Synthesis of (+)-patulolide c via an asymmetric hydroformylation/ macrocyclization cascade

Article abstract of DOI:10.1021/ol2034299

A highly atom-economical total synthesis of (+)-patulolide C has been accomplished in three steps from the known (2R)-8-nonyn-2-ol in 49% overall yield and 93% de. A Rh(I)-catalyzed asymmetric hydroformylation (AHF)/ intramolecular Wittig olefination cascade was utilized to set the C4-hydroxyl stereochemistry and E-olefin geometry as well as form the macrolactone.

Full text of DOI:10.1021/ol2034299

ORGANIC
LETTERS
2
012
Vol. 14, No. 4
180–1182
Synthesis of (þ)-Patulolide C via an
Asymmetric Hydroformylation/
Macrocyclization Cascade
1
Roberto M. Risi and Steven D. Burke*
Department of Chemistry, University of Wisconsin;Madison, 1101 University Avenue,
Madison, Wisconsin 53706-1322, United States
burke@chem.wisc.edu
Received December 22, 2011
ABSTRACT
A highly atom-economical total synthesis of (þ)-patulolide C has been accomplished in three steps from the known (2R)-8-nonyn-2-ol in 49%
overall yield and 93% de. A Rh(I)-catalyzed asymmetric hydroformylation (AHF)/ intramolecular Wittig olefination cascade was utilized to set the
C4-hydroxyl stereochemistry and E-olefin geometry as well as form the macrolactone.
2
e,i
(
þ)-Patulolide C (1) was firstdiscovered by Yamada and
has been constructed via a Jacobsen kinetic resolution,
2
CBS-reduction, ring opening of (R)-propylene oxide,
h
2b,c
co-workers in 1985 from the culture filtrate of Penicillium
urticae S11R59 mutant, along withits congeners patulolide
1
b,2d
or other chiral pool sources.
1
A and B. Exhibiting both antifungal and antibacterial
a
(þ)-Patulolide C (1) has thus served to demonstrate a
variety of approaches to macrocyclic lactone natural pro-
ducts. Many of the previously reported syntheses required
14 or more synthetic steps to produce (þ)-patulolide C (1).
Illustrated herein is a novel approach to this target based
upon asymmetric hydroformylation (AHF), affording a
very short, high-yielding synthesis of (þ)-patulolide C (1).
The overall synthesis strategy is outlined in Scheme 1.
We envisioned forming the C2,C3 alkene of 1 by intra
molecular Wittig olefination from the stabilized ylide de-
rived from 2 and (triphenylphosphoranylidene)ketene 4,
1
b
activities, the patulolides have been the targets of several
2
total syntheses. Some general strategies in these syntheses
for macrolide formation include utilizing the Yamaguchi
2
aꢀf
2g
Mitsunobu lactonization, Shiina
macrolactonization,
h
2
2i
lactonization, or ring-closing metathesis. The olefin
has been constructed by various methods including
2
d,e
HornerꢀWadsworthꢀEmmons and Wittig olefinations
and a photochemical rearrangement of an epoxydia-
2
b,c
zomethylketone.
lished via a Sharpless asymmetric epoxidation
derived from the chiral pool.
The C4-stereocenter has been estab-
2
b,c,i
or
The C11-stereocenter
1
b,2a,2d
3
also known as the Bestmann ylide. Two different, highly
stereoselective rhodium(I) catalyzed reactions would be
used to install both the oxygen (as an acetate) and the
(
1) (b) Rodphaya, D.; Sekiguchi, J.; Yamada, Y. J. Antibiot. 1986, 5,
29–635. (b) Mori, K.; Sakai, T. Liebigs Ann. Chem. 1988, 1, 13–17.
2) For previous total syntheses of (þ)-patulolide C: (a) Yang, H.;
Kuroda, H.; Miyashita, M.; Irie, H. Chem. Pharm. Bull. 1992, 6, 1616–
4
formyl group at the C4 position on the known alkyne 3.
6
(
Specifically, alkyne 3 was seen as the substrate for a re-
gio- and stereospecific addition of acetic acid to yield the
Z-C4-enol acetate. This would be subjected to a catalytic
asymmetric hydroformylation, envisioned to afford the
1
1
618. (b) Leemhuis, F. M. C.; Thijs, L.; Zwanenburg, B. J. Org. Chem.
993, 25, 7170–7179. (c) Thijs, L.; Egenberger, D. M.; Zwanenburg, B.
Tetrahedron Lett. 1989, 30, 2153–2156. (d) Takano, S.; Murakami, T.;
Samizu, K.; Ogasawara, K. Heterocycles 1994, 39, 67–72. (e) Sabitha,
G.; Chandrashekhar, G.; Yadagiri, K.; Yadav, J. S. Tetrahedron Lett.
2
1
010, 51, 3824–3826. (f) Dorling, E. K.; Thomas, E. J. Tetrahedron Lett.
999, 40, 471–474. (g) Kaisalo, L.; Koskimies, J.; Hase, T. Synth.
(3) Bestmann, H. J.; Kellermann, W.; Pecher, B. Synthesis 1993, 1,
149–152.
Commun. 1999, 29, 399–407. (h) Tian, J.; Yamagiwa, N.; Matsunaga,
S.; Shibasaki, M. Org. Lett. 2003, 5, 3021–3024. (i) Babu, K. V.; Sharma,
G. V. M Tetrahedron: Asymmetry 2008, 19, 577–583.
(4) Alkynol 3 is available in two steps from commercially available
(R)-propylene oxide: Morandi, S.; Pellati, F.; Benvenuti, S.; Prati, F.
Tetrahedron 2008, 64, 6324–6328.
1
0.1021/ol2034299 r 2012 American Chemical Society
Published on Web 02/03/2012

