Diastereoselective, three-component cascade synthesis of tetrahydrofurans and tetrahydropyrans employing the tandem Mukaiyama aldol-lactonization process

Article abstract of DOI:10.1021/jo801604k

(Chemical Equation Presented) A full account of studies leading to the development of a cascade sequence that generates as many as two C-C bonds, one C-O bond, and three new stereocenters providing substituted tetrahydrofurans (THFs) from simple γ-ketoaldehydes and thiopyridyl ketene acetals is described. The process involves a tandem Mukaiyama aldol-lactonization (TMAL) and accumulated evidence suggests the intermediacy of a silylated β-lactone that is intercepted by the pendant ketone. Formation of a cyclic oxocarbenium is followed by reduction with silicon-based nucleophiles leading to a highly diastereoselective synthesis of tetrahydrofurans. This cascade process has now been extended to the synthesis of tetrahydropyrans from simple δ-ketoaldehydes. The stereochemical outcome of the cascade processes described was determined by NOE correlations, coupling constant analysis, and X-ray crystallography of the derived oxygen heterocycles and is in accord with established and recently proposed models for nucleophilic additions to cyclic 5- and 6-membered oxocarbenium ions. The utility of this process was demonstrated by the synthesis of the tetrahydrofuran fragment of colopsinol B.

Full text of DOI:10.1021/jo801604k

Diastereoselective, Three-Component Cascade Synthesis of
Tetrahydrofurans and Tetrahydropyrans Employing the Tandem
Mukaiyama Aldol-Lactonization Process†
T. Andrew Mitchell, Cunxiang Zhao, and Daniel Romo*
Department of Chemistry, Texas A&M UniVersity, P.O. Box 30012, College Station, Texas 77842-3012
romo@tamu.edu
ReceiVed July 22, 2008
A full account of studies leading to the development of a cascade sequence that generates as many as
two C-C bonds, one C-O bond, and three new stereocenters providing substituted tetrahydrofurans
(THFs) from simple γ-ketoaldehydes and thiopyridyl ketene acetals is described. The process involves
a tandem Mukaiyama aldol-lactonization (TMAL) and accumulated evidence suggests the intermediacy
of a silylated ꢀ-lactone that is intercepted by the pendant ketone. Formation of a cyclic oxocarbenium is
followed by reduction with silicon-based nucleophiles leading to a highly diastereoselective synthesis of
tetrahydrofurans. This cascade process has now been extended to the synthesis of tetrahydropyrans from
simple δ-ketoaldehydes. The stereochemical outcome of the cascade processes described was determined
by NOE correlations, coupling constant analysis, and X-ray crystallography of the derived oxygen
heterocycles and is in accord with established and recently proposed models for nucleophilic additions
to cyclic 5- and 6-membered oxocarbenium ions. The utility of this process was demonstrated by the
synthesis of the tetrahydrofuran fragment of colopsinol B.
Introduction
are the most commonly encountered of the cyclic ethers, THFs6
and THPs7 have received extensive attention from the synthetic
community, and approaches to these heterocycles can be divided
into three major strategies (Figure 1). Furthermore, multi-
component cascade, tandem, or domino processes that form
The synthesis of saturated cyclic ethers represents one of the
most vibrant research areas in organic chemistry and has a rich
history within the realm of natural products. The synthesis of
epoxides, oxetanes, tetrahydrofurans (THFs), tetrahydropyrans
(THPs), and medium-ring ethers have all played important roles
in the total synthesis of natural products and are common
moieties in some of the most bioactive natural products
discovered thus far including the epothilones,1 taxanes,2 hat-
erumalides,3 altohyrtins,4 and brevetoxins.5 Perhaps since they
(6) (a) For a recent review of THF synthesis, see: Wolfe, J. P.; Hay, M. B.
Tetrahedron 2007, 63, 261. For selected recent examples, see: (b) Brovetto, M.;
Seoane, G. J. Org. Chem. 2008, 73, 5776. (c) Parsons, A. T.; Campbell, M. J.;
Johnson, J. S. Org. Lett. 2008, 10, 2541. (d) Donohoe, T. J.; Williams, O.;
Churchill, G. H. Angew. Chem., Int. Ed. 2008, 47, 2869. (e) Shi, M.; Lu, J.-M.
