The total synthesis of (-)-7-deoxyloganin via N-heterocyclic carbene catalyzed rearrangement of α,β-unsaturated enol esters

Article abstract of DOI:10.1021/ol101983h

The diastereoselective N-heterocyclic carbene (NHC) catalyzed rearrangement of α,β-unsaturated enol ester (S)-2b has been used to assemble dihydropyranone (S)-3b, a material embodying the bicyclic core of the iridoid family of natural products. Elaboration of this intermediate, by chemoselective reduction followed by stereoselective β-glycosylation, has allowed the total synthesis of (-)-7-deoxyloganin (1) to be achieved in four subsequent steps.

Full text of DOI:10.1021/ol101983h

ORGANIC
LETTERS
2
010
Vol. 12, No. 21
836-4839
The Total Synthesis of
4
(-)-7-Deoxyloganin via N-Heterocyclic
Carbene Catalyzed Rearrangement of
r,ꢀ-Unsaturated Enol Esters
Lisa Candish and David W. Lupton*
School of Chemistry, Monash UniVersity, Clayton Campus 3800, Victoria, Australia
daVid.lupton@monash.edu
Received August 21, 2010
ABSTRACT
The diastereoselective N-heterocyclic carbene (NHC) catalyzed rearrangement of r,ꢀ-unsaturated enol ester (S)-2b has been used to assemble
dihydropyranone (S)-3b, a material embodying the bicyclic core of the iridoid family of natural products. Elaboration of this intermediate, by
chemoselective reduction followed by stereoselective ꢀ-glycosylation, has allowed the total synthesis of (-)-7-deoxyloganin (1) to be achieved
in four subsequent steps.
Iridoids are an expansive family of monoterpenoid natural
products with over 250 members from marine and terrestrial
origins. Structurally, the cyclopenta[c]pyran core has a cis
significance, continue to inspire new approaches to their
4
preparation. While investigating the use of N-heterocyclic
1
5,6
carbenes (NHCs) as nucleophilic catalysts, we uncovered
relationship between H-5 and H-9 in the majority of cases (i.e.,
their capacity to rearrange R,ꢀ-unsaturated enol esters to
form dihydropyranones. Using substrates derived from
1,3-diketones, this reaction provided access to materials
7
,8
1), although members lacking this functionality are known.
Iridoids have biological relevance, due to their medicinal
1d,e,2
3
activity,
as well as their key role in alkaloid biosynthesis.
(
4) For a review on iridoid synthesis, see: (a) Nangia, A.; Prasuna, G.;
Challenges associated with accessing these molecules in
a stereocontrolled fashion, along with their biological
Rao, P. B. Tetrahedron 1997, 53, 14507. For recent selected highlights in
synthesis, see: (b) Chavez, D. E.; Jacobsen, E. N. Org. Lett. 2003, 5, 2563.
(
(
c) Piccinini, P.; Vidari, G.; Zanoni, G. J. Am. Chem. Soc. 2004, 126, 5088.
d) Mangion, I. K.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127,
(
1) (a) El-Naggar, L. J.; Beal, J. L. J. Nat. Prod. 1980, 43, 649. (b)
3696. (e) Jones, R. A.; Krische, M. J. Org. Lett. 2009, 11, 1849. (f)
D’Alfonson, A.; Pasi, M.; Porta, A.; Zanoni, G.; Vidari, G. Org. Lett. 2010,
12, 566. (g) Beckett, J. S.; Beckett, J. D.; Hofferberth, J. E. Org. Lett. 2010,
12, 1408.
Boros, C. A.; Stermitz, F. R. J. Nat. Prod. 1991, 54, 1173. (c) Dinda, B.;
Debnath, S.; Harigaya, Y. Chem. Pharm. Bull. 2007, 55, 159. (d) Dinda,
B.; Debnath, S.; Harigaya, Y. Chem. Pharm. Bull. 2007, 55, 689. (e) Dinda,
B.; Debnath, S.; Harigaya, Y. Chem. Pharm. Bull. 2009, 57, 765.
