A phosphate tether-mediated, one-pot, sequential ring-closing metathesis/cross-metathesis/chemoselective hydrogenation protocol

Article abstract of DOI:10.1021/ol301007h

A versatile three-step, one-pot, sequential reaction protocol involving ring-closing metathesis, cross-metathesis, and chemoselective hydrogenation is reported. This phosphate tether-mediated process occurs without intermediate isolation, is chemoselectiv

Full text of DOI:10.1021/ol301007h

ORGANIC
LETTERS
2012
Vol. 14, No. 10
2634–2637
A Phosphate Tether-Mediated, One-Pot,
Sequential Ring-Closing Metathesis/
Cross-Metathesis/Chemoselective
Hydrogenation Protocol
Phanindra K. M. Venukadasula, Rambabu Chegondi, Gregory M. Suryn, and
Paul R. Hanson*
Department of Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence,
Kansas 66045-7582, United States
phanson@ku.edu
Received April 17, 2012
ABSTRACT
A versatile three-step, one-pot, sequential reaction protocol involving ring-closing metathesis, cross-metathesis, and chemoselective hydro-
genation is reported. This phosphate tether-mediated process occurs without intermediate isolation, is chemoselective, and is governed by
stereoelectronic properties innate to phosphate tethers, which ultimately act to preserve the integrity of the bisallylic, bicyclic phosphate for
subsequent nucleophilic additions. Overall, this process can be used to efficiently generate advanced polyol synthons.
The development ofreaction methods enabling the facile
synthesis of complex structural motifs in minimum func-
tional group manipulations is an important goal in organic
synthesis. In this regard, sequential, one-pot reaction strat-
egies have emerged as versatile approaches, due to their
ability to form multiple bonds and stereocenters, while
invoking step, atom, and green economy.1 Several advan-
tages associated with one-pot transformations exist,
among the more notable, include achievement of step
economyÀmultiple transformations without isolating the
intermediatesÀand higher efficiency, as only one workup/
purification step is needed in a given sequence. Taken
collectively, a combination of several steps into a single
pot integrates synthesis and purification to achieve an
overall streamlined process.
Olefin metathesis has emerged as an invaluable method
for the formation of CdC bonds where catalysts show
tremendous activity, selectivity, functional group tolerance,
and stability in both ring-closing metathesis (RCM) and
cross-metathesis (CM).2 Recently, this versatility has been
explored in several elegant one-pot reaction pathways,3
including tandem RCM/hydrogenation,3a tandem
RCM/Kharasch addition,3b tandem CM/intramolecular
aza-Michael,3e and tandem RCM/CM/hydrogenation3f as
outlined in Figure 1. Despite these successes, several chal-
lenges associated with one-pot reactions remain, includ-
ing (i) the development of suitable reaction conditions
allowing compatibility of reactants, (ii) influence of excess
reagents and byproducts generated from the previous
(1) For a review on step economy, see: (a) Wender, P. A.; Verma,
V. A. 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. Engl. 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. For reviews on domino/cascade reactions, see: (f) Nicolaou, K. C.;
Montagnon, T.; Snyder, S. A. Chem. Commun. 2003, 551–564. (g) Tietze,
L. F.; Brasche, G.; Gericke, K. M. Domino Reactions in Organic
Synthesis; Wiley-VCH: Weinheim, 2006. (h) Nicolaou, K. C.; Edmonds,
D. J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45, 7134–7186. (i) Enders,
€
D.; Grondal, C.; Huttl, M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570–
1581. (j) Grondal, C.; Jeanty, M.; Enders, D. Nat. Chem. 2010, 2, 167–
178. (k) Ishikawa, H.; Honma, M.; Hayashi, Y. Angew. Chem., Int. Ed.
2011, 50, 2824–2827.
(2) Grubbs, R. H. Handbook of Metathesis; Wiley-VCH: Weinheim,
2003.
r
10.1021/ol301007h
Published on Web 05/08/2012
2012 American Chemical Society

