Enantioenriched bifunctional crotylsilanes for the asymmetric synthesis of orthogonally protected 2-methyl-1,3-diols

Article abstract of DOI:10.1021/ol4026167

Enantiomerically pure α-substituted crotylsilane reagents I and ent-I undergo asymmetric aldehyde crotylation followed by Ir(I)-catalyzed diastereoselective allylic etherification to give a variety of orthogonally protected 2-methyl-1,3-diols at the synthetically useful level of yields and stereoselectivity. The reagents are air-stable and bifunctional so that they can be used in these reactions sequentially without recourse to functional group adjustments.

Full text of DOI:10.1021/ol4026167

ORGANIC
LETTERS
2013
Vol. 15, No. 19
5142–5145
Enantioenriched Bifunctional
Crotylsilanes for the Asymmetric
Synthesis of Orthogonally Protected
2‑Methyl-1,3-diols
Dongeun Kim, Jae Seung Lee, Lucia Lozano, Suk Bin Kong, and Hyunsoo Han*
Department of Chemistry, University of Texas at San Antonio, San Antonio,
Texas 78249, United States
Hyunsoo.han@utsa.edu
Received September 10, 2013
ABSTRACT
Enantiomerically pure R-substituted crotylsilane reagents I and ent-I undergo asymmetric aldehyde crotylation followed by Ir(I)-catalyzed
diastereoselective allylic etherification to give a variety of orthogonally protected 2-methyl-1,3-diols at the synthetically useful level of yields and
stereoselectivity. The reagents are air-stable and bifunctional so that they can be used in these reactions sequentially without recourse to
functional group adjustments.
Enantioenriched R-substituted allyl/crotylsilanes have
synthetically useful structures can be accessed through
the use of these reagents.2 Furthermore, numerous total
syntheses of biologically and therapeutically important
compounds have been accomplished by employing these
reagents in the key step.3 As such, developing new such
reagents and/or novel synthetic strategies based on these
reagents has been a focus of recent studies.4
played an important role in organic synthesis.1 Many
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Numerous studies, mainly from Panek’s group, have
established that acid-mediated asymmetric crotylation of
aldehydes and acetals by chiral R-substituted crotylsilanes
(2) (a) Panek, J. S.; Yang, M. J. Am. Chem. Soc. 1991, 113, 9868–
9870. (b) Micalizio, G. C.; Roush, W. R. Org. Lett. 2000, 2, 461–464. (c)
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J. S. J. Am. Chem. Soc. 2004, 126, 2425–2430. (f) Su, Q.; Panek, J. S.
Angew. Chem., Int. Ed. 2005, 44, 1223–1225. (g) Binanzer, M.; Fang,
G. Y.; Aggarwal, V. K. Angew. Chem., Int. Ed. 2010, 49, 4264–4268. (h)
Wu, J.; Zhu, K.-C.; Yuan, P.-W.; Panek, J. S. Org. Lett. 2012, 14, 3624–
3627. (i) Wu, J.; Becerril, J.; Lian, Y.; Davies, H. M. L.; Porco, J. A., Jr.;
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1021. (k) Lipomi, D. J.; Panek, J. S. Org. Lett. 2005, 7, 4701–4704.
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J.; Panek, J. S. Angew. Chem., Int. Ed. 2010, 49, 6165–6168. (c)
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r
10.1021/ol4026167
Published on Web 09/24/2013
2013 American Chemical Society

