Synthesis of the Prelog-Djerassi lactone via an asymmetric hydroformylation/crotylation tandem sequence

Article abstract of DOI:10.1021/ol3008765

A synthesis of the Prelog-Djerassi lactone [(+)-1] has been accomplished in three isolations and 57% overall yield from the known vinyl ortho ester 2. A Rh(I)-catalyzed asymmetric hydroformylation/crotylation tandem sequence has been developed and used to set the C2-C4 stereochemistry. A Rh(I)-catalyzed asymmetric hydrogenation was employed to set the C6 sterechemistry, resulting in an unusually short and efficient enantioselective synthesis of this touchstone molecule from achiral starting material.

Full text of DOI:10.1021/ol3008765

ORGANIC
LETTERS
2012
Vol. 14, No. 10
2572–2575
Synthesis of the PrelogꢀDjerassi Lactone
via an Asymmetric Hydroformylation/
Crotylation Tandem Sequence
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 April 5, 2012
ABSTRACT
A synthesis of the PrelogꢀDjerassi lactone [(þ)-1] has been accomplished in three isolations and 57% overall yield from the known vinyl ortho
ester 2. A Rh(I)-catalyzed asymmetric hydroformylation/crotylation tandem sequence has been developed and used to set the C2ꢀC4
stereochemistry. A Rh(I)-catalyzed asymmetric hydrogenation was employed to set the C6 sterechemistry, resulting in an unusually short and
efficient enantioselective synthesis of this touchstone molecule from achiral starting material.
The PrelogꢀDjerassi lactone (1) was originally isolated
in 1956 by Prelog and by Djerassi as an oxidative degrada-
tion product from neomethymycin, methymycin, narbo-
mycin, and picromycin.1,2 Rickards and Smith elucidated
the full stereochemistry in 1970.3,4 Since then, the PD
lactone (1) has served as a touchstone molecule to show-
case synthetic strategies and methods.5 An instructive
variety of strategies have been used to synthesize 1, includ-
ing two nonstereoselective approaches, the use of architec-
turally biased scaffolds, and carbohydrate-based syntheses.
Many methods have been employed to construct this
stereochemically rich lactone, including various aldol reac-
tions, carbonyl crotylations, and pericyclic reactions such
as [4 þ 2] cycloaddition, the ene reaction, and Claisen- and
[2,3] Wittig-rearrangements. Electrophilic additions to
alkeneshave also been used, including mercuric ion induced
cyclization, acyclic 1,5-diene hydroboration, Sharpless
asymmetric epoxidation, and phenyldimethylsilylcuprate
1,4-addition to an R,β-unsaturated ester.5
Since 1990 several syntheses have been published includ-
ing one from trans-pulegenic acid,6 three from the Roche
ester,7ꢀ9 a racemic synthesis from cyclopentanone,10
a
desymmetrization of a meso dialdehyde,11 and an Irelandꢀ
Claisen rearrangement.12 Clearly, the PD lactone (1) has
provided a popular context to display a diverse range of
methods and strategies for polypropionate natural product
synthesis.
Mindful of these benchmarks, we wish to present herein
a novel and efficient synthesis of (þ)-PD lactone (1) based
on a catalytic asymmetric hydroformylation/crotylation tandem
sequence developed in our laboratory. Asymmetric hydro-
formylation (AHF) generates chiral, R-branched aldehydes
(6) Hacini, S.; Santelli, M. Tetrahedron 1990, 46, 7787–7792.
(7) Miyashita, M.; Hoshino, M.; Yoshikoshi, A.; Kawamine, K.;
Yoshihara, K.; Irie, H. Chem. Lett. 1992, 6, 1101–1104.
(8) Pilli, R. A.; de Andrade, C. K. Z.; Souto, C. R. O. J. Braz. Chem.
Soc. 1996, 7, 279–283.
(9) Bluet, G.; Bazan-Tejeda, B.; Campagne, J. Org. Lett. 2001, 3,
3807–3810.
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1994, 35, 6101–6104.
(11) Oppolzer, W.; Walther, E.; Balado, C. P.; De Brabander, J.
(1) Anliker, R.; Dvornik, D.; Gubler, K.; Heusser, H.; Prelog, V.
Helv. Chim. Acta 1956, 39, 1785–1790.
(2) Djerassi, C.; Zderic, J. A. J. Am. Chem. Soc. 1956, 78, 6390–6395.
(3) Manwaring, D. G.; Rickards, R. W.; Smith, R. M. Tetrahedron
Lett. 1970, 11, 1029–1032.
(4) Rickards, R. W.; Smith, R. M. Tetrahedron Lett. 1970, 11, 1025–
1028.
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(5) For a review of syntheses prior to 1990, see: Martin, S. F.; Guinn,
D. E. Synthesis 1991, 4, 245–262.
(12) Hiscock, S. D.; Hitchcock, P. B.; Parsons, P. J. Tetrahedron
1998, 54, 11567–11580.
r
10.1021/ol3008765
Published on Web 05/04/2012
2012 American Chemical Society

