An efficient, modular approach for the synthesis of (+)-strictifolione and a related natural product

Article abstract of DOI:10.1021/ol403110p

An efficient, library amenable, "pot economical" total synthesis of (+)-strictifolione and the related natural product, (6R)-6[(E,4R,6R)-4,6- dihydroxy-10-phenyl-1-decenyl]-5,6-dihydro-2H-2-pyrone, are reported. This modular approach takes advantage of tw

Full text of DOI:10.1021/ol403110p

Letter
pubs.acs.org/OrgLett
An Efficient, Modular Approach for the Synthesis of (+)-Strictifolione
and a Related Natural Product
Susanthi Jayasinghe, Phanindra K. M. Venukadasula, and Paul R. Hanson*
Department of Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, Kansas 66045-7582, United States
S
* Supporting Information
ABSTRACT: An efficient, library amenable, “pot economical” total synthesis of (+)-strictifolione and the related natural
product, (6R)-6[(E,4R,6R)-4,6-dihydroxy-10-phenyl-1-decenyl]-5,6-dihydro-2H-2-pyrone, are reported. This modular approach
takes advantage of two consecutive phosphate tether-mediated, one-pot, sequential protocols, followed by a final cross metathesis
to deliver both antifungal natural products in a three-pot process from the respective enantiomeric (R,R)- and (S,S)-trienes with
minimal purification. A salient feature of this route is that additional protecting groups are not required as a result of the
orthogonal protecting- and leaving-group properties innate to phosphate triesters.
(+)-Strictifolione (1) was isolated and structurally characterized
by Aimi and co-workers from the stem bark of Cryptocaria
stritifolia, a member of the family Lauraceae that grows in the
rainforests of west Kalimantan, Indonesia.1 The structure of 1,
including the absolute configuration of the stereogenic centers,
was also confirmed by Aimi and co-workers after accomplishing
its first total synthesis, employing (S)-malic acid and (S)-
glycidol in 18 steps.2 A related compound, (6R)-6[(E,4R,6R)-
4,6-dihydroxy-10-phenyl-1-decenyl]-5,6-dihydro-2H-2-pyrone
(2), was isolated by Hostettmann and co-workers in 2001 from
the leaves and bark of Ravensara crassifolia, which is an endemic
genus in Madagascar, along with another structurally similar
Figure 1. Natural products 1−3.
compound (6S)-5,6-dihydro-6-[(2R)-2-hydroxy-6-phenylexyl]-
2H-pyran-2-one (3).3 Krishna and co-workers accomplished
steps, starting from 3-phenylpropionaldehyde, that utilized the
the first total synthesis of 2 by iterative use of Jacobsen’s
hydrolytic kinetic resolution with a longest linear sequence
(LLS) of 17 steps.4 All three compounds (1−3, Figure 1) have
been shown to possess antifungal activity.3
dual use of enantioselective allyltitanation in conjunction with
cross metathesis (CM).6a In 2010, Das and co-workers devised
a comparable pathway with an LLS of 10 steps using Sharpless
kinetic resolution and olefin cross metathesis.6g In 2010, She
and co-workers6h developed an efficient route employing a one-
pot, double allylboration comprised of a pathway with a 7-step
LLS using an Ipc2BH-derived boryl-substituted allylborane,
derived in two steps from propargyl bromide,7 3-butenal,
derived in two steps from glyoxal, and a ketal-protected
aldehyde.8 Despite significant attributes of these syntheses,6 the
development of simple, efficient, scalable strategies that are
Key structural features in 1 and 2 include a Michael accepting
5,6-dihydro-α-pyrone moiety in the eastern subunit, a central
1,3-anti diol, and lipophilic substitution in the western subunit.