J. Org. Chem. 2008, 73, 2206. (f) Jervis, P. J.; Kariuki, B. M.; Cox, L. R.
Tetrahedron Lett. 2008, 49, 2514. (g) Xu, L.; Huang, X. Tetrahedron Lett. 2008,
49, 500. (h) Nasveschuk, C. G.; Rovis, T. J. Org. Chem. 2008, 73, 612. (i) Kim,
S.-H.; Oh, S.-J.; Ho, P.-S.; Kang, S.-C.; O, K.-J.; Yu, C.-M. Org. Lett. 2008,
10, 265. (j) Colobert, F.; Choppin, S.; Ferreiro-Mederos, L.; Obringer, M.; Arrata,
S. L.; Urbano, A.; Carreno, M. C. Org. Lett. 2007, 9, 4451. (k) Rajender, A.;
Gais, H.-J. Org. Lett. 2007, 9, 579. (l) Bernard, A. M.; Frongia, A.; Guillot, R.;
Piras, P. P.; Secci, F.; Spiga, M. Org. Lett. 2007, 9, 541. (m) Alcaide, B.;
Almendros, P.; del Campo, T. M. Angew. Chem., Int. Ed. 2007, 46, 6684. (n)
Desai, L. V.; Sanford, M. S. Angew. Chem., Int. Ed. 2007, 46, 5737. (o) Solorio,
D. M.; Jennings, M. P. J. Org. Chem. 2007, 72, 6621. (p) Jahn, U.; Rudakov,
D. Org. Lett. 2006, 8, 4481. (q) Marshall, J. A.; Mikowski, A. M. Org. Lett.
2006, 8, 4375. (r) Chavre, S. N.; Choo, H.; Cha, J. H.; Pae, A. N.; Choi, K. I.
Org. Lett. 2006, 8, 3617. (s) Blanc, A.; Toste, F. D. Angew. Chem., Int. Ed.
2006, 45, 2096. (t) Reddy, L. V. R.; Roy, A. D.; Roy, R.; Shaw, A. K. Chem.
Commun. 2006, 3444. (u) Barbasiewicz, M.; Makosza, M. Synthesis 2006, 1190.
† In memory of Prof. A. I. Meyers: mentor, friend, and a father of asymmetric
synthesis.
(1) For a review of epothilones, see: Nicolaou, K. C.; Ritzen, A.; Namoto,
K. Chem. Commun. 2001, 1523.
(2) For a review of taxanes, see: Nicolaou, K. C.; Dai, W.-M.; Guy, R. K.
Angew. Chem., Int. Ed. 1994, 33, 15.
(3) For a lead reference to the haterumalides, see: Schomaker, J. M.; Borhan,
B. J. Am. Chem. Soc. 2008, 130, 12228, and references cited therein.
(4) For a review of altohyrtins (spongistatins) and other marine macrolides,
see: Yeung, K. S.; Paterson, I. Chem. ReV. 2005, 105, 4237.
(5) For reviews of brevetoxin and other polycyclic ether marine toxins, see:
(a) Nakata, T. Chem. ReV. 2005, 105, 4314. (b) Inoue, M. Chem. ReV. 2005,
105, 4379.
9544 J. Org. Chem. 2008, 73, 9544–9551
10.1021/jo801604k CCC: $40.75 2008 American Chemical Society
Published on Web 11/16/2008

Cascade Synthesis of Tetrahydrofurans and -pyrans
SCHEME 1. Divergent Product Distribution in the
ZnCl2-Mediated Tandem Mukaiyama Aldol-Lactonization
(TMAL) Process
FIGURE 1. General strategies toward tetrahydrofurans and tetrahy-
dropyrans.