in the presence of TMSOR0 can give rise to E-homoallylic
ethers with high enantio- and diastereoselectivities (eq 1).1a,5
However, the resulting homoallylic ethers have been used
primarily for simple functional group interconversions and
have rarely been employed in catalytic asymmetric reac-
tions where a new bond is stereoselectively introduced
by using a pair of enantiomeric catalysts/ligands. This
may be in large part due to the fact that almost all prior
chiral R-substituted crotylsilanes, to our knowledge, pro-
duce homoallylic ethers, which are not appropriately
appended with functional groups for subsequent catalytic
asymmetric reactions.6 In this regard, new chiral R-sub-
stituted crotylsilanes that can undergo an asymmetric
crotylation immediately followed by a catalytic asymmetric
reaction without recourse to functional group adjustments
would be highly desirable. We considered this need in rela-
tion with our recent reports that described Ir(I)-catalyzed
Table 1. Asymmetric Crotylation of Aldehydes by the
Crotylsilanes I and ent-I
a Isolated yields. b Determined by the 1H NMR spectrum of reaction
mixtures. c Determined by chiral HPLC.
diastereoselective allylic etherification of p-methoxy-
phenyl (PMP) allyl carbonates (eq 2)7,8 and wondered
whether it would be possible to merge Panek’s asym-
metric aldehyde crotylation with our Ir(I)-catalyzed dia-
stereoselective allylic etherification to devise a new chiral
bifunctional crotylsilane I (eq 3). Herein we report that
the crotylsilane I and its enantiomer ent-I indeed undergo
the above two reactions sequentially to deliver orthogon-
ally protected 2-methyl-1,3-diols in a highly stereoselec-
tive and efficient fashion, which are common structural
motifs in many natural products.9 We believe that the
developed synthetic strategy utilizing I and ent-I are
compared very favorably with other state-of-art meth-
ods for the asymmetric synthesis of 2-methyl-1,3-diol
derivatives.9
The enantioenriched crotylsilanes I and ent-I were pre-
pared by acylating the corresponding known alcohols5
with ClCO2PMP in the presence of pyridine in methylene
(9) For recent approaches, see: (a) Gao, X.; Han, H.; Krische, M. J.
J. Am. Chem. Soc. 2011, 133, 12795–12800. (b) Ichibakase, T.; Nakajima,
M. Org. Lett. 2011, 13, 1579–1581. (c) Rohr, K.; Herre, R.; Mahrwald, R.
J. Org. Chem. 2009, 74, 3744–3749. (d) Mlynarski, J.; Rakiel, B.;
(5) Wu, J.; Chen, Y.; Panek, J. S. Org. Lett. 2010, 12, 2112–2115.
(6) (a) Wu, J.; Zhu, K.-C.; Yuan, P.-W.; Panek, J. S. Org. Lett. 2012,
14, 3624–3627. (b) Panek, J. S.; Yang, M.; Solomon, J. S. J. Org. Chem.
1993, 58, 1003–1010. In these papers, crotylation products were used in
Pd(II)-catalyzed intramolecular allylic acetate transposition and Pd(0)-
catalyzed intramolecular allylic substitution reactions. Since these reac-
tions are intramolecular reactions and their stereochemistry is controlled
by substrate stereochemistry or solvents used, they are not true catalytic
asymmetric reactions, where a new bond is stereoselectively introduced
by a pair of enantiomeric catalysts/ligands.
ꢀ
Stodulski, M.; Suszczynska, A.; Frelek, J. Chem.;Eur. J. 2006, 12,
8158–8167. (e) Gnanadesikan, V.; Horiuchi, Y.; Oshima, T.; Shibasaki,
M. J. Am. Chem. Soc. 2004, 126, 7782–7783. (f) Mascarenhas, C. M.;
Miller, S. P.; White, P. S.; Morken, J. P. Angew. Chem., Int. Ed. 2001, 40,
601–603. (g) Evans, D. A.; Hoveyda, A. H. J. Am. Chem. Soc. 1990, 112,
6447–6449. (h) Dorgan, P. D.; Durrani, J.; Cases-Thomas, M. J.; Hulme,
A. N. J. Org. Chem. 2010, 75, 7475–7478. (i) Esteve, J.; Matas, S.;
(7) (a) Kim, D.; Reddy, S.; Singh, O. V.; Lee, J. S.; Kong, S. B.; Han,
H. Org. Lett. 2013, 15, 512–515. (b) Kim, D.; Lee, J. S.; Kong, S. B.; Han,
H. Angew. Chem., Int. Ed. 2013, 52, 4203–4206.
Pellicena, M.; Velasco, J.; Romea, P.; Urpı, F.; Font-Bardia, M. Eur. J.
´
Org. Chem. 2010, 3146–3151. (j) Zbieg, J. R.; Yamaguchi, E.; McInturff,
E. L.; Krische, M. J. Science 2012, 336, 324–327. (k) McInturff, E. L.;
Yamaguchi, E.; Krische, M. J. J. Am. Chem. Soc. 2012, 134, 20628–20631.
(l) Kim, I. S.; Han, S. B.; Krische, M. J. J. Am. Chem. Soc. 2009, 131,
2514–2520. (m) Gao, X.; Townsend, I. A.; Krische, M. J. J. Org. Chem.
2011, 76, 2350–2354.
(8) For reviews on Ir(I)-catalyzed allylation: (a) Hartwig, J. F.; Pouy,
M. J. Top. Organomet. Chem. 2011, 34, 169–208. (b) Helmchen, G.;
€
Dahnz, A.; Dubon, P.; Schelwies, M.; Weihofen, R. Chem. Commun.
2007, 675–691.
Org. Lett., Vol. 15, No. 19, 2013
5143