It is generally believed that the unsaturated pyranone functional
group can react with the nucleophilic warhead of a target
enzyme and, thus, attenuate its activity.5
Among several synthetic methods for the construction of 1,6
notable streamlined efforts have recently been made. In 2003,
Cossy and co-workers developed a concise and elegant
synthetic pathway consisting of a longest linear sequence of 9
Received: October 29, 2013
Published: December 2, 2013
© 2013 American Chemical Society
122
dx.doi.org/10.1021/ol403110p | Org. Lett. 2014, 16, 122−125

Organic Letters
Letter
library amenable for installation of key diversity elements in a
divergent manner, is notably absent in the literature. In this
regard, one-pot protocols have emerged as powerful synthetic
strategies to achieve total/intermediate/analog synthesis, due to
the ability to form multiple bonds and stereocenters, while
invoking step, atom,9 green, and pot economy,10 thus saving
time and resources. Herein, we disclose an efficient, modular
approach for the total synthesis of both naturally occurring
antifungal compounds 1 and 2, highlighting the utility of two
consecutive phosphate tether-mediated one-pot, sequential
protocols, namely a one-pot, sequential, RCM/CM/chemo-
selective hydrogenation protocol,11 followed by a one-pot,
sequential reductive allylic transposition/tether removal
method and final CM with overall minimal purification. A
critical feature of this strategy is modular installation of the
western and eastern 5,6-dihydro-α-pyrone subunits via two
facile CM reactions, thus opening future opportunities in
library development.
NBSH).11,12 Triene (R,R)-7 is readily prepared in two steps via
sequential tripodal coupling of the C2-symmetric anti-diene diol
(R,R)-813 and allyl alcohol with POCl3 or in one step utilizing
phosphoramidite chemistry.13c Similarly, phosphate 10 can be
synthesized following the same sequence of RCM/CM/“H2”
starting with enantiomeric triene (S,S)-7 which is obtained
from 1,3-anti-diene diol (S,S)-8 and employing phenyl-but-3-
ene as the cross-coupling partner. Vinyl lactone 5 can be readily
derived (5 LLS) from diene 11 and TIPS-protected propargyl
aldehyde 12 using Jacobsen hetero-Diels−Alder chemistry.14
Following the previously reported optimized conditions for
RCM/CM/“H2”,11 triene (R,R)-7 was first subjected to an
RCM reaction with the second generation Hoveyda−Grubbs
catalyst (HG-II) 1415 (6 mol %) in CH2Cl2 (0.007 M), and
upon completion, solvent was evaporated and the cross
metathesis partner cis-stilbene in DCE was introduced with
continued heating for 2 h (Scheme 2). It should be noted that
Retrosynthetic analysis reveals that both natural products 1
and 2 can be readily derived from key diol-containing
intermediates 4 and 9, respectively, via CM with vinyl lactone
5 (Scheme 1). The pivotal diol 4 in turn can be synthesized
Scheme 2. Consecutive One-Pot, Sequential Protocols and
CM
Scheme 1. Retrosynthetic Analysis of Natural Products 1 and
2
cross metathesis with styrene was not productive in comparison
to cis-stilbene due to deleterious homodimerization of styrene, a
type I olefin.16 Subsequent chemoselective diimide reduction
by simple addition of o-NBSH into the reaction mixture
provided the phenyl-substituted phosphate 6 in 52% overall
yield, representing an 81% average yield/reaction in the one-
pot, sequential protocol.
We next developed a one-pot Pd-catalyzed, reductive allylic
transposition17 and tether removal protocol. In this regard,
allylic transposition [Pd(OAc)2, HCOONH4, PPh3]18 on
phosphate 6 generated the requisite terminal olefin that was
followed by in situ tether removal by consecutive addition of
dimethyl sulfate (Me2SO4) (reflux 3 h) and LiAlH4 (0 °C),
followed by facile Feiser workup,19 to furnish diol 4 as a single
diastereomer in 65% overall yield (87% average yield/
reaction).20
With the advanced fragment 4 in hand, the total synthesis of
1 was accomplished via CM of diol alkene 4 and the readily
prepared vinyl lactone 5, vide infra (Scheme 2), in the presence
of the HG-II catalyst in CH2Cl2 in 77% yield and with excellent
E-selectivity. The spectral data (H1, C13, IR, HRMS) and
optical rotation of 1 were in complete agreement with those
from phosphate 6, employing a regioselective Pd(0)-catalyzed
reductive allylic transposition and phosphate tether removal
under reductive conditions. The phenyl substituted bicyclic
phosphate 6 can be achieved from triene (R,R)-7 via a one-pot,
sequential RCM/CM/“H2” with cis-stilbene as the CM partner,
followed by chemoselective hydrogenation employing diimide
reduction conditions with o-nitrobenzenesulfonyl hydrazine (o-
123
dx.doi.org/10.1021/ol403110p | Org. Lett. 2014, 16, 122−125

Organic Letters
Letter
reported in the literature.2 Overall, the three-pot process
afforded 1 in 26% yield from triene (R,R)-7.
