174.0 (s), 138.6 (s),
128.3 (d, 2C), 127.7 (d, 2C), 127.5 (d), 72.8 (t), 70.5 (t), 60.1
(t), 32.5 (d), 32.2 (t), 32.1 (t), 23.4 (d), 19.9 (q), 16.3 (d), 14.2
(q), 8.5 (t); MS-EI m/z (relative intensity) 290 (M+•, 0.1), 199
(2), 183 (4), 153 (4), 142 (8), 108 (10), 95 (10), 92 (13), 91 (100).
Anal. Calcd for C18H26O3: C, 74.45; H, 9.02. Found: C, 74.59;
H, 9.24.
Eth yl (E),(4R)-4-{(1R,2R)-2-[(Ben zyloxy)m eth yl]cyclo-
p r op yl}p en t-2-en oa te (8b). To a solution of 6b (2.72 g, 12.4
mmol) in CH2Cl2/MeCN (9/1, 30 mL) at 0 °C were successively
added NMO (2.26 g, 19.3 mmol, 1.6 equiv), 4 Å powdered
molecular sieves (6.2 g), and TPAP (260 mg, 0.740 mmol, 0.06
4638 J . Org. Chem., Vol. 69, No. 14, 2004

Total Synthesis of Zincophorin and Its Methyl Ester
(4S)-4-((1R,2R)-2-{[(ter t-Bu tyldiph en ylsilyl)oxy]m eth yl}-
cyclop r op yl)p en ta n a l (10a ). To a solution of 9a (2.73 g, 6.22
mmol) in toluene (30 mL) at -78 °C was added dropwise
Dibal-H (6.4 mL, 1 M in hexanes, 6.4 mmol, 1.03 equiv). After
1 h at -78 °C, the reaction mixture was poured into a
saturated aqueous solution of Rochelle’s salt (15 mL) and ether
(20 mL) was added. After the mixture was stirred for 3 h at
rt, the layers were separated, the aqueous phase was extracted
with ether, and the combined extracts were washed with brine,
dried over MgSO4, filtered, and concentrated under reduced
pressure. The crude material was purified by flash chroma-
tography (petroleum ether/EtOAc gradient 100/0 at 95/5) to
(s, 2C), 133.2 (d), 129.7 (d, 2C), 129.5 (2d + s, 2C + 1C), 128.4
(d, 2C), 127.6 (d, 2C), 127.5 (d, 2C), 74.7 (d), 73.2 (d), 64.4 (t),
48.5 (d), 32.8 (t), 32.1 (d), 31.8 (t), 26.9 (q, 3C), 24.2 (d), 19.8
(q), 19.1 (s), 18.6 (d), 15.6 (q), 14.3 (q), 7.9 (t).
(1S,3S,4S,7S)-7-{(1R,2R)-2-[(Ben zyloxy)m et h yl]cyclo-
pr opyl}-4-h ydr oxy-1,3-dim eth yl-2-oxooctylben zoate (12b).
This compound was synthesized from 10b (89 mg, 0.36 mmol)
and ethyl ketone (R)-1131 (159 mg, 0.771 mmol, 2.1 equiv)
according to the procedure described for the preparation of 12a
from 10a and (R)-11. Two successive purifications by flash
chromatography (CH2Cl2/Et2O gradient 99/1 to 94/6) afforded
142 mg (87%) of 12b as a colorless solid: mp 66 °C; [R]20D -23.7
(c 0.5, CHCl3); IR (CHBr3) 3480, 1720, 1270, 1070, 1030, 1000,
give 2.39 g (97%) of 10a as a colorless oil: [R]20 -13.3 (c 1.0,
D
715 cm-1 1H NMR δ 8.09 (m, 2H), 7.59 (m, 1H), 7.49-7.43
;
CHCl3); IR (film) 3060, 2710, 1725, 1715, 1110, 1060, 825, 790,
745, 710, 700 cm-1; 1H NMR δ 9.71 (t, J ) 1.8 Hz, 1H), 7.71-
7.65 (m, 4H), 7.44-7.35 (m, 6H), 3.78 (dd, J ) 11.1 and 5.7
Hz, 1H), 3.53 (dd, J ) 11.1 and 8.5 Hz, 1H), 2.53-2.34 (m,
2H), 1.99 (m, 1H), 1.63 (m, 1H), 1.21-1.00 (m, 2H), 1.05 (s,
9H), 0.97 (d, J ) 6.2 Hz, 3H), 0.70-0.55 (m, 2H), -0.17 (m,
1H); 13C NMR δ 203.0 (d), 135.6 (d, 2C), 135.5 (d, 2C), 133.9
(2s, 2C), 129.6 (d, 2C), 127.6 (d+d, 2C+2C), 64.1 (t), 41.7 (t),
32.1 (d), 29.4 (t), 26.9 (q, 3C), 23.7 (d), 20.0 (q), 19.2 (s), 18.9
(d), 7.6 (t); MS-EI m/z (relative intensity) 337 (M - t-Bu+, 10),
281 (14), 259 (9), 203 (20), 200 (18), 199 (100), 181 (16), 183
(20), 139 (11), 135 (10), 121 (26). Anal. Calcd for C25H34O2Si:
C, 76.09; H, 8.68. Found: C, 76.13; H, 8.82.
(m, 2H), 7.35-7.24 (m, 5H), 5.40 (q, J ) 7.0 Hz, 1H), 4.55 (d,
J ) 11.8 Hz, 1H), 4.50 (d, J ) 11.8 Hz, 1H), 3.73 (m, 1H), 3.56
(dd, J ) 10.7 and 6.6 Hz, 1H), 3.40 (dd, J ) 10.7 and 8.8 Hz,
1H), 2.82 (dq, apparent quintet, J ) 7.3 Hz, 1H), 2.73 (d, J )
5.5 Hz, 1H, OH), 1.70 (m, 1H), 1.54 (d, J ) 7.0 Hz, 3H), 1.56-
1.32 (m, 3H), 1.25-1.12 (m, 1H), 1.19 (d, J ) 7.0 Hz, 3H),
1.04-0.93 (m, 1H), 0.99 (br s, 3H), 0.74-0.67 (m, 2H), -0.05
(m, 1H); 13C NMR δ 211.5 (s), 165.8 (s), 138.4 (s), 133.2 (d),
129.8 (d, 2C), 129.6 (s), 128.4 (d, 2C), 128.3 (d, 2C), 127.7 (d,
2C), 127.5 (d), 74.8 (d), 72.8 (d), 72.6 (t), 70.8 (t), 48.5 (d), 32.6
(t), 31.8 (d), 31.5 (t), 24.1 (d), 19.9 (q), 16.0 (d), 15.6 (q), 14.2
(q), 8.5 (t). Anal. Calcd for C28H36O5: C, 74.31; H, 8.02.
Found: C, 74.15; H, 8.22.
(4S)-4-{(1R,2R)-2-[(Ben zyloxy)m et h yl]cyclop r op yl}-
p en ta n a l (10b). This compound was synthesized from 9b
(1.29 g, 4.43 mmol) according to the procedure described for
the preparation of 10a from 9a . Purification by flash chroma-
tography (petroleum ether/EtOAc 90/10) afforded 978 mg (90%)
(1S,3S,4S,7S)-4-Hyd r oxy-7-[(1R,2R)-2-(h yd r oxym eth yl-
)cyclop r op yl]-1,3-d im eth yl-2-oxooctylben zoa te (12c). To
a solution of 12a (0.18 g, 0.30 mmol) in THF (7 mL) [polyeth-
ylene container] at 0 °C was added dropwise HF‚Pyridine (0.7
mL). After 2 h at rt, the reaction mixture was diluted with
water and ether and neutralized by portionwise addition of
solid NaHCO3. The resulting mixture was extracted with ether,
and the combined extracts were dried over MgSO4, filtered,
and concentrated under reduced pressure. The crude material
was crystallized from pentane/CH2Cl2 to afford 93 mg (86%)
of 12c as a white solid: mp 123 °C; [R]20D -29.8 (c 1.0, CHCl3);
IR (KBr) 3420, 3289, 1733, 1719, 1290, 1268, 1122, 1000, 713
cm-1; 1H NMR δ 8.08 (m, 2H), 7.59 (m, 1H), 7.46 (m, 2H), 5.44
(q, J ) 7.1 Hz, 1H), 3.82 (dd, J ) 11.6 and 5.9 Hz, 1H), 3.78
(m, 1H), 3.40 (dd, J ) 11.6 and 9.4 Hz, 1H), 3.19 (br s, 1H,
OH), 2.87 (dq, apparent quintet, J ) 7.3 Hz, 1H), 2.24 (br s,
1H, OH), 1.80 (m, 1H), 1.57 (m, 1H), 1.57 (d, J ) 7.0 Hz, 3H),
1.48-1.32 (m, 2H), 1.24 (d, J ) 7.0 Hz, 3H), 1.18-1.02 (m,
2H), 0.99 (d, J ) 5.9 Hz, 3H), 0.75-0.62 (m, 2H), -0.01 (m,
1H); 13C NMR δ 211.8 (s), 165.9 (s), 133.3 (d), 129.8 (d, 2C),
129.5 (s), 128.4 (d, 2C), 74.8 (d), 72.3 (d), 63.3 (t), 48.4 (d), 32.6
(t), 31.0 (t), 30.9 (d), 24.4 (d), 19.8 (q), 18.7 (d), 15.8 (q), 14.3
(q), 8.0 (t); MS-CI+ (CH4) m/z (relative intensity) 345 (M + H+
- H2O, 52), 223 (23), 207 (98), 205 (19), 139 (100), 121 (50),
105 (87); HRMS (CI+, CH4) calcd for C21H31O5 (M + H+)
363.2171, found 363.2169.
(1R,3S)-3-[(2S,5S,6S)-6-((1S)-2-Ben zyloxy-1-m eth yleth yl)-
5-m eth yltetr a h yd r o-2H-p yr a n -2-yl]-1-m eth yl-2-oxobu tyl-
ben zoa te (14b). To a degassed solution of 12b (137 mg, 0.303
mmol) in CH2Cl2 (14 mL) (argon bubbling, 15 min) was added
mercuric trifluoroacetate (292 mg, 0.684 mmol, 2.3 equiv).
After 30 min at rt with exclusion of light, the reaction mixture
was hydrolyzed with a saturated aqueous solution of KBr (4
mL). After 20 min, the resulting mixture was extracted with
EtOAc. The combined extracts were dried over MgSO4, filtered,
and concentrated under reduced pressure. The crude mixture
of organomercuric bromides was dissolved in THF/toluene
(1/1, 8 mL), and to the resulting degassed solution [argon
bubbling, 30 min] were added a catalytic amount of AIBN (ca.
4 mg) and n-Bu3SnH (0.30 mL, 1.1 mmol, 3.7 equiv). After 1
h at rt and 1 h at 55 °C, CCl4 (1 mL) was added. After 1 h at
rt, the reaction mixture was diluted with petroleum ether/CH2-
Cl2 (75/25, 20 mL), metallic mercury was removed by filtration
through glass wool and the filtrate was washed with a 5%
aqueous solution of KF (4 × 10 mL). The organic layer was
of 10b as a colorless oil: [R]20 0.0 (c 1.2, CHCl3); IR (film)
D
3060, 3020, 2720, 1720, 1090, 1075, 1025, 750, 740, 700 cm-1
;
1H NMR δ 9.69 (t, J ) 1.8 Hz, 1H), 7.36-7.26 (m, 5H), 4.55
(d, J ) 11.8 Hz, 1H), 4.49 (d, J ) 11.8 Hz, 1H), 3.55 (dd, J )
10.1 and 6.5 Hz, 1H), 3.39 (dd, J ) 10.1 and 8.3 Hz, 1H), 2.52-
2.33 (m, 2H), 1.93 (m, 1H), 1.59 (m, 1H), 1.22 (m, 1H), 1.01
(m, 1H), 1.01 (s, 3H), 0.77-0.61 (m, 2H), -0.04 (m, 1H); 13C
NMR δ 203.0 (d), 138.4 (s), 128.3 (d, 2C), 127.7 (d, 2C), 127.5
(d), 72.8 (t), 70.5 (t), 41.5 (t), 32.2 (d), 29.3 (t), 23.5 (d), 20.0
(q), 16.3 (d), 8.2 (t); MS-EI m/z (relative intensity) 246 (M+•
,
0.1), 140 (3), 122 (4), 107 (12), 94 (11), 92 (18), 91 (100), 79
(11). Anal. Calcd for C16H22O2: C, 78.01; H, 9.00. Found: C,
77.80; H, 8.99.
(1S,3S,4S,7S)-7-((1R,2R)-2-{[(ter t-Bu tyld im eth ylsilyl)-
oxy]m eth yl}cyclop r op yl)-4-h yd r oxy-1,3-d im eth yl-2-oxo-
octylben zoa te (12a ). To a solution of (c-Hex)2BCl (1.3 mL,
6.2 mmol, 2.8 equiv) in Et2O (6 mL) at -78 °C were succes-
sively added dropwise EtNMe2 (0.80 mL, 7.41 mmol, 3.4 equiv)
and a solution of ethyl ketone (R)-1131 (850 mg, 4.14 mmol,
1.9 equiv) in Et2O (16 mL). After 2 h at 0 °C, the reaction
mixture was cooled to -78 °C and a solution of aldehyde 10a
(860 mg, 2.18 mmol) in Et2O (3 mL) was added dropwise. After
4 h at -78 °C and 16 h at -23 °C, the reaction mixture was
warmed to 0 °C and a MeOH/phosphate buffer (pH 7) mixture
(1/1, 32 mL) and a 30% aqueous solution of H2O2 (16 mL) were
successively added dropwise. After 1 h at 0 °C, the resulting
mixture was extracted with CH2Cl2, and the combined extracts
were dried over MgSO4, filtered, and concentrated under
reduced pressure. The crude material was purified by flash
chromatography (petroleum ether/EtOAc gradient 94/6 to 90/
10) to afford 1.09 g (83%) of 12a as a colorless oil: [R]20D -23.5
(c 1.0, CHCl3); IR (film) 3520, 3070, 1725, 1715, 1270, 1070,
1030, 1000, 1110, 825, 745, 710, 700, 690 cm-1; 1H NMR δ 8.08
(m, 2H), 7.72-7.65 (m, 4H), 7.57 (m, 1H), 7.47-7.33 (m, 8H),
5.39 (q, J ) 7.0 Hz, 1H), 3.73 (dd, J ) 11.2 and 6.1 Hz, 1H),
3.71 (m, 1H), 3.59 (dd, J ) 11.2 and 8.3 Hz, 1H), 2.81 (qd,
apparent quintet, J ) 7.3 Hz, 1H), 2.53 (d, J ) 5.5 Hz, 1H,
OH), 1.76 (m, 1H), 1.54-1.34 (m, 3H), 1.52 (d, J ) 7.0 Hz,
3H), 1.18 (d, J ) 7.4 Hz, 3H), 1.13-0.95 (m, 2H), 1.05 (s, 9H),
0.97 (br s, 3H), 0.67 (m, 1H), 0.56 (m, 1H), -0.18 (m, 1H); 13
NMR δ 211.5 (s), 165.8 (s), 135.6 (d, 2C), 135.5 (d, 2C), 133.9
C
J . Org. Chem, Vol. 69, No. 14, 2004 4639

Defosseux et al.
dried over MgSO4, filtered, and concentrated under reduced
pressure. The residue was taken up in CH2Cl2 and the
resulting mixture was filtered through glass wool. Analysis
of the 1H NMR spectrum of the crude material indicated the
formation of two diastereomers 14b and 14′b (14b/14′b ) 85/
15). After purification by flash chromatography (petroleum
ether/EtOAc gradient 95/15 to 90/10), 63 mg (46%) of a
diastereomeric mixture of 14b et 14′b (85/15 ratio) was
obtained as a colorless oil. An analytical sample of the
separated major diastereomer was used for characterization
(only the signals corresponding to the major diatereomer 14b
extracts were washed with brine, dried over MgSO4, filtered,
and concentrated under reduced pressure. The crude material
was purified by flash chromatography (petroleum ether/EtOAc
gradient 95/5 to 90/10) to afford 1.52 g (93%) of 14a and 98
mg (6%) of 14′a as colorless oils.
