Studies toward the total synthesis of sorangiolides and their analogues. A convergent stereoselective synthesis of the macrocyclic lactone precursors

Article abstract of DOI:10.1021/ol070517g

Stereosetective synthesis of the fully protected 18-membered macrocyclic lactones as the immediate precursors of the natural products, sorangiolides A and B, is described. The key steps used in the synthesis include the sp ³-hybridized carbon-carbon Fu cross coupling, the stereosetective Evans' aldol reaction with 1,5-anti induction, the 1,3-diastereoselective syn reduction of a β-hydroxyketone intermediate, and Mukaiyama macrolactonization reactions.

Full text of DOI:10.1021/ol070517g

ORGANIC
LETTERS
2007
Vol. 9, No. 12
2273-2276
Studies toward the Total Synthesis of
Sorangiolides and Their Analogues.
A Convergent Stereoselective Synthesis
of the Macrocyclic Lactone Precursors
Sanjib Das, Sunny Abraham, and Subhash C. Sinha*
The Skaggs Institute for Chemical Biology and the Department of Molecular Biology,
The Scripps Research Institute, 10550 North Torrey Pines Road,
La Jolla, California 92037
subhash@scripps.edu
Received March 1, 2007
ABSTRACT
Stereoselective synthesis of the fully protected 18-membered macrocyclic lactones as the immediate precursors of the natural products,
sorangiolides A and B, is described. The key steps used in the synthesis include the sp3-hybridized carbon
carbon Fu cross coupling, the
-hydroxyketone intermediate, and
−
stereoselective Evans’ aldol reaction with 1,5-anti induction, the 1,3-diastereoselective syn reduction of a
Mukaiyama macrolactonization reactions.
â
Sorangiolides A and B (1a,b) are 18-membered macrocyclic
lactones isolated from Sorangium cellulosum, strain So ce12.1
They possess a weak antibiotic activity (MIC 5-20 µg/mL)
against Gram-(+) bacteria, e.g., Staphylococcus aureus.
Although the structure of these compounds was confirmed
by an X-ray analysis of 1a, no synthetic studies have so far
been reported. Moreover, the relative or absolute stereo-
chemistry of the hydroxy function in 1b at C-6 is yet to be
determined. Therefore, to synthesize the naturally occurring
sorangiolides as well as their analogues for the biological
evaluations, we designed and studied a general synthetic
strategy. Here, we report the results of this study leading to
the stereoselective synthesis of 18-membered macrolide
precursors, enroute to the proposed synthesis of 1a, 1b, and
their analogues.
Scheme 1 outlines the retrosynthesis of the naturally
occurring sorangiolides A and B, 1a and 1b, and their
analogues, which would possess the identical 18-membered
macrocyclic ring. We envisaged that the macrocyclic lactones
IIIa or IIIb could serve as the key precursors of 1a,b and
their analogues. Intermediate IIIa could undergo Fu cou-
pling2 with I to form the immediate precursors of the title
compounds. Alternatively, these precursors could be prepared
by cross metathesis3 of IIIb with II followed by a regio-
selective hydrogenation of the resulting disubstituted alkene.
Macrolides IIIa and IIIb could be prepared by the intra-
molecular esterification of the appropriately protected hy-
droxy acids IVa and IVb. The latter compounds would arise
from the 1,3-syn reduction of the aldol compounds Va and
Vb, respectively. The 1,5-anti diastereoselectivity in the aldol
(1) (a) Irschick, H.; Jansen, R.; Gerth, K.; Ho¨fle, G.; Reichenbach, H. J.
Antibiot. 1995, 48, 886. (b) Jansen, R.; Irschik, H.; Meyer, H.; Reichenbach,
H.; Wray, V.; Schomburg, D.; Hoefle, G. Liebigs Ann. 1995, 867.
(2) Netherton, M. R.; Dai, C.; Neuschu¨tz, K.; Fu, G. C. J. Am. Chem.
Soc. 2001, 123, 10099.
(3) Grubbs, R. H. Tetrahedron 2004, 60, 7117.
10.1021/ol070517g CCC: $37.00
© 2007 American Chemical Society
Published on Web 05/16/2007

