Chemoselectivity of the Ru-catalyzed cycloisomerization reaction for the synthesis of dihydropyrans; application to the synthesis of L-forosamine

Article abstract of DOI:10.1021/ol9026667

Chemical Equation presented The chemoselectivity of a Ru-catalyzed cycloisomerization reaction has been established. The preference for O- capture of the vinylidene Intermediate allows for the synthesis of 4-aminodihydropyrans that are valuable synthetic Intermediates. The synthetic utility of these structures has been demonstrated in the synthesis of L-forosamine.

Full text of DOI:10.1021/ol9026667

ORGANIC
LETTERS
2010
Vol. 12, No. 4
684-687
Chemoselectivity of the Ru-Catalyzed
Cycloisomerization Reaction for the
Synthesis of Dihydropyrans; Application
to the Synthesis of L-Forosamine
Michael J. Zacuto,* Daisuke Tomita, Zainab Pirzada, and Feng Xu
Department of Process Research, Merck and Co., Inc., Rahway, New Jersey 07065
michael_zacuto@merck.com
Received November 19, 2009
ABSTRACT
The chemoselectivity of a Ru-catalyzed cycloisomerization reaction has been established. The preference for O- capture of the vinylidene
intermediate allows for the synthesis of 4-aminodihydropyrans that are valuable synthetic intermediates. The synthetic utility of these structures
has been demonstrated in the synthesis of L-forosamine.
Vinylidenes generated from the transition metal- catalyzed
isomerization of terminal acetylenes are useful synthetic
Scheme 1. Cycloisomerization to Form Heterocycles
intermediates that can be captured by a variety of functional
groups. Intramolecular trapping of these reactive intermedi-
ates by O,1 N,2 and S3 moieties provides rapid access to five-
and six- membered heterocyclic rings (Scheme 1). Certain
cycloisomerization catalyst systems are suitable for both N-
and O- capture of the vinylidene, but this has been
demonstrated in cases where only one nucleophile is present.4
An interesting case of selectivity arises when two poten-
tially reactive moieties (such as an alcohol and a protected
amine) are present in the same substrate, and each could react
to afford a different 5- or 6- membered ring product.
Chemoselectivity in such instances would open this meth-
odology to the preparation of more diverse products.
However, little attention has been paid to this subject. One
example was reported where a tungsten-based system showed
preference for (carbamate) NH- capture of the vinylidene
(versus an alcohol OH) to form a 5-membered ring
pyrroline,1c along with one example where a rhodium catalyst
demonstrated O-selectivity of an alcohol (versus a carbamate
protected NH) to form a 6-membered ring product.1d
Interestingly, this question has not been addressed in the case
of ruthenium vinylidenes.5
(1) (a) McDonald, F. E.; Schultz, C. C. J. Am. Chem. Soc. 1994, 116,
9363. (b) McDonald, F. E.; Gleason, M. M. J. Am. Chem. Soc. 1996, 118,
6648. (c) McDonald, F. E.; Zhu, Y. H. Tetrahedron 1997, 53, 11061. (d)
Trost, B. M.; Rhee, Y. H. J. Am. Chem. Soc. 2003, 125, 7482. (e) Trost,
B. M.; Rhee, Y. H. J. Am. Chem. Soc. 2002, 124, 2528. For studies that
were published during the preparation of our manuscript, see: (f) Verela-
Ferna´ndez, A.; Gonza´lez-Rodr´ıguez, C.; Varela, J. A.; Castedo, L.; Sa´a, C.
Org. Lett. 2009, 11, 5350.
(2) (a) McDonald, F. E.; Chatterjee, A. K. Tetrahedron Lett. 1997, 44,
7687. (b) Motamed, M.; Brunelle, E. M.; Singarem, S. W.; Sarpong, R.
Org. Lett. 2007, 9, 2167. (c) Smith, C. R.; Brunelle, E. M.; Rhodes, A. J.;
Sarpong, R. Org. Lett. 2007, 9, 1169.
Our interest in such chemoselectivity arose from a
proposed synthesis of 6-deoxy-4-aminodihydropyrans from
(3) McDonald, F. E.; Burova, S. A.; Huffman, L. G. Synthesis 2000,
970.
(4) (a) Trost, B. M.; McClory, A. Angew. Chem., Int. Ed. 2007, 46,
2074. (b) Although not presented in the same study, refs 1c and 2a overlap
in demonstration of this compatibility.
(5) Intermolecular selectivity (for the carboxylic OH) has been reported
in the case of N-carbamate protected amino acids: Doucet, H.; Martin-
Vaca, B.; Bruneau, C.; Dixneuf, P. H. J. Org. Chem. 1995, 60, 7247.
10.1021/ol9026667  2010 American Chemical Society
Published on Web 01/20/2010

