Enantioselective enzymatic desymmetrization of highly functionalized meso tetrahydropyranyl diols

Article abstract of DOI:10.1021/ol902107g

The enantioselective enzymatic desymmetrization of several highly substituted meso-tetrahydropyranyl diols is described. This transformation leads to valuable building blocks containing up to five stereogenic centers, which are revealed in a single step w

Full text of DOI:10.1021/ol902107g

ORGANIC
LETTERS
2009
Vol. 11, No. 21
4950-4953
Enantioselective Enzymatic
Desymmetrization of Highly Functionalized
Meso Tetrahydropyranyl Diols†
Mathieu Candy, Ge´rard Audran, Hugues Bienayme´,‡ Cyril Bressy,* and
Jean-Marc Pons*
Aix-Marseille UniVersite´, Institut des Sciences Mole´culaires de Marseille, iSm2 CNRS
UMR6263 - e´quipe STeRe´O Campus Saint-Je´roˆme, 13397 Marseille Cedex 20, France
cyril.bressy@uniV-cezanne.fr; jean-marc.pons@uniV-cezanne.fr
Received September 11, 2009
ABSTRACT
The enantioselective enzymatic desymmetrization of several highly substituted meso-tetrahydropyranyl diols is described. This transformation
leads to valuable building blocks containing up to five stereogenic centers, which are revealed in a single step with both high yields and
excellent enantiomeric excesses. Moreover, it was shown that this kind of building blocks could provide an easy access to both enantiomers
of highly functionalized stereotetrads.
Many natural products bear a tetrahydropyran (THP) moiety
and some, such as kendomycin,1 phorboxazoles,2 and rat-
jadone A,3 present interesting biological activities (Figure
1). This observation led chemists to develop strategies and
new approaches to obtain this particular heterocycle in a
stereoselective fashion.4 Among these, the Prins reaction,5
the Petasis-Ferrier rearrangement,6 the intramolecular oxa-
Michael additions,7 and the hetero-Diels-Alder cycloaddi-
tions8 have been widely adopted.
The enantioselective desymmetrization of meso com-
pounds has become a powerful strategy in synthesis9 as it
allows to reveal and/or generate multiple stereogenic centers
in a single operation. Hence, in the context of total synthesis,
the retrosynthetic analysis is based on the detection of hidden
symmetry within the target molecule. The desymmetrization
of meso compounds containing functions such as epoxides,10
(2) Isolation: Searle, P. A.; Molinski, T. F. J. Am. Chem. Soc. 1995,
117, 8126–8127. Total syntheses of Phorboxazole A: (a) Forsyth, C. J.;
Ahmed, F.; Cink, R. D.; Lee, C. S J. Am. Chem. Soc. 1998, 120, 5597–
5598. (b) Smith, A. B., III; Verhoest, P. R.; Minbiole, K. P.; Schelhaas, M.
J. Am. Chem. Soc. 2001, 123, 10942–10953. (c) Gonzalez, M. A.; Pattenden,
G. Angew. Chem., Int. Ed. 2003, 42, 1255–1258. (d) Williams, D. R.;
Kiryanov, A. A.; Emde, U.; Clark, M. P.; Berliner, M. A.; Reeves, J. T.
Angew. Chem., Int. Ed. 2003, 42, 1258–1262. (e) White, J. D.; Lee, T. H.;
Kuntiyong, P. Org. Lett. 2006, 8, 6039–6042. (f) White, J. D.; Lee, T. H.;
Kuntiyong, P. Org. Lett. 2006, 8, 6043–6046. Total syntheses of Phorbox-
azole B: (aa) Evans, D. A.; Cee, V. J.; Smith, T. E.; Fitch, D. M.; Cho,
P. S. Angew. Chem., Int. Ed. 2000, 39, 2533–2536. (bb) Evans, D. A.; Cee,
V. J.; Smith, T. E.; Fitch, D. M.; Cho, P. S. Angew. Chem., Int. Ed. 2000,
39, 2536–2540. (cc) Li, D.-R.; Zhang, D.-H.; Sun, C.-Y.; Zhang, J.-W.;
Yang, L.; Chen, J.; Liu, B.; Su, C.; Zhou, W.-S.; Lin, G.-Q. Chem.sEur.
