Rapid stereocontrolled assembly of the fully substituted C-aryl glycoside of kendomycin with a Prins cyclization: A formal synthesis

Article abstract of DOI:10.1039/b602937j

Prins cyclization using an electron-rich benzaldehyde and a homoallylic alcohol efficiently delivered the fully substituted C-aryl tetrahydropyranoside of kendomycin. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b602937j

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Rapid stereocontrolled assembly of the fully substituted C-aryl
glycoside of kendomycin with a Prins cyclization: a formal synthesis{
Kevin B. Bahnck and Scott D. Rychnovsky*
Received (in Bloomington, IN, USA) 25th February 2006, Accepted 30th March 2006
First published as an Advance Article on the web 2nd May 2006
DOI: 10.1039/b602937j
tetrahydropyranols, such as that found in 1. Fig. 1 illustrates our
retrosynthetic strategy utilizing this approach. Tetrahydropyran
(THP) 2 was envisaged to arise from a Prins cyclization between
homoallylic alcohol and benzaldehyde components of roughly
equal complexity. This Prins approach would efficiently generate
three new stereocenters in a single synthetic transformation. While
the potential of the Prins cyclization is well precedented,7–10 its
scope and generality with highly substituted aromatic aldehydes
have not been fully developed. Our proposed strategy would
provide a concise assembly of the C-aryl pyranoside scaffold found
in 1, and it would extend the scope of the Prins reaction. Here we
present a successful application of the Prins cyclization as the key
step in the convergent synthesis of the fully substituted 2-aryl
tetrahydropyranol 2 found in kendomycin.
Prins cyclization using an electron-rich benzaldehyde and a
homoallylic alcohol efficiently delivered the fully substituted
C-aryl tetrahydropyranoside of kendomycin.
Kendomycin (1, Fig. 1), a polyketide metabolite of the common
soil bacteria Streptomyces violaceoruber, has shown remarkable
potential for use as a medicinal agent since its initial isolation by
Funahishi and coworkers in 19961 and Bode and Zeeck’s
subsequent reisolation and structure determination by Mosher’s
ester and X-ray crystallographic analysis in 2000.2
Pharmacologically,1–3 kendomycin has shown impressive cytotoxi-
city against human breast, stomach, and liver carcinoma cell lines
(GI50 , 100 nM), as well as anti-bacterial activity against both
methicillin- and vancomycin-resistant Staphylococcus aureus.
Additionally, kendomycin exhibits anti-osteoporotic activity and
potent antagonism against the endothelin receptor.
The homoallylic alcohol and benzaldehyde components for the
key Prins cyclizations were prepared from known compounds 4–6
(Scheme 1). Allylation of aldehyde 411 with Hoffmann’s boronate
512 forged (E)-homoallylic syn-alcohol 7 in excellent yield with
.95% diastereoselectivity.13,14 Acylation of known phenol 615
provided acetyloxy benzaldehyde 8.
Kendomycin’s potential as a medicinal agent and its demanding
structural topography have generated considerable interest in the
synthetic organic community. Synthetically challenging features of
this macrocyclic natural product include a fully substituted C-aryl
glycosidic core, bridged by a lipophilic ansa-polyketide chain
containing an (E)-trisubstituted olefin. The Lee group4 and the
Smith5 group have reported total syntheses of kendomycin.
Seminal investigations by Mulzer et al. developed much of the
chemistry of the natural product,6a–e and a number of other
groups have reported diverse synthetic approaches to this
fascinating compound.6
These readily available components were then studied in the key
Prins cyclization reaction. Treatment of homoallylic alcohol 7 and
benzaldehyde 8 with BF3?OEt2 and HOAc in hexane generated
tetrahydropyran acetate 9a and alcohol 9b as single diastereomers
in 65% combined yield. This Prins cyclization efficiently delivered a
C-aryl glycoside containing 19 of the 29 carbons of 1 and six of its
nine stereocenters. Reductive cleavage of the acetates and
subsequent bromination of the arene then provided target THP
2 in 35% yield over four steps from aldehyde 4. An analogous
Prins cyclization with alcohol 7 and sulfonyloxy benzaldehyde 10
generated tetrahydropyrans 11 in excellent yield; however, the
sulfonate group could not be hydrolyzed under basic methanolysis
conditions without extensive decomposition, in accordance with a
similar observation by the Willis group.9b
Our group7 and others8–10 have studied the Prins cyclization as a
convergent and highly diastereoselective means of synthesizing
Our mechanistic rationale for the key Prins cyclization is shown
in Fig. 2. Condensation of alcohol 7 and benzaldehyde 8 with
BF3?OEt2 and HOAc generates (E)-oxocarbenium ion 12a.