Major diastereomer 14a : Rf 0.41 (petroleum ether/EtOAc
80/20); [R]20D -2.86 (c 0.07, CHCl3); IR (film) 3070, 1720, 1270,
1110, 825, 750, 710, 705 cm-1; 1H NMR δ 8.08 (m, 2H), 7.73-
7.55 (m, 5H), 7.46-7.34 (m, 8H), 5.39 (q, J ) 6.9 Hz, 1H), 3.69
(ddd, apparent td, J ) 9.2 and 3.9 Hz, 1H), 3.52 (dd, J ) 10.2
and 4.4 Hz, 1H), 3.46 (dd, J ) 10.2 and 5.3 Hz, 1H), 3.19 (dd,
J ) 9.2 and 2.2 Hz, 1H), 2.96 (dq, J ) 9.2 and 7.0 Hz, 1H),
2.06 (m, 1H), 1.78-1.59 (m, 3H), 1.48 (d, J ) 7.0 Hz, 3H),
1.40-1.27 (m, 2H), 1.06 (d, J ) 7.4 Hz, 3H), 1.04 (s, 9H), 0.94
(d, J ) 7.0 Hz, 3H), 0.87 (d, J ) 6.6 Hz, 3H); 13C NMR δ 210.8
(s), 165.7 (s), 135.6 (d, 2C), 134.8 (d), 133.8 (s, 2C), 133.1 (d),
129.9 (s), 129.8 (d, 2C), 129.5 (d, 2C), 128.3 (d, 2C), 127.7 (d),
127.6 (d, 4C), 80.0 (d), 75.5 (d), 72.1 (d), 66.9 (t), 47.4 (d), 35.1
(d), 27.6 (d), 26.8 (q, 3C), 24.9 (t), 23.8 (t), 19.3 (s), 18.3 (q),
15.2 (q), 13.4 (q), 13.2 (q); MS-EI m/z (relative intensity) 543
(M - t-Bu+, 5), 309 (15), 303 (100), 183 (12), 135 (14), 105 (61);
HRMS (CI+, CH4) calcd for C37H49O5Si (M + H+) 601.3349,
found 601.3347.
could be fully attributed with certainty): [R]20 +18.1 (c 1.40,
D
CHCl3); IR (film) 1725, 1715, 1265, 1115, 715 cm-1; H NMR
1
δ 8.09 (m, 2H), 7.58 (m, 1H), 7.46 (m, 2H), 7.37-7.24 (m, 5H),
5.45 (q, J ) 7.0 Hz, 1H), 4.50 (d, J ) 12.1 Hz, 1H), 4.42 (d, J
) 12.1 Hz, 1H), 3.82 (ddd, apparent td, J ) 9.0 and 4.2 Hz
1H), 3.35 (dd, J ) 9.2 and 5.2 Hz, 1H), 3.25 (dd, J ) 9.2 and
5.9 Hz, 1H), 3.20 (dd, J ) 8.1 and 4.4 Hz, 1H), 3.06 (dq, J )
9.6 and 7.0 Hz, 1H), 2.17 (m, 1H), 1.77-1.68 (m, 2H), 1.59-
1.45 (m, 2H), 1.51 (d, J ) 7.0 Hz, 3H), 1.31 (m, 1H), 1.07 (d, J
) 7.0 Hz, 3H), 0.94 (d, J ) 7.0 Hz, 3H), 0.88 (d, J ) 6.6 Hz,
3H); 13C NMR δ 210.4 (s), 165.7 (s), 138.7 (s), 133.1 (d), 129.8
(d, 2C), 129.8 (s), 128.4 (d, 2C), 128.3 (d, 2C), 127.4 (d, 2C),
127.3 (d), 79.5 (d), 75.4 (d), 73.7 (t), 72.9 (t), 72.4 (d), 46.5 (d),
33.4 (d), 28.3 (d), 25.4 (t), 24.2 (t), 18.2 (q), 15.4 (q), 13.5 (q),
13.0 (q); MS-CI+(CH4) m/z (relative intensity) 453 (M + H+,
36), 333 (32), 303 (30), 255 (42), 247 (100), 155 (57), 139 (30),
123 (20); HRMS (CI+, CH4) calcd for C28H37O5 (M + H+)
453.2641, found 453.2646.
Minor diastereomer 14′a : Rf 0.50 (petroleum ether/EtOAc
80/20); [R]20D +16.9 (c 0.75, CHCl3); IR (film) 1720, 1270, 1110,
1
1005, 825, 745, 715, 705, 690 cm-1; H NMR δ 8.05 (m, 2H),
7.66-7.63 (m, 4H), 7.57 (m, 1H), 7.46-7.33 (m, 8H), 5.35 (q,
J ) 7.0 Hz, 1H), 3.68 (dd, J ) 9.6 and 8.1 Hz, 1H), 3.49 (dd,
J ) 9.6 and 6.4 Hz, 1H), 3.40 (m, 1H), 3.20 (dd, J ) 9.7 and
1.7 Hz, 1H), 2.95 (qd, apparent quintet, J ) 7.0 Hz, 1H), 1.93
(m, 1H), 1.76 (m, 1H), 1.56 (m, 1H), 1.46 (m, 1H), 1.45 (d, J )
7.0 Hz, 3H), 1.26-1.15 (m, 2H), 1.14 (d, J ) 7.0 Hz, 3H), 1.05
(1R,3R)-3-[(2S,5S,6S)-6-((1S)-2-Hyd r oxym eth yl-1-m eth -
yleth yl)-5-m eth yltetr a h yd r o-2H-p yr a n -2-yl]-1-m eth yl-2-
oxobu tylben zoate (14′c) an d (1R,3R)-3-[(2S,5S,6R)-6-((1S)-
2-H yd r oxym et h yl-1-m et h ylet h yl)-5-m et h ylt et r a h yd r o-
(s, 9H), 0.76 (d, J ) 7.0 Hz, 3H), 0.76 (d, J ) 6.6 Hz, 3H); 13
C
2H -p yr a n -2-yl]-1-m et h yl-2-oxob u t ylb en zoa t e
(14′c).
NMR δ 209.5 (s), 165.8 (s), 135.6 (d, 4C), 134.2 (s, 2C), 133.2
(d), 129.8 (d, 2C), 129.6 (s), 129.5 (d, 2C), 128.4 (d, 2C), 127.5
(d, 4C), 82.5 (d), 78.5 (d), 74.7 (d), 66.4 (t), 48.0 (d), 36.9 (d),
33.0 (t), 31.4 (d), 28.9 (t), 26.9 (q, 3C), 19.3 (s), 17.2 (q), 15.6
(q), 13.6 (q), 9.5 (q); MS-EI m/z (relative intensity) 543 (M -
t-Bu+, 12), 309 (17), 304 (26), 303 (100), 243 (16), 199 (32),
183 (16), 135 (15), 121 (12) 105 (76), 77 (10).
Following the procedure described for the preparation of 14b/
14′b from 12b, compound 12c (206 mg, 0.569 mmol) under-
went an intramolecular oxymercuration with mercuric triflu-
oroacetate (532 mg, 1.25 mmol, 2.2 equiv) and a subsequent
reductive demercuration with n-Bu3SnH (0.38 mL, 1.4 mmol,
2.5 equiv) in the presence of a catalytic amount of AIBN (ca.
4 mg). Analysis of the 1H NMR spectrum of the crude material
indicated the formation of two diastereomers 14c and 14′c
(14c/14′c ) 93/7). Purification by flash chromatography (pe-
troleum ether/EtOAc 80/20) afforded 176 mg (85%) of a
diastereomeric mixture of 14c and 14′c (93/7 ratio) as a
colorless oil: [R]20D +44.0 (c 0.04, CHCl3); IR (film) 3440, 1720,
1270, 1120, 720 cm-1; 1H NMR (only the signals corresponding
to the major diastereomer 14c could be fully attributed with
certainty) δ 8.08 (m, 2H), 7.59 (m, 1H), 7.48 (m, 2H), 5.60 (q,
J ) 6.9 Hz, 1H), 4.09 (m, 1H), 3.52 (m, 2H), 3.36-3.24 (m,
2H), 2.28 (br s, 1H, OH), 1.89 (m, 1H), 1.67-1.60 (m, 3H), 1.55
(d, J ) 6.8 Hz, 3H), 1.30-1.21 (m, 2H), 1.08 (d, J ) 7.0 Hz,
3H), 0.87 (d, J ) 7.0 Hz, 3H), 0.84 (d, J ) 6.5 Hz, 3H); 13C
NMR (only the signals corresponding to the major diastere-
omer 14c could be fully attributed with certainty) δ 210.3 (s),
165.8 (s), 133.3 (d), 129.8 (d, 2C), 129.6 (s), 128.5 (d, 2C), 78.8
(d), 74.7 (d), 73.2 (d), 66.6 (t), 43.9 (d), 35.6 (d), 30.3 (d), 26.4
(t), 24.8 (t), 17.9 (q), 16.1 (q), 13.9 (q), 10.4 (q); MS-CI+ (CH4)
m/z (relative intensity) 363 (M + H+, 100), 241 (20), 207 (22),
157 (92), 139 (61); HRMS (CI+, CH4) calcd for C21H31O5 (M +
H+) 363.2171, found 363.2169.
(2S)-2-((2S,5S,6S)-6-{(1S)-2-[(ter t-Bu tyld ip h en ylsilyl)-
oxy]-1-m eth yleth yl}-5-m eth yltetr a h yd r o-2H-p yr a n -2-yl)-
p r op a n oic Acid (17). To a solution of 14a (250 mg, 0.416
mmol) in THF (10 mL) at -78 °C was added a solution of
LiBH4 (530 mg, 24.3 mmol, 58 equiv) in THF (10 mL). The
reaction mixture was warmed to rt, and 15 h later, an
additional quantity of LiBH4 (297 mg, 13.6 mmol, 32 equiv)
was added. After 24 h, the reaction mixture was cautiously
hydrolyzed with water and extracted with ether. The combined
extracts were dried over MgSO4, filtered, and concentrated
under reduced pressure. The resulting crude 1,2-diol 15 was
dissolved in MeOH/H2O (2/1, 9 mL), and NaIO4 (755 mg, 3.53
mmol, 8.5 equiv) was added. After 2 h at rt, the reaction
mixture was diluted with water and extracted with ether. The
combined extracts were dried over MgSO4, filtered, and
concentrated under reduced pressure. The resulting crude
aldehyde 16 was dissolved in t-BuOH (7 mL) and H2O (2 mL),
and 2-methyl-2-butene (0.50 mL, 4.7 mmol, 10 equiv),
NaH2PO4 monohydrate (635 mg, 4.60 mmol, 11 equiv), and
NaClO2 (235 mg, 2.60 mmol, 6 equiv) were added successively
at rt. After 1.5 h, the reaction mixture was hydrolyzed with a
1 M aqueous solution of HCl (10 mL) and extracted with ether.
The combined extracts were dried over MgSO4, filtered, and
concentrated under reduced pressure. The crude material was
purified by flash chromatography (petroleum ether/EtOAc: 80/
20) to afford 176 mg (90%, 3 etapes) of 17 as a colorless oil:
(1R,3S)-3-((2S,5S,6S)-6-{(1S)-2-[(ter t-Bu t yld ip h en yl-
silyl)oxy]-1-m eth yleth yl}-5-m eth yltetr a h yd r o-2H-p yr a n -
2-yl)-1-m eth yl-2-oxobu tylben zoa te (14a ) a n d (1R,3S)-3-
((2S,5S,6S)-6-{(1R)-2-[(ter t-Bu tyld ip h en ylsilyl)oxy]-1-m e-
th yleth yl}-5-m eth yltetr a h yd r o-2H-p yr a n -2-yl)-1-m eth yl-
2-oxobu tylben zoa te (14′a ). To a solution of 14c and 14′c
(93/7 ratio, 987 mg, 2.72 mmol) in DMF (3 mL) were added
imidazole (413 mg, 6.07 mmol, 2.2 equiv) and tert-butylchlo-
rodiphenylsilane. After 5 h at rt, the reaction mixture was
hydrolyzed with a saturated aqueous solution of NH4Cl and
extracted with petroleum ether/CH2Cl2 (9/1). The combined
[R]20 +19.7 (c 0.9, CHCl3); IR (film) 3600-2300 (br), 1705,
D
1105, 1015, 820, 740, 705 cm-1; 1H NMR δ 7.67-7.62 (m, 4H),
7.46-7.34 (m, 6H), 3.74 (m, 1H), 3.59 (dd, J ) 10.3 and 5.5
Hz, 1H), 3.54-3.47 (m, 2H), 2.69 (dq, apparent quintet, J )
7.3 Hz, 1H), 2.03 (m, 1H), 1.80-1.50 (m, 4H), 1.29 (m, 1H),
1.15 (d, J ) 7.0 Hz, 3H), 1.05 (s, 9H), 0.97 (d, J ) 7.0 Hz, 3H),
4640 J . Org. Chem., Vol. 69, No. 14, 2004

Total Synthesis of Zincophorin and Its Methyl Ester
0.95 (d, J ) 6.6 Hz, 3H); 13C NMR δ 177.2 (s), 135.6 (d, 4C),
133.8 (s), 133.7 (s), 129.5 (d, 2C), 127.6 (d, 4C), 79.2 (d), 72.7
(d), 66.7 (t), 42.5 (d), 35.4 (d), 28.8 (d), 26.9 (q, 3C), 25.4 (t),
24.2 (t), 19.2 (s), 18.1 (q), 13.7 (q), 12.1 (q); MS-CI+ (CH4) m/z
(relative intensity) 469 (M + H+, 78), 347 (59), 333 (85), 313
(80), 289 (54), 269 (100), 213 (65), 195 (37), 139 (38); HRMS
(CI+, CH4) calcd for C28H41O4Si (M + H+) 469.2774, found
469.2779.
chromatography (pentane/Et2O 70/30) to afford 50 mg (100%)
of 20 as a colorless oil: [R]20 +7.1 (c 0.7, CHCl3); IR (film)
D
1730, 1265, 1195, 1165, 1015, 970 cm-1; H NMR δ 9.56 (d, J
1
) 1.1 Hz, 1H), 3.91 (dd, J ) 8.8 and 4.0 Hz, 1H), 3.87 (m, 1H),
3.67 (s, 3H), 3.05 (dq, J ) 10.7 and 7.0 Hz, 1H), 2.56 (qdd, J
) 7.0, 4.0 and 1.1 Hz, 1H), 1.79-1.55 (m, 4H), 1.32 (m, 1H),
1.07 (d, J ) 7.4 Hz, 3H), 1.05 (d, J ) 7.0 Hz, 3H), 0.92 (d, J )
6.6 Hz, 3H); 13C NMR δ 204.4 (d), 175.4 (s), 75.3 (d), 75.0 (d),
51.7 (q), 47.8 (d), 40.6 (d), 31.1 (d), 26.6 (t), 24.7 (t), 17.6 (q),
14.2 (q), 6.3 (q); MS-CI+ (CH4) m/z (relative intensity) 243 (M
+ H+, 58), 225 (100), 211 (60), 207 (33), 193 (48), 185 (65), 155
(45), 153 (36), 147 (27), 124 (23), 106 (35); HRMS (CI+, CH4)
calcd for C13H23O4 (M + H+) 243.1596, found 243.1604.