reaction in a sequence, (iii) expansion of the number of
compatible steps in the overall process, and (iv) improve-
ment of average and total yields.
synthesis of tetrahydrolipstatin5 and dolabelide C6 and the
formal total synthesis of salicylihalamides A and B.7
During the synthesis of tetrahydrolipstatin and dolabelide
C, it was demonstrated that a stepwise sequence of RCM,
CM, and chemoselective hydrogenation could be incorpo-
rated into a one-pot procedure to further streamline the
synthetic route, albeit in nonoptimal conditions.5 Advan-
tages of this one-pot, sequential method were manyfold,
namely in terms of the reaction time, waste generation, and
ease of purification. Moreover, several properties innate to
phosphate tether-mediated processes, namely trivalent
activation and stereoelectronic effects, were deemed ideal
for further development of this method. In this regard, we
herein report a versatile one-pot, sequential reaction pro-
tocol where three steps, namely RCM, CM, and chemose-
lective hydrogenation, are performed in a single pot
without intermediate isolation to generate advanced polyol
subunits with application to several 1,3-diol-containing
natural products (Figure 2). To the best of our knowledge
this is the first example of a chemoselective hydrogenation
that is followed by an RCM/CM in a tandem reaction.
Figure 1. Tandem metathesis reactions.
Interest in the development of phosphate-based meth-
odologies has led us to investigate the potential of a
phosphate tether to mediate a sequence of reactions
cleanly, selectively, and in one pot. Previously, metathesis
strategies incorporating multivalent activation of phos-
phate triesters for use in diastereoselective differentiation
of 1,3-anti diol subunits4 have been developed for the total
Figure 2. One-pot, sequential RCM/CM/chemoselective
hydrogenation.
(3) For tandem, metathesis/hydrogenation, see: (a) Louie, J.; Bielawski,
C. W.; Grubbs, R. H. J. Am. Chem. Soc. 2001, 123, 11312–11313. For CM/
Wittig olefination, see: (b) Murelli, R. P.; Snapper, M. L. Org. Lett. 2007, 9,
1749–1752. For RCM/oxidation, see: (c) Scholte, A. A.; An, M.-H.;
Snapper, M. L. Org. Lett. 2006, 8, 4759–4762. For RCM/Kharasch
addition, see: (d) Seigal, B. A.; Fajardo, C.; Snapper, M. L. J. Am. Chem.
Soc. 2005, 127, 16329–16332. For tandem CM/intramolecular aza-
Michael, see: (e) Fustero, S.; Jimenez, D.; Sanchez-Rosello, M.; del
Pozo, C. J. Am. Chem. Soc. 2007, 129, 6700–6701. For tandem RCM/
CM and hydrogenation, see: (f) Quinn, K. L.; Curto, J. M.; McGrath,
K. P.; Biddick, N. A. Tetrahedron Lett. 2009, 50, 7121–7123. (g) Quinn,
K. J.; Isaacs, A. K.; Arvary, R. A. Org. Lett. 2004, 6, 4143–4145.
(h) Virolleaud, M-. A.; Bressy, C.; Piva, O. Tetrahedron Lett. 2003, 44,
8081–8084. (i) Virolleaud, M-.A.; Piva, O. Tetrahedron Lett. 2007, 48,
1417–1420. For CM/hydrogenation/cyclization, see: (j) Cossy, J.;
Bargiggia, F.; BouzBouz, S. Org. Lett. 2003, 5, 459–462. For tandem
CM/amidation, see: (k) Ferrie, L.; BouzBouz, S.; Cossy, J. Org. Lett.
2009, 11, 5446–5448. For other tandem metathesis processes, see:
(l) Ferrie, L.; BouzBouz, S.; Cossy, J. Org. Lett. 2009, 11, 5446–5448.
(m) Riache, N.; Blond, A.; Nay, B. Tetrahedron 2008, 64, 10853–10859.
(n) Cross, F.; Pelotier, B.; Piva, O. Eur. J. Org. Chem. 2010, 5063–5070.
(o) O’Leary-Steele, C.; Pedersen, P. J.; James, T.; Lanyon-Hogg, T.;
Leach, S.; Hayes, J.; Nelson, A. Chem.;Eur. J. 2010, 16, 9563–9571.
(4) (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.
Initial studies focused on type I olefin cross partners
during the CM event as outlined in Scheme 1 and Table 1.
In accordance with olefin reactivity patterns reported by
Grubbs, reactive olefin partners in CM steps are charac-
terized as type I and type II olefins based on their propen-
sity to undergo homodimerization and CM with other
olefin partners.8 Previous studies suggested that bicyclic
phosphate (R,R,RP)-2 behaves as a near type III olefin
based on its ability to undergo an efficient CM reaction
with both type I and II olefins.9 Type III olefin character is
ideal for CM reactions, especially in tandem processes such
as those described herein, thus enabling advancement of
this method to more precious metathesis partners.
The initial RCM reaction was carried out using a
HoveydaÀGrubbs catalyst (6 mol %), after which the
(7) Chegondi, R.; Tan, M. M. L.; Hanson, P. R. J. Org. Chem. 2011,
76, 3909–3916.
(8) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H.
J. Am. Chem. Soc. 2003, 125, 11360–11370.
(5) Venukadasula, P. K. M.; Chegondi, R.; Maitra, S.; Hanson, P. R.
Org. Lett. 2010, 12, 1556–1559.
(6) Hanson, P. R.; Chegondi, R.; Nguyen, J.; Thomas, C. D.; Waetzig,
J. D.; Whitehead, A. J. Org. Chem. 2011, 76, 4358–4370.
(9) Waetzig, J. W.; Hanson, P. R. Org. Lett. 2006, 8, 1673–1676.
Org. Lett., Vol. 14, No. 10, 2012
2635

