Studies on a urea-directed Stork-Crabtree hydrogenation. Synthesis of the C1-C9 subunit of (+)-zincophorin

Article abstract of DOI:10.1021/jo7017922

(Chemical Equation Presented) A detailed account on the stereoselective synthesis of the C1-C9 subunit of (+)-zincophorin is described here. This approach features the first application of a stereoselective inverse electron demand hetero-[4 + 2] cycloaddi

Full text of DOI:10.1021/jo7017922

Studies on a Urea-Directed Stork-Crabtree Hydrogenation.
Synthesis of the C1-C9 Subunit of (+)-Zincophorin
Zhenlei Song, Richard P. Hsung,* Ting Lu, and Andrew G. Lohse
DiVision of Pharmaceutical Sciences and Department of Chemistry, Rennebohm Hall,
777 Highland AVenue, UniVersity of Wisconsin, Madison, Wisconsin 53705
rhsung@wisc.edu
ReceiVed August 24, 2007
A detailed account on the stereoselective synthesis of the C1-C9 subunit of (+)-zincophorin is de-
scribed here. This approach features the first application of a stereoselective inverse electron demand
hetero-[4 + 2] cycloaddition of chiral allenamides in natural product synthesis. The C1-C9 subunit
matches Cossy’s intermediate, thereby constituting a formal total synthesis. In addition, details of an
unusual urea-directed Stork-Crabtree hydrogenation observed during these efforts are also disclosed
here.
Introduction
Polyoxygenated ionophore-containing natural products exhibit
potent anti-infectious properties through proton-cation ex-
change processes across biological membranes. This activity is
due to the ability of ionophores to form lipophilic complexes
with various cations such as Li+, Na+, and K+, and divalent
alkaline earth cations such as Ca2+ and Mg2+.1 In 1984, two
new monocarboxylic acid ionophores, griseocholin and antibiotic
M144255, were isolated from cultured strains of Streptomyces
griseus.2 Extensive NMR experiments of griseocholin and X-ray
diffraction of the zinc-magnesium salt of M144255 revealed
that these two compounds are actually structurally identical with
the same absolute configuration.2b On the basis of its ability to
strongly bind with Zn2+, it was given the trivial name (+)-
zincophorin (Figure 1). (+)-Zincophorin possesses strong in vivo
activity against Gram-positive bacteria and Clostridium coelchii.
FIGURE 1. (+)-Zincophorin and its methyl ester.
SCHEME 1. An Inverse Electron Demand Hetero-[4 + 2]
Cycloaddition
(1) (a) Polyether Antibiotics; Westley, J. W., Ed.; Marcel Dekker: New
York, Vol. 1, 1982; Vol. 2, 1983. (b) Dobler, M. Ionophores and their
Structures; Wiley: New York, 1981.
(2) For isolation, see: (a) Grafe, U.; Schade, W.; Roth, M.; Radics, L.;
Incze, M.; Ujszaszy, K. J. Antibiot. 1984, 37, 836-846. (b) Brooks, H. A.;
Gardner, D.; Poyser, J. P.; King, T. J. J. Antibiot. 1984, 37, 1501-1504.
(c) Radics, L. J. Chem. Soc., Chem. Commun. 1984, 599-601. (d) Gra¨fe,
U. German. [East] DD 231,793.
Its ammonium and sodium salts display significant anti-coccidal
activity against Eimeria tenella in chicken embryos, and its
methyl ester was reported in a patent as having strong inhibitory
properties against influenza WSN/virus with reduced toxicity
for the host cells.2d,3
10.1021/jo7017922 CCC: $37.00 © 2007 American Chemical Society
Published on Web 11/03/2007
9722
J. Org. Chem. 2007, 72, 9722-9731

Synthesis of the C1-C9 Subunit of (+)-Zincophorin
SCHEME 2. An Approach to the C1-C9 Subunit of (+)-Zincophorin
SCHEME 3. Synthesis of Chiral Allenamide 9
SCHEME 4. Synthesis of Chiral Enone 16
of the observation of an unusual urea-directed Stork-Crabtree
hydrogenation.
Results and Discussions
Over the last twenty plus years, (+)-zincophorin has attracted
an impressive array of synthetic efforts including Danishefsky’s
first total synthesis along with two recent elegant total syntheses
reported by Cossy and Miyashita.4 We recently communicated
our formal total syntheses of (+)-zincophorin via interception
of Miyashita’s advanced intermediate.5 The key strategy features
our previously reported stereoselective inverse electron demand
hetero-[4 + 2] cycloaddition of chiral allenamides (Scheme
1).6-9 Herein, we report the synthesis of Cossy’s C1-C9 subunit
of (+)-zincophorin based on this approach, as well as details
1. Retrosynthetic Plan. The construction of Cossy’s inter-
mediate 6, or the C1-C9 subunit of (+)-zincophorin, could be
realized from tetrahydropyran 7, which contains all prerequisite
stereocenters by several transformations (Scheme 2). In turn,
tetrahydropyran 7 could be prepared from pyran 8 via (1)
stereoselective hydrogenation of exo- and endo-cyclic olefins
from the less hindered top face of the pyranyl ring and (2) a
(6) Wei, L.-L.; Hsung, R. P.; Xiong, H.; Mulder, J. A.; Nkansah, N. T.
Org. Lett. 1999, 1, 2145-2148.