J. 2006, 12, 1185–1204. (dd) Lucas, B. S.; Gopalsamuthiram, V.; Burke,
S. D. Angew. Chem., Int. Ed. 2007, 46, 769–772.
† Dedicated to Professor Mark Lautens on the occasion of his 50th
birthday.
‡ TARGEON, 4 Avenue de l’Observatoire, 75006 Paris, France.
(1) Isolation: Funahashi, Y.; Kawamura, N.; Ishimaru, T. Japan Patent
08231551 [A2960910], 1996; Chem. Abstr. 1997, 126, 6553; Japan Patent
08231552, 1996; Chem. Abstr. 1996, 125, 326518. Total syntheses: (a) Yuan,
Y.; Men, H.; Lee, C. J. Am. Chem. Soc. 2004, 126, 14720–14721. (b) Smith
III, A. B.; Mesaros, E. F.; Meyer, E. A. J. Am. Chem. Soc. 2005, 127,
6948–6949. (c) Smith III, A. B.; Mesaros, E. F.; Meyer, E. A. J. Am. Chem.
Soc. 2006, 128, 5292–5299. (d) Lowe, J. T.; Panek, J. S. Org. Lett. 2008,
10, 3813–3816. (e) Magauer, T.; Martin, H. J.; Mulzer, J. Angew. Chem.,
Int. Ed. 2009, 48, 6032–6036. Formal syntheses: Bahnck, K. B.; Rych-
novsky, S. D. J. Am. Chem. Soc. 2008, 130, 13177–13180.
10.1021/ol902107g CCC: $40.75
Published on Web 10/07/2009
 2009 American Chemical Society

so far: (1) the enzyme-mediated hydrolysis of diesters19 or
mono-transesterification of diols which, when applied to
2,4,6-substitued meso-THP, lead to the generation of up to
three new stereogenic centers, and (2) the asymmetric ring-
opening cross-metathesis involving chiral catalysts.20
In this paper, we report the synthesis of a new class of
meso compounds II bearing a 2,3,4,5,6-substituted tetrahy-
dropyranyl diol motif easily obtained from oxabicycles of
type I and their enantioselective enzymatic desymmetrization,
which reveals and creates up to five new stereogenic centers21
in a one-pot fashion (Scheme 1).
Scheme 1
.
Synthetic Strategy toward THP Containing up to
Five Stereogenic Centers
Figure 1. Natural products containing a highly substituted THP
subunit.
anhydrides,11 diols12 and polyols,13 dienes,14 ketones,15 or
oxabicycles16 has been successfully applied to the total
synthesis of various challenging natural products.17 However,
as highlighted by Hoffmann in a recent review,18 the use of
meso compounds in asymmetric synthesis is greatly depend-
ent on how easy these meso building blocks are built.
Syntheses of THP subunits through enantioselective de-
symmetrization using a preformed THP ring are rare. Indeed,
to our knowledge, only two methods have been described
The synthesis of the meso compounds relied on the
oxabicycles of type I easily available through a highly
diastereoselective [4 + 3] cycloaddition between furan
derivatives and oxyallyl cation precursors following the
procedure developed by Lubineau and Bouchain22 (Scheme
(12) For recent examples of enantioselective catalytic desymmetrization
of meso diols, see: (a) Ku¨ndig, E. P.; Enriquez Garcia, A.; Lomberget, T.;
Perez Garcia, P.; Romanens, P. Chem. Commun. 2008, 3519–3521. (b)
Birman, V. B.; Jiang, H.; Li, X. Org. Lett. 2007, 9, 3237–3240. (c) Zhao,
Y.; Rodrigo, J.; Hoveyda, A. H.; Snapper, M. L. Nature 2006, 443, 67–70.
(d) Shimizu, H.; Onitsuka, S.; Egami, H.; Katsuki, T. J. Am. Chem. Soc.
2005, 127, 5396–5413.
(3) Isolation: Schummer, D.; Gerth, K.; Reichenbach, H.; Ho¨fle, G.
Liebigs Ann. 1995, 685–688. Total Syntheses: (a) Williams, D. R.; Ihle,
D. C.; Plummer, S. V. Org. Lett. 2001, 3, 1383–1386. (b) Bhatt, U.;
Christmann, M.; Quitschalle, M.; Claus, E.; Kalesse, M. J. Org. Chem.
2001, 66, 1885–1893.
