Diastereoselective additions of allylmetal reagents to free and protected syn-α,β-dihydroxyketones enable efficient synthetic routes to methyl trioxacarcinoside A

Article abstract of DOI:10.1021/ol300377a

Two routes to the 2,6-dideoxysugar methyl trioxacarcinoside A are described. Each was enabled by an apparent α-chelation-controlled addition of an allylmetal reagent to a ketone substrate containing a free α-hydroxyl group and a β-hydroxyl substituent, either free or protected as the corresponding di-tert-butylmethyl silyl ether. Both routes provide practical access to gram quantities of trioxacarcinose A in a form suitable for glycosidic coupling reactions.

Full text of DOI:10.1021/ol300377a

ORGANIC
LETTERS
2012
Vol. 14, No. 7
1812–1815
Diastereoselective Additions of Allylmetal
Reagents to Free and Protected
syn-r,β-Dihydroxyketones Enable
Efficient Synthetic Routes to
Methyl Trioxacarcinoside A
ꢀ
Daniel J. Smaltz, Jakub Svenda, and Andrew G. Myers*
Department of Chemistry and Chemical Biology, Harvard University, Cambridge,
Massachusetts 02138, United States
myers@chemistry.harvard.edu
Received February 20, 2012
ABSTRACT
Two routes to the 2,6-dideoxysugar methyl trioxacarcinoside A are described. Each was enabled by an apparent R-chelation-controlled addition of
an allylmetal reagent to a ketone substrate containing a free R-hydroxyl group and a β-hydroxyl substituent, either free or protected as the
corresponding di-tert-butylmethyl silyl ether. Both routes provide practical access to gram quantities of trioxacarcinose A in a form suitable for
glycosidic coupling reactions.
Trioxacarcinose A (1) is a rare deoxysugar found within
many trioxacarcins, densely oxygenated bacterial metabo-
lites with antiproliferative effects in cultured human cancer
cells.1 Trioxacarcin A (2), the most potent member of the
trioxacarcin natural product class (Figure 1), contains
both trioxacarcinose A and B residues, each with an
R-linkage. The desacetyl form of trioxacarcinose A, axenose
(3), is also naturally occurring and was earlier known,
appearing within the natural products axenomycin, poly-
ketomycin, and dutomycin.2 Two prior synthetic routes to
axenose have been published.3,4 The first proceeded in 13
steps (1.6% yield) from L-fucose as starting material,3a and
the second proceeded in 12 steps (∼4% yield) from 2-deoxy-
D-ribose as starting material.3b Here we describe two differ-
ent synthetic routes to the axenoseÀtrioxacarcinose A
carbohydrate class. Both routes rely upon diastereoselective
addition reactions of allylmetal reagents to R,β-dioxy-
genated ketones and employ the crystalline substance 4-phe-
nylbenzyl (2R,3S)-dihydroxybutyrate as starting material.5
The routes we present have allowed us to prepare gram
quantities of optically pure trioxacarcinose A in a form
suitable for glycosidic coupling reactions.
(1) (a) Tomita, F.; Tamaoki, T.; Morimoto, M.; Fujimoto, K.
J. Antibiot. 1981, 34, 1519–1524. (b) Tamaoki, T.; Shirahata, K.; Iida,
T.; Tomita, F. J. Antibiot. 1981, 34, 1525–1530.
(2) Axenomycin: (a) Arcamone, F.; Barbieri, W.; Franceschi, G.;
Penco, S.; Vigevani, A. J. Am. Chem. Soc. 1973, 95, 2008–2009.
Polyketomycin: (b) Momosa, I.; Chen, W.; Kinoshita, N.; Iinuma, H.;
Hamada, M.; Takeuchi, T. J. Antibiot. 1998, 51, 21–25. (c) Momosa, I.;
Chen, W.; Nakamura, H.; Naganawa, H.; Iinuma, H.; Takeuchi, T.
J. Antibiot. 1998, 51, 26–32. Dutomycin: (d) Xuan, L.-J.; Xu, S.-H.;
Zhang, H.-L. J. Antibiot. 1992, 45, 1974–1976.
Considering the open-chain or aldehydic form of triox-
acarcinose A (Scheme 1), we focused on retrosynthetic
(4) For a synthetic route to 3-epi-axenose, see: Roush, W.; Hagadorn,
S. Carbohydr. Res. 1985, 136, 187–193.
(5) Smaltz, D. J.; Myers, A. G. J. Org. Chem. 2011, 76, 8554–8559.
The Sharpless asymmetric dihydroxylation reaction was central to this
preparation of 4-phenylbenzyl (2R,3S)-dihydroxybutyrate; for a review,
see: Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev.
1994, 94, 2483–2547.