(5) For general reviews on NHC catalysis, see: (a) Enders, D.; Niemeier,
O.; Henseler, A. Chem. ReV. 2007, 107, 5606. (b) Zeitler, K. Angew. Chem.,
Int. Ed. 2005, 44, 7506. (c) Johnson, J. S. Angew. Chem., Int. Ed. 2004,
43, 1326–1328. For a review on homoenolates, see: (d) Nair, V.; Vellalath,
(2) For a review on bioactive iridoids, see: (a) Tundis, R.; Loizzo, M. R.;
Menichini, F.; Statti, G. A.; Menichini, F. Mini-ReV. Med. Chem. 2008, 8,
3
99. For resent studies using iridoid scafolds as antiproliferative agents,
see: (b) Garc ´ı a, C.; Le o´ n, L. G.; Pungitore, C. R.; R ´ı os-Luci, C.; Daranas,
A. H.; Montero, J. C.; Pandiella, A.; Tonn, C. E.; Mart ´ı n, V. S.; Padr o´ n,
S.; Babu, B. P. Chem. Soc. ReV. 2008, 37, 2691
(6) For a review on Lewis base catalysis, see: Denmark, S. E.; Beutner,
G. L. Angew. Chem., Int. Ed. 2008, 47, 1560
.
J. M. Bioorg. Med. Chem. 2010, 18, 2515
.
.
(
3) For a useful discussion of iridoids in alkaloid biosynthesis, see: (a)
(7) Ryan, S. J.; Candish, L.; Lupton, D. W. J. Am. Chem. Soc. 2009,
Tietze, L. F. Angew. Chem., Int. Ed. 1983, 22, 828. and references therein.
For recent reviews, see: (b) Oudin, A.; Courtois, M.; Rideau, M.; Clastre,
M. Phytochem. ReV. 2007, 6, 259. (c) Loyola-Vargas, V. M.; Galaz-Avalos,
R. M.; Ku-Cauich, R. Phytochem. ReV. 2007, 6, 307.
131, 14176
.
(8) For a NHC-catalyzed transformation exploiting propargyl aldehydes
to access related ring-opened pyranones, see: Kaeobamrung, J.; Mahattha-
nanchai, J.; Zheng, P.; Bode, J. W. J. Am. Chem. Soc. 2010, 132, 8810
.
10.1021/ol101983h  2010 American Chemical Society
Published on Web 09/28/2010

bearing oxygenation as found in various medicinal agents
and natural products. Expanding upon these observations
and focusing on the iridoid family of natural products, we
envisaged the rearrangement of cyclic R,ꢀ-unsaturated esters
Studies commenced with the preparation of hindered tert-
butyl ester 2a, a substrate chosen to minimize the possibility
of NHC-catalyzed transesterification. Two syntheses of 2a
were investigated; the first involved the RCM of a citronellal
9
4b
(
3
i.e., 2) as a method to access bicyclic dihydropyranones (i.e.,
derivative to deliver the aldehydic variant of 8, which was
1
0,11
16
).
Herein, we report the outcome of such studies for
then oxidized to the acid. This strategy gave the required
the preparation of cyclopenta[c]pyran 3, a molecule repre-
senting the core of the iridoid family. Subsequent elaboration
to (-)-7-deoxyloganin (1), a natural product prepared by total
material. However, for the scalable synthesis of 2a, it was
more practical to start with tetrahydrofuran 7 and use an
intercepted Horner-Wadsworth-Emmons reaction to deliver
12
17
synthesis once previously, has also been achieved (Scheme
).
allylic alcohol 6 (Scheme 2). Conversion to ester 8 followed
1
Scheme 2. Preparation of R,ꢀ-Unsaturated Enol Ester 2a
Scheme 1. Synthetic Strategy to (-)-7-Deoxyloganin (1)
by hydrolysis then provided acid 9, which was converted to
acid chloride 4.
The central challenge to our synthesis of (-)-7-deoxylo-
ganin (1) involved the NHC-catalyzed rearrangement of diene
1
3
Esterification of acid chloride 4, using tert-butyl formyl
2
, in the presence of a spectating ester group. In addition
18
acetate (5) in the presence of pyridine, gave an inseparable
mixture of the desired ester 2a, along with the Knoevenagel
adduct 10. Fortunately, by using H u¨ nig’s base, the formation
of 10 was eliminated.
to chemoselectivity, this reaction must proceed with substrate-
directed stereoselectivity. Finally, elaboration of dihydro-
pyranone 3 to (-)-7-deoxyloganin (1) requires a chemo- and
stereoselective reduction and a challenging ꢀ-glycosyla-
1
4,15
Initial attempts to rearrange enol ester 2a to dihydro-
pyranone 3a using the NHC derived from diaryl imida-
zolium A met with limited success (Table 1, entries 1 and
tion.
