Aldehyde-selective Wacker oxidation in a thiyl-mediated vinyl group transfer route to daunosamine

Article abstract of DOI:10.1021/ol063010z

(Chemical Equation Presented) Asymmetric dihydroxylation, thiyl radical mediated transfer of a silicon-tethered vinyl group to a hydrazone and an unconventional aldehyde-selective Wacker oxidation are sequenced for an efficient synthesis of methyl N-trifl

Full text of DOI:10.1021/ol063010z

ORGANIC
LETTERS
2007
Vol. 9, No. 5
777-780
Aldehyde-Selective Wacker Oxidation in
a Thiyl-Mediated Vinyl Group Transfer
Route to Daunosamine
Gregory K. Friestad,* Tao Jiang, and Alex K. Mathies
Department of Chemistry, UniVersity of Iowa, Iowa City, Iowa 52242
gregory-friestad@uiowa.edu
Received December 13, 2006
ABSTRACT
Asymmetric dihydroxylation, thiyl radical mediated transfer of a silicon-tethered vinyl group to a hydrazone and an unconventional aldehyde-
selective Wacker oxidation are sequenced for an efficient synthesis of methyl N-trifluoroacetyl-
L
-daunosaminide in 32% overall yield from
crotonaldehyde.
Asymmetric carbon-carbon bond constructions leading to
chiral R-branched amines continue to offer challenges to the
development of efficient methodology.1 Among these meth-
ods, radical additions to imino compounds are endowed with
certain advantages in chemoselectivity which make them
attractive complements to polar methods.2 However, methods
for intermolecular addition of carbon-centered radicals are
generally limited to alkyl radicals and do not accommodate
intermolecular addition of a vinyl group. This goal has
considerable synthetic potential due to the wide range of
functional group transformations enabled by alkene func-
tionality. We have developed such a vinyl addition in an
indirect manner (Scheme 1), using a temporary silyl ether
linkage between the radical precursor and acceptor groups
Scheme 1
with fluoride then cleaves the temporary tether and causes
elimination of benzenethiolate to regenerate the vinyl group
of an allylic amino alcohol. The favored anti relative
configuration is consistent with a chairlike Beckwith-Houk
transition state4 with the exocyclic substituent R equatorial.
Thus, a tin-free diastereoselective radical addition of a vinyl
group with “formal acyclic stereocontrol” may be realized
under mild conditions using the silicon tether approach.5
The presence of additional hydroxyl groups proved to be
of little consequence to the excellent diastereocontrol (eq
to circumvent the intermolecular process.3 In these reactions,
thiyl radicals add to the vinyl group, generating an interme-
diate alkyl radical which undergoes 5-exo cyclization with
the CdN bond of the hydrazone functionality. Treatment
(1) Reviews: (a) Vilaivan, T.; Bhanthumnavin, W.; Sritana-Anant, Y.
Curr. Org. Chem. 2005, 9, 1315-1392. (b) Friestad, G. K. Eur. J. Org.
Chem. 2005, 3157-3172. (c) Zhou, P.; Chen, B.; Davis, F. A. Tetrahedron
2004, 60, 8003-8030. (d) Job, A.; Janeck, C. F.; Bettray, W.; Peters, R.;
Enders, D. Tetrahedron 2002, 58, 2253-2329. (e) Ellman, J. A.; Owens,
T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984-995. (f) Kobayashi, S.;
Ishitani, H. Chem. ReV. 1999, 99, 1069-1094. (g) Bloch, R. Chem. ReV.
1998, 98, 1407-1438.
(2) Friestad, G. K. Tetrahedron 2001, 57, 5461-5496.
(3) (a) Friestad, G. K.; Massari, S. E. Org. Lett. 2000, 2, 4237-4240.
(b) Friestad, G. K.; Massari, S. E. J. Org. Chem. 2004, 69, 863-875.
(4) (a) Beckwith, A. L. J.; Schiesser, C. H. Tetrahedron 1985, 41, 3925-
3941. (b) Spellmeyer, D. C.; Houk, K. N. J. Org. Chem. 1987, 52, 959-
974.