the cycloisomerization of amino- substituted bis-homopro-
pargylic alcohols (Scheme 2). Such dihydropyran products
separation of the minor diastereomer, the desired alcohol
was obtained in 80% over two steps. Aminoalcohol 3 was
then exposed to the Ru- catalyzed cycloisomerization
reaction conditions: CpRu(PPh3)2Cl, NaHCO3, N-hydroxy-
succinimide, and Bu4NPF6 in DMF at 80 °C for 8 h. To
our delight, dihydropyran 4 was obtained in 85% isolated
yield.11 Furthermore, no products arising from N- cycliza-
tion were detected.
Scheme 2. Retrosynthetic Analysis
As a means of comparison, 3 was subjected to other catalytic
systems reported for the formation of dihydropyrans. The
use of McDonald’s tungsten- catalyzed cycloisomerization
conditions1c,12 resulted in the formation of a product which
was consistent with the N-Boc-pyrroline (see Scheme 3).13
In this case, 4 was not observed as part of the reaction
mixture. By contrast, the use of Trost’s more expensive
rhodium- based catalytic system1d led to the exclusive
formation of 4. Nonetheless, we deemed the ruthenium
system optimal for the rest of our studies due to cost and to
ease of operation. Furthermore, we were interested in
expanding upon the identification of selectivity with ruthe-
nium vinylidenes.
are useful reagents for the selective installation of the
biologically important6 forosamine and ossamine glycosides
favoring the desired equatorial7 (ꢀ in the case of L- sugars)
isomer.6a,8,9 Among the known cycloisomerization catalysts,
we were initially attracted to Trost’s ruthenium system1e due
to its demonstrated efficiency of forming dihydropyrans.
Although we required the selective cycloisomerization of the
alcohol moiety, in principle either a dihydropyran or a
2-pyrroline product could form (via O- or N- cyclization,
respectively). In this communication, we report the discovery
of O- selectivity in this reaction as part of an efficient
synthetic route to amino-substituted dihydropyrans, and
demonstrate the utility of these products in a concise total
synthesis of L-forosamine.
The observed selectivity was further examined by subjec-
tion of the methyl ether 5 to the reaction conditions. In the
event, N-Boc-pyrroline 6 was obtained in 7% yield after 24 h
at 85 °C (Scheme 4). The remainder of the crude reaction
Scheme 4. Cycloisomerization of Ether 5
We began by securing a suitably functionalized amino
alcohol, targeting the synthesis of a forosaminide dihydro-
pyran as a means to validate the proposed strategy. N-
Carbamate protection was selected for compatibility of the
dihydropyran with glycosylation conditions.1d,6,8 Hence,
commercially available racemic N-Boc-propargyl glycine (1)
was converted to the Weinreb amide 2 using CDI and
(MeO)MeNH2Cl in DMF in 96% yield (Scheme 3). MeMgBr
mixture consisted of unreacted 5, as determined by 1H NMR
spectroscopy. On the basis of this result, we conclude that
(carbamate) NH- capture of the ruthenium vinylidene to form
Scheme 3. Cycloisomerization of Amino Alcohol 3
(6) (a) Graupner, P. R.; Martynow, J.; Anzeveno, P. B. J. Org. Chem.
2005, 70, 2154. (b) Zongbao, Z.; Hong, L. Liu, H-w. J. Am. Chem. Soc.
2005, 127, 7692. (c) He, X.; Liu, H.-w. Annu. ReV. Biochem. 2002, 71,
701. (d) Weymouth-Wilson, A. C. Nat. Prod. Rep. 1997, 14, 99.
(7) The known natural products incorporating these 2,3,6-trideoxy-4-
dimethylamino glycosides (such as the spiramycins, spinosyns, ossamycin
and dunaimycin D2S) bear ꢀ linkages to a macrocyclic core.
(8) Suhara, Y.; Sasaki, F.; Koyama, G.; Maeda, K.; Umezawa, H.; Ohno,
M. J. Am. Chem. Soc. 1972, 94, 6501. Chloronitration of a dihydropyran
demonstrated a high equatorial selectivity for the Cl atom. As the mechanism
is considered to be stepwise (see Rasmussen, J. K.; Hassner, A. J. Org.
Chem. 1974, 39, 2558) equatorial selectivity is expected in the coupling of
an alcohol moiety.
(9) By contrast, imidate and glycosyl bromide derivatives of these sugars
give predominantly a coupling products. For example, (a) Evans, D. A.;
Black, W. C. J. Am. Chem. Soc. 1993, 115, 4497. . (b) Paquette, L. A.;
Collado, I.; Purdie, M. J. Am. Chem. Soc. 1998, 120, 2553.
(10) Yin, J.; Huffman, M. A.; Conrad, K. M.; Armstrong, J. D., III. J.
Org. Chem. 2006, 71, 840.
was then added to 2 to form a methyl ketone that was
directly subjected to a diastereoselective reduction10 to
afford 3 as a 95:5 mixture of diastereomers. Following
(11) The analytical yield was 95% based on HPLC assay of the crude
reaction mixture. The lower isolated yield is associated with the volatility
of 4.
Org. Lett., Vol. 12, No. 4, 2010
685