(
9) For medicinally relevant pyran natural products, see: Prisinzano, T. E.
J. Nat. Prod. 2009, 72, 581.
10) For other NHC-catalyzed approaches to pyranones, see: (a) He,
2
). In related studies, we have found the highly reactive
(
tetramethyl carbene B1 to be useful with unreactive
substrates. In this case, using carbene B1 at -78 °C in
THF gave the desired dihydropyranone 3a, along with
isomeric 3a′, the former being favored (Table 1, entry 3).
Moving to the diisopropyl dimethyl carbene B2 and
decreasing catalyst loading improved the yield and dias-
tereoselectivity (Table 1, entry 4). Conducting the reaction
in toluene increased the diastereoselectivity further but
decreased the yield (Table 1, entry 5).
M.; Struble, J. R.; Bode, J. W. J. Am. Chem. Soc. 2006, 128, 8418. (b) He,
M.; Uc, G. J.; Bode, J. W. J. Am. Chem. Soc. 2006, 128, 15088. (c) He,
M. H.; Beahm, B. J.; Bode, J. W. Org. Lett. 2008, 10, 3817. (d) Wang, L.;
Thai, K.; Gravel, M. Org. Lett. 2009, 11, 891. (e) Li, G.-Q.; Dai, L.-X.;
You, S.-L. Org. Lett. 2009, 11, 1623
11) For selected transition-metal-based approaches to pyranones, see:
a) Itoh, K.; Hasegawa, M.; Tanaka, J.; Kanemasa, S. Org. Lett. 2005, 7,
.
(
(
9
79. (b) Evans, D. A.; Thomson, R. J.; Francisco, F. J. Am. Chem. Soc.
005, 127, 10816. For organocatalytic approaches not using NHCs, see:
2
(
c) Tozawa, T.; Nagao, H.; Yamane, Y.; Mukaiyama, T. Chem. Asian J.
007, 2, 123. (d) Calter, M. A.; Wang, J. Org. Lett. 2009, 11, 2205
12) Tietze, L. F.; Denzer, H.; Holdgr u¨ n, X.; Neumann, M. Angew.
Chem., Int. Ed. Engl. 1987, 12, 1295.
13) For applications of NHCs in transesterification catalysis, see: (a)
2
.
(
(
Grasa, G. A.; Singh, R.; Nolan, S. P. Synthesis 2004, 971. (b) Grasa, G. A.;
Kissling, R. M.; Nolan, S. P. Org. Lett. 2002, 4, 3583. (c) Nyce, G. W.;
Lamboy, J. A.; Connor, E. F.; Waymouth, R. M.; Hedrick, J. L. Org. Lett.
(14) In B u¨ chi’s seminal contributions, glycosylation was achieved in
very low yield: B u¨ chi, G.; Carlson, J. A.; Powell, J. E., Jr.; Tietze, L. F.
J. Am. Chem. Soc. 1973, 95, 540, and references cited therein.
(15) For glycosylation with TMSOTf, see: (a) Tietze, L.-F.; Fischer, R.
Tetrahedron Lett. 1981, 22, 3239. (b) Tietze, L.-F.; Fischer, R. Angew.
Chem., Int. Ed. 1983, 22, 888, and references cited therein.
(16) Bal, B. S.; Childers, W. E.; Pinnick, H. W. Tetrahedron 1981, 37,
2091.