10.1021/ol063010z CCC: $37.00
© 2007 American Chemical Society
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1),3 and therefore this method was envisioned to be a
potentially useful route for generation of polyhydroxylated
amines such as aminosugars.6 Oxidation of the vinyl group
few isolated examples of reversed regioselectivity in Wacker
oxidations, observed in the presence of C-O or C-N bonds
at the allylic position.12,13 The requisite terminal alkene for
this Wacker oxidation tactic could arise through silicon-
tethered vinyl addition to a chiral 2,3-dihydroxyhydrazone.3
This in turn would be conveniently available from crotonal-
dehyde via Sharpless asymmetric dihydroxylation.14
The synthesis began with the condensation of trans-
crotonaldehyde with dibenzylhydrazine (Scheme 3). Sharp-
less asymmetric dihydroxylation of the resulting (E)-R,â-
unsaturated hydrazone 2 afforded the syn-diol 3 (70% yield,
89% ee by HPLC). Silylation with chlorodimethylvinylsilane
then provided the radical cyclization precursor 4 in 98%
yield.
In the key step, exposure to thiyl radicals generated from
PhSH and azo-bisisobutyronitrile (AIBN) led to radical
cyclization of dibenzylhydrazone 4a. The unstable cyclic
intermediate was then directly treated with fluoride to afford
vinyl adduct 5a in 77% yield (dr 91:9).15 Configurational
assignment of the indicated syn,anti-stereotriad of 5a was
based on analogy with the strong precedents and was
ultimately confirmed through synthesis of a daunosamine
derivative (vide infra). The yield in this transformation
improves on an earlier result with the corresponding diphen-
ylhydrazone (63%, dr 88:12).16 It is also notable that the
would be required to reach such targets, thereby offering an
opportunity to broaden the scope of projected applications
of the radical addition. Here we report the realization of these
goals in a concise and efficient asymmetric synthesis of a
2,3-dideoxy-3-aminosugar from achiral precursors, using
an unusual aldehyde-selective Wacker oxidation as a key
step.
Aminosugars such as daunosamine are found within
oligosaccharides, glycopeptides, and anthracycline antitumor
antibiotics; their importance as synthetic targets stems from
not only their presence within natural products but also their
interesting applications in bioorganic and medicinal chem-
istry.7,8 Typically, these building blocks are prepared in
lengthy sequences from carbohydrates, a strategy which is
inherently limited to those sugar starting materials which are
readily available. We hoped to demonstrate a novel combi-
nation of the Si-tethered radical addition method with
asymmetric catalysis to access L-daunosamine (1)9 as a
prototypical member of this class of targets.10
(8) Importance of daunosamine for DNA binding: Portugal, J.; Cashman,
D. J.; Trent, J. O.; Ferrer-Miralles, N.; Przewloka, T.; Fokt, I.; Priebe, W.;
Chaires, J. B. J. Med. Chem. 2005, 48, 8209-8219.
(9) (a) Arcamone, F.; Franceschi, G.; Orezzi, P.; Babier, W.; Mondelli,
R. J. Am. Chem. Soc. 1964, 86, 5334-5335. (b) Arcamone, F.; Cassinelli,
G.; Orezzi, P.; Franceschi, G.; Mondelli, R. J. Am. Chem. Soc. 1964, 86,
5335-5336.
From the retrosynthetic perspective, the open chain form
of daunosamine (1b, Scheme 2) could be produced by
(10) For recent syntheses of aminosugars, see: (a) Parker, K. A.; Chang,
W. Org. Lett. 2005, 7, 1785-1788. (b) Trost, B. M.; Jiang, C. H.; Hammer,
K. Synthesis 2005, 3335-3345. (c) Parker, K. A.; Chang, W. Org. Lett.
2003, 5, 3891-3893. (d) Avenoza, A.; Busto, J. H.; Corzana, F.; Peregrina,
J. M.; Sucunza, D.; Zurbano, M. M. Tetrahedron: Asymmetry 2003, 14,
1037-1043. (e) Ginesta, X.; Pasto, M.; Pericas, M. A.; Riera, A. Org. Lett.
2003, 5, 3001-3004. (f) Cutchins, W. W.; McDonald, F. E. Org. Lett. 2002,
4, 749-752. (g) Liberek, B.; Dabrowska, A.; Frankowski, R.; Matuszewska,
M.; Smiatacz, Z. Carbohydr. Res. 2002, 337, 1803-1810. (h) Saotome,
C.; Ono, M.; Akita, H. Tetrahedron: Asymmetry 2000, 11, 4137-4151.
(i) Davey, R. M.; Brimble, M. A.; Mcleod, M. D. Tetrahedron Lett. 2000,
41, 5141-5145. (j) Effenberger, F.; Roos, J. Tetrahedron: Asymmetry 2000,
11, 1085-1095. (k) Davies, S. G.; Smyth, G. D.; Chippindale, A. M. J.