(4) For a review on THP, see: (a) Clarke, P. A.; Santos, S. Eur. J. Org.
Chem. 2006, 2045–2053. (b) Larrosa, I.; Romea, P.; Urpi, F. Tetrahedron
2008, 64, 2683–2723.
(13) For recent examples of enantioselective catalytic desymmetrization
of meso polyols, see: (a) Lucas, B. S.; Burke, S. D. Org. Lett. 2003, 5,
3915–3918. (b) Harada, T.; Egusa, T.; Igarashi, Y.; Kinugasa, M.; Oku, A.
J. Org. Chem. 2002, 67, 7080–7090. (c) Cheˆnevert, R.; Rose, Y. S. J. Org.
Chem. 2000, 65, 1707–1709.
(5) For recent examples of Prins reaction in total synthesis, see: (a) Woo,
S. K.; Kwon, M. S.; Lee, E. Angew. Chem., Int. Ed. 2008, 47, 3242–3244.
(b) Cheung, L. L.; Marumoto, S.; Anderson, C. D.; Rychnovsky, S. D. Org.
Lett. 2008, 10, 3101–3104. (c) Seden, P.; Charmant, J. P. H.; Willis, C. L.
Org. Lett. 2008, 10, 1637–1640. For a deeply mechanistic investigations,
see: Jasti, R.; Rychnovsky, S. D J. Am. Chem. Soc. 2006, 128, 13640–
13648.
(14) For examples, see: (a) Gerber-Lemaire, S.; Vogel, P. Eur. J. Org.
Chem. 2003, 2959–2963. (b) Schreiber, S. L.; Goulet, M. T.; Schulte, G.
J. Am. Chem. Soc. 1987, 109, 4718–4720.
(15) For recent examples of catalytic desymmetrization of meso ketones,
see: (a) Chandler, C. L.; List, B. J. Am. Chem. Soc. 2008, 130, 6737–6739.
(b) Ramachary, D. B.; Barbas, C. F. Org. Lett. 2005, 7, 1577–1580.
(16) Lautens, M.; Fagnou, K.; Hiebert, S. Acc. Chem. Res. 2003, 36,
48–58.
(6) Smith III, A. B.; Fox, R. J.; Razler, T. M. Acc. Chem. Res. 2008,
41, 675–687.
(7) For a general review on the Oxa-Michael including THP formation,
see: Nising, C. F.; Bra¨se, S. Chem. Soc. ReV. 2008, 37, 1218–1228.
(8) Dossetter, A. G.; Jamison, T. F.; Jacobsen, E. N. Angew. Chem.,
Int. Ed. 1999, 38, 2398–2400.
(17) Some significant examples: Vannusal B: Nicolaou, K. C.; Zhang,
H.; Ortiz, A.; Dagneau, P. Angew. Chem., Int. Ed. 2008, 47, 8605–8610.
Tamiflu: Zutter, U.; Iding, H.; Spurr, P.; Wirz, B. J. Org. Chem. 2008, 73,
4895–4902. Ionomycin: Lautens, M.; Colucci, J. T.; Hiebert, S.; Smith,
N. D.; Bouchain, G. Org. Lett. 2002, 4, 1879–1882. Quadrigemine C and
Psycholeine: Lebsack, A. D.; Link, J. T.; Overman, L. E.; Stearns, B. A.
J. Am. Chem. Soc. 2002, 124, 9008–9009.
(9) Prochiral and meso compounds bearing with a mirror plan: Willis,
M. C. J. Chem. Soc., Perkin Trans. 1999, 1, 1765–1784. Centro-symmetric
molecules: Anstiss, M.; Holland, J. M.; Nelson, A.; Titchmarsh, J. R. Synlett
2003, 1213–1220. Enzymatic desymmetrizations: Garcia-Urdiales, E.; Al-
fonso, I.; Gotor, V. Chem. ReV. 2005, 105, 313–354.
(10) For selected examples on catalytic enantioselective desymmetri-
zation of meso epoxides by ring opening of a nucleophile, see: (a) Arai,
K.; Salter, M. M.; Yamashita, Y.; Kobayashi, S. Angew. Chem., Int. Ed.
2007, 46, 955–957. (b) Matsunaga, S.; Das, J.; Roels, J.; Vogl, E. M.;
Yamamoto, N.; Iida, T.; Yamaguchi, K.; Shibasaki, M. J. Am. Chem. Soc.
