Epoxyamide-based strategy for the synthesis of polypropionate-type frameworks

Article abstract of DOI:10.1021/jo801728s

(Chemical Equation Presented) A new approach to the stereoselective synthesis of polypropionate-type frameworks is reported utilizing reactions of amide-stabilized sulfur ylides with chiral aldehydes. To establish a new strategy for macrolide fragment synthesis, the stereoselectivity of these reactions in the construction of epoxy amides was the most important aspect of this study. In this aspect, we found a strong influence of the protecting groups employed in the starting aldehydes upon the stereochemical outcome of their reactions with the sulfur ylide 1. Thus, numerous aldehydes showed remarkable stereofacial differentiation, providing a major diastereoisomer, in contrast to others that displayed a poor or no stereoselectivity. Despite the difficulties encountered for some cases with respect to their diastereomeric yields, we were able to prepare various stereotetrads and stereopentads, thus enhancing the synthetic value of this new methodology for the preparation of typical polypropionate frameworks found in many natural products, in particular the macrolide class of antibiotics.

Full text of DOI:10.1021/jo801728s

Epoxyamide-Based Strategy for the Synthesis of
Polypropionate-Type Frameworks
Francisco Sarabia,* Francisca Martín-Gálvez, Miguel García-Castro, Samy Chammaa,
Antonio Sánchez-Ruiz, and Jose´ F. Tejón-Blanco
Department of Biochemistry, Molecular Biology and Organic Chemistry, Faculty of Sciences, UniVersity of
Malaga, Campus de Teatinos, 29071, Malaga, Spain
frsarabia@uma.es
ReceiVed August 6, 2008
A new approach to the stereoselective synthesis of polypropionate-type frameworks is reported utilizing
reactions of amide-stabilized sulfur ylides with chiral aldehydes. To establish a new strategy for macrolide
fragment synthesis, the stereoselectivity of these reactions in the construction of epoxy amides was the
most important aspect of this study. In this aspect, we found a strong influence of the protecting groups
employed in the starting aldehydes upon the stereochemical outcome of their reactions with the sulfur
ylide 1. Thus, numerous aldehydes showed remarkable stereofacial differentiation, providing a major
diastereoisomer, in contrast to others that displayed a poor or no stereoselectivity. Despite the difficulties
encountered for some cases with respect to their diastereomeric yields, we were able to prepare various
stereotetrads and stereopentads, thus enhancing the synthetic value of this new methodology for the
preparation of typical polypropionate frameworks found in many natural products, in particular the
macrolide class of antibiotics.
Introduction
diverse asymmetric synthetic methodologies5 to achieve the total
syntheses of members of this family of natural products.6
Despite all the chemistry devoted to this field in the past 30
years,7 it is gratifying that one can still find in the literature
outstanding and elegant new contributions in this area.8
The stereoselective synthesis of epoxides has represented one
of the most outstanding chapters of the history of Organic
Synthesis,1 comprising an important number of significant
contributions that have enabled the access of numerous scaffolds
of great utility in total synthesis. Among these structural
frameworks, a key structural motifs is that derived from the
polypropionate biosynthetic pathway,2 found in many diverse
natural products. The macrolide-type antibiotics,3 in particular,
represent a prominent example of this type of compounds, owing
to their biological properties and medicinal applications,4 and
have prompted the chemical community to design and develop
(4) (a) Schunzen, F.; Zarivach, R.; Harms, J.; Bachan, A.; Tocilj, A.; Albrecht,
R.; Yonath, A.; Franceschi, F. Nature 2001, 413, 814–821. (b) Omura, S. In
Macrolide Antibiotics: Chemistry, Biology and Practice; Academic Press: San
Diego, 2002. (c) Zotchev, S. B. Curr. Med. Chem. 2003, 10, 211–223. (d) Labro,
M.-T. Exp. Opin. Pharm. 2004, 5, 541–550. (e) Jain, R.; Danziger, L. H. Curr.
Pharm. Design 2004, 10, 3045–3053.
(5) (a) Grieco, P. A.; Ohfune, Y.; Yokoyama, Y.; Owens, W. J. Am. Chem.
Soc. 1979, 101, 4749–4752. (b) Ireland, R. E.; Daub, J. P. J. Org. Chem. 1981, 46,
479–485. (c) Evans, D. A. Aldrichim. Acta 1982, 15, 318–327. (d) Masamune, S.;
Choy, W. Aldrichim. Acta 1982, 15, 335–352. (e) Hoffmann, R. W. Angew. Chem.,
Int. Ed. Engl. 1987, 26, 489–503. (f) Cowden, C. J.; Paterson, I. Org. React. 1997,
51, 1–200. (g) Hanessian, S.; Wang, W.; Gai, Y.; Olivier, E. J. Am. Chem. Soc.
1997, 119, 10034–10041. (h) Marshall, J. A. Chem. ReV. 2000, 100, 3163–3186.
(6) (a) Nicolaou, K. C. Tetrahedron 1977, 33, 683–710. (b) Paterson, I.;
Mansuri, M. M. Tetrahedron 1985, 41, 3569–3624. (c) Mulzer, J. Angew. Chem.,
Int. Ed. Engl. 1991, 30, 1452–1454. (d) Norcross, R. D.; Paterson, I. Chem.
ReV. 1995, 95, 2041–2114. (e) Bode, J. W.; Carreira, E. M. In The Chemical
Synthesis of Natural Products; Hale, K. J., Ed.; Sheffield Academic Press:
London, 2000; pp 40-62.
* Fax: 34-952 131941.
(1) Yudin, A. K., Ed. In Aziridines and Epoxides in Organic Synthesis; Wiley-
VCH: Weinheim, 2006.
(2) (a) O’Hagan, D. Nat. Rep. Prod. 1995, 12, 1–32. (b) Rawlings, B. Nat.
Prod. Reports 1997, 523–556. (c) Dewick, P. M. In Medicinal Natural Products:
A Biosynthetic Approach; John Wiley & Sons Ltd: New York, 2002; Chapter 3,
pp 92-111.
(3) Omura, S., Ed. In Macrolidge Antibiotics. Chemistry, Biology and
Practice, 2nd ed.; Academic Press: New York, 2002.