Ad d ition of a Ch ir a l Cr otyltita n iu m Rea gen t to Ald e-
h yd e 20. To a suspension of Cp((R,R)-TADDOL)TiCl (228 mg,
0.372 mmol, 2 equiv) in ether (3 mL) at -78 °C was added
dropwise a solution of crotylmagnesium chloride (880 µL, 0.37
M in THF, 0.326 mmol, 1.75 equiv). After 30 min at -78 °C
and 3 h at 0 °C, the resulting dark solution was cooled to -78
°C, and a solution of 20 (45 mg, 0.186 mmol) in ether (3 mL)
was added dropwise. After 5 h at -78 °C, the reaction mixture
was hydrolyzed with a 45% aqueous solution of NH4F (2 mL).
After 12 h at rt, the reaction mixture was filtered through
Celite and the insoluble material was throroughly washed with
ether. The organic layer was washed with brine, dried over
MgSO4, filtered and concentrated under reduced pressure.
Analysis of the 1H NMR spectrum of the crude material
indicated the formation of the diastereomeric homoallylic
alcohols 26 and 27 in a 70/30 ratio. Purification by flash
chromatography (pentane/Et2O 90/10) afforded 29 mg (52%)
of 26 as an amorphous solid. The minor diastereomer 27 could
not be efficiently separated from (R,R)-TADDOL.
Meth yl (2S)-2-((2S,5S,6S)-6-{(1S)-2-[(ter t-Bu tyld ip h en -
ylsilyl)oxy]-1-m e t h yle t h yl}-5-m e t h yl-t e t r a h yd r o-2H -
p yr a n -2-yl)p r op a n oa te (18). To a solution of 17 (159 mg,
0.339 mmol) in C6H6 (10 mL) and CH3OH (4 mL) was added
trimethylsilyldiazomethane (0.60 mL, 2 M in hexanes, 1.2
mmol, 3.5 equiv) so that a bright yellow color persisted. After
1.5 h at rt, the reaction mixture was concentrated under
reduced pressure and the crude material was purified by flash
chromatography (petroleum ether/Et2O 90/10) to afford 139
mg (85%) of 18 as a colorless oil: [R]20 +36.1 (c 1.0, CHCl3);
D
IR (film) 1740, 1265, 1195, 1165, 1110, 1065, 1015, 820, 740,
1
705, 690 cm-1; H NMR δ 7.72-7.67 (m, 4H), 7.47-7.36 (m,
6H), 3.78 (m, 1H), 3.59 (dd, J ) 9.9 and 4.4 Hz, 1H), 3.50 (dd,
J ) 9.9 and 7.7 Hz, 1H), 3.35 (s, 3H), 3.32 (m, 1H), 2.82 (dq,
J ) 9.9 and 7.0 Hz, 1H), 2.02 (m, 1H), 1.72-1.51 (m, 4H), 1.28
(m, 1H), 1.08 (s, 9H), 1.04 (d, J ) 7.0 Hz, 3H), 1.00 (d, J ) 6.6
Hz, 3H), 0.93 (d, J ) 6.6 Hz, 3H); 13C NMR δ 175.7 (s), 135.6
(d, 4C), 134.1 (s), 133.9 (s), 129.5 (d, 2C), 127.5 (d, 4C), 78.1
(d), 73.5 (d), 67.5 (t), 51.2 (q), 41.8 (d), 36.2 (d), 29.9 (d), 26.8
(q, 3C), 26.2 (t), 24.2 (t), 19.2 (s), 18.0 (q), 14.0 (q), 11.1 (q);
MS-EI m/z (relative intensity) 467 (M - Me+, 0.1), 426 (M -
i-C4H8+•, 28), 451 (M - OMe+, 2), 425 (M - t-Bu+, 85), 396
(20), 395 (63), 214 (20), 213 (100), 199 (93), 197 (22), 183 (55),
181 (21), 177 (27), 153 (24), 149 (23), 135 (31), 121 (52). Anal.
Calcd for C29H42O4Si: C, 72.16; H, 8.77. Found: C, 72.16; H,
8.90.
Meth yl (2S)-2-[(2S,5S,6S)-6-((1S,2S,3S)-2-Hyd r oxy-1,3-
d im et h ylp en t -4-en yl)-5-m et h yl-t et r a h yd r o-2H-p yr a n -2-
yl]p r op a n oa te (26): mp 57 °C; [R]20 +43.6 (c 1.0, CHCl3);
Meth yl (2S)-2-[(2S,5S,6S)-6-((1S)-2-Hyd r oxy-1-m eth yl-
eth yl)-5-m eth yltetr ah ydr o-2H-pyr an -2-yl]pr opan oate (19).
To a solution of 18 (839 mg, 1.74 mmol) in THF (20 mL)
(polyethylene container) at 0 °C was added HF‚Pyridine (4.0
mL). After 8 h at rt, the reaction mixture was diluted with
water and ether and cautiously neutralized by portionwise
addition of solid NaHCO3. The resulting mixture was extracted
with ether, and the combined extracts were dried over MgSO4,
filtered, and concentrated under reduced pressure. The re-
sidual traces of pyridine were removed from the crude material
by evaporation with cyclohexane under reduced pressure and
the residue was purified by flash chromatography (petroleum
ether/EtOAc gradient 80/20 to 60/40) to afford 383 mg (90%)
D
IR (CH2Cl2) 3540, 1740, 1720, 1640, 1280, 1260, 1170, 1120,
1085, 1020, 970, 910 cm-1; 1H NMR δ 5.93 (ddd, J ) 16.9, 10.7,
and 8.1 Hz, 1H), 5.08-5.01 (m, 2H), 3.97 (ddd, J ) 11.0, 5.5,
and 1.5 Hz, 1H), 3.72 (s, 3H), 3.64 (dd, J ) 9.7 and 1.7 Hz,
1H), 3.38 (d, J ) 6.2 Hz, 1H, OH), 3.23 (m, 1H), 3.16 (dq, J )
11.0 and 7.0 Hz, 1H), 2.36 (m, 1H), 1.82-1.52 (m, 5H), 1.24
(m, 1H), 1.08 (d, J ) 7.0 Hz, 3H), 1.07 (d, J ) 6.6 Hz, 3H),
0.82 (d, J ) 7.0 Hz, 3H), 0.80 (d, J ) 6.3 Hz, 3H); 13C NMR δ
176.5 (s), 140.1 (d), 114.4 (t), 75.5 (d), 75.1 (d), 75.0 (d), 52.0
(q), 39.9 (d+d, 2C), 37.0 (d), 31.8 (d), 27.4 (t), 25.2 (t), 18.2 (q),
17.6 (q), 14.2 (q), 9.3 (q); MS-CI+ (CH4) m/z (relative intensity)
299 (M + H+, 100), 281 (34), 243 (36), 213 (18), 185 (50), 135
(61), 103 (17); HRMS (CI+, CH4) calcd for C17H31O4 (M + H+)
299.2222, found 299.2227.
of 19 as a colorless oil: [R]20 +65.6 (c 1.2, CHCl3); IR (film)
D
3460, 1740, 1730, 1275, 1255, 1235, 1170, 1040, 1020 cm-1
;
1H NMR δ 3.92 (ddd, J ) 10.9, 5.4, and 1.6 Hz, 1H), 3.73 (s,
3H), 3.52 (dd, J ) 9.6 and 2.6 Hz, 1H), 3.48-3.41 (m, 2H),
3.15 (dq, J ) 10.9 and 7.0 Hz, 1H), 3.02 (br s, 1H, OH), 1.84
(m, 1H), 1.76-1.49 (m, 4H), 1.24 (m, 1H), 1.06 (d, J ) 6.6 Hz,
3H), 0.82 (d, J ) 7.0 Hz, 3H), 0.81 (d, J ) 6.3 Hz, 3H); 13C
NMR δ 176.3 (s), 76.7 (d), 75.1 (d), 65.7 (t), 51.9 (q), 40.0 (d),
35.7 (d), 31.8 (d), 27.2 (t), 25.1 (t), 17.4 (q), 14.2 (q), 8.8 (q);
MS-CI+ (CH4) m/z (relative intensity) 245 (M + H+, 100), 227
(29), 213 (51), 185 (19), 157 (29), 139 (12); HRMS (CI+, CH4)
calcd for C13H25O4 (M + H+) 245.1753, found 245.1750.
Meth yl (2S)-2-[(2S,5S,6S)-6-((1R)-1-Meth yl-2-oxoeth yl)-
5-m eth yltetr a h yd r o-2H-p yr a n -2-yl]p r op a n oa te (20). To a
solution of 19 (50 mg, 0.21 mmol) in CH2Cl2 (2 mL) at 0 °C,
were successively added pyridine (70 µL, 0.87 mmol, 4 equiv)
and Dess-Martin periodinane (180 mg, 0.424 mmol, 2 equiv).
After 3 h at rt, the reaction mixture was hydrolyzed with a
mixture of a 1.5 M aqueous solution of Na2S2O3 (7 mL) and a
saturated aqueous solution of NaHCO3 (7 mL). After extraction
with CH2Cl2, the combined extracts were washed with brine,
dried over MgSO4, filtered, and concentrated under reduced
pressure. The residual traces of pyridine were removed from
the crude material by evaporation with cyclohexane under
reduced pressure and the residue was purified by flash
Meth yl (2S)-2-[(2S,5S,6S)-6-((1S,2R,3R)-2-Hyd r oxy-1,3-
d im et h ylp en t -4-en yl)-5-m et h yl-t et r a h yd r o-2H-p yr a n -2-
yl]p r op a n oa te (27): amorphous white solid; [R]20 +51.7 (c
D
0.6, CHCl3); IR (CH2Cl2) 3500, 1730, 1720, 1235, 1015, 965,
900 cm-1 1H NMR δ 5.94 (ddd, J ) 17.3, 10.4, and 7.4 Hz,
;
1H), 5.05 (ddd, J ) 17.3, 1.8, and 1.1 Hz, 1H), 4.99 (ddd, J )
10.4, 1.8, and 0.7 Hz, 1H), 3.99 (ddd, J ) 11.0, 5.2, and 1.8
Hz, 1H), 3.74 (s, 3H), 3.49 (dd, J ) 9.7 and 2.8 Hz, 1H), 3.36
(d, J ) 8.8 Hz, 1H), 3.27 (s, 1H, OH), 3.12 (dq, J ) 11.0 and
6.9 Hz, 1H), 2.25 (m, 1H), 1.91-1.55 (m, 5H), 1.27 (m, 1H),
1.08 (d, J ) 7.0 Hz, 3H), 0.92 (d, J ) 7.0 Hz, 3H), 0.86 (d, J )
7.0 Hz, 3H), 0.83 (d, J ) 6.6 Hz, 3H); 13C NMR δ 175.5 (s),
142.7 (d), 113.4 (t), 82.6 (d), 79.4 (d), 75.1 (d), 51.9 (q), 41.2
(d), 39.9 (d), 34.4 (d), 31.6 (d), 26.9 (t), 24.9 (t), 17.6 (q), 16.8
(q), 14.6 (q), 4.8 (q); MS-CI+ (CH4) m/z (relative intensity) 299
(M + H+, 66), 281 (44), 243 (20), 185 (100), 171 (13); HRMS
(CI+, CH4) calcd for C17H31O4 (M + H+) 299.2222, found
299.2220.
Ad d ition of th e Ch ir a l Allen ylzin c (P )-29 to Ald eh yd e
20. To a solution of Pd(OAc)2 (26 mg, 0.12 mmol, 0.17 equiv)
in THF (20 mL) at -78 °C was added a solution of PPh3 (30
mg, 0.12 mmol, 0.17 equiv) in THF (2 mL). After 10 min at
-78 °C were successively added a solution of 20 (162 mg, 0.669
J . Org. Chem, Vol. 69, No. 14, 2004 4641

Defosseux et al.
mmol, 1 equiv) and (R)-28 (300 mg, 2.03 mmol, 3 equiv) in
THF (5 mL) and Et2Zn (4.0 mL, 1 M in hexanes, 4.0 mmol, 6
equiv) dropwise. After 14 h at -30 °C, the reaction mixture
was poured into a saturated aqueous solution of NH4Cl, and
a 1 M aqueous solution of hydrochloric acid (10 mL) was added
dropwise. After extraction with ether, the combined extracts
were washed with brine, dried over MgSO4, filtered and
concentrated under reduced pressure. Analysis of the GC-
MS and 1H NMR spectra of the crude material indicated the
formation of the three diastereomeric homopropargylic alcohols
Similarly, hydrogenation of 31 (25 mg, 0.084 mmol) followed
by purification by flash chromatography (pentane/Et2O: 80/
20) afforded 12 mg (48%) of 27 as an amorphous white solid.
Meth yl (2S)-2-((2S,5S,6S)-6-{(1R,2S,3S)-2-[(ter t-Bu tyl-
d im et h ylsilyl)oxy]-1,3-d im et h ylp en t -4-en yl}-5-m et h yl-
tetr a h yd r o-2H-p yr a n -2-yl)p r op a n oa te (33). To a solution
of 26 (59 mg, 0.20 mmol) in CH2Cl2 (5 mL) at -78 °C, were
successively added 2,6-lutidine (90 µL, 0.77 mmol, 3.9 equiv)
and tert-butyldimethylsilyl triflate (140 µL, 0.609 mmol, 3.1
equiv). After 4 h at -78 °C, the reaction mixture was poured
into a saturated aqueous solution of NaHCO3 and extracted
with ether. The combined extracts were dried over MgSO4,
filtered and concentrated under reduced pressure. The crude
material was purified by flash chromatography (petroleum
ether/Et2O gradient 99/1 to 95/5) to afford 71 mg (87%) of 33
30, 31, and 32 in
a 80/12/8 ratio. Purification by flash
chromatography (petroleum ether/Et2O gradient 80/20 to 60/
40) afforded 13 mg (7%) of 32 as an amorphous solid, 124 mg
(63%) of 30, and 18 mg (9%) of 31 as white solids.