Table 2. Ir(I)-Catalyzed Decarboxylative Double Diastereo-
selective Allylic Etherification of PMP Allyl Carbonates 2 in
the Presence of Phosphoramidite Ligand L*a
Table 3. Ir(I)-Catalyzed Decarboxylative Double Diastereo-
selective Allylic Etherification of PMP Allyl Carbonates 2 in
the Presence of Phosphoramidite Ligand ent-L*a
a PMP allyl carbonate (0.2 mmol), [Ir(dbcot)Cl]2 (0.004 mmol), ent-
L* (0.008 mmol), DBU (0.2 mmol) in THF (3 mL) at 60 °C. b Isolated
yields. c Determined by the 1H NMR spectrum of reaction mixtures.
d Linear product/branched product=1:1.
a PMP allyl carbonate (0.2 mmol), [Ir(dbcot)Cl]2 (0.004 mmol), L*
(0.008 mmol), DBU (0.2 mmol) in THF (3 mL) at 60 °C. b Isolated yields.
1
c Determined by the H NMR spectrum of reaction mixtures. d Linear
product/branched product=1:1.
byproduct started to form.5,10 The crotylsilane I tended to
decompose to give PMPOH at higher temperatures than
ꢀ20 °C. All attempts to generate the corresponding homo-
allylic alcohol were unsuccessful.
chloride (eq 4). The crotylsilanes I and ent-I are air-stable
and can be stored without any precautions.
The optimal conditions were applied to a group of
aldehydes, and the results are presented in Table 1. Un-
branched linear aliphatic aldehydes (entries 1 and 2) re-
sulted in high yields, but exhibited modest syn/anti selec-
tivities (4ꢀ7:1). On the other hand, branched (entries 3 and
4) and cyclic (entry 5) aliphatic aldehydes worked well to
give the corresponding homoallylic ethers in good yields
and with excellent syn/antiselectivities (>25:1). Uniformly
high yields (g88%) and excellent syn/anti selectivities
(>25:1) were obtained with all aromatic aldehydes tested
(entries 6ꢀ11). The electron-donating and -withdrawing
ability of a substituent on the benzene ring of aromatic
Acid-mediated asymmetric crotylation of benzaldehyde
by I in the presence of TMSOBn was used to determine the
optimal conditions. After various acids (TfOH, TMSOTf,
TMSI, TiCl4, and BF3 OEt2), solvents (EtCN, MeCN,
3
CH2Cl2, and toluene), and temperatures (ꢀ78, ꢀ50, ꢀ20,
and 0 °C) were screened, as well as the amounts of TMSOBn,
the reaction conditions involving TfOH (3 equiv) and
TMSOBn (3 equiv) in EtCN at ꢀ78 °C were determined
to be optimal to give the corresponding homoallylic ether
in 95% yield in 5 h. The conditionsusing1.5 equiv of TfOH
could be used, but the reaction became very sluggish,
taking >24 h to complete. When less than 3 equiv of
TMSOBn were used, the corresponding tetrahydrofuran
(10) Heitzman, C. L.; Lambert, W. T.; Mertz, E.; Shotwell, J. B.;
Tinsley, J. M.; Va, P.; Roush, W. R. Org. Lett. 2005, 7, 2405–2408.
5144
Org. Lett., Vol. 15, No. 19, 2013