(3) Tonew, E.; Tonew, M.; Gra¨fe, U.; Zopel, P. Pharmazie 1988, 43,
717-719.
(7) For reviews on allenamides, see: (a) Hsung, R. P.; Wei, L.-L.; Xiong,
H. Acc. Chem. Res. 2003, 36, 773-782. (b) Tracey, M. R.; Hsung, R. P.;
Antoline, J.; Kurtz, K. C. M.; Shen, L.; Slafer, B. W.; Zhang, Y. In Science
of Synthesis, Houben-Weyl Methods of Molecular Transformations; Weinreb,
S. M., Ed.; Georg Thieme Verlag KG: Stuttagart, Germany, 2005; Chap-
ter 21.4.
(4) For approaches, see: (a) Cossy, J.; Blanchard, N.; Defosseux, M.;
Meyer, C. Angew. Chem., Int. Ed. 2002, 41, 2144-2146. (b) Guindon, Y.;
Murtagh, L.; Caron, V.; Landry, S. R.; Jung, G.; Bencheqroun, M.; Faucher,
A.-M.; Guerin, B. J. Org. Chem. 2001, 66, 5427-5437. (c) Burke, S. D.;
Ng, R. A.; Morrison, J. A.; Alberti, M. J. J. Org. Chem. 1998, 63, 3160-
3161. (d) Marshall, J. A.; Palovich, M. R. J. Org. Chem. 1998, 63, 3701-
3705. (e) Chemler, S. R.; Roush, W. R. J. Org. Chem. 1998, 63, 3800-
3801. (f) Booysen, J. F.; Holzapfel, C. W. Synth. Commun. 1995, 25, 1473-
1488. (g) Cywin, C. L.; Kallmerten, J. Tetrahedron Lett. 1993, 34, 1103-
1106. (h) Balestra, M.; Wittman, M. D.; Kallmerten, J. Tetrahedron Lett.
1988, 29, 6905-6908. (i) Zelle, R. E.; DeNinno, M. P.; Selnick, H. G.;
Danishefsky, S. J. J. Org. Chem. 1986, 51, 5032-5036. The first total
synthesis, see: (j) Danishefsky, S. J.; Selnick, H. G.; DeNinno, M. P.; Zelle,
R. E. J. Am. Chem. Soc. 1987, 109, 1572-1574. (k) Danishefsky, S. J.;
Selnick, H. G.; Zelle, R. E.; DeNinno, M. P. J. Am. Chem. Soc. 1988, 110,
4368-4378. For Cossy’s total synthesis, see: (l) Cossy, J.; Meyer, C.;
Defosseux, M.; Blanchard, N. Pure Appl. Chem. 2005, 77, 1131-1137.
(m) Defosseux, M.; Blanchard, N.; Meyer, C.; Cossy, J. J. Org. Chem.
2004, 69, 4626-4647. (n) Defosseux, M.; Blanchard, N.; Meyer, C.; Cossy,
J. Org. Lett. 2003, 5, 4037-4040. For Miyashita’s total synthesis, see: (o)
Komatsu, K.; Tanino, K.; Miyashita, M. Angew. Chem., Int. Ed. 2004, 43,
4341-4345.
(8) For recent reports on the allenamide chemistry, see: (a) Parthasarathy,
K.; Jeganmohan, M.; Cheng, C.-H. Org. Lett. 2006, 8, 621-623. (b)
Fena´ndez, I.; Monterde, M. I.; Plumet, J. Tetrahedron Lett. 2005, 46, 6029-
6031. (c) de los Rios, C.; Hegedus, L. S. J. Org. Chem. 2005, 70, 6541-
6543. (d) Alouane, N.; Bernaud, F.; Marrot, J.; Vrancken, E.; Mangeney,
P. Org. Lett. 2005, 7, 5797-5800. (e) Antoline, J. E.; Hsung, R. P.; Huang,
J.; Song, Z.; Li, G. Org. Lett. 2007, 9, 1275-1278. (f) Huang, J.; Ianni, J.
C.; Antoline, J. E.; Hsung, R. P.; Kozlowski, M. C. Org. Lett. 2006, 8,
1565-1568. (g) Berry, C. R.; Hsung, R. P.; Antoline, J. E.; Petersen, M.
E.; Rameshkumar, C.; Nielson, J. A. J. Org. Chem. 2005, 70, 4038-4042.
(h) Shen, L.; Hsung, R. P.; Zhang, Y.; Antoline, J. E.; Zhang, X. Org. Lett.
2005, 7, 3081-3084. (i) Huang, J.; Hsung, R. P. J. Am. Chem. Soc. 2005,
127, 50-51.
(9) For some recent elegant studies on related inverse demand hetero-[4
+ 2] cycloaddition of chiral enamides, see: (a) Gohier, F.; Bouhadjera,
K.; Faye, D.; Gaulon, C.; Maisonneuve, V.; Dujardin, G.; Dhal, R. Org.
Lett. 2007, 9, 211-214. (b) Tardy, S.; Tatiboue¨t, A.; Rollin, P.; Dujardin,
G. Synlett 2006, 1425-1427 and reference cited therein. Also see: (c)
Palasz, A. Org. Biomol. Chem. 2005, 3, 3207-3212.
(5) Song, Z.; Hsung, P. R. Org. Lett. 2007, 9, 2199-2202.