10.1021/jo801728s CCC: $40.75
Published on Web 10/15/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 8979–8986 8979

Sarabia et al.
SCHEME 1. General Synthesis of Polypropionate Chains by
the Chemistry of Sulfur Ylides
In this publication, we wish to report our synthetic studies
on the stereoselective synthesis of macrolide fragments utilizing
epoxy amides as key building blocks, which can be readily
prepared by reaction of carbonyl compounds with amide-
stabilized sulfur ylides.9 Our experience and preliminary results
in this field10,11 prompted us to explore and exploit the chemistry
of sulfur ylides for the stereoselective synthesis of this type of
structural motifs. The general synthetic strategy is summarized
in Scheme 1, and accordingly, a starting chiral aldehyde would
react with sulfur ylide 1 in a stereoselective fashion induced
by the presence of an asymmetric center in the R-position of
the aldehyde. The resulting trans epoxy amide would then be
subjected to a synthetic sequence that would entail an epoxide
opening reaction mediated by an organocuprate reagent, fol-
lowed by protection of the resulting alcohol, as a silyl ether for
instance, and reduction of the amide to the aldehyde, which in
turn would be ready for a second sequence of reactions with 1.
The sequence could be done iteritatively giving access to a
polypropionate chain, whose stereochemistry would be a
consequence of the asymmetric induction produced by the
starting chiral aldehyde coupled with the trans-selectivity
showed by the stabilized sulfur ylide reaction, providing the
anti relative configuration between the highlighted chiral centers
present in the resulting polypropionate chain (Scheme 1).12
Results and Discussion
To initiate the synthetic study, epoxy amide 213 was chosen
as a valid starting point for the preparation of the required chiral
aldehyde. To this end, epoxy amide 2 was treated with lithium
dimethylcuprate to obtain hydroxy amide 3 in an excellent 90%
yield, followed by protection of the secondary alcohol of two
different manners, to give the silylether 4 and benzylether 5,
respectively. The preparation of the aldehydes required a
reduction of the amide function to the alcohol, mediated by the
action of Super-H,14 to furnish alcohols 6 and 7 in 96 and 73%
yields respectively, followed by subsequent Swern oxidation,15
that provided the corresponding aldehydes 8 and 9 in very good
yields (90% for 8 and without purification for 9). With both
aldehydes in hand, we proceeded in exploring their reactions
with the sulfur ylide 1, which was prepared previously by
treatment of its corresponding sulfonium salt with sodium
hydride.16 Thus, after exposure of aldehydes 8 and 9 to the
action of 3.0 equivalents of 1 in methylene chloride for 8 h,
the result was the obtention of separable mixtures of epoxy
amides for both cases, 10a:10b in a 85:15 ratio and 89%
combined yield, for aldehyde 8, and 11a:11b in a 1:1 ratio and
85% combined yield, for aldehyde 9. The different diastereo-
meric ratios found in both cases revealed the influence of the
protecting group employed in alcohol 3 upon the stereochemical
outcome. Additionally, these results also reflect the difficulty
of predicting the stereochemical result in reactions of 1 with
chiral aldehydes (Scheme 2). Given the poor or practically null
stereoselectivity found for the reaction of 1 with aldehyde 9,
we opted to discard this product and to continue our synthetic
studies with the silylether derivatives 10a:10b.
(7) (a) Nicolaou, K. C.; Sorensen, E. J. Classics in Total Synthesis; VCH:
New York, 1996; pp 167-184. (b) Masamune, S.; Bates, G. S.; Corcoran, J. W.
Angew. Chem., Int. Ed. Engl. 1977, 16, 585–607. (c) Masamune, S.; Ellingboe,
J. W.; Choy, W. J. Am. Chem. Soc. 1982, 104, 5526–5528. (d) Nagaoka, H.;
Rutsch, W.; Schmid, G.; Iio, H.; Johnson, M. R.; Kishi, Y. J. Am. Chem. Soc.
1980, 102, 7962–7965. (e) Iio, H.; Nagaoka, H.; Kishi, Y. J. Am. Chem. Soc.
1980, 102, 7965–7967. (f) Nagaoka, H.; Kishi, Y. Tetrahedron 1981, 37, 3873–
3888. (g) Masamune, S.; Hirama, M.; Mori, S.; Aliand, S. A.; Garvey, D. S.
J. Am. Chem. Soc. 1981, 103, 1568–1571. (h) Roush, W. R.; Halterman, R. L.
J. Am. Chem. Soc. 1986, 108, 294–296. (i) Ziegler, F. E.; Kneisley, A.; Thottathil,
J. K.; Wester, R. T. J. Am. Chem. Soc. 1988, 110, 5434–5442. (j) Ziegler; Cain,
W. T.; Kneisley, A.; Stirchak, E. P.; Wester, R. T. J. Am. Chem. Soc. 1988,
110, 5442–5452. (k) Evans, D. A.; Dew, R. L.; Shih, T. L.; Takacs, J. M.; Zahler,
R. J. Am. Chem. Soc. 1990, 112, 5290–5313. (l) Myles, D. C.; Danishefsky,
S. J. J. Org. Chem. 1990, 55, 1636–1648. (m) Sviridov, A. F.; Borodkin, V. S.;
Ermolenko, Y.; Kochetkov, N. K. Tetrahedron 1991, 47, 2291–2316.
(8) Polyketide synthesis on solid support: (a) Reggelin, M.; Brenig, V.
Tetrahedron Lett. 1996, 37, 6851–6852. (b) Reggelin, M.; Brenig, V.; Welcker,
R. Tetrahedron Lett. 1998, 39, 4801–4804. (c) Hanessian, S.; Ma, J.; Wang, W.
Tetrahedron Lett. 1999, 40, 4631–4634. (d) Paterson, I.; Donghi, M.; Gerlach,
K. Angew. Chem., Int. Ed. 2000, 39, 3315–3319. (e) Paterson, I.; Temal-Laib,
T. Org. Lett. 2002, 4, 2473–2476. New asymmetric aldol reactions in polypro-
pionate or acetate networks: (f) Gijsen, H. J. M.; Wong, C.-H. J. Am. Chem.