Nucleophilic capture from an equatorial trajectory in the expected
chair-like transition state at the C(4)-position of cation 12a delivers
THP 9a. With a poorly nucleophilic anion, trapping and
cyclization to THP 9 become slow relative to oxonia-Cope
equilibration to the higher energy, non-conjugated cation 12b.
Because each oxocarbenium ion 12 preserves the inherited
stereochemistry, trapping either entity at the C(4) position leads
to THPs 9. Slower trapping, however, provides oxocarbenium ion
12b increased opportunity to undergo an undesired fragmentation
or hydrolysis to generate aldehyde 4.9b,e Alcohol 7 reacts
Fig. 1 Retrosynthetic analysis of kendomycin.
Department of Chemistry, 1102 Natural Sciences II, University of
California, Irvine, Irvine, CA, 92697, USA. E-mail: srychnov@uci.edu;
Fax: +1 949-824-6379; Tel: +1 949-824-8292
{ Electronic supplementary information (ESI) available: Complete
experimental procedures and characterization for all compounds, includ-
ing improved laboratory-scale preparations of known intermediates 5 and
6. See DOI: 10.1039/b602937j
2388 | Chem. Commun., 2006, 2388–2390
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Fig. 2 Mechanistic rationale for cyclizations to THPs 9 and 13.
and counterproductive side processes, such as fragmentation.
Replacing TFA with AcOH as a trapping agent and using
BF3?OEt2 as a promoter strongly suppressed the production of
THP 13 to ,10%. Finally, we reasoned that a less polar solvent
should further disfavor fragmentation. Changing the solvent from
DCM to non-polar n-hexane increased the yields of THPs 9 and
11 to 65% and 86%, respectively. The optimized reaction
conditions are heterogeneous, as the benzaldehyde and THP
product are essentially insoluble in the hexane solvent. The low
solubilities of the aldehydes 8 and 10 result in their low reaction
concentrations, which presumably play a role in reducing the
formation of side product 13.
The tetrahydropyran 15 was an intermediate in Smith and
coworkers’ synthesis of kendomycin.5 We set out to prepare THP
15 using our Prins cyclization approach, both to secure the
structure of 2 and to complete a formal synthesis of kendomycin
(Scheme 2). Introduction of the terminal olefin of 15 was first
pursued using a Prins cyclization with an unsaturated analog of
alcohol 7.17 The Prins reaction between benzaldehyde 10 and the
diene alcohol,17 however, generated a complex product mixture.
Scheme 1 (a) i. n-hexane, 0 uC, 36 h; ii. NaOH, H2O2, 91%; (b) AcCl,
pyr., 88%; (c) BF3-OEt2, AcOH, n-hexane, 0 uC to rt, 12 h; (d) DIBAL-H,
278 uC, DCM, 91%; (e) Br2, CHCl3 65%.
preferentially with newly formed aldehyde 4 in a Prins cyclization,
leading to side-chain exchange product 13. Yields of THP 13 were
used to estimate the amount of aldehyde 4 formed during the Prins
cyclization reactions.
The successful Prins cyclizations depicted in Scheme 1 required
the optimization of several parameters to control the problematic
fragmentation. First, we found that attenuation of the phenolic
electrons with an electron-withdrawing group was necessary to
suppress the fragmentation of oxocarbenium ion 12b.9b
Acetylation (8) and sulfonylation (10) of the phenol successfully
accomplished this requirement.16 A second consideration was the
competency of the trapping agent. Initial cyclization studies using
TFA in DCM as solvent9 generated the trifluoroacetate analogs of
9a and 11a in only 25–35% yields, while side-chain exchange
products such as 13 (35–55%) and decomposition dominated the
product mixtures. We hypothesize that the poor nucleophilicity of
the trifluoroacetate anion prevents efficient trapping of cations 12
and thus increases the population of the kinetically competitive
Scheme 2 (a) TBSOTf, 2,6-lutidine, 80%; (b) H2, Pd/C, 89%; (c) Br2,
propylene oxide, CH2Cl2, 75%; (d) i. 2-(NO2)-C6H4-SeCN, PBu3; ii. H2O2,
THF, 73%.
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8 For reviews on the Prins cyclization, see: (a) L. E. Overman and
L. D. Pennington, J. Org. Chem., 2003, 68, 7143; (b) B. B. Snider, in The
Prins Reaction and Carbonyl Ene Reactions, ed. B. M. Trost, I. Fleming
and C. H. Heathcock, Pergamon Press, New York, 1991, vol. 2, p. 527;
(c) D. R. Adams and S. P. Bhatnagar, Synthesis, 1977, 661; (d)
E. Arundale and L. A. Mikeska, Chem. Rev., 1952, 52, 505.
9 For studies from the Willis group: (a) C. S. Barry, N. Bushby, J. P. H.
Charmant, J. D. Elsworth, J. R. Harding and C. L. Willis, Chem.