from alkenes.13 Among the attributes of the catalytic AHF
protocol are high atom economy, moderate temperature
and pressure, low catalyst/ligand loadings, high substrate
concentration, neutral conditions, and operational simpli-
city (pressure bottle). The only reagents, CO and H2, are
easily removed at the end of the reaction, yielding a
substantially pure solution of the R-chiral branched alde-
hyde in high enantiomeric excess.13 These characteristics
suggest employing AHF in a tandem sequence.14 Since
crotylation of R-chiral aldehydes is well established,15 we
sought to couple this powerful reaction with the AHF in
order to create three new asymmetric centers with the
alternating of methyl, hydroxyl, and methyl substituents
characteristic of polypropionates.
unmasking of the orthoester andlactonizationtocomplete
the synthesis of the PD lactone (1).
Figure 1. Landis’ AHF Ligands.
Scheme 1. Synthesis Strategy
Landis has developed bisdiazaphospholane (BDP) li-
gands (Figure 1) that enable highly regio- and enantiose-
lective Rh(I)-catalyzed hydroformylation of numerous
olefins, favoring branched (chiral) over linear (achiral)
aldehydes.13 We have initiated a program to develop and
apply the AHF reaction using the BDP ligands to problems
in synthesis.19
When considering masked acrylate substrates for the
AHF/crotylation tandem sequence, an orthoester moiety
was expected to maximize the steric distinction between
the R-substituents on the aldehyde product for increased
FelkinꢀAnh selectivity in the crotylation,15 while avoid-
ing the involvement of an enolizable β-dicarbonyl. With
these objectives in mind, the known 1-vinyl-4-methyl-
2,6,7-trioxabicyclo[2.2.2]octane ortho ester [vinyl-OBO
substrate (2) Scheme 1] was chosen.16,17 Vinyl-OBO 2
smoothly underwent AHF with very low catalyst loading
to afford the branched aldehyde 5 with excellent regio-
and enantioselectivity (Scheme 2). To the same pot, trans-
2-butenyl pinacolato boronic ester (6)15a,b was added
at ambient temperature and reacted for 24 h to give the
2,3-syn, 3,4-anti-homoallylic alcohol 3. The neutral con-
ditions of both the AHF and the crotylation avoided
epimerization of the R-chiral aldehyde and transferred
stereogenicity from both 5 and 6 to 3 with high fidelity
via the ZimmermanꢀTraxler transition state T1.15,20 The
harmonious combination of the AHF and the substrate-
controlled crotylation efficiently telescopes the influence
of the chiral catalyst to yield three new asymmetric centers
in a single pot. Subjection of homoallylic alcohol 3 to
an ozonolysis/Wittig olefination with ylide 721 yielded
the R,β-unsaturated methyl ester 4 in excellent yield and
stereoselectivity.
The synthesis strategy for 1 is shown in Scheme 1. The
C2 stereochemistry would be established via an AHF of an
appropriate vinyl ortho ester 216,17 followed by a substrate
controlled crotylation to set C3 and C4 in the requisite
C2ꢀC3 syn, C3ꢀC4 anti relationship in homoallylic alco-
hol 3. The C6 methyl as well as the C7 carbonyl would be
incorporated via an ozonolysis/Wittig tandem to afford
R,β-unsaturated ester 4. Finally, a hydroxyl-directed ca-
tionic Rh(I)-catalyzed asymmetric hydrogenation18 would
set the C6 stereochemistry, which would be followed by
(13) (a) McDonald, R. I.; Wong, G. W.; Neupane, R. P.; Stahl, S. S.;
Landis, C. R. J. Am. Chem. Soc. 2010, 132, 14027–14029. (b) Watkins,
A. L.; Landis, C. R. J. Am. Chem. Soc. 2010, 132, 10306–10317.
(c) Clark, T. P.; Freed, S. L.; Klosin, J.; Abboud, K. A.; Landis, C. R.
J. Am. Chem. Soc. 2005, 127, 5040–5042. (d) Watkins, A. L.; Hashiguchi,
B. G.; Landis, C. R. Org. Lett. 2008, 10, 4553–4556. (e) Thomas, P. J.;
Axtell, A. T.; Klosin, J.; Peng, W.; Rand, C. L.; Clark, T. P.; Abboud,
K. A.; Landis, C. R. Org. Lett. 2007, 9, 2665–2668.
(14) (a) Eilbracht, P.; Baerfacker, L.; Buss, C.; Hollmann, C.; Kitsos-
Rzychon, B. E.; Kranemann, C. L.; Rische, T.; Roggenbuck, R.;
Schmidt, A. Chem. Rev. 1999, 99, 3329–3366. (b) Eilbracht, P.; Schmidt,
A. M. Top. Organomet. Chem. 2006, 18, 65–95.
(15) (a) Roush, W. R.; Walts, A. E.; Hoong, L. K. J. Am. Chem. Soc.
1985, 107, 8186–8190. (b) Roush, W. R.; Adam, M. A.; Walts, A. E.;
Harris, D. J. J. Am. Chem. Soc. 1986, 108, 3422–3434. (c) Denmark,
S. E.; Fu, J. Chem. Rev. 2003, 103, 2763–2794. (d) Hoffmann, R. W. In
Sterocontrolled Organic Synthesis; Trost, B. M., Ed.; Blackwell Scientific
Publications: Cambridge; 1994; pp 259ꢀ274.
Cationic Rh(I)- and Ir(I)-catalyzed, hydroxyl-directed
olefin hydrogenations have been shown to transfer chirality
(16) (a) Corey, E. J.; Raju, N. Tetrahedron Lett. 1983, 24, 5571–5574.
(b) Richardson, S. K.; Jeganathan, A.; Watt, D. S. Tetrahedron Lett.
1987, 28, 2335–2338.
(19) (a) Risi, R. M.; Burke, S. D. Org. Lett. 2012, 14, 1180–1182.
(b) Clemens, A. J. L.; Burke, S. D. J. Org. Chem. 2012, 77, 2983–2985.
(20) Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79,
1920–1923.
(21) Handa, M.; Scheidt, K. A.; Bossart, M.; Zheng, N.; Roush,
W. R. J. Org. Chem. 2008, 73, 1031–1035.
(17) Ortho ester 2 is available in three steps from commercially
available 3-methyl-3-oxetanemethanol via the scalable procedure de-
scribed in the Supporting Information.
(18) (a) Evans, D. A.; Morrissey, M. M.; Dow, R. L. Tetrahedron
Lett. 1985, 26, 6005–6008. (b) Hoveyda, A. H.; Fu, G. C.; Evans, D. A.
Chem. Rev. 1993, 93, 1307–1370.
Org. Lett., Vol. 14, No. 10, 2012
2573