using the identical set of reactions as reported by Roush6
with the exception that Brown’s method7 (trans-2-butene and
(-)-Ipc2BOMe) was used for crotylboration. The resulting
alcohol 5 was then protected as its TIPS ether to give 5a.
Next, we examined the Fu coupling reaction of bromide
4 with alkene 5a. Thus, alkene 5a was first treated with
9-BBN for 6 h at room temperature and the hydroborated
product was then reacted with bromide 4 in the presence of
Pd(OAc)2/PCy3/K3PO4‚H2O. The desired coupling product
6 was obtained in a moderate yield. We also attempted Fu
coupling between different bromide and alkene partners, such
as 4 and 9, 5a and 10, or 9 and 10, but to our surprise no
coupling products were obtained. Without going into further
depth, we focused on compound 6 and converted it to
aldehydes 7a and 7b (viz., VIIa and VIIb in Scheme 1).
For this, the TBS ether in 6 was selectively removed by an
acid treatment, and the resulting alcohol was oxidized by
TPAP-catalyzed oxidation to give 7a. In another set of
experiments, the PMB group in 6 was removed by oxidative
cleavage, and the corresponding alcohol was oxidized to
aldehyde and then olefinated by Wittig reaction. The resulting
product underwent TBS cleavage and TPAP-catalyzed
oxidation as above to give 7b.
Scheme 1. Retrosynthesis of Sorangiolides A and B and Their
Analogues (P ) a Protecting Group)
Synthesis of the Key Hydroxy Acid via Evans’ Aldol
and 1,3-Syn Reduction Steps. Moving ahead with the
synthesis, we prepared ketone 14 from aldehyde 11 via the
previously reported compound 128 in three steps (Scheme
2B). Here, the primary alcohol in 12 was oxidized to
aldehyde and olefinated by Wittig reaction with (carbethoxy-
ethylidene)triphenylphosphorane to afford the unsaturated
ester 13, and the terminal alkene was oxidized by using the
modified Wacker process.9 Next we carried out the Evans’
aldol reaction of ketone 14 with aldehydes 7a and 7b using
Bu2BOTf. As expected, the aldol compounds 15a and 15b
were obtained in good yields and diastereoselectivities. These
compounds underwent the proposed stereoselective 1,3-syn
reduction10 with use of Et2BOMe-NaBH4 to afford the
corresponding diols, 16a and 16b, which were protected as
their MOM ethers with MOMCl/iPr2EtN to yield 17a and
17b. The ester function in compounds 17a and 17b was next
hydrolyzed and the TIPS group was removed to give the
hydroxy acids 18a and 18b (intermediates IVa and IVb in
Scheme 1).
Here, stereochemistry of the newly generated hydroxyl
functions in the aldol products 15a and 15b, as well as the
diol functions in the reduced products, 16a and 16b, was
forwarded on the basis of the reported precedence. We also
gained credence for the assigned stereochemistry of com-
pounds 15a,b and 16a,b using acetonides 23, 25, and 26,
which were prepared from diol 22 (Scheme 2C). Compound
22 was synthesized by Evans’ aldol reaction of aldehyde 1911
with ketone 2012 followed by 1,3-syn reduction, as described
products could be achieved by Evans’ methodology,4 using
ketone VI and aldehydes VIIa and VIIb. Finally, these
aldehydes could be easily derived from the Fu coupling
product of bromide VIII and alkene IX.
Synthesis of the First Key Intermediate with Use of
the Fu Coupling Reaction. Obviously, among all five key
steps listed in the retrosynthesis of sorangiolides (Scheme
1), Fu coupling has been the least studied methodology. In
fact, most compounds prepared by this method with use of
a bromide and the 9-BBN derivative of an alkene were
devoid of any complexity. In contrast, the proposed starting
materials, VIII and IX, for the Fu coupling reaction were
highly functionalized. Nevertheless, we prepared intermedi-
ates 4 and 5a (VIII and IX in Scheme 1) as shown in Scheme
2A. Compound 4 was synthesized from the commercially
available methyl (S)-(+)-3-hydroxy-2-methyl propionate via
compound 2,5 which was converted to bromide 4 in four
steps. First the alcohol function in 2 was protected as a TBS
ether and the PMB group was removed under the oxidizing
conditions to yield alcohol 3. The latter was then mesylated
with MsCl and Et3N, and the product was reacted with LiBr
in refluxing THF. Compound 5a was prepared from methyl
(R)-(-)-3-hydroxy-2-methyl propionate via compound 5,
(6) Chemler, S. R.; Roush, W. R. J. Org. Chem. 2003, 68, 1319.
(7) Brown, H. C.; Bhat, K. S.; Randad, R. S. J. Org. Chem. 1989, 54,
1570.
(4) (a) Evans, D. A.; Coˆte´, B.; Coleman, P. J.; Connell, B. T. J. Am.
Chem. Soc. 2003, 125, 10893. (b) Evans, D. A.; Coleman, P. J.; Coˆte´, B.
J. Org. Chem. 1997, 62, 788.
(5) Smith, A. B., III; Adams, C. M.; Lodise Barbosa, S. A.; Degnan, A.
P. J. Am. Chem. Soc. 2003, 125, 350.
(8) Drouet, K. E.; Theodorakis, E. A. Chem. Eur. J. 2000, 6, 1987.
(9) Smith, A. B., III; Cho, Y. S.; Friestad, G. K. Tetrahedron Lett. 1998,
39, 8765.
(10) Chen, K.-M.; Hardtmann, G. E.; Prasad, K.; Repic, O.; Shapiro,
M. J. Tetrahedron Lett. 1987, 28, 155.
2274
Org. Lett., Vol. 9, No. 12, 2007