Commun., 2005, 5097; (b) C. S. Barry, N. Bushby, J. R. Harding,
R. A. Hughes, G. D. Parker, R. Roe and C. L. Willis, Chem. Commun.,
2005, 3727; (c) C. S. Barry, N. Bushby, J. R. Harding and C. L. Willis,
Org. Lett., 2005, 7, 2683; (d) C. S. J. Barry, S. R. Crosby, J. R. Harding,
R. A. Hughes, C. D. King, G. D. Parker and C. L. Willis, Org. Lett.,
2003, 5, 2429; (e) S. R. Crosby, J. R. Harding, C. D. King, G. D. Parker
and C. L. Willis, Org. Lett., 2002, 4, 3407; (f) S. R. Crosby, J. R. Harding,
C. D. King, G. D. Parker and C. L. Willis, Org. Lett., 2002, 4, 577; (g)
E. H. Al-Mutairi, S. R. Crosby, J. Darzi, J. R. Harding, R. A. Hughes,
C. D. King, T. J. Simpson, R. W. Smith and C. L. Willis, Chem.
Commun., 2001, 835.
10 (a) K. N. Cossey and R. L. Funk, J. Am. Chem. Soc., 2004, 126, 12216;
(b) K. V. Yadav and N. V. Kumar, J. Am. Chem. Soc., 2004, 126, 8652;
(c) P. O. Miranda, D. D. Diaz, J. I. Padron, J. Bermejo and V. S. Martin,
Org. Lett., 2003, 5, 1979; (d) D. J. Hart and C. E. Bennet, Org. Lett.,
2003, 5, 1499; (e) F. Lopez, L. Castedo and J. L. Mascarenas, J. Am.
Chem. Soc., 2002, 124, 4218; (f) Y. S. Cho, H. Y. Kim, J. H. Cha,
A. N. Pae, H. Y. Koh, J. H. Choi and M. H. Chang, Org. Lett., 2002, 4,
2025; (g) W. R. Roush and G. J. Dilley, Synlett, 2001, 955; (h) L. D. M.
Lolkema, C. Semeyn, L. Ashek, H. Hiemstra and W. N. Speckamp,
Tetrahedron, 1994, 50, 7129.
Apparently the remote alkene reacts with the oxocarbenium ion
intermediates (e.g. Fig. 2). Undaunted by this result, we employed
a five step procedure to convert THPs 9 to Smith and coworkers’
intermediate 15. Silylation of diol 14, available by reductive
cleavage of acetates 9, and subsequent hydrogenolysis of the
benzyl group provided a primary alcohol. After arene bromina-
tion,18 the alcohol was eliminated using Grieco and coworkers’
procedure19 to deliver alkene 15 in 35% yield from THPs 9. The
spectral data for 15 matched that reported by the Smith group,
and this correlation completes a formal synthesis of kendomycin.
In conclusion, we have successfully synthesized the C-aryl
glycoside found in kendomycin with a highly diastereoselective
Prins cyclization. Attenuation of the electron rich benzaldehyde
and the use of acetic acid as a trapping agent were necessary to
suppress problematic side reactions. The selective generation of
three new stereocenters in the Prins cyclization facilitated the short
and highly convergent assembly of the kendomycin fragment.
Support was provided by the National Cancer Institute (CA-
81635).
Dedicated to the life and memory of Norman Bahnck.
Notes and references
1 (a) Y. Funahishi, N. Kawamura and T. Ishimaru, Chem. Abs., 1996,
125, 326518; (b) Y. Funahishi, N. Kawamura and T. Ishimaru, Chem.
Abs., 1997, 126, 6553.
2 (a) H. B. Bode and A. Zeeck, J. Chem. Soc., Perkin Trans. 1, 2000, 323;
(b) H. B. Bode and A. Zeeck, J. Chem. Soc., Perkin Trans. 1, 2000, 2665
and references cited therein.
3 M. H. Su, M. I. Hosken, B. J. Hotovec and T. L. Johnston, US Patent
5728727 [A 980317], 1998; Chem. Abs., 1998, 128, 239489.
4 Y. Yuan, H. Men and C. Lee, J. Am. Chem. Soc., 2004, 126, 14720.
5 A. B. Smith, E. F. Mesaros and E. A. Meyer, J. Am. Chem. Soc., 2005,
127, 6948.
11 R. Breitenbach, C. K.-F. Chiu, S. S. Massett, M. Meltz,
C. W. Murtiashaw, S. L. Pezzullo and T. Staigers, Tetrahedron:
Asymmetry, 1996, 7, 435.
