Synthesis of the fully glycosylated cyclohexenone core of lomaiviticin A

Article abstract of DOI:10.1021/ol901710b

We describe two four-step sequences for conversion of the inexpensive reagent ethyl sorbate to either O-allyl-N,N-dimethyl-D-pyrrolosamine or O-allyl-L-oleandrose, protected forms of the 2,6-dldeoxy sugar residues found in the complex bacterial metabolite

Full text of DOI:10.1021/ol901710b

ORGANIC
LETTERS
2009
Vol. 11, No. 19
4322-4325
Synthesis of the Fully Glycosylated
Cyclohexenone Core of Lomaiviticin A
Shivajirao L. Gholap, Christina M. Woo, P. C. Ravikumar, and Seth B. Herzon*
Department of Chemistry, Yale UniVersity, New HaVen, Connecticut 06520
seth.herzon@yale.edu
Received July 25, 2009
ABSTRACT
We describe two four-step sequences for conversion of the inexpensive reagent ethyl sorbate to either O-allyl-N,N-dimethyl-D-pyrrolosamine
or O-allyl-L-oleandrose, protected forms of the 2,6-dideoxy sugar residues found in the complex bacterial metabolite lomaiviticin A. We also
report a gram-scale synthesis of the highly-oxygenated cyclohexenone ring of this metabolite, and show this may be coupled with the
aforementioned donors to form the bis(glycoside) 6. The longest linear sequence to 6 is nine steps.
In 2001, He and co-workers reported the isolation of the
complex (fw ) 1364 Da) dimeric metabolite lomaiviticin A
(1) from a strain of Micromonospora lomaiVitiensis (Figure
1).1 Extensive NMR, MS, and IR analysis led to formulation
of the structure shown, though the absolute stereochemistry
(suggested as depicted) was not rigorously established.
Lomaiviticin A (1) was reported to be a powerful antipro-
liferative agent, with IC50 values in the 0.01-100 nM range;
it was also shown to inhibit the growth of Gram-positive
bacteria at ng/mL concentrations.1 Lomaiviticin A (1) bears
some homology to the kinamycins (2-5), antiproliferative
metabolites isolated in the 1970s by Omura and co-workers.2
The structure of the kinamycins was initially proposed to
(1) He, H.; Ding, W. D.; Bernan, V. S.; Richardson, A. D.; Ireland,
C. M.; Greenstein, M.; Ellestad, G. A.; Carter, G. T. J. Am. Chem. Soc.
2001, 123, 5362.
Figure 1. Structures of lomaiviticin A (1) and kinamycins A-D
(2-5).
(2) Isolation: (a) Ito, S.; Matsuya, T.; Omura, S.; Otani, M.; Nakagawa,
A. J. Antibiot. 1970, 23, 315. (b) Hata, T.; Omura, S.; Iwai, Y.; Nakagawa,
A.; Otani, M. J. Antibiot. 1971, 24, 353. (c) Omura, S.; Nakagawa, A.;
Yamada, H.; Hata, T.; Furusaki, A.; Watanabe, T. Chem. Pharm. Bull. 1971,
19, 2428. Syntheses: (d) Lei, X.; Porco, J. A. J. Am. Chem. Soc. 2006,
128, 14790. (e) Kumamoto, T.; Kitani, Y.; Tsuchiya, H.; Yamaguchi, K.;
Seki, H.; Ishikawa, T. Tetrahedron 2007, 63, 5189. (f) Nicolaou, K. C.; Li,
H.; Nold, A. L.; Pappo, D.; Lenzen, A. J. Am. Chem. Soc. 2007, 129, 10356.
contain an N-cyanocarbazole unit, but subsequent syntheses
of a biosynthetic precursor3 and re-evaluation of the spectral
data of the isolates4 prompted reconsideration of this
proposal, eventually leading to incorporation of an unusual
10.1021/ol901710b CCC: $40.75
Published on Web 08/31/2009
 2009 American Chemical Society