SCHEME 2. Mead Reductive Cyclization of Keto-ꢀ-lactones
5/6 toward THFs 7 and THP 8
complex THFs and THPs from simple starting materials in a
single reaction mixture have become more prevalent in recent
years.8
We have previously described both diastereo- and enatiose-
lective methods for ꢀ-lactone synthesis and their utility as
strained heterocycles toward a variety of other useful moieties.9
In the course of optimizing the ZnCl2-mediated tandem Mu-
kaiyama10 aldol-lactonization (TMAL),11 we observed diver-
gent product distributions based solely on the size of the silyl
group of the thiopyridyl ketene acetal leading to either ꢀ-lactones
3 or ꢀ-chloro acids 4 (Scheme 1).12 This and other observations
led us to propose the intermediacy of a silylated ꢀ-lactone in
these reactions.13 Related to the reductive cyclization of
SCHEME 3. Tandem Three-Component Synthesis of THFs
13 and THPs 14
(7) (a) For a recent review of THP synthesis toward natural products, see:
Clarke, P. A.; Santos, S. Eur. J. Org. Chem. 2006, 2045. For selected recent
examples, see: (b) De Brabander, J. K.; Liu, B.; Qian, M. Org. Lett. 2008, 10,
2533. (c) Lee, H.; Kim, K. W.; Park, J.; Kim, H.; Kim, S.; Kim, D.; Hu, X.;
Yang, W.; Hong, J. Angew. Chem., Int. Ed. 2008, 47, 4200. (d) Lu, L.-Q.; Xing,
X.-N.; Wang, X.-F.; Ming, Z.-H.; Wang, H.-M.; Xiao, W. J. Tetrahedron Lett.
2008, 49, 1631. (e) Kartika, R.; Taylor, R. E. Angew. Chem., Int. Ed. 2007, 46,
6874. (f) Yadav, J. S.; Reddy, B. V. S.; Kumar, G. G. K. S. N.; Reddy, G. M.
Tetrahedron Lett. 2007, 48, 4903. (g) Tian, G.-Q.; Shi, M. Org. Lett. 2007, 9,
2405. (h) Lee, H. G.; Lysenko, I. L.; Cha, J. K. Angew. Chem., Int. Ed. 2007,
46, 3326. (i) Liu, F.; Loh, T. P. Org. Lett. 2007, 9, 2063. (j) Chan, K.-P.; Seow,
A.-H.; Loh, T. P. Tetrahedron Lett. 2007, 48, 37. (k) Epstein, O. L.; Rovis, T.
J. Am. Chem. Soc. 2006, 128, 16480. (l) Jervis, P. J.; Kariuki, B. M.; Cox, L.
Org. Lett. 2006, 8, 4649. (m) Kawai, N.; Lagrange, J.-M.; Ohmi, M.; Uenishi,
J. J. Org. Chem. 2006, 71, 4530. (n) Puglisi, A.; Lee, A.-L.; Schrock, R. R.;
Hoveyda, A. H. Org. Lett. 2006, 8, 1871. (o) Bolla, M. L.; Patterson, B.;
Rychnovsky, S. D. J. Am. Chem. Soc. 2005, 127, 16044. (p) Trost, B. M.; Yang,
H.; Wuitschik, G. Org. Lett. 2005, 7, 4761.
(8) For reviews of tandem reactions, see: (a) Domino Reactions in Organic
Synthesis, Tietze, L. F., Bell, H. P., Brasche, G., Eds.; Wiley-VCH: Weinheim,
2006. (b) Enders, D.; Grondal, C.; Huttl, M. R. M. Angew. Chem., Int. Ed. 2007,
46, 1570. (c) Nicolaou, K. C.; Montagnon, T.; Snyder, S. A. Chem. Commun.
2003, 551. (d) Tietze, L. Chem. ReV. 1996, 96, 115. (e) Tietze, L.; Beifuss, U.
Angew. Chem., Int. Ed. 1993, 32, 131.
