A formal total synthesis of (+)-zincophorin. observation of an unusual urea-directed stork - Crabtree hydrogenation

Article abstract of DOI:10.1021/ol070791a

A formal total synthesis of (+)-zincophorin via interception of Miyashita's advanced intermediates is described here. This effort features the first synthetic application of an inverse demand hetero [4 + 2] cycloaddition of a chiral allenamide, and the ob

Full text of DOI:10.1021/ol070791a

ORGANIC
LETTERS
2007
Vol. 9, No. 11
2199-2202
A Formal Total Synthesis of
)-Zincophorin. Observation of an
(+
Unusual Urea-Directed Stork−Crabtree
Hydrogenation†
Zhenlei Song and Richard P. Hsung*
DiVision of Pharmaceutical Sciences and Department of Chemistry,
UniVersity of Wisconsin-Madison, Rennebohm Hall, 777 Highland AVenue,
Madison, Wisconsin 53705
rhsung@wisc.edu
Received April 2, 2007
ABSTRACT
A formal total synthesis of (
first synthetic application of an inverse demand hetero [4
directed Stork Crabtree hydrogenation.
+
)-zincophorin via interception of Miyashita’s advanced intermediates is described here. This effort features the
+
2] cycloaddition of a chiral allenamide, and the observation of an unusual urea
−
(+)-Zincophorin (1), also referred to as M144255 or
griseochellin, is a polyoxygenated ionophoric antibiotic that
was isolated from Streptomyces griseus in 1984.1 It possesses
strong in vivo activity against Gram-positive bacteria and
Clostridium coelchii. Its methyl ester was reported in a
patent1d as having strong inhibitory properties against
influenza WSN/virus with reduced toxicity for the host cell.
Its ability to strongly bind with Zn2+, which is also present
in its X-ray structure,1a is the basis for its name. Over the
last two decades, (+)-zincophorin (1) has attracted an
impressive array of synthetic effort2 including Danishefsky’s3
first total synthesis along with two recent elegant total
syntheses reported by Cossy4 and Miyashita.5
Our effort some years ago6,7 in developing a stereoselective
inverse electron-demand hetero [4 + 2] cycloaddition of
chiral allenamides8-10 led us to (+)-zincophorin (1). Specif-
ically, we envisioned constructing the tetrahydropyran unit
(2) For approaches, see: (a) Cossy, J.; Blanchard, N.; Defosseux, M.;
Meyer, C. Angew. Chem., Int. Ed. 2002, 41, 2144. (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. (c) Burke, S. D.; Ng, R. A.;
Morrison, J. A.; Alberti, M. J. J. Org. Chem. 1998, 63, 3160. (d) Marshall,
J. A.; Palovich, M. R. J. Org. Chem. 1998, 63, 3701. (e) Chemler, S. R.;
Roush, W. R. J. Org. Chem. 1998, 63, 3800. (f) Booysen, J. F.; Holzapfel,
C. W. Synth. Commun. 1995, 25, 1473. (g) Cywin, C. L.; Kallmerten, J.
Tetrahedron Lett. 1993, 34, 1103. (h) Balestra, M.; Wittman, M. D.;
Kallmerten, J. Tetrahedron Lett. 1988, 29, 6905. (i) Zelle, R. E.; DeNinno,
M. P.; Selnick, H. G.; Danishefsky, S. J. J. Org. Chem. 1986, 51, 5032.
(3) The first total synthesis, see: (a) Danishefsky, S. J.; Selnick, H. G.;
DeNinno, M. P.; Zelle, R. E. J. Am. Chem. Soc. 1987, 109, 1572. (b)
Danishefsky, S. J.; Selnick, H. G.; Zelle, R. E.; DeNinno, M. P. J. Am.
Chem. Soc. 1988, 110, 4368.
† With deepest appreciation and respect, this paper is dedicated to
Professor Gilbert Stork on the special occasion of his 85th birthday.
(1) For isolation, see: (a) Brooks, H. A.; Gardner, D.; Poyser, J. P.;
King, T. J. J. Antibiot. 1984, 37, 1501. (b) Grafe, U.; Schade, W.; Roth,
M.; Radics, L.; Incze, M.; Ujszaszy, K. J. Antibiot. 1984, 37, 836. (c) Radics,
L. J. Chem. Soc., Chem. Commun. 1984, 599. (d) Grafe, U. German patent
[East] DD 231,793.