Scheme 5. Consecutive One-Pot, Sequential Protocols and
CM
Since diol 4 was obtained in high purity without
chromatography, the protocol outlined in Scheme 2 was
further optimized to employ simple cannulation after the
aforementioned Feiser workup (i.e., before CM). Thus, after
reduction with LiAlH4, and Fieser workup, the resulting THF
solution was transferred via cannula, concentrated, and
subjected to CM with vinyl lactone 5 in CH2Cl2 to afford 1
in 26% overall yield (72% average yield/reaction, Scheme 3).
Scheme 3. One-Pot, Pd-Catalyzed Reductive Allylic
Transposition, Tether Removal Protocol, and CM
PPh3, and Cs2CO3], followed by tether removal utilizing
consecutive additions of Me2SO4, and LiAlH4, and final Feiser
workup19 furnished diol 9, which was transferred via cannula
into a new flask and subjected to CM in CH2Cl2 with vinyl
lactone 5 to furnish the natural product 2 in 28% overall yield
(73% average yield/reaction) and excellent E-selectivity.
Overall, the three-pot process afforded 2 in 15% yield from
triene (S,S)-8.
The aforementioned vinyl lactone 5 was readily synthesized
utilizing Jacobsen hetero-Diels−Alder chemistry as outlined in
Scheme 4. The isopropyl acetal alkyne 17 was obtained
In conclusion, we have reported synthetic routes to the
antifungal natural products 1 and 2 employing a three-pot
process from the readily prepared trienes (R,R)-7 and (S,S)-7,
respectively. Taken collectively, the orthogonal protecting and
leaving group ability of the phosphate triester tether stream-
lined the synthesis of 1 and 2. We anticipate that our modular
approach can be further exploited for the synthesis of an array
of analogues to explore SAR within 1 and 2.
Scheme 4. Synthesis of Vinyl Lactone 5
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details and spectroscopic data of new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
following the Jacobsen protocol employing hetero-Diels−Alder
catalyst 13.14 Subsequent Lindlar hydrogenation with Pd−
CaCO3, in the presence of freshly distilled quinoline in EtOAc
under H2, afforded olefin 18 in 80% yield on gram scale
(Scheme 4). The required vinyl lactone 5 was obtained in good
yield via direct oxidation of the isopropyl acetal olefin 18 with
PCC in CH2Cl2 in the presence of AcOH.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: phanson@ku.edu.
Notes
The authors declare no competing financial interest.
We next highlighted this approach in the synthesis of the
natural product (6R)-6[(E,4R,6R)-4,6-dihydroxy-10-phenyl-1-
decenyl]-5,6-dihydro-2H-2-pyrone (2) using the enantiomeric
triene (S,S)-7 and CM partners 19 and 5 as outlined in Scheme
5. The synthesis of 2 was achieved following a similar sequence
starting with the enantiomerically pure diene diol (S,S)-8. After
completion of the RCM reaction with triene (S,S)-7, CM was
carried out with phenyl-but-1-ene (19) with subsequent
diimide reduction affording phosphate 10 in 54% overall
yield in the one-pot, three-reaction protocol. Subsequent Pd-
catalyzed reductive allylic transposition [Pd(OAc)2, HCOOH,
ACKNOWLEDGMENTS
■
This investigation was generously supported by funds provided
by the National Institute of General Medical Sciences (NIH
R01 GM077309). The authors thank Dr. Justin Douglas and
Sarah Neuenswander (KU) for assistance with NMR measure-
ments and Dr. Todd Williams (KU) for HRMS analysis. The
authors also thank the University of Kansas and the State of
Kansas for support of our program. The authors also thank
Materia, Inc. for supplying the metathesis catalyst and helpful
suggestions.