J. Org. Chem, Vol. 72, No. 25, 2007 9723

Song et al.
SCHEME 5. Hetero-[4 + 2] Cycloadditions with Chiral Enone 16
SCHEME 6. Hydrogenation of the C6 Exo-Cyclic Olefin in
17
Lewis acid-promoted stereoselective crotylation to remove
imidazolidinone auxiliary.10 Finally, the inverse electron demand
hetero-[4 + 2] cycloaddition of chiral allenamide 9 with enone
10 could establish the pyranyl skeleton in 8.
2. Synthesis of Chiral Allenamide 9 and Enone 16.
Synthesis of chiral allenamide 9 commenced from (+)-ephedrine
hydrochloride salt 11 and urea. By condensation of the mixture
at 175 °C for 0.5 h and then 200-210 °C for 1.5 h, the so-
called Close auxiliary 12 could be obtained in 48% yield after
recrystallization.11 Subsequently, propargylation followed by
base-catalyzed isomerization of propargyl amide 13 furnished
chiral allenamide 9 in 93% overall yield (Scheme 3). In the
same manner, with the enantiomer of ephedrine, allenamide
ent-9 was also prepared.
Chiral enone 16 was prepared from the commercially
available chiral hydroxy ester 14 as shown in Scheme 4.
Protection of the hydroxyl group as a TBDPS ether followed
by reduction of the ester group with DIBALH afforded aldehyde
15 in 76% overall yield.12 Subsequent vinyl Grignard addition
and Swern oxidation of the resulting isomeric mixture (1:1) of
allylic alcohols gave rise to chiral enone 16 with an overall
yield of 66%.
3. Inverse Demand Hetero-[4 + 2] Cycloaddition. With
chiral allenamides 9 and ent-9 in hand, we pursued the key
inverse demand hetero-[4 + 2] cycloaddition. Concerned with
the fact that the stereochemical outcome could be controlled
through either the chiral auxiliary of the allenamide or the chiral
enone, leading potentially to matched and/or mismatched
scenarios, we examined both reactions of chiral allenamides 9
and ent-9 with enone 16 (Scheme 5). By using our reported
cycloaddition protocol with CH3CN as the solvent and the
sealed tube as the reaction vessel, after heating at 85 °C for 48
h, both reactions of 9 and ent-9 with 16 proceeded readily
to provide pyrans 17 and 18 in 58% and 54% yield, respect-
ively, as single isomers. The stereochemistry of 18 was
unambiguously confirmed by its single-crystal X-ray diffraction
analysis.
Given that the reaction of chiral allenamide 9 should proceed
through the matched transition state model shown in Scheme 5
[on the right side], the stereochemical assignment for 18 and
the high level of selectivity imply that the cycloaddition of ent-9
also proceeded through the related transition state, although
potentially mismatched [on the left side]. However, any
mismatching perceived or real clearly did not impede the
reaction or the stereoselectivity. A closer examination reveals
that to allow the chiral enone to still approach the open π-face
of the internal olefin of allenamide ent-9 as dictated by the chiral
Close auxiliary, and to avoid any mismatching as well as allylic
strain, the heterodiene 16 would need to position the Me group
on the R carbon orthogonal to the plane of the chiral enone
(Scheme 5).
(10) (a) Berry, C. R.; Hsung, R. P. Tetrahedron 2004, 60, 7629-7636.
(b) Wei, L.-L.; Xiong, H.; Douglas, C. J.; Hsung, R. P. Tetrahedron Lett.
1999, 40, 6903-6907. (c) Berry, C. R.; Rameshkumar, C.; Tracey, M. R.;
Wei, L.-L.; Hsung, R. P. Synlett 2003, 791-796. (d) Rameshkumar, C.;
Hsung, R. P. Synlett 2003, 1241-1246.
(11) Close, W. J. J. Org. Chem. 1950, 15, 1131-1134.
(12) (a) Fuerstner, A.; Kattnig, E.; Lepage, O. J. Am. Chem. Soc. 2006,
128, 9194-9204. (b) Bergmeier, S. C.; Stanchina, D. M. J. Org. Chem.
1997, 62, 4449-4456.
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Synthesis of the C1-C9 Subunit of (+)-Zincophorin
SCHEME 7. A Proposed Mechanism for the Formation of Ketone 20
SCHEME 8. Hydrogenation of Pyran 19
4. Hydrogenations of Pyran 17 and a Urea-Directed
Stork-Crabtree Hydrogenation. (a) Hydrogenation of the
C6 Exo-Cyclic Olefin. Our efforts then encountered a serious
obstacle at what we had believed to be the most trivial stage:
sequential hydrogenations of the two olefins at C6 and C3.
Given that the exo-cyclic olefin at C6 is more accessible
sterically, we intended to accomplish this hydrogenation via mild
conditions to ensure good stereoselectivity. As shown in Scheme
6, Lindlar catalyst in MeOH was initially deployed (entry 1),
but after stirring for 2 d at 1 atm H2, the desired monohydro-
genation product 19 was obtained with a best yield of 44% while
being contaminated with 23% of the ring-opened byproduct
ketone 20 as a 3:2 isomeric mixture with regards to C6.
Although increasing the H2 pressure to 60 psi did shorten the
reaction time (entry 2), the yield dropped drastically while
providing a large amount of ketone 20.