a 5-membered ring is possible, but inefficient compared to
OH capture that forms a 6-membered ring.14
avoid this destabilization by undergoing conformational
adjustment that decreases the distance between the OH and
the electrophilic center, which would account for the slower
reaction rate.16 The beneficial role of excess PPh3 is believed
to result from stabilization of the vinylidene species against
competing nonproductive pathways,17 which require ligand
dissociation prior to engagement.18
Given the superior reactivity of 3, the scope of this
cycloisomerization process was broadened through various
erythro substrates decorated with an aromatic moiety (Table
1). The reaction tolerated both electron- rich and electron-
Cycloisomerization of the threo substrate 715 was less
efficient than that of 3, requiring 10 mol % of CpRu(PPh3)2Cl
to achieve full conversion and furnishing dihydropyran 8 in
only 30% yield under otherwise identical conditions. After
extensive experimentation we discovered that the combina-
tion of 8 mol % CpRu(PPh3)2Cl and 16 mol % PPh3
improved the yield to 60% (Scheme 5). The pyrroline product
Scheme 5. Cycloisomerization of Amino Alcohol 7
Table 1. Cycloisomerization of Erythro Analogsa
obtained from from N- capture of the vinylidene was not
observed under either set of conditions. Methylation of 8
afforded 9, which is a carbamate analogue (N-Boc vs N-Troc)
of the dihydropyran used to install the ossaminide moiety
in the synthesis of spinosyn G.6
The difference in reactivity profiles between 3 and 7 is
not fully understood but may result from steric congestion
in the vinylidene transition state (Scheme 6). The vinylidene
Scheme 6. Proposed Vinylidene Intermediates
a Conditions: 5 mol % CpRu(PPh3)2Cl, 0.5 equiv of NaHCO3, 0.5 equiv
of N-hydroxysuccinimide, 0.13 equiv of Bu4NPF6, DMF, 80 °C. b Isolated
yield.
formed from 3 can adopt a pseudo chairlike formation with
equatorial substituents. In this conformation, the OH moiety
is proximate to the electrophilic carbon of the vinylidene.
In the case of 7, the likely pseudo chairlike conformation
(with an axial methyl group) may suffer from steric
repulsion between the methyl group and the extended
ligand sphere of the metal. The vinylidene species may
poor benzene rings, and in each case only one product
diastereomer was observed. Products arising from N- capture
of the vinylidene intermediate were not observed in any case.
Entries 1a-c demonstrate the tolerance for various carbamate
protecting groups, and further highlight the preference for
O- cyclization. While there is no apparent reason why Boc
(12) Koo, B.-S.; McDonald, F. E. Org. Lett. 2007, 9, 1737.
(16) Alternatively the reaction may proceed through a higher energy
boat-like transition state that minimizes steric repulsions.
1
(13) Based on H NMR. This product was obtained in ∼25% yield as
part of a complex reaction mixture.
(17) Such as alkyne dimerization, which was observed without sufficient
ligand in the related rhodium catalyzed cycloisomerization (ref 1d). For a
recent example of dimerization using a closely related ruthenium catalyst,
see: Daniels, M.; Kirss, R. U. J. Organomet. Chem. 2007, 692, 1716.
(18) The desired pathway, by contrast, does not require dissociation of
a PPh3 ligand prior to nucleophilic attack by oxygen. For relevant discussions
see reference 1e and Trost, B. M.; Kulawiec, R. J. J. Am. Chem. Soc. 1992,
114, 5579.
(14) The preferential formation of an N-Boc-pyrroline in related systems
(i.e., tungesten vinylidenes in refs 1c, 13) suggests that factors other than
product ring size contribute to the observed rate difference.
(15) Prepared as a racemate by reduction of Weinreb amide 2 followed
by the addition of Me2CuLi according to the procedure of Reetz Reetz,
M. F.; Rolfing, K.; Griebenow, N. Tetrahedron Lett. 1994, 35, 1969. See
Supporting Information.
686
Org. Lett., Vol. 12, No. 4, 2010