Meth yl (2S)-2-[(2S,5S,6S)-6-((1S,2S,3S)-2-Hyd r oxy-1,3-
d im eth ylp en t-4-yn yl)-5-m eth yl-tetr a h yd r o-2H-p yr a n -2-
yl]p r op a n oa te (30): Rf 0.31 (petroleum ether/EtOAc 80/20);
mp 90 °C; [R]20D +44.2 (c 1.15, CHCl3); IR (CH2Cl2) 3530, 3280,
1710, 1275, 1255, 1245, 1105, 1080, 1040, 1020, 970 cm-1; 1H
NMR δ 3.94 (m, 1H), 3.72 (s, 3H), 3.67 (dd, J ) 9.9 and 1.8
Hz, 1H), 3.49 (d, J ) 6.6 Hz, 1H, OH), 3.22 (m, 1H), 3.17 (dq,
J ) 11.0 and 6.8 Hz, 1H), 2.67 (m, 1H), 2.05 (d, J ) 2.2 Hz,
1H), 1.93 (m, 1H), 1.82-1.54 (m, 3H), 1.29 (d, J ) 7.0 Hz, 3H),
1.34-1.17 (m, 2H), 1.06 (d, J ) 6.6 Hz, 3H), 0.83 (d, J ) 6.3
Hz, 3H), 0.82 (d, J ) 7.0 Hz, 3H); 13C NMR δ 176.7 (s), 85.4
(s), 75.3 (d), 74.7 (d), 73.8 (d), 69.6 (d), 52.0 (q), 39.8 (d), 38.2
(d), 31.8 (d), 29.2 (d), 27.5 (t), 25.3 (t), 18.5 (q), 17.6 (q), 14.2
(q), 9.2 (q); MS-CI+ (CH4) m/z (relative intensity) 297 (M +
H+, 100), 279 (13), 265 (8), 243 (23), 185 (35), 171 (7); HRMS
(CI+, CH4) calcd for C17H29O4 (M + H+) 297.2068, found
297.2065.
as a colorless oil: [R]20 +28.6 (c 0.5, CHCl3); IR (film) 3060,
D
1740, 1255, 1165, 1110, 1040, 1005, 860, 830, 775 cm-1 1H
;
NMR δ 5.98 (ddd, J ) 17.6, 10.3, and 8.5 Hz, 1H), 4.96-4.87
(m, 2H), 3.75 (ddd, apparent td, J ) 8.6 and 4.5 Hz, 1H), 3.69
(s, 3H), 3.54 (dd, J ) 5.1 and 2.2 Hz, 1H), 3.39 (dd, J ) 7.2
and 4.6 Hz, 1H), 2.63 (dq, J ) 9.2 and 7.0 Hz, 1H), 2.29 (m,
1H), 2.06 (m, 1H), 1.79-1.68 (m, 2H), 1.61-1.47 (m, 2H), 1.39
(m, 1H), 1.08 (d, J ) 7.0 Hz, 3H), 1.00 (d, J ) 6.6 Hz, 6H),
0.92 (s, 9H), 0.87 (d, J ) 7.4 Hz, 3H), 0.08 (s, 3H), 0.06 (s,
3H); 13C NMR δ 175.9 (s), 141.8 (d), 113.3 (t), 79.2 (d), 77.5
(d), 72.1 (d), 51.6 (q), 44.5 (d), 41.0 (d), 39.1 (d), 28.4 (d), 26.0
(q, 3C), 25.7 (t), 23.9 (t), 20.5 (q), 18.4 (q), 18.3 (s), 13.5 (q),
10.2 (q), -3.9 (q), -4.5 (q); MS-CI+ (CH4) m/z (relative
intensity) 413 (M + H+, 100), 397 (21), 355 (11), 281 (48), 185
(79); HRMS (CI+, CH4) calcd for C23H45O4Si (M + H+) 413.3088,
found 413.3087.
Meth yl (2S)-2-[(2S,5S,6S)-6-((1S,2R,3R)-2-Hyd r oxy-1,3-
d im et h ylp en t -4-yn yl)-5-m et h ylt et r a h yd r o-2H -p yr a n -2-
yl]p r op a n oa te (31): Rf 0.22 (petroleum ether/EtOAc 80/20);
mp 93 °C; [R]20D +61.4 (c 0.7, CHCl3); IR (CH2Cl2) 3480, 3260,
Meth yl (2S)-2-((2S,5S,6S)-6-{[(1R,2R,3R)-2-(ter t-Bu tyl-
d im et h ylsilyl)oxy]-1,3-d im et h yl-4-oxoh exyl}-5-m et h yl-
tetr a h yd r o-2H-p yr a n -2-yl)p r op a n oa te (23). To a solution
of 34 (95 mg, 0.23 mmol) in acetone/water (9/1, 1.5 mL) at 0
°C were added NMO (41 mg, 0.35 mmol, 1.5 equiv) and OsO4
(0.14 mL, 4% in water, 0.023 mmol, 0.1 equiv). Additional
quantities of NMO (20 mg and 39 mg, 0.17 and 0.33 mmol,
0.7 equiv and 1.4 equiv) and OsO4 (30 µL and 140 µL, 4% in
water, 4.9 µmol and 23 µmol, 0.02 equiv and 0.1 equiv) were
added after 19 h and then after 40 h. After 46 h of stirring,
finely crushed Na2S2O3 (107 mg) and Celite (396 mg) were
added to the reaction mixture. After 1.5 h, the resulting
mixture was filtered through glass wool, the filtrate was
evaporated under reduced pressure, and the residue was
dissolved in EtOAc. The resulting solution was successively
washed with a 25% aqueous solution of Na2S2O3 and brine,
dried over MgSO4, filtered, and concentrated under reduced
pressure. The crude intermediate diol was dissolved in THF/
water (1/1, 6 mL), and NaIO4 was added (120 mg, 0.561 mmol,
2.4 equiv). After 40 min at rt, the reaction mixture was
extracted with ether. The combined extracts were successively
washed with a 25% aqueous solution of Na2S2O3 and brine,
dried over MgSO4, filtered, and concentrated under reduced
pressure. The crude aldehyde 34 was not purified and was
directly engaged in the next step. EtLi‚LiBr (9.0 mL, 0.46 M
in ether, 4.1 mmol, 18 equiv) (prepared from EtBr and Li
metal, Et2O, 0-5 °C) was added dropwise to a suspension of
CuI (398 mg, 2.09 mmol, 9 equiv) in ether (10 mL) at -78 °C.
The reaction mixture was warmed to -40 °C, and after 15 min
a brown homogeneous solution of the Gilman cuprate was
obtained. The reaction mixture was cooled to -78 °C, and a
solution of 34 in ether (4 mL) was added dropwise. After 15
min, the reaction mixture was poured into a NH4Cl/NH4OH
mixture (pH ) 8). After 1.5 h of stirring, the resulting
homogeneous mixture was extracted with ether. The combined
extracts were washed with brine, dried over MgSO4, filtered,
and concentrated under reduced pressure. The crude inter-
mediate secondary alcohol was dissolved in CH2Cl2 (10 mL),
and to the resulting solution at 0 °C were successively added
pyridine (80 µL, 0.99 mmol, 4.3 equiv) and Dess-Martin
periodinane (222 mg, 0.523 mmol, 2.3 equiv). After 18 h at rt,
1
1730, 1710, 1280, 1255, 1230, 1110, 1015, 985, 970 cm-1; H
NMR δ 4.01 (m, 1H), 3.78 (s, 3H), 3.53-3.46 (m, 2H), 3.14. (d,
J ) 1.5 Hz, 1H, OH), 3.11 (dq, J ) 11.0 and 6.9 Hz, 1H), 2.60
(dqd, apparent quintet d, J ) 7.0, 2.2 Hz, 1H), 2.08 (d, J ) 2.2
Hz, 1H), 1.86 (m, 1H), 1.78-1.57 (m, 3H), 1.32-1.23 (m, 2H),
1.18 (d, J ) 7.0 Hz, 3H), 1.09 (d, J ) 6.6 Hz, 3H), 0.91 (d, J )
7.0 Hz, 3H), 0.84 (d, J ) 6.6 Hz, 3H); 13C NMR δ 175.6 (s),
87.1 (s), 81.6 (d), 78.0 (d), 75.1 (d), 69.2 (d), 52.0 (q), 39.9 (d),
35.2 (d), 31.5 (d), 30.5 (d), 26.8 (t), 24.9 (t), 17.8 (q), 17.5 (q),
14.6 (q), 5.2 (q); MS-CI+ (CH4) m/z (relative intensity) 297 (M
+ H+, 100), 279 (18), 243 (14), 185 (50); HRMS (CI+, CH4) calcd
for C17H29O4 (M + H+) 297.2066, found 297.2062.
Meth yl (2S)-2-[(2S,5S,6S)-6-((1S,2R,3S)-2-Hyd r oxy-1,3-
d im et h ylp en t -4-yn yl)-5-m et h ylt et r a h yd r o-2H -p yr a n -2-
yl]p r op a n oa te (32): Rf 0.42 (petroleum ether/EtOAc 80/20);
[R]20D +46.9 (c 0.6, CHCl3); IR (CH2Cl2) 3480, 3300, 1735, 1195,
1
1170, 1075, 1015, 965 cm-1; H NMR δ 4.02 (m, 1H), 3.76 (s,
3H), 3.55 (dd, J ) 10.1 and 2.4 Hz, 1H), 3.49 (s, 1H, OH), 3.45
(d, J ) 9.9 Hz, 1H), 3.17 (dq, J ) 11.2 and 6.8 Hz, 1H), 2.49
(m, 1H), 2.32 (m, 1H), 2.05 (d, J ) 2.6 Hz, 1H), 1.85-1.55 (m,
3H), 1.33-1.20 (m, 2H), 1.28 (d, J ) 6.6 Hz, 3H), 1.09 (d, J )
6.6 Hz, 3H), 0.86 (d, J ) 7.4 Hz, 3H), 0.84 (d, J ) 6.6 Hz, 3H);
13C NMR δ 175.7 (s), 86.7 (s), 82.6 (d), 79.4 (d), 75.4 (d), 69.9
(d), 51.8 (q), 39.4 (d), 35.1 (d), 32.0 (d), 30.1 (d), 26.9 (t), 25.0
(t), 18.1 (q), 17.4 (q), 14.7 (q), 4.4 (q); MS-CI+ (CH4) m/z
(relative intensity) 297 (M + H+, 100), 279 (11), 243 (16), 185
(30); HRMS (CI+, CH4) calcd for C17H29O4 (M + H+) 297.2066,
found 297.2061.
Hyd r ogen a tion of 30 a n d 31. To a solution of 30 (33 mg,
0.11 mmol) in toluene (1 mL) were successively added quino-
line (18 µL, 0.15 mmol, 1.4 equiv) and Pd/BaSO4 (38 mg, 5%
Pd, 0.018 mmol, 0.16 equiv). The resulting mixture was stirred
under an atmosphere of hydrogen. After 30 min, the reaction
mixture was diluted with CH2Cl2 and filtered through Celite.
The filtrate was evaporated under reduced pressure, and the
crude material was purified by flash chromatography (pentane/
Et2O 80/20) to afford 31 mg (93%) of 26 as a white solid.
4642 J . Org. Chem., Vol. 69, No. 14, 2004

Total Synthesis of Zincophorin and Its Methyl Ester
the reaction mixture was hydrolyzed with a 1.5 M aqueous
solution of Na2SO3 (12 mL) and a saturated aqueous solution
of NaHCO3 (12 mL). After extraction with CH2Cl2, the com-
bined extracts were washed with brine, dried over MgSO4,
filtered, and concentrated under reduced pressure. The crude
material was purified by flash chromatography (petroleum
ether/Et2O gradient 90/10 to 80/20) to afford 70 mg (68%, from
added a solution of PPh3 (195 mg, 0.743 mmol, 0.074 equiv)
in THF (1 mL). After 10 min at -78 °C, a solution of 37 (1.88
g, 10.0 mmol) and (S)-28 (2.21 g, 15.0 mmol, 1.5 equiv) in THF
(10 mL) and Et2Zn (30.0 mL, 1 M in hexanes, 30.0 mmol, 3.0
equiv) were successively added dropwise. After 14 h at -20
°C, the reaction mixture was cautiously poured into a satu-
rated aqueous solution of NH4Cl, and a 1 M aqueous solution
of hydrochloric acid (10 mL) was added dropwise. After
extraction with ether, the combined extracts were washed with
brine, dried over MgSO4, filtered, and concentrated under
reduced pressure. The crude material was purified by flash
chromatography (petroleum ether/Et2O gradient 90/10 at 85/
33) of 23 as a colorless oil: [R]20 -10.8 (c 0.65, CHCl3); IR
D
(film) 1740, 1720, 1255, 1165, 1050, 835, 775 cm-1; 1H NMR δ
3.93 (dd, J ) 7.0 and 4.0 Hz, 1H), 3.71 (s, 3H), 3.70 (m, 1H),
3.43 (dd, J ) 8.5 and 3.7 Hz, 1H), 2.77 (m, 1H), 2.59 (dq, J )
8.8 and 7.0 Hz, 1H), 2.51 (q, J ) 7.2 Hz, 2H), 2.13 (m, 1H),
1.87-1.72 (m, 2H), 1.54-1.38 (m, 3H), 1.08 (d, J ) 7.0 Hz,
3H), 1.03 (d, J ) 7.0 Hz, 3H), 1.01 (t, J ) 7.2 Hz, 3H), 0.97 (d,
J ) 7.4 Hz, 3H), 0.89 (d, J ) 7.0 Hz, 3H), 0.87 (s, 9H), 0.10 (s,
3H), 0.01 (s, 3H); 13C NMR δ 213.7 (s), 175.8 (s), 78.8 (d), 75.9
(d), 71.8 (d), 51.6 (q), 49.2 (d), 44.8 (d), 39.2 (d), 36.6 (t), 28.1
(d), 25.9 (q, 3C), 25.5 (t), 23.6 (t), 18.2 (q), 18.0 (s), 13.6 (q),
13.4 (q), 9.6 (q), 7.4 (q), -4.3 (q), -4.8 (q); MS-EI m/z (relative
intensity) 413 (M - Et+, 0.2), 385 (M - t-Bu+, 2), 229 (14),
186 (11), 185 (100), 173 (14), 153 (70), 125 (16), 97 (11), 75
(15), 57 (18); HRMS (CI+, CH4) calcd for C24H47O5Si (M + H+)
443.3193, found 443.3185.
15) to give 1.81 g (75%) of 36 as a colorless oil: [R]20 +29.6 (c
D
0.67, CHCl3) (lit.50 [R]20D +36.0 (c 2.57, CHCl3)); IR (film) 3430,
3270, 1260, 1250, 1090, 1070, 1005, 940, 840, 780 cm-1 1H
;
NMR δ 3.76 (dq, J ) 7.3 and 6.0 Hz, 1H), 3.17 (ddd, J ) 8.5,
7.3, and 3.7 Hz, 1H), 2.91 (m, 1H), 2.13 (d, J ) 2.6 Hz, 1H),
1.90 (d, J ) 8.5 Hz, 1H, OH), 1.26 (d, J ) 7.4 Hz, 3H), 1.22 (d,
J ) 6.0 Hz, 3H), 0.89 (s, 9H), 0.10 (s, 3H), 0.09 (s, 3H); 13C
NMR δ 84.9 (s), 78.6 (d), 71.1 (d), 69.9 (d), 28.5 (d), 25.8 (q,
3C), 19.6 (q), 18.0 (q), 17.9 (s), -4.3 (q), -4.9 (q); MS-EI m/z
(relative intensity) 227 (M - Me+, 0.3), 185 (M - t-Bu+, 14),
173 (11), 159 (62), 141 (15), 131 (89), 119 (29), 115 (17), 103
(17), 75 (100), 73 (61).