Soc. 1995, 117, 7585–7591. (g) Northrup, A. B.; MacMillan, D. W. Science
2004, 305, 1752–1755. (h) Casas, J.; Engqvist, M.; Ibrahem, I.; Kaynak, B.;
Co´rdova, A. Angew. Chem., Int. Ed. 2005, 44, 1343–1345. (i) Shen, X.; Wasmuth,
A. S.; Zhao, J.; Zhu, C.; Nelson, S. G. J. Am. Chem. Soc. 2006, 128, 7438–
7439. (j) Bahadoor, A. B.; Micalizio, G. C. Org. Lett. 2006, 8, 1181–1184. (k)
Ward, D. E.; Beye, G. E.; Sales, M.; Alarcon, I. Q.; Gillis, H. M.; Jheengut, V.
J. Org. Chem. 2007, 72, 1667–1674. (l) Shang, S.; Iwadare, H.; Macks, D. E.;
Ambrosini, L. M.; Tan, D. S. Org. Lett. 2007, 9, 1895–1898. (m) Ghosh, P.;
Lotesta, S. D.; Williams, L. J. J. Am. Chem. Soc. 2007, 129, 2438–2439.
(9) (a) Valpuesta-Ferna´ndez, M.; Durante-Lanes, P.; Lo´pez-Herrera, F. J.
Tetrahedron 1993, 49, 9547–9560. (b) Lo´pez-Herrera, F. J.; Heras-Lo´pez, A.;
Pino-Gonza´lez, M. S.; Sarabia-Garc´ıa, F. J. Org. Chem. 1996, 61, 8839–8848.
(c) Lo´pez-Herrera, F. J.; Sarabia-Garc´ıa, F.; Heras-Lo´pez, A.; Ortega-Alca´ntara,
J. J.; Pedraza-Cebria´n, G. M.; Pino-Gonza´lez, M. S. Tetrahedron Asymm. 1996,
7, 2065–2071. (d) Lo´pez-Herrera, F. J.; Sarabia-Garc´ıa, F.; Heras-Lo´pez, A.;
Pino-Gonza´lez, M. S. J. Org. Chem. 1997, 62, 6056–6059. (e) Heras-Lo´pez,
A.; Pino-Gonza´lez, M. S.; Sarabia-Garc´ıa, F.; Lo´pez-Herrera, F. J. J. Org. Chem.
1998, 63, 9630–9634. (f) Lo´pez-Herrera, F. J.; Sarabia-Garc´ıa, F. R.; Pino-
Gonza´lez, M. S. Recent Res. DeVel. Org. Chem. 2000, 4, 465–490. (g) Lo´pez-
Herrera, F. J.; Assiego, C.; Pino-Gonza´lez, M. S. Tetrahedron Lett. 2003, 44,
8353–8356. (h) Sarabia, F.; Mart´ın-Ortiz, L.; Lo´pez-Herrera, F. J. Org. Lett.
2003, 5, 3927–3930. (i) Assiego, C.; Pino-Gonza´lez, M. S.; Lo´pez-Herrera, F. J.
Tetrahedron Lett. 2004, 45, 2611–2613. (j) Mart´ın-Ortiz, L.; Chammaa, S.; Pino-
Gonza´lez, M. S.; Sa´nchez-Ruiz, A.; Garc´ıa-Castro, M.; Assiego, C.; Sarabia, F.
Tetrahedron Lett. 2004, 45, 9069–9072. (k) Sarabia, F.; Sa´nchez-Ruiz, A.
Tetrahedron Lett. 2005, 46, 1131–1135. (l) Sarabia, F.; Sa´nchez-Ruiz, A.;
Chammaa, S. Bioorg. Med. Chem. 2005, 13, 1691–1705. (m) Sarabia, F.; Mart´ın-
Ortiz, L. Tetrahedron 2005, 61, 11850–11865.
(12) For a related strategy for the construction of polypropionate chains based
on the use of γ,δ-Epoxy acrylates see: (a) Miyashita, M.; Hoshino, M.;
Yoshikoshi, A. J. Org. Chem. 1991, 56, 6483–6485. (b) Miyashita, M.; Shiratani,
T.; Kawamine, K.; Hatakeyama, S.; Irie, H. Chem. Commun. 1996, 1027–1028.
(13) Valpuesta-Ferna´ndez, M.; Durante-Lanes, P.; Lo´pez-Herrera, F. J.
Tetrahedron 1990, 46, 7911–7922.
(14) Brown, H. C.; Kim, S. C.; Krishnamurthy, S. J. Org. Chem. 1980, 45,
1–12.
(15) Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978, 43, 2480–
2482.
(16) See Experimental Section.
(10) Lo´pez-Herrera, F. J.; Sarabia, F.; Pedraza-Cebria´n, G. M.; Pino-Gonza´lez,
M. S. Tetrahedron Lett. 1999, 40, 1379–1380.
(11) Sarabia, F.; Sa´nchez-Ruiz, A.; Mart´ın-Ortiz, L.; Garc´ıa-Castro, M.;
Chammaa, S. Org. Lett. 2007, 9, 5091–5094.
(17) (a) Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968, 2199–
2204. (b) Ahn, N. T.; Eisenstein, O. Tetrahedron Lett. 1976, 155–158. (c)
Heathcock, C. H.; Buse, C. T.; Kleschick, W. A.; Pirrung, M. C.; Sohn, J. E.;
Lampe, J. J. Org. Chem. 1980, 45, 1066–1081.
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Synthesis of Polypropionate-Type Frameworks
SCHEME 2. Synthesis of Epoxy Amides 10 and 11
SCHEME 3. Confirmation of Absolute Stereochemistry for
Epoxy Amides 10a and 10b
influence the stereochemical induction of the sulfur ylide
addition, the minor epoxy amide 10b was transformed in a
similar way into aldehyde 23 following the same synthetic
pathway as described before for 18 and reacted with sulfur ylide
1. However, this reaction also furnished an inseparable mixture
of epoxy amides 24a:24b in a 64% combined yield, although
in a 2:1 ratio (Scheme 4).