aldehydes, as well as its position, had very little influence
on the diastereoselectivity and reaction yield. In all cases
studied, excellent enantionselectivities (g94%) were ob-
tained, indicating that the reactions proceeded with near-
perfect chirality transfer. The relative and absolute stereo-
chemistry of 2 were assigned by hydrolyzing 2f to the
known allylic alcohol (see the Supporting Information)
and analogy to the literature.5
Table 2 depicts Ir(I)-catalyzed decarboxylative double
diastereoselective allylic etherification of 2 in the presence
of phosphoramidite ligand L*, which gives rise to ortho-
gonally protected 2-methyl-1,3-diols.11 The catalytic con-
ditions involving [Ir(dbcot)Cl]2 (2 mol %), L* (4 mol %),
and DBU (100 mol %) in THF that we recently reported
for Ir(I)-catalyzed enantioselective decarboxylative all-
ylic etherification were used at 60 °C.7 Gratifyingly, high
yields and diastereoselectivities were obtained with al-
most all aliphatic and aromatic substrates studied. Only
the o-chlorophenyl substrate (entry 8) exhibited a modest
yield (36%) due to the formation of the corresponding
linear allylation product, but still showed excellent >25:1
diastereoselectivity.
the diastereofacial preference to favor the other diaste-
reomers 4. The stereochemistry of the allylic etherification
was assigned by converting 3c and 4c to the respective
known compound (see the Supporting Information) and
by analogy to the literature.8,12 Taken together with those
in Table 2, these stereochemical outcomes clearly indi-
cate that double diastereoselectivity in the Ir(I)-catalyzed
decarboxylative allylic etherification of 2 is primarily
governed by ligand/catalyst stereochemistry (reagent-
controlled stereochemistry).11
In summary, we report new bifunctional chiral crotyl-
silanes I and ent-L*, which are air-stable and can undergo
highly enantio-/diasteoselective aldehyde crotylation fol-
lowed by Ir(I)-catalyzed double diastereoselective decar-
boxylative allylic etherification. To the best of our knowl-
edge, these reagents represent the first example of chiral
R-substituted crotylsilanes that can undergo asymmetric al-
dehyde crotylation followed by a catalytic asymmetric reac-
tion without recourse to functional group adjustments. Con-
sidering the prevalence of 2-methyl-1,3-diol motifs in natural
products and biologically interesting compounds, the meth-
od should find broad applications in organic synthesis.
Ir(I)-catalyzed decarboxylative double diastereoselec-
tive allylic etherification of 2 was also conducted with
phosphoramidite ligand ent-L* under otherwise identical
conditions, and the results are shown in Table 3. Again,
high yields and diastereoselectivities were observed in all
cases except for the o-chlorophenyl substrate (entry 8),
which suffered from modest yield. Compared with o-tolyl
and p-chlorophenyl substrates that gave a good branched
to linear ratio and reaction yield, these results are surpris-
ing and the reason is not clear. The use of ent-L* reversed
Acknowledgment. Research reported in this publication
was supported by the National Science Foundation (CHE
0911134).
Supporting Information Available. Experimental pro-
cedures and spectroscopic data for all new compounds.
This material is available free of charge via the Internet
at http://pubs.acs.org.
(12) Welter, C.; Koch, O.; Lipowsky, G.; Helmchen, G. Chem.
Commun. 2004, 896–897.
(11) Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R. Angew.
Chem., Int. Ed. 1985, 24, 1–30.
The authors declare no competing financial interest.
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