124
dx.doi.org/10.1021/ol403110p | Org. Lett. 2014, 16, 122−125

Organic Letters
Letter
(15) (a) Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J., Jr.;
Hoveyda, A. H. J. Am. Chem. Soc. 1999, 121, 791−799. (b) Garber, S.
B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem. Soc.
2000, 122, 8168−8179. (c) Gessler, S.; Randl, S.; Blechert, S.
Tetrahedron Lett. 2000, 41, 9973−9976.
REFERENCES
■
(1) Juliawaty, L. D.; Kitajima, M.; Takayama, H.; Achmad, S. A.;
Aimi, N. Phytochemistry 2000, 54, 989−993.
(2) Juliawaty, L. D.; Watanabe, Y.; Kitajima, M.; Takayama, H.;
Achmad, S. A.; Takayama, H.; Aimi, N. Tetrahedron Lett. 2002, 43,
8657−8660.
(3) (a) Raoelison, G. E.; Terreaux, C.; Queiroz, E. F.; Zsila, F.;
Simonyi, M.; Antus, S.; Randriantsova, A.; Hostettmann, K. Helv.
Chim. Acta 2001, 84, 3470−3476. (b) Jaconnet, A.; Avelona, I.;
Sahpaz, S.; Terreaux, C.; Hostettmann, K.; Stoeckli-Evans, H.;
Rasolondramanitra, J. Phytochemistry 1999, 52, 265−269.
(4) Krishna, P. R.; Srinivas, R. Tetrahedron Lett. 2007, 48, 2013−
2015.
(16) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J.
Am. Chem. Soc. 2003, 125, 11360−11370.
(17) (a) Tsuji, J.; Mandai, T. Synthesis 1996, 1−24 and references
therein. (b) Tsuji, J.; Minami, I.; Shimizu, I. Synthesis 1986, 623−627.
(c) Mandai, T.; Matsumoto, T.; Kawada, M.; Tsuji, J. Tetrahedron
1993, 49, 5483−5493. (d) Tsuji, J.; Yamakawa, T. Tetrahedron Lett.
1979, 7, 613−616. (e) Hayashi, T. Acc. Chem. Res. 2000, 33, 354−362.
(f) Hayashi, T. J. Organomet. Chem. 1999, 576, 195−202. (g) Lautens,
M.; Paquin, J.-F. Org. Lett. 2003, 5, 3391−3394.
(18) Use of H(Bu3P)BF4 provided the branch olefin in a 1:3 (b:l)
ratio, while use of PPh3 provided mainly the terminal olefin.
(19) (a) Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis, Vol. 1;
Wiley: New York, 1967; pp 581−595. (b) See Supporting
Information.
̆
(5) (a) Kasaplar, P.; Çakmak, Y.; Çagır, A. Bioorg. Chem. 2010, 38,
186−189. (b) Kalesse, M.; Christmann, M.; Bhatt, U.; Quitschalle, M.;
Claus, E.; Saeed, A.; Burzlaff, A.; Kasper, C.; Haustedt, L. O.; Hofer,
E.; Scheper, T.; Beil, W. ChemBioChem 2001, 2, 709−714. (c) Kalesse,
E.; Christmann, M. Synthesis 2002, 981−1003. (d) Bialy, L.;
Waldmann, H. Chem. Commun. 2003, 1872−1873. (e) Buck, S. B.;
Hardouin, C.; Ichikawa, S.; Soenen, D. R.; Gauss, C. M.; Hwang, I.;
Swingle, M. R.; Bonness, K. M.; Honkanen, R. E.; Boger, D. L. J. Am.
Chem. Soc. 2003, 125, 15694−15695.
(20) It should be noted that use of Me2SO4 facilitated the
methylation in the presence of Pd which allowed us to operate
using a one-pot sequence, whereas previous use of TMS−diazo-
methane did not.
(6) (a) Bouz, B. S.; Cossy, J. Org. Lett. 2003, 5, 1995−1997.
(b) Tosaki, S.-Y.; Nemoto, T.; Ohshima, T.; Shibasaki, M. Org. Lett.