10.1021/ol070791a CCC: $37.00
© 2007 American Chemical Society
Published on Web 05/05/2007

in 1 via the hetero cycloadduct 4 derived from a cycload-
dition of chiral allenamide 5 with enone 6 (Scheme 1).
(1) TBDPS-silylation, (2) DIBAL-H reduction,16 (3) vinyl
Grignard addition, and (4) Swern oxidation (Scheme 2). The
Scheme 1. A Formal Total Synthesis of (+)-Zincophorin
Scheme 2. A Stereoselective Hetero [4 + 2] Cycloaddition
Achieving this exercise would provide the first application
of chiral allenamides in natural product synthesis and
represent an approach that differs from all other efforts.13
We report here a formal synthesis of (+)-zincophorin
featuring this cycloaddition and a urea-directed Stork-
Crabtree hydrogenation.
key [4 + 2] cycloaddition of heterodiene 9 with Close
auxiliary17 substituted allenamide 5 led to pyran 10 as a single
isomer. The relative stereochemistry at C7 (the numbering
is based on the natural product) was assigned on the basis
of our previous work with this cycloaddition.6,7a Specifically,
the heterodiene (9 here) with an s-cis conformation should
approach from the less hindered π-face of the internal olefin
of allenamide 5, which is shown in its lowest energy
conformation.6,7a It is noteworthy that this was the first time
a chiral heterodiene was used, and the high level of
diastereoselectivity is a likely result of a matched transition
state (Scheme 2).
Our efforts commenced with the synthesis of chiral enone
915 from methyl (R)-3-hydroxy-2-methylpropionic ester 7 via
(4) For Cossy’s total synthesis, see: (a) Cossy, J.; Meyer, C.; Defosseux,
M.; Blanchard, N. Pure Appl. Chem. 2005, 77, 1131. (c) Defosseux, M.;
Blanchard, N.; Meyer, C.; Cossy, J. J. Org. Chem. 2004, 69, 4626. (c)
Defosseux, M.; Blanchard, N.; Meyer, C.; Cossy, J. Org. Lett. 2003, 5,
4037.
(5) For Miyashita’s total synthesis, see: Komatsu, K.; Tanino, K.;
Miyashita, M. Angew. Chem., Int. Ed. 2004, 43, 4341.
(6) Wei, L.-L.; Hsung, R. P.; Xiong, H.; Mulder, J. A.; Nkansah, N. T.
Org. Lett. 1999, 1, 2145.
(7) Also see: (a) Berry, C. R.; Hsung, R. P. Tetrahedron 2004, 60, 7629.
(b) Wei, L.-L.; Xiong, H.; Douglas, C. J.; Hsung, R. P. Tetrahedron Lett.
1999, 40, 6903.
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 (Scheme
3). In short, after much exploration to avoid hydrolysis of
the cyclic aminal via cleavage of the C7-O bond, we were
delighted to find that hydrogenation of the exo-cyclic olefin
at C6 could be achieved by using Adam’s catalyst along with
3 equiv of NaBH4, while the C3 endo-cyclic olefin could
only be reduced by using Stork-Crabtree conditions.18,19
Unsuspectingly, we proceeded to remove the silyl group in
presumably the desired tetrahydropyran 12, only to be
confronted with a product quite different as established by
the X-ray structure of 13.
(8) For reviews on allenamides, see: (a) Hsung, R. P.; Wei, L.-L.; Xiong,
H. Acc. Chem. Res. 2003, 36, 773. (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; Chapter
21.4.
(9) For a compendium on the chemistry of allenes, see: Krause, N.;
Hashmi, A. S. K., Modern Allene Chemistry; Wiley-VCH Verlag GmbH
& Co. KGaA: Weinheim, Germany, 2004; Vols. 1 and 2.
(10) For an elegant review on the synthesis of allenes, see: (a)
Brummond, K. M.; DeForrest, K. M. Synthesis 2007, 795. For an excellent
review on the synthetic applications of allenes, see: (b) Ma, S. Chem. ReV.
2005, 105, 2829.
(11) For recent reports on the allenamide chemistry, see: (a) Parthasa-
rathy, K.; Jeganmohan, M.; Cheng, C.-H. Org. Lett. 2006, 8, 621. (b)
Fena´ndez, I.; Monterde, M. I.; Plumet, J. Tetrahedron Lett. 2005, 46, 6029.
(c) de los Rios, C.; Hegedus, L. S. J. Org. Chem. 2005, 70, 6541. (d)
Alouane, N.; Bernaud, F.; Marrot, J.; Vrancken, E.; Mangeney, P. Org.
Lett. 2005, 7, 5797.