(9) For reviews of ꢀ-lactone synthesis and applications, see: (a) Wang, Y.;
Tennyson, R. L.; Romo, D. Heterocycles 2004, 64, 605. (b) Yang, H. W.; Romo,
D. Tetrahedron 1999, 55, 6403. (c) Lowe, C.; Vederas, J. C. Org. Prep. Proced.
Int. 1995, 27, 305. (d) Pommier, A.; Pons, J.-M. Synthesis 1995, 729. (e)
Pommier, A.; Pons, J.-M. Synthesis 1993, 441. For selected recent examples,
see (f) Donohoe, T. J.; Sintim, H. O.; Sisangia, L.; Harling, J. D. Angew. Chem.,
Int. Ed. 2004, 43, 2293. (g) Getzle, Y. D. Y. L.; Kundnani, V.; Lobkovsky,
E. B.; Coates, G. W. J. Am. Chem. Soc. 2004, 126, 6842. (h) Calter, M. A.;
Tretyak, O. A.; Flaschenriem, C. Org. Lett. 2005, 7, 1809. (i) Mitchell, T. A.;
Romo, D. Heterocycles 2005, 66, 627. (j) Shen, X.; Wasmuth, A. S.; Zhao, J.;
Zhu, C.; Nelson, S. G. J. Am. Chem. Soc. 2006, 128, 7438. (k) Henry-Riyad,
H.; Lee, C.; Purohit, V. C.; Romo, D. Org. Lett. 2006, 8, 4363. (l) Reddy, L. R.;
Corey, E. J. Org. Lett. 2006, 8, 1717. (m) Bottcher, T.; Sieber, S. A. Angew.
Chem., Int. Ed. 2008, 47, 4600. (n) Kull, T.; Peters, R. Angew. Chem., Int. Ed.
2008, 47, 5461.
epoxyketones leading to THFs reported by Chamberlin,14 Mead
reported an entry to THFs 715 from keto-ꢀ-lactones 5 and a
single example of a THP 816 from benzyloxy-substituted keto-
ꢀ-lactone 6 (Scheme 2). We envisioned the possibility of
combining the TMAL process with a subsequent Mead-type
reductive cyclization of the presumed silylated-ꢀ-lactone inter-
mediate 11 toward a highly diastereoselective, three-component,
cascade synthesis of THFs 13 and THPs 14 from ketoaldehydes
(()-9-10, thiopyridyl ketene acetals 2, and silicon-based
nucleophiles (Scheme 3). High diastereoselectivity was expected
based on stereoelectronic models recently developed by Woerpel
for nucleophilic additions to 5-membered cyclic oxocarbeni-
ums17 and established and recently refined models for 6-mem-
bered oxocarbeniums.18 The development of such a cascade
(14) (a) Mulholland, R. L.; Chamberlin, A. R. J. Org. Chem. 1988, 53, 1082.
(b) Fotsh, C. H.; Chamberlin, A. R. J. Org. Chem. 1991, 56, 4141.
(15) (a) Mead, K. T.; Pillai, S. K. Tetrahedron Lett. 1993, 34, 6997. (b)
For a related process utilizing keto-ꢀ-lactones derived from the TMAL, see
ref 11g.
(16) White, D.; Zemribo, R.; Mead, K. T. Tetrahedron Lett. 1997, 38, 2223.
(17) (a) Larsen, C. H.; Ridgway, B. H.; Shaw, J. T.; Woerpel, K. A. J. Am.
Chem. Soc. 1999, 121, 12208. (b) Larsen, C. H.; Ridgway, B. H.; Shaw, J. T.;
Smith, D. M.; Woerpel, K. A. J. Am. Chem. Soc. 2005, 127, 10879. For an
earlier oxocarbenium addition model, see: (c) Schmitt, A.; Reissig, H.-U. Chem.
Ber. 1995, 128, 871.