2000, 122, 2252–2260. (c) Schaus, S. E.; Jacobsen, E. N. Org. Lett. 2000,
2, 1001–1004. By based-induced rearrangement, see: So¨dergren, M. J.;
Bertilsson, S. K.; Andersson, P. G. J. Am. Chem. Soc. 2000, 122, 6610–
6618, and references therein.
(18) Hoffmann, R. W. Angew. Chem., Int. Ed. 2003, 42, 1096–1109.
(19) (a) Lampe, T. F. J.; Hoffmann, H. M. R.; Bornsheuer, U. T.
Tetrahedron: Asymmetry 1996, 7, 2889–2900. (b) Cheˆnevert, R.; Goupil,
D.; Rose, Y. S.; Be´dard, E. Tetrahedron: Asymmetry 1998, 9, 4285–4288.
(20) (a) Gillingham, D. G.; Kataoka, O.; Garber, S. B.; Hoveyda, A. H.
J. Am. Chem. Soc. 2004, 126, 12288–12290. (b) Gillingham, D. G.;
Hoveyda, A. H. Angew. Chem., Int. Ed. 2007, 46, 3860–3864. (c) Ibrahem,
I.; Yu, M.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131,
3844–3845.
(11) For a general review on enantioselective stereoselective ring opening
of meso anhydrides, see: Atodiresei, L.; Schiffers, I.; Bolm, C. Chem. ReV.
2007, 107, 5683–5712.
(21) We use the term “reveal” because the stereogenic centers pre-exist
before the operation of desymmetrization and “create” because in our case
one carbon is prochiral (C4).
Org. Lett., Vol. 11, No. 21, 2009
4951

2). Hence, multigram amounts of meso oxabicycle 1a could
be obtained by simple crystallization of the crude material.
The synthetic sequence toward diol 2a from oxabicycle 1a
required three steps: first, a highly stereoselective reduction
of the ketone using sodium borohydride followed by an
alkylation of the free hydroxyl group mediated by KH and
an ozonolysis [MeOH/CH2Cl2 (1.5/2), -60 °C] terminated
by a reduction with an excess of sodium borohydride. Based
on this strategy, a variety of meso-tetrahydropyranyl diols
2a-i was synthesized.23
biguously by X-ray analysis of its corresponding iodide
derivative 426 (Scheme 3).
Scheme 3. Synthesis of the Iodide Derivative 4 from the
Desymmetrized Compound 3a and Its ORTEP View
Scheme 2. Synthesis of the meso-Tetrahydropyranyl Diol 2a
We then examined the scope of the RML-promoted
desymmetrization using the variously substituted meso THP
diols 2a-i. The modification of the substituent at C4 on the
THP ring (R4) was first tested: the hydroxyl group in this
position can be protected by several groups with different
hindrances without effect on the yields or the selectivities
(Table 2, entries 1-4). Even more interestingly, it appeared
that the inversion of configuration on C4 (Table 2, entry 5)
or the total reduction of this position (Table 2, entry 6) had
no significant effect on ee. Increasing the steric hindrance
at C3 positions (R2) resulted only in a very slight decrease
of the enantioselectivity when a methyl was changed for an
ethyl group (96% ee) (Table 2, entry 7), but a dramatic fall
of reactivity and enantioselectivity of the reaction was
observed when a methyl group was changed for a phenyl
group (Table 2, entry 8). Finally, desymmetrized THP 3i
bearing three quaternary centers could be obtained in 72%
yield and 94% ee from meso-triol 2i bearing a free tertiary
alcohol in C4 position.
Five commercially available lipases were screened.24
A
typical experiment was conducted at room temperature with
a mixture of meso diol 2a (0.245 mmol, 50 mg) and lipase
(30 mg) in the presence of vinyl acetate25 (2 mL) and
diisopropyl ether (2 mL). The outcome of this initial
screening indicated that Rhizomucor miehei lipase (RML)
was the enzyme of choice for the transesterification of 2a
(Table 1, entry 3) leading to the corresponding monoacetate
in high yield (90%) and excellent molecular recognition (ee
>98%) within 24 h. Pseudomonas fluorescens lipase (PFL)
also exhibited an interesting activity (Table 1, entry 2);
however, the yield and ee were slightly lower.