We initially believed that the formation of ketone 20 was
initiated via hydrolysis of the cyclic aminal through protonation
of the electron-rich C3 endo-cyclic olefin. Given this consid-
eration, EtOAc and anhydrous hexanes (entries 3 and 4) were
employed as solvents, but the formation of 20 still persisted.
Changing metal catalyst from Pd to Pt appeared not to be useful
either (entry 5). However, intriguingly, we found that without
H2, pyran 17 was actually quite stable in the presence of Pt/C
catalyst in MeOH (entry 6).
These observations led us to speculate that the formation of
ketone 20 is likely promoted by the catalyst-activated H2. As
shown in Scheme 7, the same Pt-complex 21 from pyran 17
that could lead to the desired monohydrogenation product 19
could also protonate the electron-rich endo-cyclic double bond
as shown in Pt-complex 22. This would result in ring-opening
to give the Pt-π-allyl type complex 23, leading to alkene 24
after reductive elimination. Further hydrogenation of 24 should
give 20 as an isomeric mixture as observed. Alternatively, the
monohydrogenation of pyran 17 could take place predominantly
to exclusively afford dihydropyran 19 initially, but 19 could be
subsequently converted into 20 via complex 25 through an
analogous sequence.
(b) Hydrogenation of the C3 Endo-Cyclic Olefin. Further
hydrogenation of the C3 endo-cyclic olefin, which is more
electron rich and sterically less accessible, turned out to be much
more difficult by using any heterogeneous catalysts under 15-
70 psi of H2. The formation of the ring-opening product 20 was
observed as the major product in most cases with no desired
product found (Scheme 8).
However, by using Stork-Crabtree’s conditions,13 the C3
endo-cyclic olefin was reduced smoothly and provided presum-
ably the desired tetrahydropyran 26 in 74% yield. Unsuspect-
ingly, we proceeded to remove the silyl group in 26, only to be
confronted with a product quite different as established by the
X-ray structure of 27. While the stereochemistry at C6 is as
expected, both stereocenters at C3 and C7 are opposite from
what we had expected. These expectations were based on our
earlier analyses in which the monohydrogenated pyran would
assume a unique conformation as shown for 19 (Scheme 8).
Hydrogenations of C3 olefin should show a distinct preference
at the top face of a flat pyranyl ring away from the urea group,
which shields the bottom face while being pseudoaxially
situated.
Given this proposed process, it seemed that identifying a
catalyst with appropriative activity that is effective to hydro-
genate the exo-cyclic olefin but slow to protonate is very
important. Ultimately, by screening several kinds of base-
poisoned catalysts, we were delighted to find that the hydro-
genation of this exo-cyclic olefin could be achieved in 64% yield
with only 12% of 20 by using Adam’s catalyst along with 3.0
equiv of NaBH4 (entry 8 in Scheme 6).
(13) (a) Crabtree, R. H.; Davis, M. W. J. Org. Chem. 1986, 51, 2655-
2661. (b) Crabtree, R. H. Acc. Chem. Res. 1979, 12, 331-337.
J. Org. Chem, Vol. 72, No. 25, 2007 9725

Song et al.
SCHEME 9. A Urea-Directed Hydrogenation vs Epimerization
SCHEME 10. Experimental Support for Pathway b
(c) A Urea-Directed Stork-Crabtree Hydrogenation.14-16
This unexpected outcome implies a number of possibilities. We
considered the following two possibilities as illustrated in
Scheme 9. First, the monohydrogenation product 19 could
epimerize at C7 to give 28 in which the hydrogenation could
occur at the bottom face, leading to 27 after desilylation
(pathway a). While this pathway is very likely and provides a
sound rationale, we suspected a second scenario involving a
urea-directed Stork-Crabtree hydrogenation as shown in 29 to
give tetrahydropyran 30 prior to a C7-epimerization that would
afford 31 (pathway b). Tetrahydropyran 30 differs from 27 only
in the protection of the primary OH group.
Toward this end, we carried out the reaction using 2.0 equiv
of Na2CO3 to scavenge protic species or decrease the Lewis
acidity of Ir(I) that could promote the C7-epimerization, and
found 11% of 30 (a 1:2 inseparable mixture with 19) along with
35% of 31. The relative stereochemistry in 30 was assigned
based on the J value between H6 and H7 being in the
equatorial-axial range (Scheme 10). Treatment of the mixture
of 30 and 19 in CH2Cl2 with a trace amount of p-TsOH quickly
gives 31 via epimerization at C7 in about 60-70% yield.
Meanwhile, the relative stereochemistry in 31 was confirmed
via silylation of 27 (Scheme 9). These results collectively imply
that the hydrogenation at the hindered bottom face of 19 is
possible under the Stork-Crabtree conditions.
While pathway b is supported via the above experiment, we
still could not rule out pathway a by now. Thus, the following
reaction to make dihydropyran 28 was examined. When
subjecting 19 to pre-activated Crabtree’s catalyst in CH2Cl2,
19 was transformed to 28 in 40% yield via epimerization. The
relative stereochemistry in 28 was assigned by the J value
between H6 and H7 being in the axial-axial range (Scheme
10). However, under the same directed hydrogenation condi-
tions, dihydropyran 28 could not be converted into 31 and only
the ring-opening byproduct 20 was formed in about 40% yield.