Table 1. Catalyst Screen
Scheme 2. Tandem AHF/Crotylation and Ozonolysis/Wittig
Olefination
dr (R:β)
for C6-
Mea
%
yielda
entry
catalyst
1
2
3
4
5
6
10% Pd/C
39
61
66
63
30
76
1:1
2.5:1
3:1
15% [Rh(nbd)(dppb)]BF4
0.9% [Ir(pyr)(Cy3P)]PF6
3% Burgess cat.
1.6:1
5:1
5% [Rh(COD)(S)-BINAP]BF4
1% [Rh(COD)(S)-BINAP]ClO4
>31:1
a Yield and diastereomer ratio measured on 1 before recrystalliza-
1
tion; dr determined by comparing integrations of C3-12Cꢀ H minor
1
diastereomer vs 13Cꢀ H satellite of 1 in C6D6 at 600 MHz.24 See
Supporting Information for details.
bulky OBO containing substituent in equatorial positions
on the chairlike complex 8. Insertion of dihydrogen would
generate intermediate 9, followed by alkene insertion to
give 10 and reductive elimination to afford the open chain
methyl ester 11, which spontaneously underwent lactoni-
zation to afford OBO-lactone 12.
in unsaturated esters similar to 4.18,22,23 We explored several
catalyst systems for the hydrogenation (Scheme 3, Table 1)
followed by a one-pot conversion of the hydrogenation
product to the targeted PD lactone (1), in which the
hydrogenation diastereoselectivity (C6 R-Me desired) was
determined.24 Simple hydrogenation with Pd/C imparted
no diastereoselectivity while [Rh(nbd)(dppb)]BF4 gave a
2.5:1 mixture of products favoring the desired diastereo-
mer. Crabtree’s catalyst22 (entry 3) gave slightly better
selectivity (3:1), and Burgess’ cationic Ir(I) catalyst23
(entry 4) gave lower selectivity (1.6:1). Incorporating a
chiral ligand with the hydroxyl-directed Rh(I)-catalyzed
hydrogenation has been shown to increase the diastereos-
electivity via double stereodifferentiation.18 Using [Rh(COD)-
(S)-BINAP]BF4 afforded a 5:1 mixture in favor of the PD
lactone (1). Superior results were obtained when the
noncoordinating perchlorate counterion was incorpo-
rated into the catalyst (entry 6), affording a much higher
diastereoselectivity (>31:1).
Scheme 4. Directed Asymmetric Hydrogenation
Following the hydrogenation of 4 to afford OBO-
lactone 12 (Scheme 5), the acid catalyzed decomposition
of the OBO-ortho ester gave diol ester 13,25 which upon
saponification gave a mixture of 14 and 15. Esterification
Scheme 3. Directed Hydrogenation/Lactonization/OBO
Cleavage
26
of the C1 carboxylic acid with TMSCHN2 produced a
(22) (a) Crabtree, R. H.; Morris, G. E. J. Organomet. Chem. 1977,
135, 395–403. (b) Crabtree, R. H.; Davis, M. W. Organometallics 1983, 2,
681–682. (c) Crabtree, R. H.; Morehouse, S. M. Inorg. Synth. 1986, 24,
173–176.
(23) Zhao, J.; Burgess, K. J. Am. Chem. Soc. 2009, 131, 13236–13237.
(24) Claridge, T. D. W.; Davies, S. G.; Polywka, M. E. C.; Roberts,
P. M.; Russell, A. J.; Savory, E. D.; Smith, A. D. Org. Lett. 2008, 10,
5433–5436.
(25) Kwok, P. Y.; Muellner, F. W.; Chen, C. K.; Fried, J. J. Am.
Chem. Soc. 1987, 109, 3684–3692.
(26) Martin, L. J.; Marzinzik, A. L.; Ley, S. V.; Baxendale, I. R. Org.
The proposed model for the optimized diastereoselec-
tivity of entry 6 is presented in Scheme 4.18 Initial coordi-
nation of both the hydroxyl group and the olefin face
shown with the rhodium would put the C4 methyl and the
Lett. 2011, 13, 320ꢀ323 and references cited therein.
2574
Org. Lett., Vol. 14, No. 10, 2012