(12) (a) Antoline, J. E.; Hsung, R. P.; Huang, J.; Song, Z.; Li, G. Org.
Lett. 2007, 9, 1275. (b) Huang, J.; Ianni, J. C.; Antoline, J. E.; Hsung, R.
P.; Kozlowski, M. C. Org. Lett. 2006, 8, 1565. (c) Berry, C. R.; Hsung, R.
P.; Antoline, J. E.; Petersen, M. E.; Rameshkumar, C.; Nielson, J. A. J.
Org. Chem. 2005, 70, 4038. (d) Shen, L.; Hsung, R. P.; Zhang, Y.; Antoline,
J. E.; Zhang, X. Org. Lett. 2005, 7, 3081. (e) Huang, J.; Hsung, R. P. J.
Am. Chem. Soc. 2005, 127, 50.
While the stereochemistry at C6 is as expected, both
stereocenters at C3 and C7 are opposite from what we had
expected. These expectations are based on our earlier
(14) Danishefsky’s synthesis featured a normal demand hetero [4 + 2]
cycloaddition of a diene with aldehyde. See ref 3.
(15) See the Supporting Information.
(16) For the synthesis of ent-8, see: (a) Alois, F.; Egmont, K.; Olivier,
Lepage J. Am. Chem. Soc. 2006, 128, 9194. (b) Bergmeier, S. C.; Stanchina,
D. M. J. Org. Chem. 1997, 62, 4449.
(17) Close, W. J. J. Org. Chem. 1950, 15, 1131.
(13) For some recent elegant studies on related inverse demand hetero
[4 + 2] cyclocadidition of chiral enamides, see: (a) Gohier, F.; Bouhadjera,
K.; Faye, D.; Gaulon, C.; Maisonneuve, V.; Dujardin, G.; Dhal, R. Org.
Lett. 2007, 9, 211. (b) Tardy, S.; Tatiboue¨t, A.; Rollin, P.; Dujardin, G.
Synlett 2006, 1425 and reference cited therein. Also see: (c) Palasz, A.
Org. Biomol. Chem. 2005, 3, 3207.
(18) 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. For some leading applications, also see: (b) Evans, D.
A.; Morrissey, M. M. J. Am. Chem. Soc. 1984, 106, 3866. (c) Ginn, J. D.;
Padwa, A. Org. Lett. 2002, 4, 1515.
(19) Crabtree, R. H.; Davis, M. W. J. Org. Chem. 1986, 51, 2655.
2200
Org. Lett., Vol. 9, No. 11, 2007

Toward this end, we carried out the reaction using 2.0
equiv of Na2CO3 to scavenge protic species that could
promote the C7-epimerization, and found 11% of 16 along
with 35% of 17. The relative stereochemistry in 16 is
assigned on the basis of the J value between H6 and H7
being in the equatorial-axial range (Scheme 4). The relative
stereochemistry in 17 was confirmed via silylation of 13.
This result implies that hydrogenation at the hindered bottom
face of 11 (shown in its lowest energy conformation20) is
possible under Stork-Crabtree conditions without a prior
C7-epimerization.
Scheme 3. Hydrogenations of Pyran 10
To be more definitive, we employed the model pyran 18
(with the (R)-Close auxiliary) because we had unambiguously
established the stereochemical outcome of its hydrogenations
(Scheme 5).6,20a Specifically, the monohydrogenated product
Scheme 5. A Urea-Directed Stork-Crabtree Hydrogenation
analyses6,7,20 in which these pyranyl hetero cycloadducts
assume a unique conformation as shown for 10 (Scheme 3).
Hydrogenations of both the C6 and C3 olefins should show
a preference at the top face of a flat pyranyl ring away from
the urea group, which shields the bottom face while being
pseudoaxially situated.
This unexpected outcome can imply a number of things
including that we had wrongfully assigned the stereochem-
istry of cycloadduct 10. However, we considered the fol-
lowing two possibilities illustrated in Scheme 4. First, the
Scheme 4. A Urea-Directed Hydrogenation vs Epimerization
19 obtained from standard hydrogenations contains exclu-
sively a cis relationship for Ha and Hb with a small J value.
When hydrogenating pyran 18 with Crabtree’s catalyst, we
isolated 20 with a large J constant, distinctly suggesting a
trans relationship between Ha and Hb. Stork-Crabtree
hydrogenation of 10 afforded the monohydrogenated product
21 also with a large J value in contrast to that of 11 (from
standard hydrogenations of 10: see Scheme 3), indicating
again a trans relationship between H6 and H7 in 21. Given
the unique conformational preference of 10 or 18,6,7,20 these
studies unequivocally support a urea-directed21,22 Stork-
Crabtree hydrogenation (see the box in Scheme 5).