We then explored the synthetic potential of the transfor-
mation and showed that the desymmetrized building block
3a27 could easily be converted into both enantiomers 7 and
ent-7 of a syn-anti-anti stereotetrad just by changing the order
of the synthetic sequence (Scheme 4). Iodination of the free
primary alcohol of 3a followed by saponification, protection
of the alcohol as its p-methoxybenzyl ether using PMB-
trichloroacetimidate (PMBTCA) in the presence of a catalytic
amount of Yb(OTf)3,28 and a Zn-mediated ring-opening of
the THP ring furnished the valuable polyfunctionalized tetrad
7 in 64% overall yield.
Table 1. Screening of Lipases for the Enantioselective
Enzymatic Desymmetrization of Tetrahydropyranyl Diols
reaction
time (h)
entry
lipase
yielda (%)
eeb (%)
1
2
3
4
5
PPL
PFL
RML
CAL-B
CRL
48
24
24
20
20
0
81
>94
>98
Its enantiomer ent-7 could be obtained by starting with
the PMB protection, then saponification, followed by iodi-
nation and Zn-mediated ring-opening in a similar 69% overall
yield. In this non-aldol strategy to polypropionate fragments,
90
100c
100c
a Isolated yields after column chromatography. b Determined by chiral
HPLC (Sepapak-2-HR) after purification by column chromatography.
c Formation of the meso-diacetate.
(24) PPL: Pig Pancreatic Lipase; PFL: Pseudomonas fluorescens; RML:
Rhizomucor miehei Lipase; CAL-B: Candida antarctica B Lipase; CRL:
Candida rugosa Lipase type VII.
(25) Vinyl acetate was used here as reagent and co-solvent to solubilize
the meso diol during the desymmetrization reaction.
The absolute configuration of alcohol 3a, obtained through
RML-promoted transesterification was determined unam-
(26) CCDC 739869 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
(27) The desymmetrization of 2a was performed on 2 grams scale in
87% and identical ee.
(22) (a) Lubineau, A.; Bouchain, G. Tetrahedron Lett. 1997, 38, 8031–
8032. (b) Lautens, M.; Bouchain, G. Org. Synth. 2002, 79, 251–253.
(23) See Supporting Information.
(28) Rai, A. N.; Basu, A. Tetrahedron Lett. 2003, 44, 2267–2269.
4952
Org. Lett., Vol. 11, No. 21, 2009

Table 2. Enantioselective Enzymatic Desymmetrization of
Tetrahydropyranyl Diols 2a-ia
Scheme 4. Synthesis of Both Enantiomers 7 and ent-7 of the
syn-anti-anti-Tetrade from the Desymmetrized Monoacetate 3a
lipase-catalyzed transesterification to afford tetrahydropyrans
with up to five stereogenic centers.
The reaction tolerated several variations on the structures
of these meso substrates with only slight effects on enantio-
selectivities and yields. We demonstrated the synthetic
potential of this kind of building block by obtaining both
enantiomers of a syn-anti-anti stereotetrad starting from the
same desymmetrized monoacetate 3a. Synthetic applications
of this novel methodology will be presented in due course.
Acknowledgment. We thank gratefully Professor P.
Kocienski (University of Leeds) for his interest in our work.
Dr N. Vanthuyne (chiral HPLC analysis) and Dr M. Giorgi
(X-ray analysis and determination of the absolute configu-
ration of compound 4) are deeply acknowledged. The
University Paul Ce´zanne and the CNRS are gratefully
acknowledged. M.C. thanks the CNRS and the Re´gion
Provence Alpes Coˆte d’Azur for funding.
a Typical experiment: diol 2a (0.245 mmol, 50 mg) and R. miehei lipase
(30 mg) in i-Pr2O (2 mL) and vinyl acetate (2 mL), 24 h. b Isolated yields
after column chromatography. c Determined by chiral HPLC. d Reaction
over 3 h, 27% of meso-diacetate was isolated. e Reaction over 72 h, 75%
of diol was recovered.
Supporting Information Available: Full characterization
data and copies of H NMR and 13C NMR spectra of all
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
1
it is important to note that the stereochemistry of the four
stereogenic centers of the tetrad is controlled in a single step.
In conclusion, a new class of meso-tetrahydropyranyl diols
2a-i were synthesized that underwent efficient R. miehei
OL902107G
Org. Lett., Vol. 11, No. 21, 2009
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