(18) For early work with 6-membered cyclic iminium ions, see: (a) Stevens,
R. V.; Lee, A. W. M. J. Am. Chem. Soc. 1979, 101, 7032. (b) Stevens, R. V.
Acc. Chem. Res. 1984, 17, 289. For 6-membered cyclic oxocarbenium ions, see:
(c) Deslongchamps, P. Stereoelectronic Effects in Organic Chemistry; Pergamon:
New York, 1983; pp 209-221. (d) Ayala, L.; Lucero, C. G.; Romero, J. A. C.;
Tabacco, S. A.; Woerpel, K. A. J. Am. Chem. Soc. 2003, 125, 15521. (e) Lucero,
C. G.; Woerpel, K. A. J. Org. Chem. 2006, 71, 2641.
(10) (a) Mukaiyama, T.; Narasaka, K.; Banno, K. Chem. Lett. 1973, 1011–
1014. (b) Mukaiyama, T.; Banno, T.; Narasaka, K. J. Am. Chem. Soc. 1974, 96,
7503–7509. (c) Heathcock, C. H. Science 1981, 214, 395–400. (d) Mukaiyama,
T. Aldrichim. Acta 1996, 29, 59–76.
(11) (a) Yang, H. W.; Romo, D. J. Org. Chem. 1997, 62, 4. (b) Yang, H. W.;
Zhao, C.; Romo, D. Tetrahedron 1997, 53, 16471. (c) Yang, H. W.; Romo, D.
J. Org. Chem. 1998, 63, 1344. (d) Schmitz, W. D.; Messerschmidt, B.; Romo,
D. J. Org. Chem. 1998, 63, 2058. (e) Wang, Y.; Romo, D. Org. Lett. 2002, 4,
3231. (f) Cho, S. W.; Romo, D. Org. Lett. 2007, 9, 1537. (g) Mitchell, T. A.;
Romo, D. J. Org. Chem. 2007, 72, 9053.
(12) Mitchell, T. A.; Zhao, C.; Romo, D. Angew. Chem., Int. Ed. 2008, 47,
5026, and references cited therein.
(13) For a related proposed silylated ꢀ-lactone in a SnCl4-mediated synthesis
of cis-ꢀ-lactones, see: Wang, Y.; Zhao, C.; Romo, D. Org. Lett. 1999, 1, 1197.
J. Org. Chem. Vol. 73, No. 24, 2008 9545

Mitchell et al.
TABLE 1. Optimization of the Cascade, Three-Component
SCHEME 4. Preparation of Ketoaldehyde Substrates (()-9
and 10 for the Cascade Process
Process with r-Benzyloxy-γ-Ketoaldehyde (()-9a Leading to
Tetrahydrofuran 19a
ZnCl2
(E)-2c
ratio 19a/20aa
entry (equiv) (equiv) Et3SiH (equiv) T (°C) (% yield of 19a)b
1
2
3
4
5
6
7
8
9
10
2.0
2.0
2.0
2.0
4.0
4.0
4.0
4.0
8.0
4.0
2.0
2.0
2.0
1.2
1.2
1.2
1.2
1.2
1.2
1.2
10.0
0.0
23
23
0 f 23
23
0 f 23
23
0 f 23
0 f 23
0 f 23
0
1.0/3.5 (9)
20a only (0)
1.0/2.0 (24)
1.2/1.0 (ND)c
2.0/1.0 (42)
6.7/1.0 (40)
6.2/1.0 (50)
1.0/3.5 (10)d
9.0/1.0 (38)
6.2/1.0 (54)
10.0
10.0
10.0
50.0
50.0
50.0
100.0
50.0
a Estimated by crude 1H NMR (300 MHz) analysis of the
corresponding silyl esters. b Isolated yield over two steps. c Not
determined. d No precoordination between ketene acetal (E)-2a and
ZnCl2 was utilized in this reaction.
process was attractive since overall it could lead to the
generation of up to two C-C bonds, one C-O bond, and three
additional stereocenters. In a preliminary communication, we
recently reported the realization of this three-component cascade
sequence for THF synthesis, and herein, we provide a full
account of our development of this process and its application
to a colopsinol B fragment.12 In addition, we describe an
extension of this cascade process to the synthesis of tetrahy-
dropyrans, which in fact are found to proceed with greater
efficiency.