Chem. Soc., Perkin Trans. 1 1999, 3089-3104. (l) Szechner, B.; Achma-
towicz, O.; Badowska-Roslonek, K. Pol. J. Chem. 1999, 73, 1133-1141.
(m) Nicolaou, K. C.; Mitchell, H. J.; Jain, N. F.; Bando, T.; Hughes, R.;
Winssinger, N.; Natarajan, S.; Koumbis, A. E. Chem.-Eur. J. 1999, 5,
2648-2667. (n) Daley, L.; Roger, P.; Monneret, C. J. Carbohydr. Chem.
1997, 16, 25-48. (o) Sibi, M.; Lu, J.; Edwards, J. J. Org. Chem. 1997, 62,
5864-5872. Sibi et al. (ref 10o) provide an extensive list of references to
earlier syntheses.
Scheme 2
Wacker oxidation11 at the terminus of the corresponding
allylic amine. The feasibility of this approach rested on a
(11) Reviews: Takacs, J. M.; Jiang, X.-T. Curr. Org. Chem. 2003, 7,
369-396. Tsuji, J. Synthesis 1984, 369-384.
(12) (a) Feringa, B. L. J. Chem. Soc., Chem. Commun. 1986, 909-910.
(b) Kang, S.-K.; Jung, K.-Y.; Chung, J.-U.; Namkoong, E.-Y.; Kim, T.-H.
J. Org. Chem. 1995, 60, 4678-4679. (c) Stragies, R.; Blechert, S. J. Am.
Chem. Soc. 2000, 122, 9584-9591.
(5) For other functionalized radical synthons, see: Friestad, G. K. Org.
Lett. 1999, 1, 1499-1501. Friestad, G. K.; Jiang, T.; Fioroni, G. M.
Tetrahedron: Asymmetry 2003, 14, 2853-2856.
(6) Review: Hauser, F. M.; Ellenberger, S. R. Chem. ReV. 1986, 86,
35-67.
(7) Use of daunosamine as a linkage point in biologically active chimeric
structures: (a) Acton, E. M.; Tong, G. L.; Mosher, C. W.; Wolgemuth, R.
L. J. Med. Chem. 1984, 27, 638-645. (b) Zhang, G.; Fang, L.; Zhu, L.;
Aimiuwu, J. E.; Shen, J.; Cheng, H.; Muller, M. T.; Lee, G. E.; Sun, D.;
Wang, P. G. J. Med. Chem. 2005, 48, 5269-5278. (c) Jeffrey, S. C.;
Nguyen, M. T.; Andreyka, J. B.; Meyer, D. L.; Doronina, S. O.; Senter, P.
D. Bioorg. Med. Chem. Lett. 2006, 16, 358-362. (d) Ciesielska, E.;
Studzian, K.; Wasowska, M.; Oszczapowicz, I.; Szmigiero, L. Cell Biol.
Toxicol. 2005, 21, 139-147.
(13) (a) Hosokawa, T.; Aoki, S.; Takano, M.; Nakahira, T.; Yoshida,
Y.; Murahashi, S.-I. J. Chem. Soc., Chem. Commun. 1991, 1559-1560.
(b) Lai, J.; Shi, X.; Dai, L. J. Org. Chem. 1992, 57, 3485-3487.
(14) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483-2547.
(15) The diastereomeric ratio was determined by 1H NMR spectroscopy.
The inseparable mixture was carried through subsequent steps, after which
the minor diastereomer was no longer detected.
(16) The earlier result was complicated by the presence of syn-anti
diastereomers in the diol precursor. See ref 3. Subsequent experiments with
diastereomerically pure diphenylhydrazone resulted in similar yield (65%)
and improved selectivity (dr > 98:2).
778
Org. Lett., Vol. 9, No. 5, 2007

Scheme 3
dibenzylhydrazones are more stable during handling and
Three substrates, 6a-c, with different N-substituents were
prepared efficiently through a three-step protocol leading to
the corresponding trifluoroacetamide 6a in 98% overall yield
(Scheme 3).
Attempted Wacker oxidations (Table 1) with the inter-
mediates in the pathway from 5a to 6a, either allylic
storage, presumably due to greater resistance to air oxidation.
The silicon-tethered vinyl group was attached to both
hydroxyls of the 2,3-dihydroxyhydrazone, leaving an am-
biguity in the mechanism: Which vinyl group was trans-
ferred? We previously offered indirect evidence that the vinyl
additions involving such 2,3-bis(silyloxy)hydrazones likely
proceed through a 5-exo cyclization.3b We have now tested
this proposition by submitting the two regioisomeric monoben-
zyl ether derivatives 4b and 4c to the vinyl addition
conditions (Scheme 4). Tethering the vinyl group to the
Table 1.