Syn t h esis of t h e C13-C25 Su b u n it of Zin cop h or in .
E t h yl (2S)-2-[(ter t-Bu t yld im et h ylsilyl)oxy]p r op a n oa t e
(38).51 To a solution of L-ethyl lactate (14 mL, 0.12 mol) in
THF (120 mL) at rt were successively added Et3N (44 mL, 0.32
mol, 2.6 equiv), DMAP (1.55 g, 12.7 mmol, 0.1 equiv), and tert-
butylchlorodimethylsilane (25 g, 0.17 mol, 1.3 equiv). After 24
h at rt, additional quantities of Et3N (9.0 mL, 65 mmol, 0.5
equiv), DMAP (0.32 g, 2.6 mmol, 0.02 equiv), and tert-
butylchlorodimethylsilane (5.0 g, 33 mmol, 0.27 equiv) were
added. After 60 h, the reaction mixture was concentrated
under reduced pressure, and the residue was taken up in Et2O
and filtered through Celite. The filtrate was successively
washed with a 15% aqueous solution of AcOH (100 mL), water
(100 mL) and a saturated aqueous solution of NaHCO3 (100
mL). The organic phase was dried over MgSO4, filtered, and
concentrated under reduced pressure. The residue was distilled
under reduced pressure (110 °C, 15 mmHg) to afford 24.3 g
(3R ,4R ,5S )-5-[(t er t -Bu t yld im e t h ylsilyl)oxy]-4-m e t h -
oxym eth oxy-3-m eth ylh ex-1-yn e (39). To a solution of 36
(4.88 g, 20.1 mmol) in CH2Cl2 (100 mL) at 0 °C were
successively added i-Pr2NEt (8.50 mL, 48.8 mmol, 2.4 equiv)
and MOMCl (3.70 mL, 48.7 mmol, 2.4 equiv) dropwise. After
24 h at rt, additional quantities of i-Pr2NEt (0.80 mL, 4.6
mmol, 0.2 equiv) and MOMCl (0.40 mL, 5.3 mmol, 0.3 equiv)
were added at 0 °C. After 14 h at rt, the reaction mixture was
hydrolyzed with a saturated aqueous solution of NaHCO3 and
extracted with ether. The combined extracts were washed with
brine, dried over MgSO4, filtered, and concentrated under
reduced pressure. The crude material was purified by flash
chromatography (petroleum ether/Et2O 90/10) to afford 5.08
g (88%) of 39 as a colorless oil: [R]20 +26.3 (c 1.21, CHCl3);
D
IR (film) 3310, 3290, 3270, 1260, 1150, 1105, 1040, 1005, 835,
780 cm-1; 1H NMR δ 4.77 (d, J ) 6.8 Hz, 1H), 4.73 (d, J ) 6.8
Hz, 1H), 3.93 (dq, apparent quintet, J ) 6.3 Hz, 1H), 3.42 (s,
3H), 3.22 (dd, J ) 6.8 and 3.5 Hz, 1H), 2.90 (m, 1H), 2.07 (d,
J ) 2.2 Hz, 1H), 1.26 (d, J ) 7.4 Hz, 3H), 1.21 (d, J ) 5.9 Hz,
3H), 0.87 (s, 9H), 0.09 (s, 3H), 0.07 (s, 3H); 13C NMR δ 98.2
(t), 85.8 (d+s, 2C), 69.8 (d), 69.5 (d), 56.2 (q), 28.3 (d), 25.8 (q,
3C), 20.0 (q), 18.3 (q), 17.9 (s), -4.3 (q), -4.9 (q); MS-EI m/z
(relative intensity) 255 (M - OMe+, 0.1), 233 (M - CH(CH3)-
CtCH+, 3), 197 (15), 159 (46), 131 (100), 123 (14), 115 (17),
103 (16), 89 (45), 75 (25), 73 (52), 59 (12). Anal. Calcd for
(85%) of 38 as a colorless oil: [R]20 -29.4 (c 1.44, CHCl3); IR
D
(film) 1755, 1735, 1255, 1150, 1060, 1025, 975, 830, 810, 780
1
cm-1; H NMR δ 4.31 (q, J ) 6.6 Hz, 1H), 4.18 (m, 2H), 1.40
(d, J ) 6.6 Hz, 3H), 1.28 (t, J ) 7.2 Hz, 3H), 0.90 (s, 9H), 0.10
(s, 3H), 0.07 (s, 3H); 13C NMR δ 174.1 (s), 68.4 (d), 60.7 (t),
25.7 (q, 3C), 21.3 (q), 18.3 (s), 14.2 (q), -5.0 (q), -5.3 (q); MS-
EI m/z (relative intensity) 217 (M - Me+, 2), 175 (M - t-Bu+,
72), 159 (42), 147 (100), 119 (40), 103 (49), 75 (64), 73 (49), 59
(12).
(2S)-2-[(ter t-Bu tyld im eth ylsilyl)oxy]p r op a n a l (37).50 To
a solution of 38 (3.00 g, 12.9 mmol) in Et2O (50 mL) at -78 °C
was added dropwise Dibal-H (15.5 mL, 1 M in hexanes, 15.5
mmol, 1.2 equiv). After 1 h at -40 °C, the reaction mixture
was poured into a mixture of a saturated aqueous solution of
Rochelle’s salt (140 mL) and ether (100 mL) was added. After
the mixture was stirred for 2 h at rt, the layers were separated
and the aqueous phase was extracted with ether. The com-
bined extracts were washed with brine, dried over MgSO4,
filtered, and concentrated under reduced pressure (bath tem-
perature e 20 °C) to afford 2.43 g (100%) of 37 as a colorless
oil. This sensitive compound was directly engaged in the next
step without purification. An analytical sample was obtained
after purification by flash chromatography (petroleum ether/
Et2O: 50/50): [R]20 -12.6 (c 1.1, CHCl3) (lit.50 [R]19 -12.0 (c
1.5, CHCl3)); IR (film) 2860, 2790, 1740, 1260, 1110 (br), 835,
810, 780 cm-1; 1H NMR δ 9.62 (d, J ) 1.1 Hz, 1H), 4.10 (qd, J
) 7.0 and 1.1 Hz, 1H), 1.28 (d, J ) 7.0 Hz, 3H), 0.92 (s, 9H),
0.11 (s, 3H), 0.09 (s, 3H); 13C NMR δ 204.1 (d), 73.8 (d), 25.7
(q, 3C), 18.5 (q), 18.1 (s), -4.8 (2q, 2C).
(1R,2R)-1-{(1S)-1-[(ter t-Bu tyld im eth ylsilyl)oxy]eth yl}-
2-m eth ylbu t-3-yn -1-ol (36).50 To a solution of Pd(OAc)2 (164
mg, 0.731 mmol, 0.073 equiv) in THF (220 mL) at -78 °C was
C
15H30O3Si: C, 62.89; H, 10.55. Found: C, 62.90; H, 10.69.
(6R,7R,8S)-1-Ben zyloxy-8-[(ter t-b u t yld im et h ylsilyl)-
oxy]-7-m eth oxym eth oxy-6-m eth yln on -4-yn e (40). To a
solution of 39 (1.49 g, 5.20 mmol) in THF (30 mL) at -78 °C
was added dropwise n-BuLi (2.70 mL, 2.5 M in hexanes, 6.75
mmol, 1.3 equiv). The reaction mixture was warmed to -50
°C, stirred for 5 min, and cooled again to -78 °C. A solution
of 1-benzyloxy-3-bromopropane (1.20 mL, 6.80 mmol, 1.3 equiv)
in THF (10 mL) and HMPA (4.80 mL, 27.6 mmol, 5.3 equiv)
were successively added. After 1.5 h at rt, the reaction mixture
was poured into a saturated aqueous solution of NH4Cl and
extracted with ether. The combined extracts were washed with
brine, dried over MgSO4, filtered, and concentrated under
reduced pressure. The crude material was purified by flash
chromatography (petroleum ether/EtOAc gradient 95/5 to 90/
D
D
10) to give 2.22 g (98%) of 40 as a colorless oil: [R]20 +8.3 (c
D
1.0, CHCl3); IR (film) 1255, 1155, 1105, 1035, 920, 830, 810,
780, 740, 700 cm-1; 1H NMR δ 7.36-7.25 (m, 5H), 4.79 (d, J )
6.6 Hz, 1H), 4.74 (d, J ) 6.6 Hz, 1H), 4.52 (s, 2H), 3.94 (dq,
apparent quintet, J ) 6.3 Hz, 1H), 3.57 (t, J ) 6.4 Hz, 2H),
3.44 (s, 3H), 3.24 (dd, J ) 6.3 and 4.0 Hz, 1H), 2.83 (m, 1H),
2.31 (td, J ) 7.2 and 2.2 Hz, 2H), 1.81 (m, 2H), 1.21 (d, J )
5.9 Hz, 3H), 1.21 (d, J ) 7.0 Hz, 3H), 0.89 (s, 9H), 0.10 (s,
J . Org. Chem, Vol. 69, No. 14, 2004 4643

Defosseux et al.
3H), 0.08 (s, 3H); 13C NMR δ 138.6 (s), 128.3 (d, 2C), 127.6 (d,
2C), 127.5 (d), 98.1 (t), 85.8 (d), 81.8 (s), 81.1 (s), 72.9 (t), 69.7
(d), 69.1 (t), 56.1 (q), 29.2 (t), 28.4 (d), 25.8 (q, 3C), 19.7 (q),
18.7 (q), 18.0 (s), 15.8 (t), -4.3 (q), -4.9 (q); MS-EI m/z (relative
intensity) 404 (M - CH2dO+•, 0.1), 377 (M - t-Bu+, 0.1), 225
(16), 201 (14), 159 (39), 131 (53), 125 (17), 115 (15), 103 (13),
91 (100), 89 (19), 75 (14). Anal. Calcd for C25H42O4Si: C, 69.08;
H, 9.74. Found: C, 68.99; H, 9.76.
spectrum of the crude material indicated the formation of a
9/1 diastereomeric mixture of the two tertiary allylic alcohols
42 and 42′. The crude material was purified by flash chroma-
tography (petroleum ether/EtOAc: 80/20) to give 903 mg (93%)
of a mixture of 42 and 42′ (42/42′ ) 9/1) as a colorless oil. An
analytical sample of the pure separated major diastereomer
42 was used for characterization: [R]20 -25.9 (c 1.3, CHCl3);
D
IR (film) 3450, 1650, 1150, 1100, 1035, 920, 740, 700 cm-1; 1H
NMR δ 7.36-7.26 (m, 5H), 5.56 (dq, J ) 11.8 and 7.2 Hz, 1H),
5.39 (apparent br d, J ) 11.8 Hz, 1H), 4.87 (d, J ) 6.8 Hz,
1H), 4.74 (d, J ) 6.8 Hz, 1H), 4.52 (s, 2H), 3.56 (t, J ) 6.4 Hz,
2H), 3.48 (s, 3H), 3.47 (m, 1H, OH), 3.38 (d, J ) 2.6 Hz, 1H),
2.81 (m, 1H), 2.30 (td, J ) 7.2 and 2.3 Hz, 2H), 1.89 (dd, J )
7.2 and 1.7 Hz, 3H), 1.80 (m, 2H), 1.46 (s, 3H), 1.24 (d, J ) 7.0
Hz, 3H); 13C NMR δ 138.5 (s), 133.8 (d), 128.3 (d, 2C), 127.6
(d, 2C), 127.5 (d), 127.4 (d), 99.2 (t), 89.9 (d), 82.3 (s), 81.4 (s),
76.0 (s), 72.9 (t), 69.0 (t), 56.2 (q), 29.1 (t), 28.2 (d), 25.1 (q),
20.6 (q), 15.8 (t), 14.5 (q); MS-EI m/z (relative intensity) 201
(M - C3H5C(CH3)(OH)CH(OMOM)+, 5), 189 (5), 109 (12), 91
(100), 85 (30). Anal. Calcd for C22H32O4: C, 73.30; H, 8.95.
Found: C, 73.31; H, 9.12.
(2S,3R,4R)-9-Ben zyloxy-3-m eth oxym eth oxy-4-m eth yl-
n on -5-yn -2-ol (41). To a solution of 40 (4.28 g, 9.84 mmol) in
THF (50 mL) at 0 °C was added n-Bu4NF (30 mL, 1 M in THF,
30 mmol, 3 equiv). After 16 h at rt, the reaction mixture was
hydrolyzed with a saturated aqueous solution of NH4Cl and
extracted with ether. The combined extracts were dried over
MgSO4, filtered, and concentrated under reduced pressure to
give 3.15 g (100%) of 41, which was directly engaged in the
next step without further purification. An analytical sample
was obtained after purification by flash chromatography
(petroleum ether/EtOAc 60/40): [R]20 -28.5 (c 0.98, CHCl3);
D
IR (film) 3420, 1155, 1100, 1075, 1030, 740, 700 cm-1; 1H NMR
δ 7.37-7.27 (m, 5H), 4.79 (d, J ) 6.8 Hz, 1H), 4.73 (d, J ) 6.8
Hz, 1H), 4.53 (s, 2H), 3.89 (m, 1H), 3.57 (t, J ) 6.3 Hz, 2H),
3.45 (s, 3H), 3.39 (dd, J ) 6.3 and 4.0 Hz, 1H), 3.22 (m, 1H),
2.69 (m, 1H), 2.32 (td, J ) 7.0 and 2.2 Hz, 2H), 1.81 (m, 2H),
1.22 (d, J ) 6.3 Hz, 3H), 1.18 (d, J ) 7.0 Hz, 3H); 13C NMR δ
138.4 (s), 128.2 (d, 2C), 127.4 (d+d, 2C+1C), 98.2 (t), 87.2 (d),
81.8 (s), 81.4 (s), 72.8 (t), 68.8 (t), 67.4 (d), 55.9 (q), 29.0 (t),
28.6 (d), 17.8 (q), 17.7 (q), 15.5 (t); MS-EI m/z (relative
intensity) 275 (M - CH2OMe+, 1), 201 (12), 167 (7), 155 (8),
125 (13), 123 (12), 95 (13), 91 (100), 87 (12). Anal. Calcd for
(1R,2R,3R)-8-Ben zyloxy-2-m eth oxym eth oxy-1,3-d im e-
th yl-1-((Z)-p r op -1-en yl)oct-4-yn yl 2-Oxobu ta n oa te (43)
a n d (1S,2R,3R)-8-Ben zyloxy-2-m et h oxym et h oxy-1,3-d i-
m eth yl-1-((Z)-pr op-1-en yl)oct-4-yn yl 2-Oxobu tan oate (43′).
To a solution of 42 and 42′ (9/1 ratio, 677 mg, 1.88 mmol) in
THF (20 mL) were successively added DMAP (32 mg, 0.26
mmol, 0.14 equiv) and diketene (stabilized with CuSO4) (0.19
mL, 2.5 mmol, 1.3 equiv). After 30 min at rt, an additional
quantity of diketene was added (0.19 mL, 2.5 mmol, 1.3 equiv).
After 30 min at rt, the reaction mixture was hydrolyzed with
a 0.3% aqueous solution of NaOH and extracted with ether.
The combined extracts were dried over MgSO4, filtered, and
concentrated under reduced pressure. The crude material was
purified by flash chromatography (petroleum ether/EtOAc
gradient 85/15 to 75/25) to afford 67 mg (8%) of 43′ and 737
C
19H28O4: C, 71.22; H, 8.81. Found: C, 71.07; H, 9.00.