12 Prepared by modification (see supporting information{) of the reported
procedure: (a) R. W. Hoffmann, K. Ditrich, G. Koster and R. Sturmer,
Chem. Ber., 1989, 122, 1783. See also: (b) M. W. Rathke, E. Chao and
G. Wu, J. Organomet. Chem., 1976, 122, 145; (c) W. C. Hiscox and
D. S. Matteson, J. Org. Chem., 1996, 61, 8315.
13 The syn stereochemistry and the olefin geometry govern the configura-
tions of the tetrahydropyranyl substituents upon cyclization through a
chair-like transition state with an (E)-oxocarbenium ion.
6 (a) H. J. Martin, M. Drescher, H. Kahlig, S. Schneider and J. Mulzer,
Angew. Chem., Int. Ed., 2001, 40, 3186–3188; (b) M. M. B. Marques,
S. Pichlmair, H. J. Martin and J. Mulzer, Synthesis, 2002, 2766–2770; (c)
S. Pichlmair, M. M. B. Marques, M. P. Green, H. J. Martin and
J. Mulzer, Org. Lett., 2003, 5, 4657–4659; (d) M. P. Green, S. Pichlmair,
M. M. B. Marques, H. J. Martin, O. Diwald, T. Berger and J. Mulzer,
Org. Lett., 2004, 6, 3131–3134; (e) J. Mulzer, S. Pichlmair, M. P. Green,
M. M. Marques and H. J. Martin, Proc. Natl. Acad. Sci. USA, 2004,
101, 11980; (f) K. Shamim and D. R. Williams, Org. Lett., 2005, 7, 4161;
(g) J. T. Lowe and J. S. Panek, Org. Lett., 2005, 7, 1529; (h) J. D. White
and H. Smits, Org. Lett., 2005, 7, 235; (i) T. Sengoku, H. Arimoto and
D. Uemura, Chem. Commun., 2004, 1220.
7 (a) S. D. Rychnovsky, J. J. Jaber and M. Kazuhiko, J. Org. Chem.,
2001, 66, 4679; (b) S. Marumoto, J. J. Jaber, J. P. Vitale and
S. D. Rychnovsky, Org. Lett., 2002, 4, 3919; (c) R. Jasti, C. D. Anderson
and S. D. Rychnovsky, J. Am. Chem. Soc., 2005, 127, 9939; (d)
S. D. Rychnovsky, S. Marumoto and J. J. Jaber, Org. Lett., 2001, 3,
3815; (e) R. Jasti, J. Vitale and S. D. Rychnovsky, J. Am. Chem. Soc.,
2004, 126, 9904; (f) M. L. Bolla, B. Patterson and S. D. Rychnovsky,
J. Am. Chem. Soc., 2005, 127, 16044; (g) J. E. Dalgard and
S. D. Rychnovsky, Org. Lett., 2005, 7, 1589; (h) J. P. Vitale,
S. A. Wolckhenauer, N. M. Do and S. D. Rychnovsky, Org. Lett.,
2005, 7, 3255; (i) J. E. Dalgard and S. D. Rychnovsky, J. Am. Chem.
Soc., 2004, 126, 15662; (j) D. J. Kopecky and S. D. Rychnovsky, J. Am.
Chem. Soc., 2001, 123, 8420.
14 The absolute alcohol stereochemistry of 7 was confirmed as (R) by
Mosher’s ester analysis. See: (a) J. A. Dale and H. S. Mosher, J. Am.
Chem. Soc., 1973, 95, 512; (b) D. E. Ward and K. R. Chung,
Tetrahedron Lett., 1991, 32, 7165.
15 A. Kubo, Y. Kitahara, S. Nakahara and R. Numata, Chem. Pharm.
Bull., 1985, 33, 2122. Reported in the supplementary information are
detailed and optimized experimental procedures for the economic, half-
mole scale throughput of the precursors to Kubo’s hydroxybenzalde-
hyde from commercially available 2,6-dimethoxytoluene.
16 Replacement of the electron-withdrawing acetate or sulfonate
groups with methyl resulted mostly in fragmentation products,
with only 20% yield of the desired C-aryl glycoside. The problematic
role of electron-rich aromatic rings has been previously reported. See
ref. 9b.
17 This alcohol, (E,4R,5R,8S)-4,8-dimethyldeca-2,9-dien-5-ol, was prepared
by allylation of the known aldehyde, (4S)-methyl-hex-5-enal
(P. J. Kocienski and G. J. Cernigliaro, J. Org. Chem., 1977, 42, 3622),
with Hoffmann’s boronate 5 in 95% yield. See supporting information
for details{.
18 Propylene oxide was used as an acid scavenger in the bromination
reaction to avoid loss of the phenolic TBS group.
19 (a) P. A. Grieco and M. Nishizawa, J. Org. Chem., 1977, 42, 1717; (b)
P. A. Grieco, S. Gilman and M. Nishizawa, J. Org. Chem., 1976, 41,
1485.
2390 | Chem. Commun., 2006, 2388–2390
This journal is ß The Royal Society of Chemistry 2006