Scheme 4
a Combined yield of 7a + 7b. Yields in parentheses are for the isolated
yield of 7a. bRatio (w/w) of isolated products. cDecomposition. d7b not
e
1
isolated. Ratio by H NMR.
R-hydroxyl led to modest yield (unoptimized) and excellent
stereoselectivity, consistent with the cyclization of the bissilyl
ether. In contrast, the â-tethered substrate 4c failed to cyclize,
forming the desilylated hydroxyhydrazone as the only
product after treatment with fluoride. This offers strong
evidence that the vinyl transfer in 4a involves the silicon
tether to the R-hydroxyl group through preferential 5-exo
cyclization.
hydrazine 6b or hydrazide 6c, resulted in complete degrada-
tion. After N-N bond cleavage17 to allylic trifluoroacetamide
6a, however, the Wacker oxidation furnished aldehyde 7a
and ketone 7b in yields over 80%. Although the reaction
did indeed favor the desired aldehyde, the ratio (54:46) was
unsatisfactory.
The next challenge for the synthesis was regioselective
oxidation of the terminal olefin to the aldehyde. Aldehydes
are generally undesired byproducts in Wacker oxidation, a
reaction commonly applied for reliable access to methyl
ketones. However, as noted above, this unconventional
regioselectivity in the Wacker oxidation has occasionally
been observed in the presence of polar functionality at the
allylic position.12 With vinyl adduct 5a exhibiting just such
a characteristic, it became of interest to explore Wacker
conditions for optimal aldehyde selectivity.
The effects of various copper salts were examined (Table
1). Replacing the Cu(OAc)2 with CuCl2 enhanced the
aldehyde preference, and even better results were obtained
with CuCl (64% isolated yield of aldehyde). The highest ratio
(82:18) was obtained in the presence of HMPA,12a although
the isolated yield of the aldehyde was not improved. Attempts
to increase the selectivity by addition of a lithium salt led to
the loss of the acetonide.
(17) Ding, H.; Friestad, G. K. Org. Lett. 2004, 6, 637-640.
Org. Lett., Vol. 9, No. 5, 2007
779

With a synthetically useful yield of aldehyde available,
the synthesis of protected L-daunosamine was easily com-
pleted upon exposure of 7a to methanolic HCl (eq 2). This
Acknowledgment. We thank NSF (CHE-009683) for
generously supporting this work, and we appreciate kind
assistance to T.J. by Professor Martin Kuehne (University
of Vermont).
Supporting Information Available: Preparative details
and characterization data for 2-7. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL063010Z
(18) (a) Abbaci, B.; Florent, J.-C.; Monneret, C. Bull. Soc. Chim. Fr.
1989, 667-672. (b) Shelton, C. J.; Harding, M. M. J. Chem. Res. (S) 1995,
158. (c) Shelton, C. J.; Harding, M. M. J. Chem. Res. (M) 1995, 1201-1219.
(19) In another run, after prolonged exposure to TsOH/MeOH over 5
days, the R-anomer was found to predominate. Anomeric equilibration of
â-8 to R-8 has been previously reported. See ref 18c.
(20) (a) Prior to this work, asymmetric catalytic routes to daunosamine
derivatives had been achieved in 8-10% overall yield. Xu, Z.; Johannes,
C. W.; La, D. S.; Hofilena, G. E.; Hoveyda, A. H. Tetrahedron 1997, 53,
16377-16390. Dai, L.; Lou, B.; Zhang, Y. J. Am. Chem. Soc. 1988, 110,
5195-5196. Fuganti, C.; Grasselli, P.; Pedrocchi-Fantoni, G. J. Org. Chem.
1983, 48, 910-912. (b) Other efficient syntheses of daunosamine and its
derivatives from commercially available achiral or non-carbohydrate
precursors range from five to nine steps and from 7-34% overall yield.
For details, see Supporting Information.
resulted in removal of the acetonide protecting group and
cyclization to 8,18 the methyl pyranoside form of the TFA-
protected L-daunosamine, in quantitative yield, as a 3:1
mixture of anomers.19
In summary, the application of silicon-tethered vinyl
addition under tin-free thiyl radical conditions was linked
with asymmetric dihydroxylation and a regio-reversed
Wacker oxidation to accomplish the synthesis of an L-dau-
nosamine derivative in 32% overall yield from achiral
precursors.20
780
Org. Lett., Vol. 9, No. 5, 2007