2
002, 4, 3587. (d) Nyce, G. W.; Glauser, T.; Connor, E. F.; M o¨ ck, A.;
Waymouth, R. M.; Hedrick, J. L. J. Am. Chem. Soc. 2003, 125, 3046. (e)
Suzuki, Y.; Yamauchi, K.; Muramatsu, K.; Sato, M. Chem. Commun. 2004,
2
770. (f) Kano, T.; Sasaki, K.; Maruoka, K. Org. Lett. 2005, 7, 1347. NHC-
catalyzed transesterification with amino alcohols and mechanistic comments:
g) Movassaghi, M.; Schmidt, M. A. Org. Lett. 2005, 7, 2453. (h) Schmidt,
(
(17) (a) Graff, M.; Al Dilaimi, A.; Seguineau, P.; Rambaud, M.; Villi e´ ras,
J. Tetrahedron Lett. 1986, 27, 1577. (b) Villi e´ ras, J.; Rambaud, M.; Graff,
M. Synth. Commun. 1986, 16, 149.
M. A.; M u¨ ller, P.; Movassaghi, M. Tetrahedron Lett. 2008, 49, 4316. For
a detailed mechanistic investigation, see: (i) Pignataro, L.; Papalia, T.;
Slawin, A. M. Z.; Goldup, S. M. Org. Lett. 2009, 11, 1643. For
computational studies, see: (j) Lai, C.-H.; Lee, H. M.; Hu, C.-H. Tetrahedron
Lett. 2005, 46, 6265.
(18) (a) Bihmayer, G. A.; Derkosch, D. J.; Polansky, O. E. Monatsh.
Chem. 1967, 98, 564. (b) Sato, M.; Yoneda, N.; Katagiri, N.; Watanabe,
H.; Kaneko, C. Synthesis 1986, 672.
Org. Lett., Vol. 12, No. 21, 2010
4837

a
Table 1. Selected Optimization of NHC Rearrangement of 2a or
Scheme 3. Preparation of Enantioenriched Cyclopentene (S)-8
2
b
mol %
yield of
a
b
entry
SM
catalyst temp (°C)/solvent
3
(%)/dr
t
c
1
2
3
4
5
6
a
2a (R ) Bu) 10% A
rt/toluene
t
c
a
2a (R ) Bu) 10% A
-10/toluene
-78 f rt/THF
-78 f rt/THF
-78 f rt/toluene 38 (4.4:1)
-78 f rt/THF
5
Enantiomeric excess by chiral HPLC, Daicel OD-H.
t
d
d
d
d
2a (R ) Bu) 40% B1
2a (R ) Bu) 30% B2
2a (R ) Bu) 30% B2
2b (R ) Me) 20% B2
40 (2:1)
74 (3:1)
t
purification of the more desirable methyl formyl acetate
t
2
2
proved difficult, while acylation of (S)-4 with impure
formyl acetate gave products contaminated with the Kno-
evenagel adduct. NHC-catalyzed rearrangement of 2b (R )
Me), as in Table 1, then gave dihydropyranone (S)-3b in
82 (3.4:1)
b
1
Combined isolated yield. Diastereomeric ratio from analysis of H
NMR of the unpurified residue. Carbene generated with 10 mol % KO Bu.
Carbene from the reduction of the thiourea and isolated.
c
t
d
6
3% isolated yield and without any loss of stereochemical
purity.
Having constructed cyclopenta[c]pyranone (S)-3b, it re-
While the original strategy targeted tert-butyl ester 2a, it
was decided to attempt the rearrangement with methyl ester
mained to reduce the lactone and introduce the glycoside.
The chemoselective reduction of related iridoid lactones has
19
2b, as required for the natural product. This substrate, with
20 mol % of carbene B2, provided the dihydropyranones
3b and 3b′ in a 3.4:1 ratio and 82% isolated yield (Table 1,
2
3
been achieved. However, over-reduction has also been
2
4
observed. In our hands, reduction with NaBH , followed
4
entry 6). Further optimization, through the use of chiral
carbenes, alternate solvents, and temperatures, met with
limited success. Therefore, we settled upon the previous
conditions.
by acetylation, gave lactol acetate 13 in 41% isolated yield
over two steps.
At this stage, our studies intercepted those of Tietze.
1
2
Unfortunately, spectral data was not reported for acetate 13,
making completion of the total synthesis a requirement to
allow comparison with the literature and to update the data
With proof of principle for the key step, we required access
to enantioenriched (S)-2b to complete the total synthesis. The
racemic variant of TBS alcohol 11 has been converted to
cyclopentane 12 by stereocontroled anti addition of the
2
5,26
associated with the natural product.