type I olefin cross partner and additional catalyst (4 mol %)
were added with simultaneous evaporation of CH2Cl2 to
reach an optimal concentration of 0.05 M for CM. The
reaction was continued for 2À3 h. Ofnotableimportanceis
the fact that RCM must be completed before the CM
partner is added (i.e., sequential addition), as the experi-
mental combination of all the components (i.e., triene
(R,R)-1, olefin cross partner 3, and metathesis catalyst)
for a tandem RCM/CM reaction did not yield promising
results, but rather produced a mixture of RCM and several
CMbyproducts. Presumably, thesebyproductsresultfrom
deleterious CM events as RCM precursor (R,R)-1 contains
two type II CM partners and one type I olefin.
Table 1. One-Pot, Sequential RCM/CM/Chemoselective
Hydrogenation Involving Type I Olefins
Scheme 1. General Protocol for RCM/CM/Chemoselective
Hydrogenation
The aforementioned results indicate that the RCM
reaction needs to go to completion prior to the addition
of the olefin CM partner. In addition, and in accord
with literature precedence,10 CM with the more reac-
tive HoveydaÀGrubbs catalyst produced better yields
compared to the Grubbs second-generation catalyst
[(IMesH2)(PCy3)(Cl2);RudCHPh] as demonstrated
in our earlier studies.9 Moreover, detailed freezeÀdegasÀ
thaw (FDT) solvent studies with and without various
additives11 showed that a combination of factors can
drastically improve yields.12 Subsequent chemoselective
diimide reduction at rt was next carried out by simple
a All reactions were performed using freshly distilled (over CaH2)
FDT solvents. b 1,4-Benzoquinone is not used during RCM event.
c Reaction was performed in CH2Cl2 purified by passing through basic
Al2O3 and degassed by argon purging without any additives.
(10) For a review, see: (a) Hoveyda, A. H.; Gillingham, D. G.; Van
Veldhuizen, J. J.; Kataoka, O.; Garber, S. B.; Kingsbury, J. S.; Harrity,
J. P. A. Org. Biol. Chem. 2004, 2, 8–23 and references cited therein. (b) A
study of the CM reaction using the HoveydaÀGrubbs catalyst was
reported by: Cossy, J.; BouzBouz, S.; Hoveyda, A. H. J. Organomet.
Chem. 2001, 624, 327–332. (c) Dewi, P.; Randl, S.; Blechert, S. Tetra-
hedron Lett. 2005, 46, 577–580.
(11) 1,4-Benzoquinone is generally used to suppress any Ru-H
generated during the metathesis event. CuI is generally used in conjunc-
tion with the Grubbs second generation catalyst to scavenge the
phosphine and keep open the coordination site at Ru to enhance the
rate of the metathesis reaction; Voigtritter, K.; Ghorai, S.; Lipshutz,
B. H. J. Org. Chem. 2011, 76, 4697–4702.
(12) After the CM reaction, the reaction also contained some un-
reacted bicylic phosphate (R,R,RP-2). Optimization studies substan-
tially lowered this unwarranted result.
(13) (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.
addition of o-nitrobenzenesulfonyl hydrazine (o-NBSH)
to the crude reaction mixture.13 Purification after the hydro-
genation step showed product formation along with hydro-
genated (R,R,RP)-2. This one-pot, sequential procedure with
type I olefins generated the desired products in 40À65%
overall yield with a 74À87% average yield over three steps.
Since the endocyclic olefin is doubly deactivated due to
the presence of bisallylic phosphate moieties, the chemo-
selective, diimide reduction of the exocyclic olefin is most
likely governed by electronic parameters rather than steric
considerations. While successful chemoselective reductions
of the doubly deactivated exocyclic olefin in entries 2 and 4
(Table 1) would at first glance seem to contradict this trend,
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Org. Lett., Vol. 14, No. 10, 2012