diazonapthoquinone function (diazofluorene, red in the
kinamycin structure, Figure 1), which had not been seen
before in natural products. Subsequently, this functional
group was also shown to exist in the structure of lomaiviticin
A (1).1
suitably protected N,N-dimethyl-D-pyrrolosamine and L-
oleandrose sugar donors. Both D- and L-oleandrose are well-
known, and several synthetic routes to each have been
described.7 The 2-deoxyaminosugar N,N-dimethyl-D-pyrro-
losamine is less common among natural products,8 and
preparation of pyrrolosamine, bearing the fully alkylated
tertiary amine function, has not yet been reported.9,10
Our synthetic approach to these sugars was guided by the
recognition of the pseudoenantiomeric relationship between
them, which suggested they might be accessible using parallel
synthetic routes that began with enantiomerically pure
material of opposite configurations (Figure 2). The additional
The unusual functionality, connectivity, and topology of
lomaiviticin A (1) pose great challenges to synthesis. Central
to preparation of this target is a method for the stereocon-
trolled construction of the oxygenated cyclohexenone ring
and introduction of the appended N,N-dimethyl-ꢀ-D-pyrro-
losamine and R-L-oleandrose glycoside residues. Although
syntheses of the cyclohexenone core5 and the monomeric
aglycone6 of lomaiviticin A (1) have been reported, the
preparation and incorporation of the sugar residues into
advanced intermediates has not yet been addressed.
We describe herein two exceedingly simple, four-step
sequences that deliver the N,N-dimethyl-D-pyrrolosamine
and L-oleandrose residues of lomaiviticin A (1) in pro-
tected form and high overall yield. We also report a gram-
scale synthesis of the diol 8 and the coupling of these
three intermediates to form the glycosylated core of
lomaiviticin A (1). The overall synthetic route is excep-
tionally short, requiring only nine linear steps to obtain
the bis(glycoside) 6 (Scheme 1).
Figure 2. Illustration of the pseudoenantiomeric relationship
between the L-oleandrose and N,N-dimethyl-D-pyrrolosamine sugars
of lomaiviticin A (1).
realization that both carbon skeletons are readily transcribed
onto the inexpensive commercial reagent ethyl sorbate led
to the selection of this compound for initiation of our
synthetic studies.
Scheme 1. Retrosynthetic Analysis of Bis(glycoside) 6
Synthesis of the protected N,N-dimethyl-D-pyrrolosamine
residue began by heating solutions of the epoxide 9 (prepared
in enantiomerically pure form by Shi epoxidation of ethyl
sorbate)11 in ethanol in the presence of dimethylamine at 45
°C for 2 days. Under these conditions, the aminoalcohol 10
was obtained in 51% yield, along with trace amounts of its
(separable) regioisomer. The product of conjugate addition
of dimethylamine to the unsaturated ester, without opening
of the epoxide function, was also isolated separately (28%,
not shown). The latter could be converted to the aminoal-
cohol 10 by heating in ethanol in a sealed vessel at 60 °C
for 4 days (93%, see Supporting Information). Next, the ester
(5) (a) Freed, J. D. Ph.D. Thesis, Harvard University, Cambridge, MA,
2005. (b) Nicolaou, K. C.; Denton, R. M.; Lenzen, A.; Edmonds, D. J.; Li,
A.; Milburn, R. R.; Harrison, S. T. Angew. Chem., Int. Ed. 2006, 45, 2076.
(c) Krygowski, E. S.; Murphy-Benenato, K.; Shair, M. D. Angew. Chem.,
Int. Ed. 2008, 47, 1680. (d) Zhang, W.; Baranczak, A.; Sulikowski, G. A.
Org. Lett. 2008, 10, 1939.
(6) Nicolaou, K. C.; Nold, A. L.; Li, H Angew. Chem., Int. Ed. 2009,
48, 5860.
(7) (a) Blindenbacher, F.; Reichstein, T. HelV. Chim. Acta 1948, 31,
2061. (b) Berti, G.; Catelani, G.; Colonna, F.; Monti, L. Tetrahedron 1982,
38, 3067. (c) Wuts, P. G. M.; Bigelow, S. S. J. Org. Chem. 1983, 48, 3489.
(d) Ravi, D.; Kulkarni, V. R.; Mereyala, H. B. Tetrahedron Lett. 1989, 30,
4287. (e) Tolman, R. L.; Peterson, L. H. Carbohydr. Res. 1989, 189, 113.
(f) Ford, M. J.; Ley, S. V. Synlett 1990, 771. (g) Bredenkamp, M. W.;
Holzapfel, C. W.; Toerien, F. Synth. Commun. 1992, 22, 2459. (h) Zhao,
X. Y.; Ono, M.; Akita, H.; Chi, Y. M. Chin. Chem. Lett. 2006, 17, 730. (i)
Brasholz, M.; Reissig, H.-U. Eur. J. Org. Chem. 2009, 3595.
(8) N,N-Dimethylpyrrolosamine is present in two other known isolates,
lomaiviticin B1 and pyrrolosporin. Schroeder, D. R.; Colson, K. L.; Klohr,
S. E.; Lee, M. S.; Matson, J. A.; Brinen, L. S.; Clardy, J. J. Antibiot. 1996,
49, 865.
As detailed in Scheme 1, the bis(glycoside) 6 was prepared
by sequential glycosylation reactions of the diol 8 with
(3) (a) Echavarren, A. M.; Tamayo, N.; Paredes, M. C. Tetrahedron
Lett. 1993, 34, 4713. (b) Hauser, F. M.; Zhou, M. J. Org. Chem. 1996, 61,
5722.
(4) (a) Gould, S. J.; Tamayo, N.; Melville, C. R.; Cone, M. C. J. Am.
Chem. Soc. 1994, 116, 2207. (b) Mithani, S.; Weeratunga, G.; Taylor, N. J.;
Dmitrienko, G. I. J. Am. Chem. Soc. 1994, 116, 2209. (c) Proteau, P. J.; Li,
Y.; Chen, J.; Williamson, R. T.; Gould, S. J.; Laufer, R. S.; Dmitrienko,
G. I. J. Am. Chem. Soc. 2000, 122, 8325. For a review of kinamycin
biosynthesis, see: (d) Gould, S. J. Chem. ReV. 1997, 97, 2499.
(9) For synthesis of N-protected pyrrolosamine, see: Morris, W. J.; Shair,
M. D. Org. Lett. 2008, 11, 9.
Org. Lett., Vol. 11, No. 19, 2009
4323