The ultimate solution to this dilemma was high-pressure
hydrogenation. At 1500 psi of H2 and with Pt-Alumina in
hexane, the desired pyran 12 was isolated and stereochemi-
cally confirmed by using NOE15 (Scheme 6). Epimerization
at C7 was still an issue for 12 but no longer relevant because
the next step involved the C7-crotylation with concomitant
removal of the urea group with SnBr4.20,23 Addition of E- or
monohydrogenation product 11 could epimerize at C7 to give
14 in which hydrogenation could occur at the less congested
bottom face, leading to 13 after desilylation. While this
pathway is very likely and provides a sound rationale, we
suspected a second scenario involving a urea-directed Stork-
Crabtree hydrogenation18,19 via 15 prior to any C7-epimer-
ization.
(21) For a review on directed reactions, see: (a) Hoveyda, A. H.; Evans,
D. A.; Fu, G. C. Chem. ReV. 1993, 93, 1307. (b) For a spotlight related to
Crabtree’s catalyst, see: Nell, P. G. Synlett 2001, 160.
(20) (a) Berry, C. R.; Rameshkumar, C.; Tracey, M. R.; Wei, L.-L.;
Hsung, R. P. Synlett 2003, 791. (b) Rameshkumar, C.; Hsung, R. P. Synlett
2003, 1241.
(22) For an amide directed hydroboration using Crabtree’s catalyst, see:
(a) Evans, D. A.; Fu, G. C. J. Am. Chem. Soc. 1991, 113, 4042. (b) Evans,
D. A.; Fu, G. C.; Hoveyda, A. H. J. Am. Chem. Soc. 1992, 114, 6671.
Org. Lett., Vol. 9, No. 11, 2007
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our C7-crotylation can be illustrated24 employing Danishef-
sky’s C3-crotylation model.3
Scheme 6. Key Hydrogenation and Crotylations
To complete our formal synthesis, the crotylated pyran
22b was carried on as a 3:1 isomeric mixture in a sequence
of TIPS-protection and dihydroxylation, leading to diols 24
and 25, which were readily separated (Scheme 7). Oxidative
Scheme 7. Intercepting Miyashita’s Advanced Intermediates
Z-crotylsilane to the oxocarbenium intermediate generated
in situ (not shown) gave the crotylation products 22a and
22b in opposing ratios, and the TBDPS group was also lost
in the process.
Successive oxidation of 22a/b (as a 4:1 mixture) led to
acids 23a and 23b, which could be separated. The X-ray
structure of 23a unambiguously confirmed all relative
stereochemistry. The assignment of C8 in 23a suggests that
22b would be the desired crotylation product for the
synthesis. The rationale for the stereochemical outcome in
cleavage of 25 with Pb(OAc)4 followed by a modified-Wittig
olefination and DIBAL-H reduction provided allyl alcohol
26. Sharpless asymmetric epoxidation of 26 gave epoxide
27, and the subsequent directed epoxide ring-opening with
Me-cuprate afforded alcohol 28. Both 27 and 28 spectro-
scopically matched Miyashita’s advanced intermediates.15
Our synthetic sequence leading up to this point is comparable
to Miyashita’s approach.
We have described here a formal total synthesis of (+)-
zincophorin through matching Miyashita’s advanced inter-
mediates. Our synthesis features a highly stereoselective
hetero [4 + 2] cycloaddition of an allenamide and an unusual
urea-directed Stork-Crabtree hydrogenation. This work
provides the first application of chiral allenamides in natural
product synthesis.
(23) Romero, J. A. C.; Tabacco, S. A.; Woerpel, K. A. J. Am. Chem.
Soc. 2000, 122, 168.
(24) In our C7-crotylations, when ruling out transition states from either
the anti-periplanar or the synclinal approach with excessive 2 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
22a, 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 22b.
Acknowledgment. The authors thank NIH-NIGMS
(GM066055) and UW-Madison for financial support. The
authors also thank Dr. Victor Young (University of Min-
nesota) for providing X-ray structural analysis. We also thank
the Argonne National Laboratory for access to the Chem-
MatCARS beamline, Advanced Photon Source.
Supporting Information Available: Experimental and
1H NMR spectra and characterizations for all new com-
pounds, as well as X-ray structrural data. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL070791A
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Org. Lett., Vol. 9, No. 11, 2007