On the basis of this result, pathway a in Scheme 9 can be
excluded completely. Semiempirical calculations on pyranyls
19 and 28 were also performed with the Spartan’02 program
(Figure 2). On the basis of the calculation results, 19 seems
thermodynamically more favorable than 28. This is also
supported by the acid-catalyzed epimerization experiment in
which a 2:1 ratio of 19:28 was formed after stirring with PTS
in CH2Cl2 for 5 h. The molecular models distinctly reveal that
in pyran 19, the urea group occupies the pseudoaxial position
allowing the directed hydrogenation to occur, while in pyran
28, the urea group assumes the pseudoequatorial position,
thereby preventing the coordinated metal center to reach the
C3 endo-cyclic olefin and thwarting the directed hydrogenation.
(d) Directed Hydrogenation versus C7-Epimerization. Our
efforts also led to another observation involving competition
between directed hydrogenation and epimerization at C7. As
shown in Scheme 11, it appeared that this competition is
(14) For the first application of directed hydrogenations employing
Crabtree’s catalyst, see: (a) Stork, G.; Kahne, D. E. J. Am. Chem. Soc.
1983, 105, 1072-1073. For some leading applications, also see: (b) Evans,
D. A.; Morrissey, M. M. J. Am. Chem. Soc. 1984, 106, 3866-3868. (c)
Ginn, J. D.; Padwa, A. Org. Lett. 2002, 4, 1515-1517.
(15) For an amide directed hydroboration with Crabtree’s catalyst, see:
(a) Evans, D. A.; Fu, G. C. J. Am. Chem. Soc. 1991, 113, 4042-4043. (b)
Evans, D. A.; Fu, G. C.; Hoveyda, A. H. J. Am. Chem. Soc. 1992, 114,
6671-6679.
(16) For a review on directed reactions, see: (a) Hoveyda, A. H.; Evans,
D. A.; Fu, G. C. Chem. ReV. 1993, 93, 1307-1370. (b) For a highlight
related to Crabtree’s catalyst, see: Nell, P. G. Synlett 2001, 160.
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Synthesis of the C1-C9 Subunit of (+)-Zincophorin
FIGURE 2. Molecular modeling of pyran 19 and 28.
SCHEME 11. Directed Hydrogenation versus Epimerization
J value. When hydrogenating pyran 37 with Crabtree’s catalyst,
we isolated 39 with a large J constant, distinctly suggesting a
trans relationship between Ha and Hb. Stork-Crabtree hydro-
genation of 17 afforded the monohydrogenated product 40 also
with a large J value in contrast to that of 19 from standard
hydrogenations of 17, indicating again a trans relationship
between H6 and H7 in 40. Aza-cycle 41, prepared from aza-[4
+ 2] cycloaddition of 1-azadiene and chiral allenamide 4,10a is
also suitable for this directed hydrogenation, giving the expected
stereochemistry of the product. Given the unique conformational
preference of 17, 37, and 41, these studies unequivocally support
a urea-directed Stork-Crabtree hydrogenation (see the box in
Scheme 13).
(e) High-Pressure Hydrogenations. The ultimate solution
to this dilemma was using high-pressure hydrogenation. Even
at 1500 psi of H2, catalyst and solvent were still crucial to render
this reaction feasible leading toward the desired pyran 26 rather
than 20. When the best condition of 20% Pt-alumina in hexanes
for 3 d was used, 26 was isolated as a single isomer and in the
acceptable yield of 50% and its stereochemistry was confirmed
by using NOE (see the box in Scheme 14). From molecular
modeling of 19 shown in Figure 2, both the urea group and
TBDPS group do shield the bottom face of the pyran ring,
thereby completely forcing H2 to approach from the top face.
dependent upon the pressure of H2, as higher pressure tends to
favor the directed hydrogenation product 31. A potential
mechanism was proposed as shown in Scheme 12. Upon
treatment with H2, the unsaturated Crabtree’s catalyst could
complex to the urea group and to the C3 endo-cyclic olefin,
leading to the common Ir-complex 32 in which pathways c and
d could take place depending upon the pressure of H2.
Under higher pressure (g60 psi), oxidative addition of H2
could occur to provide 33 en route to alkyl metal complex 34
via migratory insertion. Reductive elimination and epimerization
would yield tetrahydropyran 31 and regenerate the active
catalyst. However, with lower pressure (e60 psi), the com-
plexation of H2 to the Ir metal and the subsequent oxidative
addition would be slower, thereby allowing 32 to undergo ring-
opening by cleavage of the C7-O bond and form the Ir-oxo-
π-allyl complex 35. An ensuing C6-C7 bond rotation could
take place to alleviate steric interactions, leading to the more
favored conformer 36, which can afford 28 via ring-closing and
release of the Ir-catalyst.
High-pressure hydrogenations of pyrans 28 and 40 were also
examined. As shown in Scheme 15, an 89:11 isomeric ratio
with respect to C3 stereochemistry was found of 44 while a
67:33 ratio was seen for 45. At this point, we are not sure as to
why these two hydrogenations prefer the same face as the urea
group.
It is noteworthy that collectively through these hydrogenation
and epimerization studies, 6 of 8 possible diastereomers of pyran
26 could be attained from pyran 17 (Scheme 16).