(S,S,S)-bisdiazaphospholane [(S,S,S)-BDP] ligand which
displays phenomenal activity with very high enantio- and
7
regioselectivity for a variety of olefins. For example, enol
a
Scheme 1. Synthesis Strategy
esters such as vinyl acetate react exceptionally well favor-
ing the branched (B) aldehyde with high enantioselectivity
7
c
over the linear (L) aldehyde as shown in Scheme 2.
Furthermore, such chiral aldehydes can be transformed
immediately into diverse functional groups, increasing
molecular complexity from a variety of readily available
alkenes. Hydroformylations in tandemwith other reactions
a
Scheme 3. Total Synthesis of (þ)-Patulolide C
a
Atom numbering throughout corresponds to that in (þ)-patulolide
C (1)
R-acetoxyaldehyde 2. Reaction of the unprotected C11-
hydroxyl in 2 with the Bestmann ylide (4) was planned to
3
5
occur in a cascade with the AHF reaction (steps 2a and 2b)
to directly afford patulolide C acetate.
Scheme 2. AHF of Vinyl Acetate
a
Atom numbering throughout corresponds to that in (þ)-patulolide
C (1)
6
8
are known, including hydroformylation/olefination. It has
been shown that stabilized ylides or phosphonate anions will
not erode the stereochemical integrity of the newly formed
8
asymmetric center in an in situ AHF/olefination tandem.
4
In a forward sense (Scheme 3), alkyne 3 underwent
hydroacetoxylation in the presence of [RhCl(COD)] and
2
ligand 5 to afford the enol acetate 6 in 82% yield with
>
9
95% regio- and stereoselectivity. This rhodium(I) cat-
9
alyst system developed by Breit et al. produces the Z-enol
ester with remarkable anti-Markovnikov selectivity and
excellent atom economy as well as without requiring
protection of the C11-hydroxyl functionality. Since Z-
Hydroformylation converts olefins into valuable alde-
hydes with excellent atom economy, inexpensive reagents,
6
and robust catalysts. The Landis group has developed the
1,2-disubstituted enamides react with higher regio- and
enantioselectivity than their E-isomers, we expected Z-1,2-
(
5) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem.,
Int. Ed. 2006, 45, 7134–7186.
6) (a) Eilbracht, P.; Baerfacker, L.; Buss, C.; Hollmann, C.; Kitsos-
7
disubstituted enol esterstoreact analogously. Substrate 6
e
(
Rzychon, B. E.; Kranemann, C. L.; Rische, T.; Roggenbuck, R.;
Schmidt, A. Chem. Rev. 1999, 99, 3329–3365. (b) Eilbracht, P.; Schmidt,
A. M. Top. Organomet. Chem. 2006, 18, 65–95.
was subjected to AHF conditions using Rh(acac)(CO)
7
2
and (S,S,S)-BDP at 50 °C under 150 psi of syngas, and
within 24 h 100% conversion to the C11-hydroxy-
C4-acetoxyaldehyde 2 was accomplished with complete
(7) (a) Clark, T. P.; Landis, C. R.; Freed, S. L.; Klosin, J.; Abboud,
K. A. J. Am. Chem. Soc. 2005, 127, 5040–5042. (b) Klosin, J.; Landis,
C. R. Acc. Chem. Res. 2007, 40, 1251–1259. (c) Thomas, P. J.; Axtell,
A. T.; Klosin, J.; Peng, W.; Rand, C. L.; Clark, T. P.; Landis, C. R.;
Abboud, K. A. Org. Lett. 2007, 9, 2665–2668. (d) Watkins, A. L.;
Landis, C. R. J. Am. Chem. Soc. 2010, 132, 10306–10317. (e) McDonald,
R. I.; Wong, G. W.; Neupane, R. P.; Stahl, S. S.; Landis, C. R. J. Am.
Chem. Soc. 2010, 132, 14027–14029.
(8) Landis, C. R.; Wong, G. W.; Burke, S. D.; Jaffett, V. A. Unpub-
lished results.
(9) Lumbroso, A.; Vautravers, N. R.; Breit, B. Org. Lett. 2010, 12,
5498–5501.
Org. Lett., Vol. 14, No. 4, 2012
1181