To demonstrate the absolute configuration of epoxy amides
10a and 10b, which were established assuming a Felkin-Ahn
model17 for the addition process of 1 to aldehyde 8, the epoxy
alcohols 14a and 14b were independently prepared utilizing a
Sharpless asymmetric epoxidation18 of the corresponding allylic
alcohol 13, which was obtained by reduction of the R,ꢀ-
unsaturated ester 12 with DIBAL-H in a 76% yield. In parallel,
the epoxy amides 10a and 10b were subjected to the sequential
action of Red-al19 and NaBH4 to obtain the corresponding epoxy
alcohols 14a and 14b in moderate 66 and 43% overall yields
respectively. A comparison of the spectroscopic properties of
both epoxy alcohols obtained from the different synthetic routes
unambigously established the stereochemistry as assigned
(Scheme 3).
In order to proceed with the chain elongation proccess and
to determine the viability of our delineated strategy for the
construction of macrolide motifs, epoxy amide 10a was
subjected to the general synthetic sequence outlined in Scheme
1. Thus, 10a was transformed into aldehyde 18 via a ring
opening reaction of 10a with lithium dimethylcuprate, to provide
alcohol 15 in a 87% yield, followed by protection of the resulting
alcohol 15 as the silyl ether to give the amide derivative 16,
which was reduced to alcohol 17 by treatment with Superhydride
and finally oxidized to aldehyde 18 by the action of TEMPO/
BAIB20 or DMP.21 Aldehyde 18 was then reacted with the sulfur
ylide 1 under identical conditions as for 8, to obtain in this case,
a discouraging 1:1 mixture of diastereoisomers 19a:19b in a
71% combined yield, which was inseparable by chromatographic
methods. Considering that the stereochemistry at C-3 could
The remarkable sensitivity displayed by these reactions
toward the protecting groups employed in the starting aldehydes
upon the stereochemical results, led us to consider a modification
of the silyl protecting groups to other groups that would
introduce a conformational constraint. In this sense, a cyclic
acetal possessed these conformational features and, therefore,
epoxy amide 15 was transformed into the acetal derivative 26
in a 82% yield via diol 25. When amide 26 was treated with
Super-H, the expected alcohol 27 was not formed under the
conventional conditions consisting of treatment with 3.0 equiv
of Super-H in THF at room temperature. Even after long periods
of exposure and use of large excess of Super-H (15.0 equiv),
only a small amount of alcohol 27 was obtained. This
unexpected lack of reactivity displayed by amide 26 toward the
potent reducting agent Super-H was ascribed to steric factors.
This adverse result obligated us to investigate an alternative
route. To this aim, alcohol 17, previously described in Scheme
4, was protected as its pivaloate ester to obtain in virtually
quantitative yield compound 28, which, after treatment with
TBAF afforded diol 29. After protection of the 1,3-diol system
of 29 as an acetal, the pivaloyl group of the resulting product,
compound 30, was efficiently removed by the action of DIBAL-
H, to give the desired alcohol 27 in a 95% yield. Oxidation of
27 was undertaken with the oxidative system TEMPO/BAIB
to obtain the aldehyde 31 in an excellent 95% yield. The
aldehyde was then subjected to the action of sulfur ylide 1, to
provide a mixture of epoxy amides 32a:32b in a 81% combined
yield but in greater diastereoselectvity 4:1 in favor of the
expected Felkin-Ahn adduct, 32a, which was isolated as a pure
diastereoisomer after purification by flash column chromatog-
raphy (Scheme 5).
(18) (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974–
5976. (b) Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis;
Ojima, I., Ed.; VCH: Weinheim, 1993; pp 103-158.
(19) Hayashi, M.; Terashima, S.; Koga, K. Tetrahedron 1981, 37, 2797–
2803.
(20) De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli, G. J.
Org. Chem. 1997, 62, 6974–6977.
(21) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155–4156. (b)
Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277–7287.
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Sarabia et al.
SCHEME 5. Synthesis of Epoxy Amides 32a:32b
SCHEME 4. Synthesis of Epoxy Amides 19 and 24
Before continuing with the construction of a longer polypro-
pionate chain, we moved to confirm the stereochemical outcome
of the previous epoxidation reactions in favor of the expected
Felkin-Ahn adduct. In this sense, Sharpless asymmetric epoxi-
dation was again the synthetic tool of choice to ascertain the
stereochemical outcome. Therefore, allylic alcohols 34 and 36,
prepared from their corresponding Wittig products 33 and 35
respectively, were subjected to Sharpless epoxidations using (-)-
DET to afford the corresponding epoxy alcohols 37 and 38 in
72 and 95% yields respectively and diastereomeric excesses
(d.e.) greater than 95% for both cases. On the other hand,
reduction of the mixture of epoxy amides 19a/19b and 32a were
conducted by sequential reductive treatment with Red-Al and
sodium borohydride as described previously for 10a and 10b.
Thus, comparison of the epoxy alcohols obtained from these
different routes allowed us to confirm the presence of epoxy
alcohol 37 as major isomer for the mixture of epoxy amides
19a/19b, and the formation of epoxy alcohol 38 for the epoxy
amide 32a (Scheme 6).
followed by oxidation with TEMPO/BAIB to afford aldehyde
42, which displayed poor stability, therefore requiring its use
without further purification. The crude aldehyde 42 was reacted
with sulfur ylide 1, to give to our delight, epoxy amide 43 in a
56% overall yield from 41, as the only detectable epoxide. This
epoxy amide 43 was then transformed into amide 45 in a 67%
yield over two steps, consisting of ring opening reaction of the
epoxy amide 43 and silyl protection of the resulting hydroxy
amide 44 (Scheme 7).
With all the chemistry gathered on the synthesis of macrolide
fragments, we turned our attention to chiral R-methyl aldehydes,
extensively used in Organic Synthesis as key building blocks
in the synthesis of polypropionate chains. Among them,
aldehydes 46,22 47,23 and 4824 were initially chosen to test their
utilities in the stereoselective synthesis of epoxy amides. Thus,
(22) (a) Guan, Y.; Wu, J.; Sun, L.; Dai, W.-M. J. Org. Chem. 2007, 72,
4953–4960. (b) Lawhorn, B. G.; Boga, S. B.; Wolkenberg, S. E.; Colby, D. A.;
Gauss, C.-M.; Swingle, M. R.; Amable, L.; Honkanen, R. E.; Boger, D. L. J. Am.
Chem. Soc. 2006, 128, 16720–16732.