2003, 5, 495−498. (c) Enders, D.; Lenzen, A.; Muller, M. Synthesis
2004, 1486−1496. (d) Ramana, C. V.; Raghupathi, N.; Gurjar, M. K.;
Chorghade, M. S. Tetrahedron Lett. 2005, 46, 4073−4075. (e) Kumar,
P.; Pandey, M.; Gupta, P.; Naidu, S. V.; Dhavale, D. D. Eur. J. Org.
Chem. 2010, 6993−7004. (f) Sabitha, G.; Fatima, N.; Gopal, P.;
Reddy, C. N.; Yadav, J. S. Tetrahedron: Asymmetry 2009, 20, 184−191.
(g) Das, B.; Veeranjaneyulu, B.; Balasubramanyam, P.; Srilatha, M.
Tetrahedron: Asymmetry 2010, 21, 2762−2767. (h) Tang, S.; Xie, X.;
Wang, X.; He, L.; Xu, K.; She, X. J. Org. Chem. 2010, 75, 8234−8240.
(i) Ghadigaonkar, S.; Koli, M. R.; Gamre, S. S.; Choudhary, K. M.;
Chattopadhyay, S.; Sharma, A. Tetrahedron: Asymmetry 2012, 23,
1093−1099.
(7) For Ipc2BH-derived boryl-substituted allylborane derived in two
steps from propargyl bromide, see ref 6h.
(8) The ketal-protected aldehyde was synthesized in three steps from
ethyl acetoacetate; see ref 6h.
(9) For a review on step economy, see: (a) Wender, P. A.; Verma, V.
A.; Paxton, T. J.; Pillow, T. H. Acc. Chem. Soc. 2008, 41, 40−49. For
reviews on atom economy, see: (b) Trost, B. M. Science 1991, 254,
1471−1477. (c) Trost, B. M. Angew. Chem., Int. Ed. 1995, 34, 259−
281. For reviews on protecting group-free synthesis, see: (d) Young,
S. I.; Baran, P. S. Nat. Chem. 2009, 1, 193−205. (e) Hoffmann, R. W.
Synthesis 2006, 3531−3541.
(10) (a) Ishikawa, H.; Suzuki, T.; Hayashi, Y. Angew. Chem., Int. Ed.
2009, 48, 1304−1307. (b) Ishikawa, H.; Honma, M.; Hayashi, Y.
Angew. Chem., Int. Ed. 2011, 50, 2824−2827. (c) Umemiya, S.;
Hayashi, Y. Angew. Chem., Int. Ed. 2013, 52, 1−4.
(11) Venukadasula, P. K. M.; Chegondi, R.; Suryn, G. M.; Hanson, P.
R. Org. Lett. 2012, 14, 2634−2637.
(12) (a) Myers, A. G.; Zheng, B.; Movassaghi, M. J. Org. Chem. 1997,
62, 7507. (b) O’Doherty, G. A.; Haukaas, M. H. Org. Lett. 2002, 4,
1771−1774. (c) Buszek, K. R.; Brown, N. J. Org. Chem. 2007, 72,
3125−3128.
(13) (a) Whitehead, A.; McReynolds, M. D.; Moore, J. D.; Hanson,
P. R. Org. Lett. 2005, 7, 3375−3378. (b) Thomas, C. D.; McParland, J.
M.; Hanson, P. R. Eur. J. Org. Chem. 2009, 5487−5500.
(c) Venukadasula, P. K. M.; Chegondi, R.; Maitra, S.; Hanson, P. R.
Org. Lett. 2010, 12, 1556−1559.
(14) (a) Chavez, D. E. Ph. D. Thesis, Harvard University, Cambridge,
MA, 2003. (b) Gademann, K.; Chavez, D. E.; Jacobsen, E. N. Angew.
Chem., Int. Ed. 2002, 41, 3059−3061. (c) Chavez, D. E.; Jacobsen, E.
N.; Grabowski, E. J. J.; Kubryk, M. Org. Synth. 2005, 82, 34.
(d) Chavez, D. E.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2001, 40,
3667−3670.
125
dx.doi.org/10.1021/ol403110p | Org. Lett. 2014, 16, 122−125