protection gave slightly higher yields in entries 1a-c, these
examples demonstrate that the steric bulk of the N-Boc group
does not play a significant factor in the observed chemose-
lectivity since no other products were observed. This
observation is consistent with the steric argument outlined
in Scheme 6. All of these substrates were prepared following
the route in Scheme 3; thus, further variation of the Grignard
reagent should allow access to a large number of analogs.19
To demonstrate the utility of the dihydropyrans obtained
from this cycloisomerization, we completed a short enan-
tioselective total synthesis of L-forosamine (Scheme 7).
11 in 95% yield without any detectable epimerization.21 The
sequence employed in Scheme 3 (namely, MeMgBr addition
followed by the Al(OiPr)3- mediated Meerwein-Pondorf-
Verley reduction) was then implemented to afford 12 in 78%
yield after purification, as a single diastereomer in >99%
e.e. Cycloisomerization provided 13, which was then alky-
lated with MeI to give 14. The N-Boc moiety was reduced
with LiAlH4 to afford a volatile intermediate 15 that was
1
not isolated, but was identified by H NMR spectroscopy.
By incorporating an acidic aqueous quench after the LiAlH4
reaction, 15 was obtained in 62% over two steps (from 13).
We believe that the mass balance was accounted for by losses
due to the difficult isolation of 16 from an aqueous system.22
Spectroscopic data from compound 16 matched the known
data for L-forosamine.23
Scheme 7. Enantioselective Synthesis of L-Forosamine
In conclusion, we have demonstrated the chemoselectivity
for the Ru-catalyzed cyclization of carbamate protected
4-amino-bis-homopropargylic alcohols. The observed prefer-
ence for O- capture of the vinylidene intermediate allows
for the synthesis of amino- substituted dihydropyrans. The
synthetic utility of these dihydropyrans has been demon-
strated by the synthesis of L-forosamine.
Acknowledgment. We gratefully acknowledge Robert A.
Reamer and Peter G. Dormer (Merck and Co., Inc.) for NMR
assistance. Kate Vaynshteyn and Stephen M. Marcinko
(Merck and Co., Inc.) are also acknowledged for assistance
with high resolution mass spectroscopy.
Supporting Information Available: Experimental pro-
cedures, characterization data, and stereochemical proofs.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL9026667
Enantiopure (S)-N-Boc-propargyl glycine (10)20 was treated
with (MeO)MeNH2Cl, iPr2NEt, EDCI, and HOBt to afford
(22) Although the conversion of 14 to 16 appeared to be efficient,
the extraction of 16 into organic solvents was difficult. Upon concentra-
tion of the aqueous phase in order to improve the extraction efficiency,
glycal 16 was observed to partially dehydrate back to the volatile 15.
(23) For a recent synthesis of forosamine, see: (a) Tietze, L. F.; Bo¨nke,
N.; Dietz, S. Org. Lett. 2009, 11, 2948. For a sample of previous syntheses,
see: (b) Ono, M.; Saotome, C.; Akita, H. Hetereocycles 1999, 51, 1503.
(c) Malik, A.; Afza, N.; Voelter, W. J. Chem. Soc., Perkin Trans. 1 1983,
2103.
(19) For medicinal chemistry studies of forosamides, see: (a) Uesato,
S.; Tokunaga, T.; Takeuchi, K. Bioorg. Med. Chem. Lett. 1998, 8, 1969.
(b) US patent US600 1981, 1999. (c) US patent US541 2081. 1995. (d)
Eur. Pat. Appl. EP457215, 1991.
(20) Purchased from Acros Organics.
(21) Determined by chiral HPLC analysis. See Supporting Informa-
tion.
Org. Lett., Vol. 12, No. 4, 2010
687