(23) Nagaoka, H.; Rutsch, W.; Schmid, G.; Iio, H.; Johnson, M. R.; Kishi,
Y. J. Am. Chem. Soc. 1980, 102, 7962–7965.
(24) (a) Lewis, M. D.; Kishi, Y. Tetrahedron Lett. 1982, 23, 2343–2346. (b)
Ziegler, F. E.; Wester, R. T. Tetrahedron Lett. 1984, 25, 617–620. (c)
Schlessinger, R. H.; Bebernitz, G. R.; Lin, P.; Poss, A. J. J. Am. Chem. Soc.
1985, 107, 1777–1778. (d) Guindon, Y.; Murtagh, L.; Caron, V.; Landry, S. R.;
Jung, G.; Bencheqroun, M.; Faucher, A.-M.; Gue´rin, B. J. Org. Chem. 2001,
66, 5427–5437.
Following our synthetic plan toward macrolide fragments,
the epoxy amide 32a was treated with lithium dimethylcuprate
to incorporate a new methyl group, obtaining hydroxy amide
39, which was protected as the silyl ether 40 in a reasonable
63% yield over two steps. The silyl derivative 40 was subjected
to reduction with Super-H, to provide alcohol 41 in a 63% yield,
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Synthesis of Polypropionate-Type Frameworks
SCHEME 6. Confirmation of Absolute Stereochemistry for
Epoxy Amides 19a and 32a
SCHEME 8. Reaction of Simple Chiral Aldehydes with
Sulfur Ylide 1 (I)
SCHEME 7. Synthesis of Macrolide Fragment 45
SCHEME 9. Reaction of Simple Chiral Aldehydes with
Sulfur Ylide 1 (II)
reactions. In particular, we chose the bis-silylether aldehydes
5225 and 53,26 which, in contrast to the previous aldehydes,
provided excellent diastereoselections in their reactions with 1,
giving the epoxy amides 54 and 5527 together with their
diastereoisomers in 9:1 ratios, according to their 1H NMR
spectra, and very good combined yields (86 and 83% respec-
tively) (Scheme 9).
The last result was quite promising despite restricting the
stereochemical diversity to the Felkin-Ahn addition product. For
aldehydes 47 and 48, despite providing poor stereoselectivities
in their reactions with 1, they supplied sufficient amounts of
when 46 was treated with an excess of sulfur ylide 1, a
disappointing 1:1 mixture of inseparable epoxy amides 49a:
49b was obtained, albeit in a remarkable 75% yield. On the
other hand, aldehydes 47 and 48 provided the formation of a
2:1 mixture of epoxy amides 50a:50b and 51a:51b in 75 and
93% combined yields respectively. In these cases, the separation
of both diastereoisomers was acheivable by column chroma-
tography (Scheme 8).
(25) Kiyooka, S.-i.; Shahid, K. A.; Goto, F.; Okazaki, M.; Shuto, Y. J. Org.
Chem. 2003, 68, 7967–7978.
(26) Roush, W. R.; Bannister, T. D.; Wendt, M. D.; Jablonowski, J. A.;
Scheidt, K. A. J. Org. Chem. 2002, 67, 4275–4283.
(27) For demonstration of stereochemistry of epoxy amides 54 and 55, see
Supporting Information.
In light of the poor stereoselectivities obtained, we decided
to investigate new aldehydes for their synthetic potential in these
J. Org. Chem. Vol. 73, No. 22, 2008 8983

Sarabia et al.
SCHEME 11. Sulfur Ylide Methodology towards
SCHEME 10. Sulfur Ylide Methodology towards
Polypropionate Chains (I)
Polypropionate Chains (II)
as their silyl ethers 62 and 69 by treatment with TBSOTf
(Scheme 10).
In a similar way, the pure epoxy amides 51a and 51b were
subjected to the same synthetic scheme as described before, to
obtain aldehydes 70 and 74 respectively, which were reacted
with an excess of 1 to afford epoxy amides 71 and 75 in good
yields and expectable diastereomeric purities. Finally, oxirane
ring openings of both epoxy amides by the action of the copper
reagent followed by silylation of the resulting hydroxy amides
provided compounds 73 and 77 (Scheme 11).11
Finally, to advance the elongation process of the polypropi-
onate framework, we chose compounds 69 and 77 to proceed
with one more reaction with sulfur ylide 1. To this end, aldehyde
79 was prepared after reduction of 69 to alcohol 78, by the action
of Super-H (82%), followed by oxidation with TEMPO/BAIB
(85%). Then, aldehyde 79 was exposed to an excess of ylide 1
under conventional conditions and after several days a disap-
pointingly unexpected 2:1 mixture of epoxy amides 80a/80b
was obtained in a 58% yield. In contrast, aldehyde 82, obtained
from compound 77 following the same synthetic sequence as
described before for 69, afforded only one epoxy amide, epoxy
amide 83, in its reaction with sulfur ylide 1 in a very good 76%
yield. This epoxy amide was then subjected to the introduction
of a new methyl group via oxirane ring opening by the action
of Gilman reagent, to give hydroxy amide 84 in a 73% yield,
which was protected as its silyl ether 85 (Scheme 12). It is worth
note this latter compound contains the C-3/C-13 fragment of
both stereoisomers in enantiomerically pure forms after purifica-
tion. Therefore, we pursued our goal of constructing long
polypropionate chains by the synthetic course designed for this
methodology with all the stereoisomers obtained from these
reactions. Thus, ring opening reactions of the pure epoxy amides
50a and 50b were achieved by treatment with Gilman reagent,
furnishing hydroxy amides 56 and 63 in 75 and 87% yields
respectively, followed by protection of the secondary alcohols
as silyl ethers, affording amides 57 and 64. The transformation
of both amides into the corresponding aldehydes 59 and 66 was
accomplished in two steps, Super-H reduction and oxidation of
the resulting alcohols by the action of TEMPO/BAIB. With both
advanced aldehydes in hand, we proceeded with another sulfur
ylide reaction by exposing 59 and 66 to an excess of sulfur
ylide 1 (4.0 equiv). The results for both aldehydes were very
similar in terms of chemical yields and stereoselectivities. In
fact, for aldehyde 59, the result was the obtention of a mixture
of epoxy amide 60 together with its R-isomer in a 4.5:1
proportion and 75% combined yield, while aldehyde 66 afforded
epoxy amide 67 in a 72% yield as a 4:1 mixture of diastere-
oisomers. Finally, epoxy amides 60 and 67 were treated again
with lithium dimethylcuprate, and the resulting hydroxy amides
61 and 68, obtained in 82 and 75% yields respectively, protected
8984 J. Org. Chem. Vol. 73, No. 22, 2008

Synthesis of Polypropionate-Type Frameworks
SCHEME 12. Sulfur Ylide Methodology towards
Polypropionate Chains (III)
Conclusions
In conclusion, we have described the stereoselective synthesis
of macrolide-type antibiotics motifs utilizing the addition of
sulfur ylides to aldehydes. We have investigated the stereo-
chemical control exerted by the starting chiral aldehydes,
identifying the relevant role played by the protecting groups
employed in the starting aldehydes. As demonstration of this, a
collection of different aldehydes were subjected to reactions with
sulfur ylide 1 and their stereoselectivities evaluated. These
results are summarized in Table 1. Despite the poor stereose-
lectivities recorded for some cases, we have demonstrated the
potential and applicability of this methodology for the construc-
tion of typical polypropionate frameworks with the synthesis
of stereotetrads containing systems in form of compounds 45,
62, 69, 73, 77, and the product 85, which represents the C-3/
C-13 fragment of the ansa like antibiotic Streptovaricin U.