Scheme 2. Synthesis of the (A) First Key Intermediate Using Fu Coupling and (B) Key Hydroxy Acids via Evans’ Aldol and 1,3-Syn
Reduction Steps and (C) Determination of the Stereochemistry of Evans’ Aldol Addition and Et2BOMe/NaBH4 Reduction Steps
above for compounds 15a,b and 16a,b. Diacetonide 23 was
prepared by reacting 22 with an excess of 2,2-dimethoxy-
propane (DMP) in the presence of a catalytic amount of CSA.
Separately, the PMP group in 22 was removed and the
resulting tetrol was monoprotected as TBDPS ether on the
primary alcohol affording compound 24. The latter was
transformed into the regioisomeric monoacetonides 25 and
26 by using DMP and a catalytic amount of CSA. An
analysis of the 13CNMR spectra of compounds 23, 25, and
26 revealed the following facts: Compound 23 showed δC
at 98.3 and 98.4 for the ketal carbons and at 19.33, 19.25
and 30.0, 30.2 for the acetonide methyl groups. Similarly,
the ketal and two methyl carbons in 25 appeared at 98.6,
19.7, and 30.2 ppm, respectively. These 13C NMR signals
in compounds 23 and 25 were in agreement with a syn
acetonide.13 In contrast, compound 26 showed the respective
signals at 100.9, 23.7, and 25.1 ppm, as expected for an anti
acetonide.
The Macrolide Formation. Next, we carried out macro-
lactonization of hydroxy acid 18a using the Yamaguchi
(11) Compound 19 was prepared from the corresponding alcohol, which
was obtained from the commercially available methyl (S)-(+)-3-hydroxy-
2-methyl propionate in a series of reactions as described for its enantiomer
(see: Diez-Martin, D.; Kotecha, N. R.; Ley, S. V.; Mantegani, S.; Menendez,
J. C.; Organ, H. M.; White, A. D. Tetrahedron 1992, 48, 7899).
(12) Das, S.; Li, L.-S.; Sinha, S. C. Org. Lett. 2004, 6, 123.
(13) (a) Rychnovsky, S. D.; Skalitzky, D. J. Tetrahedron Lett. 1990, 31,
945. (b) Evans, D. A.; Rieger, D. L.; Gage, J. R. Tetrahedron Lett. 1990,
31, 7099.
Org. Lett., Vol. 9, No. 12, 2007
2275