(3R,4R)-9-Ben zyloxy-3-m eth oxym eth oxy-4-m eth yln on -
5-yn -2-on e (35). To a solution of 41 (3.15 g, 9.84 mmol) in
CH2Cl2 (80 mL) at 0 °C were successively added pyridine (3.20
mL, 39.6 mmol, 4 equiv) and Dess-Martin periodinane (8.43
g, 19.9 mmol, 2 equiv). After 4.5 h at rt, the reaction mixture
was hydrolyzed with a saturated aqueous solution of NaHCO3
and extracted with ether. The combined extracts were washed
with a 25% aqueous solution of Na2S2O3, dried over MgSO4,
filtered, and concentrated under reduced pressure. The re-
sidual traces of pyridine were removed by evaporation with
cyclohexane under reduced pressure, and the residue was
purified by flash chromatography (petroleum ether/EtOAc
gradient 85/15 to 75/25) to afford 2.89 g (92% from 40) of 35
mg (88%) of 43 as colorless oils. Major diastereomer 43: [R]20
D
+1.92 (c 1.0, CHCl3); IR (film) 1740, 1720, 1640, 1150, 1110,
1035, 740, 700 cm-1; 1H NMR [only the signals corresponding
to the major ketone tautomer (85%) are indicated] δ 7.36-
7.25 (m, 5H), 5.64-5.53 (m, 2H), 4.86 (d, J ) 7.0 Hz, 1H), 4.73
(d, J ) 7.0 Hz, 1H), 4.50 (s, 2H), 3.76 (d, J ) 1.8 Hz, 1H), 3.55
(t, J ) 6.3 Hz, 2H), 3.44 (s, 3H), 3.39 (s, 2H), 2.78 (m, 1H),
2.29 (td, J ) 7.0 and 2.2 Hz, 2H), 2.26 (s, 3H), 1.82 (s, 3H),
1.84-1.70 (m, 2H), 1.73 (d, J ) 5.5 Hz, 3H), 1.25 (d, J ) 7.0
Hz, 3H); 13C NMR [only the signals corresponding to the major
ketone tautomer (85%) are indicated] δ 200.6 (s), 164.9 (s),
138.5 (s), 130.6 (d), 128.3 (d, 2C), 127.7 (d), 127.5 (d+d,
2C+1C), 98.3 (t), 87.7 (s), 84.3 (d), 82.3 (s), 81.2 (s), 73.0 (t),
69.0 (t), 56.1 (q), 50.8 (t), 30.1 (q), 29.1 (t), 27.8 (d), 21.3 (q),
20.3 (q), 15.8 (t), 14.5 (q); MS-CI+ (NH3) m/z (relative intensity)
462 (M + NH4+, 92), 418 (17), 378 (42), 360 (100), 144 (15).
Anal. Calcd for C26H36O6: C, 70.24; H, 8.16. Found: C, 70.02;
as a colorless oil: [R]20 +31.0 (c 1.35, CHCl3); IR (film) 1720,
D
1215, 1150, 1110, 1075, 1035, 945, 920, 740, 700 cm-1; 1H NMR
δ 7.38-7.25 (m, 5H), 4.72 (d, AB syst., J ) 6.6 Hz, 1H), 4.68
(d, AB syst., J ) 6.6 Hz, 1H), 4.51 (s, 2H), 3.90 (d, J ) 4.8 Hz,
1H), 3.54 (t, J ) 6.3 Hz, 2H), 3.41 (s, 3H), 2.91 (m, 1H), 2.30
(td, J ) 7.2 and 2.3 Hz, 2H), 2.24 (s, 3H), 1.78 (m, 2H), 1.20
(d, J ) 7.0 Hz, 3H); 13C NMR δ 208.8 (s), 138.5 (s), 128.3 (d,
2C), 127.5 (d+d, 2C+1C), 96.9 (t), 85.2 (d), 82.3 (s), 79.9 (s),
72.9 (t), 68.8 (t), 56.2 (q), 29.3 (d), 29.0 (t), 27.2 (q), 17.6 (q),
15.6 (t); MS-EI m/z (relative intensity) 273 (M - CH2-
OMe+, 9), 201 (9), 153 (7), 109 (6), 95 (7), 92 (9), 91 (100). Anal.
Calcd for C19H26O4: C, 71.67; H, 8.23. Found: C, 71.71; H,
8.25.
H, 8.34. Minor diastereomer 43′: [R]20 +0.02 (c 1.1, CHCl3);
D
IR (film) 1740, 1720, 1645, 1245, 1150, 1105, 1035, 940, 920,
740, 700 cm-1; 1H NMR [only the signals corresponding to the
major ketone tautomer (90%) are indicated] δ 7.38-7.24 (m,
5H), 5.70 (dq, J ) 12.0 and 1.7 Hz, 1H), 5.55 (dq, J ) 12.0
and 7.2 Hz, 1H), 4.71 (s, 2H), 4.50 (s, 2H), 3.75 (d, J ) 1.8 Hz,
1H), 3.56 (t, J ) 6.3 Hz, 2H), 3.41 (s, 2H), 3.40 (s, 3H), 2.89
(m, 1H), 2.29 (td, J ) 7.4 and 2.2 Hz, 2H), 2.26 (s, 3H), 1.83-
1.67 (m, 2H), 1.76 (s, 3H), 1.73 (dd, J ) 7.2 and 1.7 Hz, 3H),
1.27 (d, J ) 7.0 Hz, 3H); 13C NMR [only the signals corre-
sponding to the major ketone tautomer (90%) are indicated] δ
200.5 (s), 165.2 (s), 138.5 (s), 131.9 (d), 128.3 (d, 2C), 127.5
(d+d, 2C+1C), 126.2 (d), 98.2 (t), 85.9 (s), 84.0 (d), 81.8 (s),
81.6 (s), 72.9 (t), 69.0 (t), 56.0 (q), 50.6 (t), 30.2 (q), 29.1 (t),
27.2 (d), 21.2 (q), 21.1 (q), 15.7 (t), 14.3 (q); MS-CI+ (NH3) m/z
(relative intensity) 462 (M + NH4+, 55), 418 (17), 360 (100),
343 (12), 311 (18), 281 (24), 215 (14), 191 (12); HRMS (CI+,
NH3) calcd for C26H40O6N (M + NH4+) 462.2856, found
462.2853.
(2Z)-(4R,5R,6R)-11-Ben zyloxy-5-m eth oxym eth oxy-4,6-
d im eth ylu n d ec-2-en -7-yn -4-ol (42) a n d (2Z)-(4S,5R,6R)-
11-Ben zyloxy-5-m eth oxym eth oxy-4,6-d im eth ylu n d ec-2-
en -7-yn -4-ol (42′). To a suspension of MgBr2‚OEt2 (5.30 g, 20.5
mmol, 7.5 equiv) in THF (50 mL) at -78 °C was added a
solution of (Z)-prop-1-enyllithium [prepared from (Z)-1-bromo-
prop-1-ene (12 g, 99 mmol) and Li (1.70 g, 245 mmol, 2.5 equiv)
in Et2O (70 mL) at 0-5 °C] (12.5 mL, 1.2 M in Et2O, 15.0 mmol,
5.6 equiv). The reaction mixture was warmed to rt, stirred for
30 min, and cooled to -78 °C. A solution of 35 (860 mg, 2.70
mmol) in THF (15 mL) was added dropwise, and after 1.25 h
at -78 °C, the reaction mixture was poured into a saturated
aqueous solution of NH4Cl and extracted with ether. The
combined extracts were dried over Na2SO4, filtered, and
concentrated under reduced pressure. Analysis of the 1H NMR
4644 J . Org. Chem., Vol. 69, No. 14, 2004

Total Synthesis of Zincophorin and Its Methyl Ester
Ca r r oll-Cla isen Rea r r a n gem en t of 43. To a solution of
43 (552 mg, 1.24 mmol) in CH2Cl2 (30 mL) was added neutral
alumina (17 g). The solvent was evaporated under reduced
pressure, and the resulting dry powder was stirred at 60 °C.
After 12 h, the solid reaction mixture was suspended in EtOAc,
filtered through Celite, and thoroughly washed with EtOAc.
The filtrate was evaporated under reduced pressure, and
analysis of the GC-MS and 1H NMR spectra of the crude
material indicated the formation of compounds 44, 45, and 46
in a 4/92/4 ratio. The crude material was purified by flash
chromatography (petroleum ether/EtOAc gradient 90/10 to 80/
20) to afford 37 mg (9%) of 44, 17 mg (3%) of 46 and 305 mg
(61%) of 45 as colorless oils.
was added (50 mL). After 2 h of stirring at rt, the layers were
separated and the aqueous phase was extracted with ether.
The combined extracts were dried over MgSO4, filtered, and
concentrated under reduced pressure. The crude material was
purified by flash chromatography (petroleum ether/ether 50/
50) to give 1.10 g (98%) of 47 as a pale yellow oil and as a
55/45 mixture of two diastereomers: IR (film) 3400, 1360,
1145, 1085, 1020, 910, 735, 700 cm-1; major diastereomer: 1H
NMR δ 7.40-7.25 (m, 5H), 5.27 (dd, J ) 9.7 and 0.9 Hz, 1H),
4.62 (d, J ) 6.6 Hz, 1H), 4.52 (d, J ) 6.6 Hz, 1H), 4.51 (s, 2H),
3.81-3.67 (m, 1H), 3.75 (d, J ) 9.2 Hz, 1H), 3.56 (t, J ) 6.3
Hz, 2H), 3.42 (s, 3H), 2.74-2.51 (m, 2H), 2.30 (td, J ) 7.2 and
2.1 Hz, 2H), 1.79 (apparent quintet, J ) 6.6 Hz, 2H), 1.56 (d,
J ) 5.9 Hz, 3H), 1.60-1.20 (m, 2H), 1.16 (d, J ) 6.3 Hz, 3H),
1.00 (d, J ) 7.0 Hz, 3H), 0.99 (d, J ) 6.6 Hz, 3H); 13C NMR δ
138.5 (s), 138.0 (d), 130.8 or 130.4 (s), 128.3 (d, 2C), 127.6 (d,
2C), 127.5 (d), 93.0 (t), 85.0 (d), 83.1 (s), 80.3 (s), 72.9 (t), 69.1
(t), 66.7 (d), 55.4 (q), 46.8 (t), 29.7 (d), 29.2 (d), 29.2 (t), 24.3 or
23.5 (q), 21.1 or 21.5 (q), 18.1 (q), 15.7 (t), 10.8 (q); MS-EI m/z
(relative intensity) 325 (M - Ph+, 1), 281 (M - CH2OBn+, 1),
253 (M - (CH2)3OBn+, 1), 201 (25), 169 (36), 140 (11), 139
(100), 95 (15), 91 (61), 69 (11); minor diastereomer: 1H NMR
δ 7.40-7.25 (m, 5H), 5.19 (dd, J ) 9.6 and 1.1 Hz, 1H), 4.63
(d, J ) 6.6 Hz, 1H), 4.52 (d, J ) 6.6 Hz, 1H), 4.51 (s, 2H),
3.81-3.67 (m, 1H), 3.76 (d, J ) 9.2 Hz, 1H), 3.56 (t, J ) 6.3
Hz, 2H), 3.42 (s, 3H), 2.74-2.51 (m, 2H), 2.30 (td, J ) 7.2 and
2.1 Hz, 2H), 1.79 (apparent quintet, J ) 6.6 Hz, 2H), 1.55 (d,
J ) 5.9 Hz, 3H), 1.60-1.20 (m, 2H), 1.17 (d, J ) 6.3 Hz, 3H),
1.01 (d, J ) 7.0 Hz, 3H), 0.98 (d, J ) 6.6 Hz, 3H);13C NMR δ
138.5 (s), 137.8 (d), 130.4 or 130.8 (s), 128.3 (d, 2C), 127.6 (d,
2C), 127.5 (d), 93.0 (t), 85.1 (d), 83.0 (s), 80.2 (s), 72.9 (t), 69.1
(t), 66.3 (d), 55.4 (q), 46.8 (t), 29.2 (d), 29.2 (t), 29.1 (d), 23.5 or
24.3 (q), 21.5 or 21.1 (q), 18.1 (q), 15.7 (t), 10.8 (q); MS-EI m/z
(relative intensity) 325 (M - Ph+, 1), 253 (M - (CH2)3OBn+,
1), 249 (3), 201 (23), 169 (36), 140 (10), 139 (100), 121 (10), 95
(14), 91 (63), 69 (12). Anal. Calcd for C25H38O4: C, 74.59; H,
9.51. Found: C, 74.58; H, 9.56.
(6R,7R,9Z)-1-Ben zyloxy-7-m eth oxym eth oxy-6-m eth yl-
8-m eth ylen eu n d ec-9-en -4-yn e (44): Rf 0.76 (petroleum
ether/EtOAc 70/30); [R]20D +77.1 (c 0.67, CHCl3); IR (film) 1150,
1100, 1030, 920, 740, 700 cm-1; (this compound appeared to
be slighlty contaminated by an inseparable and unindentified
1
impurity) H NMR δ 7.36-7.24 (m, 5H), 5.84 (apparent br d,
J ) 11.8 Hz, 1H), 5.74 (dq, J ) 11.8 and 6.6 Hz, 1H), 5.29 (d,
J ) 1.8 Hz, 1H), 5.17 (br s, 1H), 4.70 (d, J ) 6.8 Hz, 1H), 4.56
(d, J ) 6.8 Hz, 1H), 4.50 (s, 2H), 3.87 (d, J ) 8.5 Hz, 1H), 3.56
(t, J ) 6.3 Hz, 2H), 3.43 (s, 3H), 2.60 (m, 1H), 2.30 (td, J ) 7.0
and 2.2 Hz, 2H), 1.84-1.69 (m, 2H), 1.80 (dd, apparent br d,
J ) 6.6 and 1.5 Hz, 3H), 1.05 (d, J ) 7.0 Hz, 3H); 13C NMR δ
141.4 (s), 138.5 (s), 128.8 (d), 128.3 (d, 2C), 127.5 (d, 2C), 127.4
(d), 125.9 (d), 118.2 (t), 93.6 (t), 82.9 (d), 82.7 (s), 80.5 (s), 72.9
(t), 69.0 (t), 55.5 (q), 30.2 (d), 29.2 (t), 17.9 (q), 15.7 (t), 14.8
(q); MS-CI+ (NH3) m/z (relative intensity) 360 (M + NH4+, 80),
325 (19), 311 (22), 281 (23), 279 (26), 219 (26), 215 (37), 205
(21), 107 (100), 91 (24); HRMS (CI+, NH3) calcd for C22H34O3N
(M + NH4+) 360.2539, found 360.2532.