Experimental Section
Sulfur Ylide 1. To a stirred suspension of N, N-Dimethylcar-
bamoylmethyl dimethylsulfonium chloride (260 mg, 1.42 mmol)
in wet acetonitrile was added sodium hydride (68 mg, 1.69 mmol,
1.2 equiv, 60% dispersion in mineral oil) in one portion at 0 °C.
After stirring at this temperature for 3 h, the crude mixture was
filtered and the solution concentrated to obtain crude sulfur ylide 1
as a yellow oil.
General Procedures
Oxidation of Alcohols. Procedure A. To a solution of oxalyl
chloride (2.0 equiv) in CH2Cl2 was added dropwise DMSO (4.0
equiv) at -78 °C. After stirring for 15 min, a solution of alcohol
(1.0 equiv) in CH2Cl2 (0.1 M) was added dropwise at -78 °C.
The solution was stirred for 30 min at -78 °C, and TEA (6.0 equiv)
was added at the same temperature. The reaction mixture was
allowed to warm to 0 °C over 30 min, and then Et2O was added,
followed by saturated aqueous NH4Cl solution. The organic phase
was separated, and the aqueous phase was extracted with Et2O
(twice). The combined organic solution was sequentially washed
with water and brine, dried (MgSO4), filtered, and concentrated
under reduced pressure. Purification by flash column chromatog-
raphy (silica gel, 5% EtOAc in hexanes) provided the corresponding
aldehyde. Procedure B. To a solution of alcohol (1.0 equiv) in
CH2Cl2 (0.1 M) was added Dess-Martin periodinane (DMP) (1.5
equiv) at 0 °C. After 0.5 h at this temperature, a saturated aqueous
NaHCO3 solution was added and the bilayer system was allowed
to stir at 0 °C for an additional 0.5 h. The organic phase was then
separated, the aqueous layer extracted with CH2Cl2 (twice), and
the combined organic extracts were washed with brine, dried
(MgSO4), and filtered. After concentration under reduced pressure,
the crude aldehyde was purified by flash column chromatography
(silica gel, 5% AcOEt in hexanes) to obtain the corresponding
aldehyde. Procedure C. To a solution of alcohol (1.0 equiv) in
CH2Cl2 (0.1 M) was added iodobenzene diacetate (BAIB) (3.0
equiv) and TEMPO (0.3 equiv) at 0 °C. After 0.5 h at this
temperature, a saturated aqueous Na2S2O3 solution was added and
the bilayer system was allowed to stir at 0 °C for an additional
0.5 h. The organic phase was then separated, the aqueous layer
extracted with CH2Cl2 (twice), and the combined organic extracts
were washed with brine, dried (MgSO4) and filtered. After
concentration under reduced pressure, the crude aldehyde was
purified by flash column chromatography (silica gel, 5% AcOEt in
hexanes) to provide the corresponding aldehyde.
TABLE 1. Reaction of Chiral Aldehydes with Sulfur Ylide 1: A
Summary
aldehyde
epoxy amide (% yield)
stereoselectivity (isomers ratio)
8
9
10a/10b (89%)
11a/11b (85%)
4.4:1
1:1
18
23
31
42
46
47
48
52
53
59
66
70
74
79
82
19a/19b (71%)
24a/24b (64%)
32a/32b (81%)
43 (56%)
49a/49b (75%)
50a/50b (75%)
51a/51b (93%)
54 + ꢀ-epoxide (85%)
55 + R-epoxide (83%)
60 + R-epoxide (75%)
67 + ꢀ-epoxide (72%)
71 + ꢀ-epoxide (65%)
75 + R-epoxide (64%)
80a/80b (75%)
1:1
2:1
4:1
<95:5
1:1
2:1
2:1
9:1
9:1
4:1
4:1
4:1
4:1
2:1
83 (76%)
<95:5
the ansa like antibiotic Streptovaricin U,12b,28 whose total
synthesis we are currently investigating.
Aldehyde 66. Obtained by procedure C in a 89% as a colorless
oil: Rf ) 0.49 (silica gel, 10% EtOAc in hexanes); [R]25D ) +15.0
(28) (a) Knoll, W. M. J.; Rinehart, K. L., Jr.; Wiley, P. F.; Li, L. H. J. Antibiot.
1980, 33, 249–251. (b) Miyashita, M.; Yamasaki, T.; Shiratani, T.; Hatakeyama,
S.; Miyazawa, M.; Irie, H. Chem. Commun. 1997, 1787–1788.
1
(c ) 1.0, CH2Cl2); H NMR (400 MHz, CDCl3): δ ) 0.11 (s, 6
H), 0.74 (d, J ) 6.3 Hz, 3 H), 0.89 (d, J ) 7.0 Hz, 3 H), 0.92 (s,
J. Org. Chem. Vol. 73, No. 22, 2008 8985

Sarabia et al.