reaction.14 Here, though the macrolactonization proceeded
smoothly, the product obtained was not the expected lactone
27a but the corresponding double bond isomerized compound
28 (Scheme 3A). Probably the expected product 27a was
kaiyama macrolactonization gave the desired products 27a
and 27b, albeit in low yields (20-25%). The major products
isolated in the Mukaiyama macrolactonization were found
to be the δ lactones, 29a and 29b, respectively. Presumably,
the δ lactones was produced by Et3N-mediated isomerization
of the R,â-unsaturated pyridinium ester intermediate followed
by a nucleophilic attack on the ester function by the OPMB
and facilitated by the quinomethide generation.
Finally, we examined the conversion of compounds 27a
and 27b to sorangiolides. Because the selective deprotection
of the primary PMB group in 27a was unsuccessful, we
quickly moved to 27b. The cross metathesis of 27b was
carried out with alkene Ia in the presence of Grubbs’ second
generation catalyst (RuCl2[imid-H2-Mes2][CHPh]PCy3)
(Scheme 3B). As expected, product 30 was obtained in good
yield. However, the preliminary experiments for the conver-
sion of compound 30 to 1a, including removal of the
protecting groups or the dimide-mediated hydrogenation,
were unsuccessful.
Scheme 3. (A) Macrolactonization of the Hydroxy Acids to
the Expected Macrocyclic Lactones and the Unexpected
Products and (B) an Attempted Synthesis of 1a by the
Cross-Metathesis Approach
In summary, macrocyclic lactones 27a,b were prepared
via hydroxy acids 18a,b by using the carbon-carbon bond
formation by the Fu cross coupling reaction, the 1,5-anti
induction by using Evans’ aldol reaction, and the Mukaiyama
macrolactonization process as the key steps. Interestingly,
macrolactonization of hydroxy acids 18a,b was not trivial,
as the Mukaiyama reaction afforded the isomeric δ lactones
29a,b as the major side products, whereas Yamaguchi
macrolactonization of 18a yielded mainly the double bond
isomerized macrocyclic lactone 28. Further studies to
ascertain the reasons for these abnormalties and synthesize
the macrocyclic lactones 27a,b and the title compounds with
improved yields are in progress.
rapidly isomerized under the reaction conditions to the
energetically favored compound 28.15 Thereafter, using
hydroxy acid 18a and/or 18b we examined a series of
macrolactonization reactions, including the Mukaiyama
method,16 the modified Yamaguchi reaction,17 the EDC
reaction,18 and the Corey-Nicolaou double activation strat-
egy.19 Surprisingly, none of these methods except Mu-
Acknowledgment. We thank the Skaggs Institute for
Chemical Biology and NIH (R01 GM063914) for their
financial support.
Supporting Information Available: Typical experimen-
tal procedure and analytical data for selected compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(14) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989.
(15) The lowest energy conformation of compounds 27a (107.62 kcal/
mol) and 28 (71.20/kmol) was calculated with use of the Chem3D MM2
program.
(16) Mukaiyama, T.; Usui, M.; Saigo, K. Chem. Lett. 1976, 49.
(17) Shiina, I.; Kubota, M.; Oshiumi, H.; Hashizume, M. J. Org. Chem.
2004, 69, 1822.
OL070517G
(18) Paloma, C.; Oiarbide, M.; Garc`ıa, J. M.; Gonza´lez, A.; Pazos, R.;
Odriozola, J. M.; Ban˜uelos, P.; Tello, M.; Linden, A. J. Org. Chem. 2004,
69, 4126.
(19) (a) Corey, E. J.; Nicolaou, K. C. J. Am. Chem. Soc. 1974, 96, 5614.
(b) Modified Corey-Nicolaou method: Buszek, K. R.; Sato, N.; Jeong, Y.
J. Am. Chem. Soc. 1994, 116, 5511.
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