To further explore this urea-direct hydrogenation, we em-
ployed the model pyran 37 with the (R)-close auxiliary because
we had unambiguously established the stereochemical outcome
of its hydrogenations (Scheme 13).6,10c Specifically, the mono-
hydrogenated product 38 obtained from standard hydrogenations
contains exclusively a cis relationship for Ha and Hb with a small
5. Crotylation of Pyran 26 with E- and Z-Crotylsilane.
With pyran 26 in hand, crotylation was then investigated.
Promoted by SnBr4, 26 was quickly epimerized to 44 with a
large J constant meaning a trans relationship between H6 and
H7. The following reaction with both E- and Z-crotylsilane
proceeded smoothly and gave the crotylation products 50a and
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Song et al.
SCHEME 12. Competition between Directed Hydrogenation and C7-Epimerization
SCHEME 13. Scope of a Urea-Directed Stork-Crabtree
Hydrogenation
SCHEME 14. High-Pressure Hydrogenations of Pyran 19
SCHEME 15. High-Pressure Hydrogenations of Pyrans 28
and 40
50b in opposing ratios (50a:50b ) 4:1 with E-crotylsilane and
1:3 with Z-crotylsilane), and the TBDPS group was also lost in
the process. We believe that along with removal of the chiral
imidazolidinone, the likely oxocarbenium ion intermediate 49
was generated in which the bulky alkyl group at C3 predomi-
nates and assumes an equatorial position.10c,17 Then, addition
of E- or Z-crotylsilane to 49 would prefer an anomerically axial
trajectory, which is both stereoelectronically and sterically
favorable, and provide the expected stereochemical outcome at
C7. On the basis of this analysis, it turned out that 50a and 50b
should be diastereomers at C8. Successive oxidation of 50a/
50b (as a 4:1 mixture) led to carboxylic acids 51a and 51b,
which could be separated. The X-ray structure of 51a unam-
(17) Romero, J. A. C.; Tabacco, S. A.; Woerpel, K. A. J. Am. Chem.
Soc. 2000, 122, 168-169.
9728 J. Org. Chem., Vol. 72, No. 25, 2007

Synthesis of the C1-C9 Subunit of (+)-Zincophorin
SCHEME 16. Summary: 6 out of 8 Possible Diastereomers Attainable from Reduction of Pyran 17
SCHEME 17. Crotylation of 26 with E- and Z-Crotylsilane
SCHEME 18. Rationale for the Stereochemical Outcome at C8
biguously confirmed all relative stereochemistry. The assignment
of C8 in 51a suggests that 51b would be the desired crotylation
product for the synthesis.
The rationale for the stereochemical outcome at C8 can be
illustrated employing Danishefsky’s C3-crotylation model as
shown in Scheme 18.4k In our C7-crotylations, when ruling out
transition states from either the anti-periplanar or the synclinal
approach with two excessive to severe gauche interactions, and
when assuming an anomerically favored axial addition of E- or
Z-crotylsilane, what is left behind would be a synclinal approach
for the E-crotylation in which ES1 is more favored in leading to
50a, whereas both anti-periplanar and synclinal pathways could
be at play for the Z-crotylation with ZA1 playing a more dominant
role to favor the formation of 50b.
J. Org. Chem, Vol. 72, No. 25, 2007 9729

Song et al.
SCHEME 19. Intercepting Cossy’s Intermmediate: C1-C9
Subunit
Hydrogenation of Pyran 17 to 19. To a heterogeneous mixture
of Pt/C (5%w/w, 1.40 g, 0.33 mmol) and cycloadduct 17 (3.80 g,
6.55 mmol) in MeOH (140 mL) was added NaBH4 (800.0 mg, 21.0
mmol) in small portions at 0 °C carefully over 2 min. The mixture
was hydrogenated with a H2-balloon for 2 h at rt, after which the
catalyst was filtered and washed with MeOH (50 mL). The MeOH
was removed under reduced pressure and the residue was diluted
with Et2O (100 mL). This mixture was washed with water (2 × 30
mL), dried over Na2SO4, and concentrated under reduced pressure.
Purification of the crude residue via silica gel flash column
chromatography (gradient eluent: 10-17% EtOAc in hexanes)
afforded pure 19 (2.40 g, 64%) as a colorless oil. 19: Rf 0.50 [33%
1
EtOAc/hexanes]; [R]25 -29.9 [c 1.45, CH2Cl2]; H NMR (500
D
MHz, CDCl3) δ 0.67 (d, 3H, J ) 6.5 Hz), 0.76 (d, 3H, J ) 6.5
Hz), 1.14-1.16 (m, 12H), 1.22 (m, 1H), 1.94-2.04 (m, 2H), 2.43
(m, 1H), 2.75 (s, 3H), 3.63 (dd, 1H, J ) 7.0, 9.5 Hz), 3.73 (dq,
1H, J ) 6.5 Hz), 3.88 (dd, 1H, J ) 6.5, 10.0 Hz), 4.49 (dd, 1H, J
) 3.5, 4.0 Hz), 4.78 (s, 1H, J ) 8.5 Hz), 5.83 (d, 1 H, J ) 3.5
Hz), 7.33 (m, 4H), 7.43-7.52 (m, 7H), 7.75-7.76 (m, 4H); 13C
NMR (125 MHz, CDCl3) δ 14.9, 15.4, 15.6, 19.7, 27.2, 27.3, 29.0,
30.1, 41.5, 57.9, 58.8, 66.9, 83.0, 94.9, 127.89, 127.91, 127.93,
127.98, 129.84, 129.88, 134.26, 134.44, 135.87, 135.93, 139.22,
154.8, 163.5; IR (neat) cm-1 2960 s, 1710 s, 1426 s, 1393 s, 1363
m; mass spectrum (APCI) m/e (% rel intensity) 583.0 (20) (M +
H)+, 439.4 (100), 393.3 (50), 279.2 (30), 191.2 (20), 101.1 (75);
HRMS (MALDI) calcd for C36H46N2O3SiNa (M + Na)+ 605.3170,
found 605.3202.