9 H), 1.14 (d, J ) 6.7 Hz, 3 H), 1.37 and 1.44 (2 s, 6 H), 1.83-1.95
(m, 2 H), 2.74-2.81 (m, 1 H), 3.54 (dd, J ) 11.1 Hz, 1 H), 3.66
(d, J ) 10.1 Hz, 1 H), 3.73 (dd, J ) 11.2, 4.8 Hz, 1 H), 3.99 (d,
J ) 5.0 Hz, 1 H), 9.85 (d, J ) 2.0 Hz, 1 H); 13C NMR (100 MHz,
CDCl3): δ ) -4.4, 8.4, 11.3, 12.7, 18.1, 19.5, 25.8, 29.6, 30.2,
39.7, 50.5, 66.0, 74.9, 77.0, 97.8, 204.4.
treated with tertbutyldimethylsilyl trifluoromethanesulphonate (TB-
SOTf) (1.2 equiv) at 0 °C in the presence of 2,6-lutidine (1.5 equiv).
After 0.5 h at 0 °C, the reaction mixture was quenched by addition
of MeOH, followed by addition of aqueous saturated NH4Cl
solution and dilution with Et2O. After separation of both phases,
the aqueous phase was extracted with Et2O, the combined organic
layers were washed with brine and dried with MgSO4. After
filtration, the solvents were removed by reduced pressure to obtain
a crude product which was purified by flash column chromatography
(silica gel) to afford the corresponding silyl ether.
Silyl Ether 69. Silyl ether 69 was obtained by procedure B in a
71% as a colorless oil: Rf ) 0.54 (silica gel, 20% EtOAc in
hexanes); [R]25D ) -30.7 (c ) 0.4, CH2Cl2); 1H NMR (400 MHz,
CDCl3): δ ) -0.07, 0.01, 0.03 and 0.12 (4 s, 12 H), 0.66 (d, J )
6.7 Hz, 3 H), 0.79 (s, 9 H), 0.83 (d, J ) 7.0 Hz, 3 H), 0.84 (s, 9
H), 0.86 (d, J ) 7.4 Hz, 3 H), 0.95 (d, J ) 6.8 Hz, 3 H), 1.26 and
1.31 (2 s, 6 H), 1.64-1.73 (m, 1 H), 1.79-1.86 (m, 2 H), 2.80 (q,
J ) 7.0 Hz, 1 H), 2.84 and 2.99 (2 s, 6 H), 3.42 (dd, J ) 11.2 Hz,
1 H), 3.48 (dd, J ) 7.6, 4.3 Hz, 1 H), 3.52 (dd, J ) 10.3, 1.0 Hz,
1 H), 3.61 (dd, J ) 11.6, 5.1 Hz, 1 H), 4.15 (dd, J ) 7.8, 2.6 Hz,
1 H); 13C NMR (100 MHz, CDCl3): δ ) -3.9, -3.4, -3.3, 8.5,
9.8, 13.0, 13.8, 18.5, 18.9, 26.1, 29.7, 31.9, 35.7, 37.3, 40.1, 40.2,
41.4, 66.3, 73.5, 74.2, 76.6, 97.8, 174.5; FAB HRMS (NBA) m/e
596.4138, M + Na+ calcd for C30H63NO5Si2 596.4143.
Reduction of Amides with Super-H. A solution of amide (1.0
equiv) in THF (0.1 M) was treated with lithium triethylborohydride
(Super-H) (1 M in THF, 3.0 equiv) at room temperature. The
reaction mixture was stirred at room temperature until the reaction
was complete as judged by TLC (ca. 8 h). The excess of Super-H
was carefully quenched by addition of MeOH, and the resulting
solution was diluted with Et2O and washed with saturated aqueous
NH4Cl solution. The organic phase was separated, the aqueous layer
was extracted with Et2O (twice), and the combined organic extracts
were washed with brine, dried (MgSO4) and filtered. Concentration
under reduced pressure provided a crude product that was purified
by flash column chromatography (silica gel, 20% AcOEt in hexanes)
to afford the corresponding alcohol.
Synthesis of Epoxy Amides. Aldehyde (1.0 equiv) was dissolved
in CH2Cl2 (0.1 M), and N,N-dimethyl-2-(dimethylsulfuranylidene)-
acetamide 1 (3.0-4.0 equiv) was added at room temperature. The
reaction mixture was stirred at room temperature until the reaction
was complete as judged by TLC (ca. 12 h). The solvents were
removed by concentration under reduced pressure and the resulting
crude product was purified by flash column chromatography (silica
gel, 50% AcOEt in hexanes) to provide the corresponding epoxy
amide in a wide range of yields and stereoselectivities (see Table 1).
Epoxy Amide 67. Epoxy amide 67 was obtained together with
its ꢀ-epoxide isomer in a 72% total yield as a 4:1 diastereomeric
mixture: Colorless oil; Rf ) 0.34 (silica gel, 50% EtOAc in hexanes);
1H NMR (400 MHz, CDCl3): δ ) -0.05 and -0.03 (2 s, 6 H), 0.61
(d, J ) 6.7 Hz, 3 H), 0.80 (s, 9 H), 0.84 (d, J ) 7.2 Hz, 3 H), 1.02 (d,
J ) 7.0 Hz, 3 H), 1.24 and 1.31 (2 s, 6 H), 1.69 (dq, J ) 7.0, 2.1 Hz,
1 H), 1.72-1.76 (m, 1 H), 1.79-1.85 (m, 1 H), 2.88 and 3.09 (2 s, 6
H), 3.14 (dd, J ) 8.0, 2.0 Hz, 1 H), 3.44 (dd, J ) 10.0, 5.7 Hz, 1 H),
3.48 (d, J ) 2.0 Hz, 1 H), 3.55 (dd, J ) 5.4, 2.1 Hz, 1 H), 3.57-3.60
(m, 2 H); 13C NMR (100 MHz, CDCl3): δ ) -4.6, -4.5, 7.8, 12.6,
16.1, 18.0, 19.2, 25.8, 29.7, 30.3, 35.8, 36.6, 38.9, 39.6, 53.9, 60.0,
65.9, 75.4, 79.0, 97.6, 167.4; FAB HRMS (NBA) m/e 466.2968, M
+ Na+ calcd for C23H45NO5Si 466.2965.