with DIBAL-H (2 equiv) to generate the unsaturated alde-
hyde 14 (89%). Stirring solutions of the unsaturated aldehyde
14 and DBU (5 equiv) in methanol7f at 24 °C smoothly
formed the protected L-oleandrose intermediate 15 as well
as its C-3 diastereomer (91%, 1:1 mixture of C-3 diastere-
omers). These were readily separable by flash column
chromatography, and subjection of the undesired diastere-
omer to the reaction conditions re-established this mixture
and served to increase material throughput.
Scheme 2
.
Synthesis of N,N-Dimethyl-O-allyl-D-pyrrolosamine
(12) and O-Allyl-L-oleandrose (15)
With an efficient synthetic route to the sugar residues of
lomaiviticin A (1) in hand, attention turned toward prepara-
tion of the key diol intermediate 8 (Scheme 3). The synthesis
Scheme 3. Synthesis of Diol 8
of 8 began with the ketone 16, prepared from (-)-quinic
acid by an established sequence.12 Addition of excess
ethylmagnesium bromide (3 equiv) to the ketone 16 served
to form the tertiary hydroxyl group of the diol 8 as a single
detectable diastereomer (1H NMR analysis); the benzoyl
protecting group of 16 was then cleaved by exposure to
potassium carbonate in methanol, to yield the triol 17.
Oxidative cleavage of the vicinal diol function of 17 (sodium
periodate, 89%) generated the ketone 18. Deprotection of
the acetonide function of 18 via elimination of the ꢀ-oxygen
substituent (2 mol % sodium hydroxide) smoothly formed
the diol 8 (93%).13 This short sequence was easily scalable,
allowing preparation of 8 in gram quantities in a single pass.
Our efforts then focused on methods to introduce the
protected N,N-dimethyl-D-pyrrolosamine and L-oleandrose
function of 10 was reduced by treatment with diisobutyla-
luminum hydride (DIBAL-H, 2 equiv), to furnish the
aldehyde 11 in nearly quantitative yield. Stirring a solution
of the aldehyde 11 and 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU, 5 equiv) in allyl alcohol as solvent afforded the
protected N,N-dimethyl-D-pyrrolosamine derivative 12 in
88% yield, as a 2:1 mixture of R and ꢀ anomers. The
stereochemistry of the newly formed C-1 and C-3 stereo-
centers were established by 2D-NOESY experiments and
analysis of 1H-1H coupling constants (see Supporting
Information). The alternate C-3 diastereomer could not be
detected in the unpurified reaction mixture (1H NMR
analysis).
Our synthesis of the protected L-oleandrose residue follows
a parallel route. The epoxide ent-9 was opened with allyl
alcohol in the presence of sulphuric acid to form the hydroxy
ether 13 (69%). The ester function of 13 was then reduced
(12) (a) Barros, M. T.; Maycock, C. D.; Ventura, M. R. Tetrahedron
1999, 55, 3233. (b) Trost, B. M.; Romero, A. G. J. Org. Chem. 2002, 51,
2332.
(13) The relative stereochemistry of the diol 8 was confirmed by NOE
analysis of the corresponding acetonide (see Supporting Information).
(14) (a) Toshima, K.; Tatsuta, K. Chem. ReV. 1993, 93, 1503. (b)
Marzabadi, C. H.; Franck, R. W. Tetrahedron 2000, 56, 8385. (c) Nicolaou,
K. C.; Mitchell, H. J. Angew. Chem., Int. Ed. 2001, 40, 1576. (d) Zhu, X.;
Schmidt, R. R. Angew. Chem., Int. Ed. 2009, 48, 1900.
(10) For syntheses of the stereoisomeric sugar L-kedarosamine, see: (a)
Vuljanic, T.; Kihlberg, J.; Somfai, P. J. Org. Chem. 1998, 63, 279. (b)
Lear, M. J.; Hirama, M. Tetrahedron Lett. 1999, 40, 4897. (c) Priebe, W.;
Skibicki, P.; Neamati, N.; Achmatowicz, O.; Grynkiewicz, G.; Szechner,
B. Pol. J. Chem. 1999, 73, 1143. (d) Matsushima, Y.; Nakayama, T.;
Tohyama, S.; Eguchi, T.; Kakinuma, K. J. Chem. Soc., Perkin Trans. 1
2001, 569. (e) Ren, F.; Hogan, P. C.; Anderson, A. J.; Myers, A. G. Org.
Lett. 2007, 9, 1923.
(15) For example, treatment of the diol 8 with p-toluenesulfonic acid in
acetone or tert-butyldimethylsilyl triflate-2,6-lutidine in dichloromethane
resulted in rapid formation of 2-ethyl hydroquinone.
(11) (a) Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am.
Chem. Soc. 1997, 119, 11224. (b) Frohn, M.; Dalkiewicz, M.; Tu, Y.; Wang,
Z.-X.; Shi, Y. J. Org. Chem. 1998, 63, 2948. (c) Shi, Y. In Modern
Oxidation Methods; Wiley: New York, 2004; p 51.
(16) (a) Hashimoto, S.-i.; Sano, A.; Sakamoto, H.; Hakajima, M.;
Yanagiya, Y.; Ikegami, S. Synlett 1995, 1271. (b) Guo, Y.; Sulikowski,
G. A. J. Am. Chem. Soc. 1998, 120, 1392. (c) Pongdee, R.; Wu, B.;
Sulikowski, G. A. Org. Lett. 2001, 3, 3523.
4324
Org. Lett., Vol. 11, No. 19, 2009