development of an AHF/crotylation tandem sequence
yielding 3, in which three of the four needed asymmetric
centers are set in a single pot.
Scheme 5. Conversion of 4 to (þ)-PrelogꢀDjerassi Lactone (1)
An ozonolysis/Wittig homologation afforded the R,β-
unsaturated methyl ester 4 containing C1ꢀC7 of the PD
lactone (1) in good yield with excellent selectivity. Finally a
hydroxyl-directed cationic Rh(I)-catalyzed asymmetric
hydrogenation18 set the C6 stereocenter with excellent
(>31:1) diastereoselectivity. In the same pot, the OBO-
ortho ester was hydrolyzed,25 the carboxylic acid was
esterified with TMSCHN2,26 and lactonization with
Otera’s catalyst27 yielded the PD lactone (1). Further
investigations into the development of efficient AHF-based
strategies for natural products synthesis are underway.
Acknowledgment. We gratefully acknowledge Prof.
Clark R. Landis (UW-Madison Dept. of Chemistry) for
insight and discussion. We wish to thank Dr. Charles G.
Fry (UW-Madison Dept. of Chemistry) for his assistance
with high field NMR spectra. Partial financial support of
this research from the NSF (Grant CHE-0848616) and
from the UW-Madison Dept. of Chemistry is gratefully
acknowledged.
mixture of 1 and a minor amount of 16 that converged to
only 1 via neutral lactonization with Otera’s catalyst.27
In conclusion, the PrelogꢀDjerassi lactone [(þ)-1] has
been synthesized in three isolations and 57% overall yield
from vinyl-OBO 2.16,17 Featured in this synthesis is the
Supporting Information Available. Experimental pro-
cedures and characterization data for new compounds,
vinyl OBO 2, (þ)-PD lactone (1), SFC derivatives, and
NMR data for dr determination. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(27) Otera, J.; Yano, T.; Kawabata, A.; Nozaki, H. Tetrahedron Lett.
1986, 27, 2383–2386.
The authors declare no competing financial interest.
(28) Martin, S. F.; Guinn, D. E. J. Org. Chem. 1987, 52, 5588–5593.
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