(3) (a) Garegg, P. J.; Norberg, T. Acta Chem. Scand. 1975, 29, 506–
513. (b) Giuliano, R. M.; Villani, F. J., Jr. J. Org. Chem. 1995, 60,
202–211.
r
10.1021/ol300377a
Published on Web 03/09/2012
2012 American Chemical Society

Scheme 1. Retrosynthetic Analysis of Trioxacarcinose A (1)
Scheme 2. Additions to Acetonide-Protected syn-2,3-Dihy-
droxyketones
Figure 1. Structures of R-trioxacarcinose A (1), trioxacarcin A
(2), and R-axenose (3).
operations that would disconnect carbons 2 and 3. This led
us to envision, in the synthetic direction, stereocontrolled
addition of an allyl Grignard reagent to (3R,4S)-
dihydroxy-2-pentanone with the expectation that our selection
of diol protective group(s) might influence the addition;
however, the literature did not offer clear guidance on what
diol-protecting scheme might ensure the desired stereo-
chemical outcome. While R-chelation-controlled6 additions
of Grignard reagents to 2-tetrahydrofuranyl and R-benzyloxy
ketones have been featured in landmark syntheses of stereo-
chemically complex natural products,7 additions of Grignard
reagents to ketones with acyclic side chains bearing both
R- and β-oxygenated substituents are of a less certain stereo-
chemical outcome.8
We briefly explored additions of Grignard reagents to
acetonide-protected syn-2,3-dihydroxyketones 5 (methyl
ketone) and 6 (allyl ketone)9 as summarized in Scheme 2;
however, in neither case was the stereochemical outcome
favorable for the purpose of synthesizing 1. Thus, addition
of allylmagnesium chloride to methyl ketone 5 afforded
predominantly the stereoisomer 7, which is not congruent
with trioxacarcinose A at position C3, established by
conversion of the adduct 7 to methyl 3-epi-axenoside (9)
in a 3-step sequence (Scheme 2).4,10 The observed stereo-
chemical course is consistent with either “polar FelkinÀ
Anh”11 or β-chelation-controlled transition structures, but
not an R-chelation-controlled addition. Interestingly, ad-
dition of methylmagnesium chloride to the allyl ketone 6
also afforded the tertiary alcohol 7 as the major product,
which inthiscasecorrespondstoanR-chelation-controlled
process. This is not the first instance where the stereo-
chemical outcomes of addition reactions of allyl and
methyl Grignard reagents to a common ketone substrate
have been different.12
(6) (a) Cram, D. J.; Kopecky, K. R. J. Am. Chem. Soc. 1959, 81,
2748–2755. (b) Still, W. C.; McDonald, J. H. Tetrahedron Lett. 1980, 11,
1031–1034. Reviews: (c) Reetz, M. T. Acc. Chem. Res. 1993, 26, 462–
468. (d) Mengel, A.; Reiser, O. Chem. Rev. 1999, 99, 1191–1223. (e)
Reetz, M. T. Angew. Chem., Int. Ed. 2003, 23, 556–569.
(7) (a) Nakata, T.; Kishi, Y. Tetrahedron Lett. 1978, 19, 2745–2748.
(b) Collum, D. B.; McDonald, J. H., III; Still, W. C. J. Am. Chem. Soc.
1979, 102, 2117–2120.
(8) (a) Mulzer, J.; Angermann, A. Tetrahedron Lett. 1983, 24, 2843–
2846. (b) Mead, K.; Macdonald, T. L. J. Org. Chem. 1985, 50, 422–424.
(9) Both substrates 5 and 6 were derived from 4-phenylbenzyl
(2R,3S)-dihydroxybutyrate via the Weinreb amide acetonide 4, as
summarized in Scheme 2.5
(10) Cleavage of the acetonide protective group required the use of
triflic acid in trifluoroethanol, conditions first described by the Hirama
group in the context of their synthesis of N1999A2; see: Kobayashi, S.;
Reddy, R. S.; Sugiura, Y.; Sasaki, D.; Miyagawa, N.; Hirama, M. J. Am.
Chem. Soc. 2001, 123, 2887–2888.
(11) Anh, N. T. Top. Curr. Chem. 1980, 88, 145–162.
ꢁ
(12) Carda, M.; Gonzalez, F.; Rodrı
´
guez, S.; Marco, J. A. Tetrahe-
dron: Asymmetry 1993, 4, 1799–1802.