(4S,5Z,7R,8R)-13-Ben zyloxy-7-m eth oxym eth oxy-4,6,8-
tr im eth yltr id ec-5-en -9-yn -2-on e (45): Rf 0.50 (petroleum
ether/EtOAc 70/30); [R]20D + 1.1 (c 1.15, CHCl3); IR (film) 1715,
1
1150, 1095, 1030, 920, 740, 700 cm-1; H NMR δ 7.35-7.25
(m, 5H), 5.18 (br d, J ) 9.6 Hz, 1H), 4.61 (d, J ) 6.6 Hz, 1H),
4.51 (d, J ) 6.6 Hz, 1H), 4.50 (s, 2H), 3.71 (d, J ) 9.2 Hz, 1H),
3.55 (t, J ) 6.4 Hz, 2H), 3.41 (s, 3H), 2.99 (m, 1H), 2.61 (m,
1H), 2.38 (d, J ) 7.0 Hz, 2H), 2.29 (td, J ) 7.2 and 2.2 Hz,
2H), 2.09 (s, 3H), 1.79 (m, 2H), 1.56 (d, J ) 1.5 Hz, 3H), 0.99
(d, J ) 7.0 Hz, 3H), 0.95 (d, J ) 7.0 Hz, 3H); 13C NMR δ 207.7
(s), 138.6 (s), 136.2 (d), 131.2 (s), 128.3 (d, 2C), 127.6 (d, 2C),
127.5 (d), 93.0 (t), 84.9 (d), 83.1 (s), 80.2 (s), 72.9 (t), 69.1 (t),
55.4 (q), 50.7 (t), 30.5 (q), 29.2 (t), 29.1 (d), 28.6 (d), 20.8 (q),
18.0 (q), 15.7 (t), 10.8 (q); MS-EI m/z (relative intensity) 339
(M - OMOM+, 0.4), 200 (13), 199 (100), 141 (16), 137 (29),
125 (34), 121 (12), 109 (25), 95 (12), 91 (67). Anal. Calcd for
(6R,7R,8E,10R)-1-Ben zyloxy-7-m eth oxym eth oxy-6,8,10-
tr im eth yltr id ec-8-en -4-yn e (49). To a solution of 47 (345 mg,
0.857 mmol) in CH2Cl2 (10 mL) at 0 °C, were successively
added i-Pr2NEt (0.45 mL, 2.6 mmol, 3 equiv) and methane-
sulfonyl chloride (0.15 mL, 1.9 mmol, 2.3 equiv). After 2 h at
0 °C, the reaction mixture was hydrolyzed with a saturated
aqueous solution of NaHCO3 and extracted with ether. The
combined extracts were washed with brine, dried over MgSO4,
filtered, and concentrated under reduced pressure. The crude
mesylate 48 was dissolved in THF (7 mL), and the resulting
solution was added to a suspension of LiAlH4 (129 mg, 3.40
mmol, 4 equiv) in THF (10 mL). After 3 h at reflux, the reaction
mixture was cooled to 0 °C and successively cautiously treated
with water (0.13 mL), a 15% aqueous solution of NaOH (0.13
mL), and water (0.39 mL). Ether was added, and after 12 h of
stirring at rt, the resulting suspension was filtered through
Celite. The insoluble salts were washed with boiling THF, and
the filtrate was evaporated under reduced pressure. The crude
material was purified by flash chromatography (petroleum
ether/Et2O 90/10, 70/30) to give 291 mg (88% from 47) of 49
C
25H36O4: C, 74.96; H, 9.06. Found: C, 74.79; H, 9.25.
(4R,5E,7R,8R)-13-Ben zyloxy-7-m eth oxym eth oxy-4,6,8-
t r im et h ylt r id ec-5-en -9-yn -2-on e (46): Rf 0.56 (petroleum
ether/EtOAc 70/30); [R]20 + 35.0 (c 0.50, CHCl3); IR (film)
D
1715, 1150, 1095, 1035, 740, 700 cm-1; H NMR δ 7.36-7.25
1
(m, 5H), 5.28 (apparent br d, J ) 10.1 Hz, 1H), 4.57 (d, J )
6.8 Hz, 1H), 4.53 (d, J ) 6.8 Hz, 1H), 4.51 (s, 2H), 4.35 (d, J
) 9.6 Hz, 1H), 3.57 (t, J ) 6.3 Hz, 2H), 3.43 (s, 3H), 3.03 (m,
1H), 2.63 (m, 1H), 2.35 (d, J ) 6.6 Hz, 2H), 2.31 (td, J ) 7.2
and 2.0 Hz, 2H), 2.12 (s, 3H), 1.81 (m, 2H), 1.58 (d, J ) 1.5
as a colorless oil: [R]20 +6.8 (c 0.97, CHCl3); IR (film) 1150,
D
Hz, 3H), 1.02 (d, J ) 7.4 Hz, 3H), 0.98 (d, J ) 6.6 Hz, 3H); 13
C
1100, 1030, 920, 740, 700 cm-1; 1H NMR δ 7.35-7.24 (m, 5H),
5.19 (apparent br d, J ) 9.6 Hz, 1H), 4.64 (d, J ) 6.6 Hz, 1H),
4.51 (d, J ) 6.6 Hz, 1H), 4.50 (s, 2H), 3.74 (d, J ) 9.2 Hz, 1H),
3.56 (t, J ) 6.3 Hz, 2H), 3.42 (s, 3H), 2.63 (m, 1H), 2.41 (m,
1H), 2.30 (td, J ) 7.0 and 2.1 Hz, 2H), 1.79 (m, 2H), 1.50 (d,
J ) 1.1 Hz, 3H), 1.31-1.13 (m, 4H), 1.00 (d, J ) 7.0 Hz, 3H),
0.94 (d, J ) 6.6 Hz, 3H), 0.86 (br t, apparent m, 3H); 13C NMR
δ 138.9 (d), 138.5 (s), 129.6 (s), 128.3 (d, 2C), 127.5 (d, 2C),
127.4 (d), 92.8 (t), 85.2 (d), 83.3 (s), 80.0 (s), 72.9 (t), 69.0 (t),
55.3 (q), 39.6 (t), 31.9 (d), 29.2 (t), 29.1 (d), 21.1 (q), 20.6 (t),
18.1 (q), 15.7 (t), 14.1 (q), 10.6 (q); MS-EI m/z (relative
intensity) 325 (M - OMOM+, 0.3), 186 (12), 185 (100), 155
(8), 139 (24), 91 (41). Anal. Calcd for C25H38O3: C, 77.68; H,
9.91. Found: C, 77.57; H, 10.02.
NMR δ 207.6 (s), 138.6 (s), 137.0 (d), 130.6 (s), 128.3 (d, 2C),
127.6 (d, 2C), 127.5 (d), 93.1 (t), 83.1 (s), 80.3 (s), 76.2 (d), 72.9
(t), 69.1 (t), 55.3 (q), 50.9 (t), 30.8 (q), 29.2 (t), 29.1 (d), 28.1
(d), 21.1 (q), 17.8 (q), 17.4 (q), 15.8 (t); MS-CI+ (NH3) m/z
(relative intensity) 418 (M + NH4+, 100), 369 (13), 340 (20),
339 (72), 277 (11), 215 (24), 199 (26), 91 (16); HRMS (CI+, NH3)
calcd for C25H40O4N (M + NH4+) 418.2957, found 418.2961.
(2RS,4R,5E,7R,8R)-13-Ben zyloxy-7-m eth oxym eth oxy-
4,6,8-tr im eth yltr id ec-5-en -9-yn -2-ol (47). To a solution of
45 (1.11 g, 2.77 mmol) in ether (30 mL) at -78 °C was added
Dibal-H (3.4 mL, 1 M in hexanes, 3.4 mmol, 1.3 equiv). After
2 h at -78 °C, the reaction mixture was poured into a
saturated aqueous solution of Rochelle’s salt (50 mL) and ether
J . Org. Chem, Vol. 69, No. 14, 2004 4645

Defosseux et al.
(6R,7R,8E,10R)-1-Ben zyloxy-6,8,10-t r im et h ylt r id ec-8-
en -4-yn -7-ol (50). To a solution of 49 (260 mg, 0.673 mmol)
in MeOH (10 mL) at rt was added p-toluenesulfonic acid
monohydrate (130 mg, 0.683 mmol, 1 equiv). After 4 days at
rt, the reaction mixture was neutralized by addition of solid
NaHCO3 and evaporated under reduced pressure. The residue
was taken up in water and extracted with ether. The combined
extracts were washed with brine, dried over MgSO4, filtered,
and concentrated under reduced pressure. The crude material
was purified by flash chromatography (petroleum ether/
ether: 75/25) to afford 195 mg (85%) of 50 as a colorless oil:
pressure. The residue was purified by flash chromatography
(petroleum ether/ether 80/20) to give 51 mg (75% from 51) of
53 as a colorless oil: [R]20D -11.8 (c 1.0, CHCl3); IR (film) 3280,
1
1250, 1055, 835, 775 cm-1; H NMR δ 5.46 (dd, J ) 15.4 and
6.3 Hz, 1H), 5.38 (dt, J ) 15.4 and 5.9 Hz, 1H), 4.99 (dm, J )
9.6 Hz, 1H), 3.66 (t, J ) 6.6 Hz, 2H), 3.57 (d, J ) 8.1 Hz, 1H),
2.37 (m, 1H), 2.22 (m, 1H), 2.12-2.00 (m, 2H), 1.64 (m, 2H),
1.54 (d, J ) 1.5 Hz, 3H), 1.48 (br s, 1H, OH), 1.32-1.11 (m,
4H), 0.91 (d, J ) 6.6 Hz, 3H), 0.89-0.84 (m, 3H), 0.86 (s, 9H),
0.80 (d, J ) 7.0 Hz, 3H), -0.01 (s, 3H), -0.05 (s, 3H); 13C NMR
δ 134.7 (d + s, 2C), 134.1 (d), 128.6 (d), 83.8 (d), 62.7 (t), 40.8
(d), 39.9 (t), 32.5 (t), 31.7 (d), 29.1 (t), 25.9 (q, 3C), 20.8 (q),
20.7 (t), 18.2 (s), 17.1 (q), 14.2 (q), 11.2 (q), -4.5 (q), -4.9 (q);
MS-EI m/z (relative intensity) 311 (M - t-Bu+, 1), 256 (23),
255 (100), 185 (10), 171 (7), 127 (7), 75 (14), 73 (35).
[R]20 -43.5 (c 0.6, CHCl3); IR (film) 3420, 1105, 1035, 740,
D
1
700 cm-1; H NMR δ 7.36-7.24 (m, 5H), 5.17 (apparent br d,
J ) 9.6 Hz, 1H), 4.52 (s, 2H), 3.68 (dd, J ) 8.5 and 2.6 Hz,
1H), 3.56 (t, J ) 6.1 Hz, 2H), 2.59 (m, 1H), 2.45-2.28 (m, 2H),
2.32 (td, J ) 7.4 and 2.2 Hz, 2H), 1.80 (m, 2H), 1.58 (d, J )
1.5 Hz, 3H), 1.31-1.14 (m, 4H), 1.02 (d, J ) 7.0 Hz, 3H), 0.95
(d, J ) 7.0 Hz, 3H), 0.86 (br t, apparent m, 3H); 13C NMR δ
138.5 (s), 136.3 (d), 132.2 (s), 128.4 (d, 2C), 127.6 (d, 2C), 127.5
(d), 82.5 (s), 81.8 (s), 81.7 (d), 73.0 (t), 68.9 (t), 39.8 (t), 31.8
(d), 31.4 (d), 29.2 (t), 20.9 (q), 20.6 (t), 17.8 (q), 15.7 (t), 14.2
(q), 10.9 (q); MS-CI+ (CH4) m/z (relative intensity) 343 (M +
H+, 11), 341 (14), 326 (28), 325 (100), 234 (22), 233 (38), 201
(15), 161 (35), 141 (17), 111 (31), 91 (47); HRMS (CI+, CH4)
calcd for C23H35O2 (M + H+) 343.2637, found 343.2632.
(4E,6R,7R,8E,10R)-7-[(ter t-Bu tyld im eth ylsilyl)oxy]-6,8,-
10-tr im eth yltr id eca -4,8-d ien a l (54). To a solution of 56 (47
mg, 0.13 mmol) in CH2Cl2 (4 mL) at 0 °C, were successively
added pyridine (40 µL, 0.50 mmol, 4 equiv) and Dess-Martin
periodinane (123 mg, 0.290 mmol, 2.3 equiv). After 4 h at rt,
the reaction mixture was hydrolyzed with a 1.5 M aqueous
solution of Na2SO3 (12 mL) and a saturated aqueous solution
of NaHCO3 (12 mL). After extraction with CH2Cl2, the com-
bined extracts were washed with brine, dried over MgSO4,
filtered, and concentrated under reduced pressure. The crude
material was purified by flash chromatography (petroleum
ether/Et2O 92/8) to afford 40 mg (86%) of 54 as a colorless oil:
(4E,6R,7R,8E,10R)-1-Ben zyloxy-6,8,10-tr im eth yltr ideca-
4,8-d ien -7-ol (51). To a suspension of LiAlH4 (135 mg, 3.56
mmol, 11 equiv) in THF (20 mL) at 0 °C was added a solution
of 50 (110 mg, 0.321 mmol) in THF (2 mL). The reaction
mixture was heated at reflux, and additional quantities of
LiAlH4 (100 mg and 70 mg, 2.63 and 1.84 mmol, 8 equiv and
6 equiv) were added after 24 h and then after 24 h. After 72
h, the reaction mixture was cooled to 0 °C and cautiously
successively treated with water (280 µL), a 15% aqueous
solution of NaOH (280 µL), and water (840 µL). Ether (100
mL) was added, and after 3 h of stirring at rt, the resulting
mixture was filtered through Celite. The insoluble salts were
washed with boiling THF, and the filtrate was evporated under
reduced pressure. The crude material was purified by flash
chromatography (petroleum ether/ether 75/25) to afford 68 mg
[R]20 -11.8 (c 0.93, CHCl3); IR (film) 1725, 1250, 1060, 870,
D
835, 775 cm-1; 1H NMR δ 9.78 (t, J ) 1.8 Hz, 1H), 5.48 (dd, J
) 15.4 and 7.2 Hz, 1H), 5.37 (dt, J ) 15.4 and 5.9 Hz, 1H),
4.99 (dm, J ) 9.6 Hz, 1H), 3.56 (d, J ) 8.5 Hz, 1H), 2.50 (m,
2H), 2.44-2.31 (m, 3H), 2.22 (m, 1H), 1.53 (d, J ) 1.5 Hz, 3H),
1.32-1.11 (m, 4H), 0.91 (d, J ) 6.6 Hz, 3H), 0.89-0.82 (m,
3H), 0.86 (s, 9H), 0.79 (d, J ) 6.6 Hz, 3H), -0.01 (s, 3H), -0.05
(s, 3H); 13C NMR δ 202.3 (d), 135.6 (d), 134.7 (s), 134.3 (d),
126.8 (d), 83.7 (d), 43.5 (t), 40.8 (d), 39.9 (t), 31.7 (d), 25.8 (q,
3C), 25.3 (t), 20.7 (q+t, 2C), 18.2 (s), 17.0 (q), 14.2 (q), 11.1
(q), -4.5 (q), -5.0 (q); MS-CI+ (CH4) m/z (relative intensity)
367 (M + H+, 10), 351 (20), 309 (14), 255 (55), 235 (100), 217
(15), 151 (22), 111 (21); HRMS (CI+, CH4) calcd for C22H43O2-
Si (M + H+) 367.3032, found 367.3029.