4).16 The glycosylphosphinate 19 was obtained as a 2:1
mixture of R/ꢀ anomers, and these could be separated by
flash column chromatography. Treatment of a mixture of
the diol 8 and the diastereomerically pure R-glycosylphos-
phinate 19 with boron trifluoride diethyl etherate complex
in tetrahydrofuran at 0 °C afforded the ꢀ-glycosylated
product 7 in 35% yield, along with the undesired R-anomer
(23%, not shown).17 Extensive investigations of other
donors (e.g., glycosyl fluoride, phenylthioglycoside, trichlo-
roacetimidate) were less successful, primarily leading to
lower ꢀ-selectivity and/or conversion. For installation of
the second sugar residue, the glycosyl fluoride 20 was
prepared by treatment of the O-allyl-L-oleandrose 9 with
excess diethylaminosulfur trifluoride (DAST, 81%).18
Treatment of a mixture of the mono(glycoside) 7 and the
glycosyl fluoride 20 with boron trifluoride diethyl etherate
complex then afforded the key bis(glycoside) 6.
Scheme 4. Activation of N,N-Dimethyl-O-allyl-D-pyrrolosamine
(12) and O-Allyl-L-oleandrose (15) Fragments and Coupling
with 8 To Form Bis(glycoside) 6
In summary, we have developed an efficient synthetic route
to the bis(glycoside) 6 that was enabled by development of
a concise synthesis of each of the protected sugar residues
of lomaiviticin A (1), as well as a straightforward synthesis
of the key diol intermediate 8. We envision that the sugar
syntheses described herein may find application in the
preparation of other 2,6-dideoxyglycosides.
Acknowledgment. We thank Professors Miller, Micalizio,
Wiberg, Spiegel, and Moore and their respective groups
(Yale University) for generous donations of equipment and
chemicals. Financial support from Yale University and Eli
Lilly is gratefully acknowledged.
residues to the diol 8. At the outset, we were aware that these
would be challenging glycosylations, as both residues lack the
C-2 substituents that often provide anchimeric assistance and
stereocontrol for such transformations.14 Additionally, the
trialkylamino substituent of the N,N-dimethylpyrrolosamine
residue 12 was envisioned to be reactive toward the strong
Lewis acids typically used in synthetic glycosylations, and the
acceptor 8 had been established as unstable toward strong protic
or Lewis acids for prolonged periods of time.15 We found that
N,N-dimethyl-O-allyl-D-pyrrolosamine (12) was best activated
as its corresponding glycosylphosphinate (19), achieved by
treatment of 12 with 2-chloro-4,4,5,5-tetramethyl-1,3,2-diox-
aphospholane and triethylamine at low temperature (Scheme
Supporting Information Available: Experimental pro-
cedures and spectral data (1H and 13C NMR, IR, and HRMS)
for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL901710B
(17) Use of the ꢀ-anomer of 19 in the glycosylation reaction resulted in
formation of the glycosylated product with nearly exclusive R-selectivity,
suggesting the ꢀ-glycoside 7 arises from an SN2-like displacement of the
activated R-phosphinate.
(18) Posner, G. H.; Haines, S. R. Tetrahedron Lett. 1985, 26, 5.
Org. Lett., Vol. 11, No. 19, 2009
4325