regiocontrol and high diastereoselectivity. Only one alde-
quantitative yield to give (þ)-patulolide C (1) in high dr,
determined to be 96.6:3.4 by HPLC.
1
hyde was observed by H NMR as an equilibrium mixture
with the hemiacetal.
In summary, a concise total synthesis of (þ)-patulolide
The AHF reaction yielded a solution of aldehyde that is
substantially pure, which was utilized directly without
purification. The crude reaction mixture was simply di-
luted with toluene and transferred to a refluxing toluene
C (1) has been accomplished in three steps from the known
4
alkyne 3. Both Rh(I)-catalyzed reactions proceeded with
outstanding atom economy and high regio- and stereo-
selectivity. An in situ reaction of the hydroxyaldehyde 2
with the Bestmann ylide directly afforded the 12-mem-
bered lactone 7, and mild enzymatic deacetylation gave
(þ)-patulolide C (1) in 49% overall yield from 3.
3
solution of the Bestmann ylide (4). This generated a
stabilized ylide in situ from the unprotected hydroxyl
attacking the electrophilic ketene carbon followed by
concomitant intramolecular Wittig olefination of the R-
acetoxyaldehyde to effect macrocyclization, affording the
Acknowledgment. We acknowledge Mr. Victor Jaffett
(UW-Madison Dept. of Chemistry) for contributions in
1
2-membered lactone 7 in 62% yield with complete E-
synthetic efforts. We gratefully acknowledge Prof. Clark
R. Landis (UW-Madison Dept. of Chemistry) for insight
and discussion. We wish to thank Charles G. Fry (UW-
Madison Dept. of Chemistry) for his assistance with high
field NMR spectra. Partial financial support of this re-
search from the NSF (Grant CHE-0848616) is gratefully
acknowledged.
selectivity. Whereas traditional macrolactonizations typi-
cally require carboxylic acid activation and net dehydra-
tion, these requirements are built into the Bestmann ylide
3
(
4), thus expediting the synthetic sequence. The absence of
base and external nucleophile in the AHF/Bestmann
ylide olefination cascade also avoided epimerization or
1
olefin (E/Z) isomerization issues. Neutral deacetylation
0
1
of 7 with Pseudomonas florescens lipase proceeded in
1
Supporting Information Available. Experimental pro-
cedures and characterization data for new compounds.
This material available free of charge via the Internet at
http://pubs.acs.org
(
10) Olefin isomerization was observed when macrolactonizations of
the (þ)-patulolide C seco-acid were performed with base present and will
be described elsewhere.
(
11) Xie, Z. F.; Suemune, H.; Sakai, K. Tetrahedron: Asymmetry
1993, 4, 973–980.
The authors declare no competing financial interest.
1
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Org. Lett., Vol. 14, No. 4, 2012