6. Synthesis of the C1-C9 Subunit: Intercepting Cossy’s
Intermediate. To complete our synthesis of the C1-C9 subunit,
the crotylated pyran 50b was carried on as a 3:1 isomeric
mixture in a sequence of Dess-Martin periodinate oxidation
and further oxidation, leading to carboxylic acid 51b still as a
3:1 mixture (Scheme 19). Then, methylation and dihydroxylation
of the formed methyl ester furnished the diol mixture 52, in
which the major isomer at C8 was readily separated as a 8:1
mixture at C9. Finally, oxidative cleavage of 53 with Pb(OAc)4
provided aldehyde 6, which spectroscopically matched Cossy’s
advanced intermediate.4n
Hydrogenation of Pyran 19 to 26. A heterogeneous mixture
of Pt/alumina (5% w/w, 80.0 mg, 0.020 mmol) and 19 (60.0 mg,
0.10 mmol) in hexanes (5 mL) was hydrogenated under 1500 psi
in a high-pressure bomb at rt for 3 d. After which, the catalyst was
filtered and washed with EtOAc (10 mL). Concentration under
reduced pressure and purification of the crude residue via silica
gel flash column chromatography (gradient eluent: 10-17% EtOAc
in hexanes) afforded pure 26 (31.0 mg, 50%) as a colorless oil.
Conclusion
26: Rf 0.50 [33% EtOAc/hexanes]; [R]25 +49.8 [c 1.00, CH2-
D
We have described here a synthesis of the C1-C9 subunit
of (+)-zincophorin that matches Cossy’s advanced intermediate,
thereby constituting a formal total synthesis, and details of an
unusual urea-directed Stork-Crabtree hydrogenation of the
hetero-[4 + 2] cycloadduct derived from a chiral allenamide.
This work provides the first application of chiral allenamides
in natural product synthesis.
1
Cl2]; H NMR (500 MHz, CDCl3) δ 0.62 (d, 3H, J ) 6.5 Hz),
0.69 (d, 3H, J ) 6.5 Hz), 0.96 (d, 3H, J ) 7.0 Hz), 1.11 (s, 9H),
1.20-1.30 (m, 2H), 1.49 (ddd, 1H, J ) 2.0, 6.0, 13.0 Hz), 1.71-
1.80 (m, 2H), 1.93 (m, 1H), 2.70 (s, 3H), 3.50-3.60 (m, 3H), 3.75
(dd, 1H, J ) 5.5, 10.0 Hz), 4.65 (d, 1H, J ) 8.5 Hz), 5.15 (d, 1H,
J ) 2.0 Hz), 7.26-7.30 (m, 4 H), 7.42-7.48 (m, 7H), 7.26-7.30
(m, 4H); 13C NMR (125 MHz, CDCl3) δ 12.6, 13.1, 15.5, 19.6,
22.3, 27.2, 28.9, 31.5, 31.6, 41.3, 57.8, 58.8, 66.1, 80.1, 86.5, 127.5,
127.8, 127.9, 129.8, 134.40, 134.44, 135.94, 135.95, 135.96, 136.00,
139.8, 168.2; IR (neat) cm-1 2962 s, 1708 s, 1472 m, 1427 s, 1390
s; mass spectrum (APCI) m/e (% rel intensity) 585.2 (100) (M +
H)+, 507.3 (30), 431.4 (20), 329.3 (80), 191.2 (30), 101.1 (90);
HRMS (MALDI) calcd for C36H48N2O3SiNa (M + Na)+ 607.3332,
found 607.3300.
Experimental Section
Preparation of Pyran 17. To a solution of chiral enone 16 (2.48
g, 7.03 mmol) in anhyd CH3CN (50 mL) was added allenamide 9
(2.22 g, 9.72 mmol). This reaction mixture was sealed under N2
and heated to 90 °C for 2 d. Concentration under reduced pressure
and purification of the crude residue via silica gel flash column
chromatography (gradient eluent: 10-20% EtOAc in hexanes)
afforded pure cycloadduct 17 (1.96 g, 58% based on recovery of
Crotylation of Pyran 26 to 50a/50b. To a solution of 26
(340.0 mg, 0.58 mmol) and Z-crotylsilane (270.0 µL, 1.74 mmol)
in CH2Cl2 (30 mL) was added SnBr4 (1.13 g, 2.32 mmol) at -78 °C.