The stereoselective ꢀ-glycosylation of iridoid agylcons
2
0
14
methyl group. Thus, access to enantioenriched 11 should,
via 12, provide (S)-8. To prepare cyclopentene 11, lipase
resolution of the racemic alcohol 6 was undertaken providing
is a challenge using traditional methods. However, Tietze
has developed useful conditions for this reaction using
1
5
catalytic TMSOTf. Exploiting these conditions, in
2
1
15a
15b
(
S)-6 in, as reported, 50% yield and 99% ee (Scheme 3).
acetonitrile
rather than liquid SO
2
,
permitted the
2
0
Methylation and deprotection then gave alcohol 12. Me-
sylation of 12 and subsequent elimination delivered (S)-8
with good stereochemical integrity.
stereoselective conversion of acetate 13 into ꢀ-glycoside
2
7
14. We found that partial purification of 14, followed
by deprotection and further purification, gave glycoside
1
in yields consistent with the literature. Comparison of
With access to enantioenriched (S)-8, and exploiting our
previously introduced strategy (Scheme 2), the acid chloride
S)-4 was prepared and then acylated to provide (S)-2a.
Conversion of the tert-butyl ester to the methyl ester was
achieved, in two steps and 78% overall yield, by TFA
deprotection and methylation using TMS-diazomethane
1
13
the H and C NMR data derived from 1 to that
reported
2
5,26
provided confirmation of the structure as
(
(-)-7-deoxyloganin (1).
In summary, a total synthesis of (-)-7-deoxyloganin (1)
has been achieved in 18 steps from 7 and 0.8% overall yield.
(
Scheme 4). This strategy was pursued as preparation and
(
22) Methyl formyl acetate is prone to oligomerization, as reported
previously: Dinh, M.-T.; Bouzbouz, S.; P e´ glion, J.-L.; Cossy, J. Tetrahedron
2004, 64, 5703.
(
19) While the mechanism of NHC catalyzed tranesterification is not
settled, base mediated alcohol activation appears most likely, ref 13g-j.
This cannot operate under our reaction conditions; hence, the type of ester
should be irrelevant.
(23) Brown, R. T.; Ford, M. J. Tetrahedron Lett. 1990, 31, 2033, and
references therein.
(24) Balsevich, J.; Bishop, G. Heterocycles 1989, 29, 921.
(
20) (a) Dambrin, V.; Villi e´ ras, M.; Moreau, C.; Amri, H.; Toupet, L.;
(25) Kocsis, A.; Szab o´ , L. F.; Pod a´ nyi, B. J. Nat. Prod. 1993, 56, 1486.
Villi e´ ras, J. Tetrahedron Lett. 1996, 37, 6323. (b) Dambrin, V.; Villi e´ ras,
M.; Janvier, P.; Toupet, L.; Amri, H.; Leberton, J.; Villi e´ ras, J. Tetrahedron
(26) Damtoft, S.; Jensen, S. R.; Nielsen, B. J. J. Chem. Soc., Perkin
Trans. 1 1983, 1943
(27) For the application of the reaction conditions introduced in ref 15,
see ref 4d.
.
2
001, 57, 2155.
(
21) Yamane, T.; Takahashi, M.; Ogasawara, K. Synthesis 1995, 444.
4838
Org. Lett., Vol. 12, No. 21, 2010

Scheme 4. Synthesis of (-)-7-Deoxyloganin (1)
The key transformation exploits a substrate-directed NHC-
catalyzed rearrangement to generate cyclopenta[c]pyranone
Dr. Andreas Stasch (Monash University), Dr. Ben Greatrex
(University of New England), Christopher J. Gartshore
(Monash University), and Anastas Sidiropoulas (Monash
University).
(
S)-3b, the bicyclic core of the iridoid family of natural
products. The reaction was achieved in good yield and with
stereocontrol through the application of the underutilized
NHC B2. Elaboration of (S)-3b by chemoselective reduction
and glycosylation of lactol acetate 13 then completes the
synthesis.
Supporting Information Available: Experimental pro-
cedures, characterization of all new compounds, and copies
1
13
of H and C NMR spectra. This material is available free
of charge via the Internet at http://pubs.acs.org.
Acknowledgment. We acknowledge the financial sup-
port of the ARC (DP0881137) and useful discussions with
OL101983H
Org. Lett., Vol. 12, No. 21, 2010
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