Org. Lett., Vol. 14, No. 7, 2012
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In light of the unfavorable stereochemical outcomes
of addition reactions to the acetonide-protected ketone
substrates 5 and 6, we were led to prepare the di-tert-butyl-
siloxane ester derivative 11 as a substrate (95% yield, 12.7 g,
Scheme 3),13 which was easily achieved using the readily
available, optically pure diol ester 10 as starting material.5
Fortuitously, we observed that upon attempted transfor-
mation of the di-tert-butylsiloxane ester 11 into the corre-
sponding methyl ketone using the Merck single-step
process (via the Weinreb amide derivative)14,15 concomi-
tant, regioselective cleavage of the cyclic siloxane group
occurred, giving rise to the di-tert-butylmethyl silyl ether
12 (5.3 g, 65% yield). Although regioselective openings of
di-tert-butylsiloxane derivatives with n-butyllithium have
been described,16 we are unaware of corresponding trans-
formations with Grignard reagents.
Scheme 4. Syntheses of Methyl Axenoside (17) and Methyl
Trioxacarcinoside A (18)
Scheme 3. Synthesis of Methyl Ketone 12
Deprotection of the di-tert-butylmethylsilyl ether, a steri-
cally hindered and robust protective group,19 was accom-
plished in two steps. The cyclic hemiacetal 14 was first
transformed into the more stable methyl glycoside deriva-
tive 15 with p-toluenesulfonic acid in methanol (89%
yield). The methyl glycoside then underwent smooth
desilylation with TBAF at 23 °C to provide methyl furanosides
16 in 91% yield (890 mg). The latter product was isomer-
ized to the more stable methyl pyranosides 17 (methyl
R- and β-axenoside) with methanolic HCl at 23 °C, a
known transformation.3b,20 Analytical data were in accord
with those previously reported for methyl axenoside.3
Selective O-acetylation of 17 provided methyl trioxacarci-
noside A 18 (970 mg, 88% over two steps). Analytical data
were in agreement with values reported for the same
substance derived from natural sources.21 Hydrolysis of
18 in 1.0 M aqueous hydrochloric acid provided trioxa-
carcinose A itself (1), which was acetylated at the anomeric
position to give 1-O-acetyl glycoside 19 in 69% yield over
two steps (R:β ≈ 1:3). 1-O-Acetyl glycosides are known to
be effective glycosyl donors, do not require activation for
The selective transformation of the cyclic siloxane 11 to the
monosilyl ether 12 proved to be quite useful, as it enabled our
first synthetic route to trioxacarcinose A (Scheme 4). Addi-
tion of excess allylmagnesium chloride to R-hydroxyketone
12 in THF at À78 °C proceeded with 13:1 diastereoselectivity
favoring the tertiary alcohol product 13, consistent with an R-
chelation-controlled addition mechanism (3.59 g, 86% yield).17
The product (13) is stereochemically congruent with
trioxacarcinose A (1), as established by its conversion to
methyl axenoside (17), en route to 1, as detailed below.
Oxidative cleavage of the alkenyl side chain of 13
occurred in the presence of potassium osmate and sodium
metaperiodate,18 providing the furanose derivative 14 as a
mixture of anomers (1.97 g, 55% yield, R:β ≈ 1:5).
(13) (a) Trost, B. M.; Caldwell, C. G. Tetrahedron Lett. 1981, 22,
4999–5002. (b) Corey, E. J.; Hopkins, P. B. Tetrahedron Lett. 1982, 23,
4871–4874.
(14) Williams, J.; Jobson, R. B.; Yasuda, N.; Marchesini, G.; Dol-
ling, U.-H.; Grabowski, E. J. J. Tetrahedron Lett. 1995, 36, 5461–5464.
(15) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815–
3818.
(16) (a) Mukaiyama, T.; Shiina, I.; Kimura, K.; Akiyama, Y.;
Iwadare, H. Chem. Lett. 1995, 24, 229–230. (b) Tanino, K.; Shimizu,
T.; Kuwahara, M.; Kuwajima, I. J. Org. Chem. 1998, 63, 2422–2423.
(17) Chelation-controlled Grignard additions of R-hydroxyketones,
while relatively uncommon, are known. For an example, see: (a)
Matsunaga, N.; Kaku, T.; Ojida, A.; Tasaka, A. Tetrahedron: Asym-
metry 2004, 15, 2021–2028.
(19) Nicolaou, K. C.; Yue, E. W.; la Greca, S.; Nadin, A.; Yang, Z.;
Leresche, J. E.; Tsuri, T.; Naniwa, Y.; de Riccardis, F. Chem.;Eur. J.
1995, 1, 467–494.
(20) The product is a (presumably, thermodynamic) mixture of methyl
pyranoside and furanoside isomers: β-pyranoside, 62%; R-pyranoside,
34%; β-furanoside, 4%; R-furanoside, <1%.
(18) Yu, W.; Mei, Y.; Kang, Y.; Hua, Z.; Jin, Z. Org. Lett. 2004, 6,
3217–3219.
(21) Shirahata, K.; Iida, T.; Hirayama, N. Symposium on the Chem-
istry of Natural Products 1981, 24, 199–206.