The reaction was warmed to -35 °C slowly and stirred at
this temperature for 24 h with exposure to the air. Then the mix-
ture was quenched by adding sat aq NaHCO3 (10 mL), and extracted
with CH2Cl2 (3 × 50 mL). The combined organic phases were
washed with sat aq NaCl (2 × 15 mL), dried over Na2SO4, and
concentrated under reduced pressure. Purification of the crude
residue via silica gel flash column chromatography (gradient
eluent: 7-14% EtOAc in hexanes) afforded a mixture of 50a
and 50b (1:3, 80.0 mg, 65%) as a colorless oil. 50b: Rf 0.30
[20% EtOAc/hexanes]; 1H NMR (500 MHz, CDCl3) δ 0.84 (d, 3H,
J ) 7.0 Hz), 1.04 (d, 3H, J ) 7.0 Hz), 1.06 (d, 3H, J ) 7.0
Hz), 1.35-1.40 (m, 1H), 1.48-1.63 (m, 2H), 1.70-1.88 (m,
3H), 2.71 (m, 1H), 3.19 (dd, 1H, J ) 3.0, 9.0 Hz), 3.41 (br s,
1H), 3.47 (ddd, 1H, J ) 3.5, 9.0, 9.0 Hz), 3.60 (m, 1 H), 5.00
(d, 1H, J ) 10.5 Hz), 5.05 (d, 1H, J ) 16.5 Hz), 5.64 (ddd,
1H, J ) 8.0, 10.0, 17.0 Hz); 13C NMR (100 MHz, CDCl3) δ
17% 16) as a colorless oil. 17: Rf 0.50 [33% EtOAc/hexanes]; [R]25
D
1
-100.4 [c 1.00, CH2Cl2]; H NMR (500 MHz, CDCl3) δ 0.59 (d,
3H, J ) 6.5 Hz), 1.11 (d, 3H, J ) 6.5 Hz), 1.13 (s, 9H), 2.23 (dd,
1H, J ) 2.5, 20.5 Hz), 2.39 (m, 1H), 2.51 (dd, 1H, J ) 4.0, 20.0
Hz), 2.71 (s, 3H), 3.56-3.63 (m, 2H), 3.84 (dd, 1H, J ) 6.5, 10.0
Hz), 4.52 (dd, 1H, J ) 3.6, 4.0 Hz), 4.78 (s, 1H), 4.86 (d, 1H, J )
8.5 Hz), 5.03 (s, 1H), 6.26 (s, 1H), 7.09-7.10 (m, 2H), 7.24-7.28
(m, 3H), 7.42-7.52 (m, 6H), 7.71-7.74 (m, 4H); 13C NMR (125
MHz, CDCl3) δ 14.7, 14.8, 19.3, 26.9, 26.8, 28.6, 41.3, 56.7, 59.5,
66.5, 80.9, 94.4, 114.7, 127.59, 127.63, 127.68, 127.7, 129.50,
129.57, 133.8, 134.2, 135.46, 135.54, 135.59, 137.78, 137.98, 154.3,
161.4; IR (neat) cm-1 2957 s, 1710 s, 1456 m, 1396 s, 1361 s;
mass spectrum (APCI) m/e (% rel intensity) 581.2 (25) (M + H)+,
439.3 (100), 405.2 (80), 279.2 (50), 191.2 (75), 101.1 (75); HRMS
(MALDI) calcd for C36H45N2O3Si (M + H)+ 581.3199, found
581.3761.
9730 J. Org. Chem., Vol. 72, No. 25, 2007

Synthesis of the C1-C9 Subunit of (+)-Zincophorin
13.9, 16.1, 18.6, 24.9, 25.0, 28.4, 38.3, 39.1, 68.2, 76.5, 81.9, 114.9,
142.1. 50a: 1H NMR (500 MHz, CDCl3) δ 0.80 (d, 3H, J ) 6.5
Hz), 0.99 (d, 3H, J ) 7.0 Hz), 1.03 (d, 3H, J ) 7.0 Hz), 1.36-
1.41 (m, 1H), 1.50-1.60 (m, 2H), 1.69-1.78 (m, 2H), 1.81-1.87
(m, 1H), 2.65 (m, 1H), 3.06 (dd, 1H, J ) 4.0, 8.0 Hz), 3.21 (dd,
1H, J ) 4.0, 8.0 Hz), 3.48-3.55 (m, 1H), 3.57 (dd, 1 H, J ) 4.0,
10.6 Hz), 3.57-3.64 (m, 1H), 5.05 (d, 1H, J ) 10.0 Hz), 5.07 (d,
1H, J ) 15.0 Hz), 5.84 (ddd, 1H, J ) 8.5, 10.0, 15.0 Hz); 13C
NMR (100 MHz, CDCl3) δ 18.47, 18.50, 25.2, 25.7, 29.1, 38.0,
38.9, 67.7, 76.1, 81.7, 114.6, 141.4; IR (neat) cm-1 3439 s, 2961
s, 1640 w, 1459 s, 1376 m; mass spectrum (APCI) m/e (% rel
intensity) 213.3 (100) (M + H)+, 195.2 (85), 177.2 (90), 157.2
(30), 139.2 (45); HRMS (ESI) calcd for C13H24O2Na (M + Na)+
235.1674, found 235.1673.
Acknowledgment. The authors thank the NIH [GM066055]
for funding and Mr. Benjamin E. Kucera and Dr. Vic Young
from the University of Minnesota for providing X-ray structural
analysis.
Supporting Information Available: Experimental procedures,
1
characterization data for all new compounds, H NMR, 13C NMR
spectra, NOE’s, and X-ray structural data. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO7017922
J. Org. Chem, Vol. 72, No. 25, 2007 9731