it is known that innate stereoelectronic factors within the
bicyclic phosphate framework impart greater electron with-
drawing properties at the constrained PdO in 5d compared
with the acyclic, exocyclic PdO in 5d. This fact is further
substantiated by comparison of the 31P chemical shifts for
each system, where the endocyclic PdO appears further
downfield than the exocyclic PdO (À3.24 vs À11.31 ppm,
respectively in 5d, Figure 3).14
Table 2. One-Pot, Sequential RCM/CM/Chemoselective
Hydrogenation Involving Type II Olefins
Figure 3. Stereoelectronic effects governing chemoselective
hydrogenation.
The reaction sequence with type II olefins was also
carried out using a similar protocol as with type I CM
partners (Table 2). However, solvent manipulation in the
CM event [switched from CH2Cl2 to 1,2-dichloroethane
(1,2-DCE)] was required to obtain desirable yields since
high temperature conditions are more efficient with type II
olefin CM partners. Subsequent diimide reduction in DCE
was successful using a variety of olefinic CM partners. Of
particular note are entries 3j and 3l (Table 2), possessing
sterically encumbered olefins, which further substantiates
the aforementioned electronic viewpoint model for che-
moselective reduction, vide supra. This one-pot procedure
with type II olefins produced the desired product in
30À85% overall yield with a 67À95% average yield over
three steps.
In conclusion, an efficient one-pot, sequential RCM/
CM/chemoselective hydrogenation protocol has been de-
veloped. This procedure enables the synthesis of advanced
substrates in a streamlined manner. Based on observa-
tions, it is noteworthy to mention that the CM event is
deemed as the key factor in the determination of overall
yield. Further efforts in this area are in progress and will be
reported in due course.
Acknowledgment. This investigation was generously
supported by partial funds provided by the National
Institute of General Medical Sciences (NIH RO1
GM077309-05), the NSF-REU program (CHE-1004897)
for summer fellowship support (G.S.), and Research &
Graduate Studies at KU. The authors thank Dr. Justin
Douglas and Sarah Neuenswander for assistance with
NMR measurements, Dr. Todd Williams for HRMS
analysis at The University of Kansas, and Materia, Inc.
for supplying metathesis catalyst and helpful suggestions.
a All reactions were performed using freshly distilled (over CaH2)
FDT solvents. b Reaction was performed in CH2Cl2, 1,2-DCE purified
by passing through basic Al2O3 and degassed by argon purging.
Supporting Information Available. Experimental de-
tails and spectroscopic data of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(14) See Supporting Information.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 10, 2012
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