Reaction of Epoxy Amides with Lithium Dimethylcuprate.
To a suspension of CuI (2.0-3.0 equiv) in THF was added dropwise
MeLi (1.6 M in Et2O, 4.0-6.0 equiv) at 0 °C. The resulting
colorless solution of Me2CuLi was added to a solution of epoxy
amide (1.0 equiv) in THF at 0 °C. The reaction mixture was stirred
for 0.5-3.0 h at this temperature and quenched by careful addition
of aqueous saturated NH4Cl solution, followed by dilution with
Et2O. After separation of both phases, the aqueous phase was
extracted with Et2O twice and the combined organic layers were
sequentially washed with aqueous saturated NH4Cl solution, water
and brine. After treatment with MgSO4, the solvents were removed
by reduced pressure to obtain a crude product which was purified
by flash column chromatography (silica gel, 50% EtOAc in hexanes)
to afford the corresponding ring opened product.
Alcohol 78. Alcohol 78 was obtained from amide 69 in a 82%
yield: colorless oil; Rf ) 0.41 (silica gel, 10% EtOAc in hexanes);
1
[R]25 ) -17.5 (c ) 2.0, CH2Cl2); H NMR (400 MHz, CDCl3):
D
δ ) 0.01, 0.04, 0.05 and 0.06 (4 s, 12 H), 0.64 (d, J ) 6.6 Hz, 3
H), 0.79 (d, J ) 7.2 Hz, 3 H), 0.84 (s, 9 H), 0.85 (s, 9 H), 0.94 (d,
J ) 7.2 Hz, 3 H), 1.00 (d, J ) 7.1 Hz, 3 H), 1.26 and 1.34 (2 s, 6
H), 1.68-1.77 (m, 2 H), 1.83-1.88 (m, 1 H), 1.96-2.04 (m, 1 H),
3.43 (dd, J ) 11.3 Hz, 1 H), 3.53 (dd, J ) 11.1, 4.7 Hz, 1 H), 3.62
(dd, J ) 11.5, 5.1 Hz, 1 H), 3.64-3.67 (m, 2 H), 3.74 (dd, J )
8.4, 2.0 Hz, 1 H), 3.83 (dd, J ) 11.2, 4.2 Hz, 1 H); 13C NMR (100
MHz, CDCl3): δ ) -4.5, -3.4, -3.3, 9.6, 11.8, 12.8, 15.9, 18.3,
19.5, 26.0, 26.2, 29.6, 30.3, 37.6, 39.0, 43.9, 64.9, 66.1, 74.3, 74.6,
79.0, 97.8; FAB HRMS (NBA) m/e 555.3882, M + Na+ calcd for
C28H60O5Si2 555.3877.
Hydroxy Amide 68. Hydroxy amide 68 was obtained in a 75%
as a colorless oil: Rf ) 0.29 (silica gel, 50% EtOAc in hexanes);
1
[R]25 ) -19.8 (c ) 0.6, CH2Cl2); H NMR (400 MHz, CDCl3):
D
δ ) 0.01 and 0.05 (2 s, 6 H), 0.63 (d, J ) 6.7 Hz, 3 H), 0.83 (s,
9 H), 0.92 (d, J ) 7.3 Hz, 3 H), 0.94 (d, J ) 6.9 Hz, 3 H), 0.97 (d,
J ) 7.2 Hz, 3 H), 1.26 and 1.34 (2 s, 6 H), 1.73-1.83 (m, 1 H),
1.89 (q, J ) 7.0 Hz, 1 H), 1.90-1.98 (m, 1 H), 2.78 (q, J ) 7.0
Hz, 1 H), 2.91 and 3.00 (2 bs, 6 H), 3.42 (dd, J ) 11.4 Hz, 1 H),
3.53 (d, J ) 10.4 Hz, 1 H), 3.62 (dd, J ) 11.5, 5.1 Hz, 1 H), 3.67
(dd, J ) 6.4, 1.8 Hz, 1 H), 4.20 (bd, J ) 7.8 Hz, 1 H); 13C NMR
(100 MHz, CDCl3): δ ) -4.4, -3.9, 8.7, 12.4, 12.7, 18.2, 19.7,
26.0, 29.6, 30.2, 35.6, 37.3, 38.2, 38.5, 39.7, 65.9, 74.1, 74.8, 81.5,
97.6, 167.2; FAB HRMS (NBA) m/e 482.3280, M + Na+ calcd
for C24H49NO5Si 482.3278.
Acknowledgment. This work was financially supported by
Ministerio de Educacio´n y Ciencia (CTQ2007-66518), Junta de
Andaluc´ıa (FQM-3329), and Fundacio´n Ramo´n Areces and
fellowships from Junta de Andaluc´ıa (F.M.-G.), Fundacio´n
Ramo´n Areces (M.G.-C.), and Ministerio de Educacio´n y
Ciencia (J.F.T.-B.). We thank Dr. J. I. Trujillo from Pfizer (St.
Louis, MO) for assistance in the preparation of this manuscript
and Unidad de Espectroscop´ıa de Masas of Granada University
for exact mass spectroscopic assistance.
Silylation of Hydroxy Amides. Procedure A. A solution of
hydroxy amide (1.0 equiv) in DMF (0.1 M) was treated with
tertbutyldimethylsilyl chloride (TBSCl) (1.2 equiv) at 25 °C in the
presence of imidazole (2.5 equiv). After 12 h at this temperature,
the reaction mixture was quenched by addition of MeOH, followed
by addition of aqueous saturated NH4Cl solution and dilution with
Et2O. After separation of both phases, the aqueous phase was
extracted with Et2O, the combined organic layers were washed with
brine and dried with MgSO4. After filtration, the solvents were
removed by reduced pressure to obtain a crude product which was
purified by flash column chromatography (silica gel, 20% EtOAc
in hexanes) to afford the corresponding silyl ether. Procedure B.
A solution of hydroxy amide (1.0 equiv) in CH2Cl2 (0.1 M) was
Supporting Information Available: Experimental proce-
1
dures and spectroscopic data for all compounds, and H- and
13C NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO801728S
8986 J. Org. Chem. Vol. 73, No. 22, 2008