(61%) of 51 as a colorless oil: [R]20 -4.5 (c 0.4, CHCl3); IR
D
(film) 3440, 1100, 1015, 970, 735, 700 cm-1; 1H NMR δ 7.38-
7.25 (m, 5H), 5.59 (dt, J ) 15.1 and 6.8 Hz, 1H,), 5.30 (ddt, J
) 15.1, 8.7 and 1.3 Hz, 1H), 5.13 (dm, J ) 9.6 Hz, 1H), 4.50
(s, 2H), 3.53 (dd, J ) 8.8 and 1.8 Hz, 1H), 3.48 (t, J ) 6.4 Hz,
2H), 2.41 (m, 1H), 2.29-2.11 (m, 3H), 1.85 (d, J ) 1.8 Hz, 1H,
OH), 1.70 (m, 2H), 1.59 (d, J ) 1.5 Hz, 3H), 1.31-1.14 (m,
4H), 0.95 (d, J ) 6.6 Hz, 3H), 0.87 (br t, J ) 6.6 Hz, 3H), 0.83
(d, J ) 6.6 Hz, 3H); 13C NMR δ 138.6 (s), 135.9 (d), 133.3 (d),
133.0 (s), 132.3 (d), 128.3 (d, 2C), 127.6 (d, 2C), 127.5 (d), 81.8
(d), 72.9 (t), 69.7 (t), 41.3 (d), 39.8 (t), 31.8 (d), 29.5 (t), 29.3
Cou p lin g of th e C1-C12 a n d C13-25 Su bu n its. Meth yl
(2S)-2-((2S,5S,6S)-6-{(1R,2R,3R,5S,6R,9E,11R,12R,13E,-
15R)-2,12-Bis[(ter t-b u t yld im et h ylsilyl)oxy]-6-h yd r oxy-
1,3,5,11,13,15-h exa m et h yl-4-oxooct a d i-9,13-en yl}-5-m e-
th yltetr a h yd r o-2H-p yr a n -2-yl)p r op a n oa te (56). To a solu-
tion of ethyl ketone 23 (60.0 mg, 0.136 mmol) in anhydrous
CH2Cl2 (2.5 mL) at -78 °C was added a solution of freshly
distilled TiCl4 (190 µL, 0.75 M in CH2Cl2, 0.142 mmol, 1.05
equiv), and after 1 min, i-Pr2NEt (30 µL, 0.17 mmol, 1.3 equiv)
was added. After 1 h at -78 °C, a solution of aldehyde 54 (36
mg, 0.098 mmol, 0.72 equiv) in CH2Cl2 (2.5 mL) was added
dropwise and the reaction was quenched 2 h later by addition
of a saturated aqueous solution of NH4Cl. The reaction mixture
was diluted with Et2O and H2O, the layers were separated,
and the aqueous phase was extracted with ether. The com-
bined extracts were dried over Na2SO4, filtered, and concen-
(t), 20.9 (q), 20.6 (t), 17.3 (q), 14.2 (q), 10.9 (q); MS-EI m/z
(relative intensity) 344 (M+•, 0.1), 273 (M - (n-Pr)CHCH3
,
+
0.1), 141 (27), 123 (23), 113 (46), 95 (86), 92 (19), 91 (100), 71
(41), 67 (12), 55 (11).
(4E,6R,7R,8E,10R)-7-[(ter t-Bu tyld im eth ylsilyl)oxy]-6,8,-
10-tr im eth yltr id eca -4,8-d ien -1-ol (53). To a solution of 51
(63 mg, 0.18 mmol) in CH2Cl2 (3 mL) at -78 °C were
successively added 2,6-lutidine (80 µL, 0.69 mmol, 4 equiv) and
tert-butyldimethylsilyl triflate (120 µL, 0.522 mmol, 3 equiv).
After 3 h at -78 °C, the reaction mixture was poured into a
saturated aqueous solution of NaHCO3 and extracted with
ether. The combined extracts were dried over MgSO4, filtered,
and concentrated under reduced pressure. The crude silyl ether
52 was dissolved in THF/t-BuOH (6/1, 3.5 mL) and added to
liquid ammonia (20 mL) at -78 °C. Finely cut lithium pieces
(50 mg, 7.2 mmol, 39 equiv) were added all at once, and after
15 min at -78 °C, solid NH4Cl (150 mg) was cautiously added
to the reaction mixture. After evaporation of ammonia, water
and ether were added. The resulting mixture was extracted
with ether, and the combined extracts were washed with brine,
dried over MgSO4, filtered, and concentrated under reduced
1
trated under reduced pressure. The H NMR spectrum of the
crude material indicated the formation of 60 with high
diastereoselectivity (dr > 96/4). Purification by flash chroma-
tography (petroleum ether/Et2O 90/10, 85/15) afforded 55 mg
(70%) of 56 as a colorless oil and 18 mg (30%) of ethyl ketone
23 was recovered: [R]20D -21.3 (c 1.15, CHCl3); IR (film) 3440,
1740, 1695, 1255, 1165, 1060, 835, 775 cm-1; 1H NMR (CDCl3)
d 5.45 (dd, J ) 15.4 and 6.2 Hz, 1H), 5.36 (m, 1H), 4.97 (br d,
J ) 8.5 Hz, 1H), 4.04 (m, 1H), 3.90 (dd, J ) 7.0 and 3.3 Hz,
1H), 3.71 (s, 3H), 3.70 (m, 1H), 3.55 (d, J ) 8.1 Hz, 1H), 3.42
(dd, J ) 7.9 and 3.9 Hz, 1H), 3.13 (br s, 1H, OH), 3.03
(apparent quintet, J ) 7.0 Hz, 1H), 2.67-2.57 (m, 2H), 2.36
(m, 1H), 2.23-2.11 (m, 3H), 1.99 (m, 1H), 1.87-1.70 (m, 2H),
1.65-1.39 (m, 4H), 1.53 (d, J ) 1.5 Hz, 3H), 1.35-1.19 (m,
5H), 1.13 (d, J ) 7.4 Hz, 3H), 1.08 (d, J ) 7.0 Hz, 3H), 1.01 (d,
4646 J . Org. Chem., Vol. 69, No. 14, 2004

Total Synthesis of Zincophorin and Its Methyl Ester
J ) 6.6 Hz, 3H), 0.97 (d, J ) 7.0 Hz, 3H), 0.93 (d, J ) 7.0 Hz,
3H), 0.90 (d, J ) 7.0 Hz, 3H), 0.87 (s, 9H), 0.88-0.84 (m, 3H),
0.85 (s, 9H), 0.78 (d, J ) 7.0 Hz, 3H), 0.09 (s, 3H), 0.01 (s,
3H), -0.02 (s, 3H), -0.06 (s, 3H); 13C RMN (CDCl3) d 219.0
(s), 175.7 (s), 134.8 (s), 134.5 (d), 134.1 (d) 128.7 (d), 83.9 (d),
78.7 (d), 76.7 (d), 72.0 (d), 69.7 (d), 51.6 (q), 50.4 (d), 46.7 (d),
44.4 (d), 40.8 (d), 40.0 (d), 39.9 (t), 33.6 (t), 31.6 (d), 29.4 (t),
28.3 (d), 25.94 (q, 3C), 25.87 (q, 3C), 25.6 (t) 23.7 (t), 20.8 (q),
20.7 (t), 18.2 (q), 18.1 (s, 2C), 17.0 (q), 14.23 (q), 14.16 (q), 13.5
(q), 11.1 (q), 9.3 (q), 8.7 (q), -4.4 (q), -4.5 (q, 2C), -4.9 (q);
HRMS (CI+, NH3) calcd C46H92NO7Si2 (M + NH4+) 826.6412,
found 826.6417.
39.9 (t), 39.7 (d), 38.4 (d), 37.5 (d), 34.4 (t), 34.0 (d), 31.8 (d),
31.6 (d), 29.1 (t), 26.3 (t), 25.0 (t), 21.0 (q), 20.6 (t), 17.7 (q),
17.5 (q), 14.8 (q), 14.2 (q), 13.3 (q), 11.25 (q), 11.20 (q), 10.8
(q); HRMS (CI+, NH3) calcd for C34H63O7 (M + H+) 583.4574,
found 583.4578.
Zin cop h or in (1). To a solution of zincophorin methyl ester
2 (11 mg, 0.018 mmol) in THF/MeOH (2/1, 1.5 mL) was added
a 2 M aqueous solution of LiOH (0.5 mL). After 1 h at 50 °C,
the reaction mixture was acidified by addition of 35% aqueous
hydrochloric acid (1 drop), diluted with deionized water (10
mL), and extracted with ether (4 × 15 mL). The combined
extracts were dried over Na2SO4, filtered, and concentrated
under reduced pressure. After purification by flash chroma-
tography (hexane/ether: 60/40), an amorphous solid (11 mg),
presumably an undetermined metal salt of zincophorin, was
dissolved in ether and the resulting solution was washed with
an aqueous solution of Na2EDTA. The organic phase was dried
over Na2SO4, filtered, and concentrated to afford 8 mg of
zincophorin 1, contaminated by traces of structurally unrelated
impurities from organic solvents: 1H NMR δ 5.49 (ddd, J )
15.1, 7.9, and 5.3 Hz, 1H), 5.36 (dd, J ) 15.1 and 8.8 Hz, 1H),
5.11 (dd, J ) 9.6 and 1.1 Hz, 1H), 4.07-4.00 (m, 2H), 3.74
(dd, J ) 9.9 and 1.8 Hz, 1H), 3.69 (dd, J ) 9.6 and 2.2 Hz,
1H), 3.57 (br d, J ) 9.5 Hz, 1H), 3.47 (m, 1H), 3.27 (m, 1H),
2.46-2.10 (m, 4H), 2.08-1.96 (m, 2H), 1.82-1.57 (m, 4H), 1.59
(d apparent s, J ) 1.1 Hz, 3H), 1.50 (m, 1H), 1.40-1.20 (m,
6H), 1.16 (d, J ) 7.3 Hz, 3H), 1.13 (d, J ) 7.0 Hz, 3H), 1.08 (d,
J ) 7.0 Hz, 3H), 0.93 (d, J ) 6.6 Hz, 3H), 0.88 (m, 3H), 0.84
(d, J ) 7.0 Hz, 3H), 0.78 (d, J ) 6.6 Hz, 3H), 0.67 (d, J ) 6.6
Hz, 3H) [structurally unrelated impurities: aromatic signals
7.4-7.8 ppm and paraffins: 1.25 (br s) and 0.86 (m)]; 13C NMR
δ 176.1 (s), 135.7 (d), 134.6 (d), 133.2 (s), 132.4 (d), 84.3 (d),
83.3 (d), 82.0 (d), 76.1 (d), 74.1 (d), 69.3 (d), 42.1 (d), 39.9 (t),
37.7 (d), 37.1 (d), 36.5 (d), 34.2 (t), 33.0 (d), 31.9 (d), 31.8 (d),
28.6 (t), 26.2 (t), 25.0 (t), 21.0 (q), 20.6 (t), 17.4 (q), 17.0 (q),
15.6 (q), 14.2 (q), 12.3 (q), 11.2 (q), 10.73 (q), 10.68 (q).
Met h yl (2S)-2-[(2S,5S,6S)-6-((1S,2S,3S,4S,5S,6R,9E,-
11R,12R,13E,15R)-2,4,6,12-Tet r a h yd r oxy-1,3,5,11,13,15-
h exa m eth ylocta d i-9,13-en yl)-5-m eth yltetr a h yd r o-2H-p y-
r a n -2-yl]p r op a n oa te (Zin cop h or in Meth yl Ester ) (2). To
a solution of 56 (23 mg, 0.028 mmol) in MeOH (5 mL) at 0-5
°C was added portionwise NaBH4 (40 mg, 0.11 mmol, 4 equiv)
(four portions every 20 min). After 1 h, the reaction mixture
was hydrolyzed with a saturated aqueous solution of Rochelle’s
salt and diluted with H2O and Et2O. The layers were sepa-
rated, and the aqueous phase was extracted with Et2O. The
combined extracts were dried over MgSO4, filtered, and
concentrated under reduced pressure. The crude intermediate
diol 57 was dissolved in THF (5 mL) and to the resulting
solution at 0-5 °C (polyethylene container), was added HF‚
Pyridine complex (1 mL). After 1.5 h at rt, the reaction mixture
was diluted with Et2O and H2O, cautiously neutralized by
addition of solid NaHCO3, and extracted with Et2O. The
combined extracts were dried over Na2SO4, filtered, and
concentrated under reduced pressure. The crude material was
purified by flash chromatography (n-hexane/EtOAc 50/50) to
afford 11 mg (66%) of zincophorin methyl ester 2: Rf 0.6 (n-
hexane/EtOAc 50/50); Rf 0.4 (C6H6/Et2O 50/50); [R]20 +21.3
D
(c 0.4, CHCl3) (lit.8 [R]D +22.4 (c 0.89, CHCl3), authentic
sample: [R]D +20.9 (c 2.0, CHCl3)1,6); IR (CHCl3) 3380, 1730,
1460, 1380, 1280, 1260, 1215, 1120, 1080, 1020, 970 cm-1; 1H
NMR (CDCl3) d 5.93 (s, 1H), 5.61 (dt, J ) 15.1 and 6.6 Hz,
1H), 5.34 (dd, J ) 15.1 and 8.8 Hz, 1H), 5.11 (br d, J ) 9.2
Hz, 1H), 4.43 (d, J ) 8.1 Hz, 1H), 4.12-4.06 (m, 3H), 3.76 (d,
J ) 10.3 Hz, 1H), 3.72 (s, 3H), 3.63 (dd, J ) 8.8 and 1.8 Hz,
1H), 3.55 (d, J ) 9.6 Hz, 1H), 3.44 (m, 1H), 3.23 (apparent dq,
J ) 10.8 and 7.0 Hz, 1H), 2.41 (m, 1H), 2.29-2.14 (m, 3H),
2.12 (br s, 1H), 2.08-1.96 (m, 2H), 1.78-1.52 (m, 4H), 1.60 (d,
J ) 1.5 Hz, 3H), 1.41-1.15 (m, 6H), 1.10 (d, J ) 6.6 Hz, 3H),
1.08 (d, J ) 6.6 Hz, 3H), 1.06 (d, J ) 7.0 Hz, 3H), 0.94 (d, J )
6.6 Hz, 3H), 0.90-0.80 (m, 5H), 0.84 (d, J ) 6.6 Hz, 3H), 0.82
(d, J ) 6.2 Hz, 3H), 0.66 (d, J ) 6.6 Hz, 3H); 13C NMR (CDCl3)
d 175.6 (s), 135.7 (d), 133.4 (d), 133.3 (s), 133.2 (d), 84.4 (d),
84.0 (d), 81.8 (d), 76.1 (d), 74.5 (d), 68.9 (d), 52.3 (q), 41.8 (d),
Ack n ow led gm en t. M.D. and N.B. thank the MRES
for a grant.
Su p p or tin g In for m a tion Ava ila ble: Tables of compari-
son of the NMR data of synthetic zincophorin methyl ester 2
and zincophorin 1 with those reported in the literature, and
additional studies supporting the configurational assignment
of ketones 45 and 46 and diol 57. Copies of the NMR spectra
of compounds 12a ,c, 14a -c, 14′a , 17, 19, 20, 23, 26, 27, 30-
33, 43, 43′, 44, 46, 50, 51, 53, 54, 56, 2, and 1. This material
is available free of charge via the Internet at http://pubs.acs.org.
J O0496042
J . Org. Chem, Vol. 69, No. 14, 2004 4647