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Org. Lett., Vol. 14, No. 7, 2012

coupling,22 and can also be transformed into a number of
other different types of glycosyl donors.23
Scheme 6. Second-Generation Synthesis of 1-O-Acetyl Triox-
acarcinose A (19)
Scheme 5. Indium-Mediated Allylations of Hydroxyaldehydes
as Described by Paquette and Mitzel24a
While the route outlined in Scheme 4 provided an
effective and scalable means of synthesizing trioxacarcinose
A and derivatives, an even shorter sequence was consid-
ered for investigation based upon a remarkable series of
publications from Paquette et al. describing diastereose-
lective, indium-mediated allylation reactions of aldehyde
and ketone substrates containing free hydroxyl groups, in
water as solvent.24 For example (summarized inScheme5),
Paquette and Mitzel showed that In-mediated allylation of
the R-hydroxyaldehyde 20 proceeded with high diastereo-
selectively to afford mainly the syn product, consistent
with an R-chelation-controlled addition mechanism, while
allylation of the β-hydroxyaldehyde 21 provided primarily
the anti product, consistent with a β-chelation-controlled
mechanism. They also reported the very interesting case of
In-mediated allylation of the polyol D-arabinose 22, where
in principle the directing effects of the R- and β-hydroxyl
groups were nonreinforcing (and the effects of γ- and
δ-hydroxyl groups were unknown); the product of
apparent R-chelation control was formed with high
diastereoselectivity.24a The latter result was particularly
germane, for it suggested that allylation of the specific
dihydroxy ketone substrate (3R,4S)-dihydroxy-2-pentanone
(23), with nonreinforcing R- and β-directing effects, might
proceed in the desired sense (with R-chelation control) to
provide a practicable and extraordinarily short sequence to
trioxacarcinose A.
To investigate the feasibility of the shorter sequence we
envisioned, we first transformed the Weinreb amide sub-
strate 45,9 into ketone 23 (9.89 g, 98% yield), in a single
operation (Scheme 6). Allylation of the latter product (23,
3.43 g) under conditions typical of those employed by
Paquette and Mitzel,24b using In powder (1.6 equiv) and
allyl bromide (1.6 equiv) in water at 23 °C, did indeed
proceed with predominant R-chelation control to provide
the water-soluble triol 24 as a 15:1 mixture of diastereomers.
Direct ozonolysis followed by reductive quenching with
dimethylsulfide led to cleavage of the terminal alkene(s) to
afford axenose (3), predominantly in its pyranose form. The
crude product was then acetylated to afford 1-O-acetyl
trioxacarcinose A (19, 42% yield over three steps from 23,
2.97 g, R:β ≈ 1:12) in >95% purity after chromatographic
purification.25
Methanolysis of 1-O-acetyl trioxacarcinose A (19)
synthesized by this second route (using acetyl chloride in
methanol) produced methyl trioxacarcinoside A (18, 74%
yield, see Supporting Information), which provided ana-
lytical data indistinguishable from those of 18 from our
first route, described above. By virtue of its greater brevity
and convenience, the second synthetic route provides an
especially useful means of access to trioxacarcinose A in an
anomerically activated form.
Acknowledgment. Financial support from the National
Institutes of Health (Grant CA047148) and the Department
of Defense (National Defense Science and Engineering
Graduate Fellowship to D.J.S.) is gratefully acknowledged.
(22) Toshima, K.; Tatsuta, K. Chem. Rev. 1993, 93, 1503–1531.
(23) (a) Ogawa, T.; Kitajima, T.; Nukada, T. Carbohydr. Res. 1983,
123, C8–C11. (b) Hayashi, M.; Hashimoto, S.; Noyori, R. Chem. Lett.
1984, 13, 1747–1750. (c) Kihlberg, J. O.; Leigh, D. A.; Bundle, D. R.
J. Org. Chem. 1990, 55, 2860–2863. (d) Sarkar, S.; Lombardo, S. A.;
Herner, D. N.; Talan, R. S.; Wall, K. A.; Sucheck, S. J. J. Am. Chem.
Soc. 2010, 132, 17236–17246.
(24) (a) Paquette, L. A.; Mitzel, T. M. Tetrahedron Lett. 1995, 36,
6863–6866. (b) Paquette, L. A.; Mitzel, T. M. J. Am. Chem. Soc. 1996,
118, 1931–1937. (c) Paquette, L. A.; Lobben, P. C. J. Org. Chem. 1998,
63, 5604–5616.
Supporting Information Available. Experimental proce-
dures and characterization data (1H and 13C NMR, FT-IR,
and HRMS) for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.
org.
(25) The highly polar intermediates 24 and 3 were difficult to purify
chromatographically and so were carried through subsequent transfor-
mations without purification. We believe that this contributed to the
moderate yield of 19 over the three-step sequence.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 7, 2012
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