2, prepared according to known procedures,11 were utilized
instead of the corresponding tert-butyldiphenylsilyl (TBDPS)
thiopyridyl ketene acetals (i.e., 2b, Scheme 1) due to the relative
ease of preparation and initial success in the tandem process as
described below.23
Synthesis of Tetrahydrofurans via the Tandem Mukai-
yama Aldol-Lactonization/Mead Reductive Cyclization
Cascade Process. We began our studies of the cascade process
using ketene acetal (E)-2c (4:1), Et3SiH, and R-benzyloxy-ꢀ-
ketoaldehyde (()-9a, a substrate we predicted would give high
diastereoselectivity for both the TMAL process and subsequent
reductive cyclization (Table 1).12 Building on our previous
studies of the TMAL process with aldehydes bearing pendant
nucleophiles, a solution of ketene acetal (E)-2c in CH2Cl2 was
added to freshly fused ZnCl2 and stirred for 4 h until a
homogeneous solution resulted, in order to modulate the Lewis
acidity and increase the rate of the desired TMAL process.24
Initial results with these “precoordination” conditions provided
a complex reaction mixture that included silyl esters (i.e., 13,
Results and Discussion
Preparation of Ketoaldehyde Substrates (()-9 and 10. The
preparation of racemic ketoaldehydes (()-9 and 10 was
performed using straightforward known procedures (Scheme 4).
Initial attempts to rapidly access R-benzyloxy-γ-ketoaldehyde
(()-9a via ozonolysis of the corresponding bis-olefin (not
shown)19 were thwarted by difficulties in purification following
ozonolysis. Our second approach involving a double Swern
oxidation of a diol was more tractable, albeit significantly longer
(Scheme 4, eq 1). Beginning with aldehyde 15, standard
procedures were utilized20 to access diols 16a-g and following
Swern oxidation provided ketoaldehydes (()-9a-g.21 In contrast
to the difficulty in obtaining pure R-benzyloxy-γ-ketoaldehyde
(()-9a via ozonolysis, ꢀ-silyloxy-γ-ketoaldehydes (()-9h,i
derived from methacrolein 17 could be accessed via this
procedure (Scheme 4, eq 2). Successful ozonolysis in these cases
is in part due to the fact that the ketoaldehydes bearing bulky
silicon protecting groups were found to be more stable than
R-benzyloxy-γ-ketoaldehydes (()-9a-g and less susceptible to
the formation of inseparable byproduct. R-Benzyloxy-δ-ketoal-
dehyde (()-10 was prepared from cyclic enone 18 by a three-
step sequence involving Luche reduction,22 benzyl protection,
and ozonolysis (Scheme 4, eq 3). Although ketoaldehydes (()-9
and 10 could be stored neat at ∼10 °C for several weeks without
degradation, we typically stored larger quantities of the more
stable, immediate precursors and performed the final oxidations
to deliver substrates for the cascade process immediately prior
to use. Finally, triisopropylsilyl (TIPS) thiopyridyl ketene acetals
1
Scheme 3) as minor products (as judged by crude H NMR).
However, several attempts to separate these silyl esters25 or the
corresponding carboxylic acids following desilylation proved
challenging.13 Eventually, we determined that isolation was best
accomplished following reduction of the crude reaction mixture
with DIBAl-H which simplified isolation of THF alcohol 19a,
albeit in only 9% yield under these initial conditions ac-
companied by the volatile furan 20a (Table 1, entry 1).
Regardless of the relative amount of Et3SiH added (2-50 equiv),
no improvement in the ratio of THF 19a to furan 20a could be
obtained, and a control experiment revealed that not adding
triethylsilane led to exclusive formation of the furan 20a as
expected (entry 2). This suggested that the TMAL process was
proceeding efficiently but an intervening, competitive aroma-
tization process was decreasing the yield of the desired THF.
Lowering the reaction temperature to 0 °C led to an increase in
(23) Early comparisons between TIPS ketene acetal (E)-2c and the corre-
sponding TBDPS ketene acetal indicated that optimal yields were obtained with
the former reagent.
(24) Zhao, C. Ph. D. Dissertation, Texas A&M University, 1999.
(25) For an example of the stability and utility of several triisopropylsilyl
esters, see: Lowe, J. T.; Wrona, I. E.; Panek, J. S. Org. Lett. 2007, 9, 327.
(19) For the ozonolysis of similar bis-olefins, see: Molander, G. A.; Cameron,
K. O. J. Am. Chem. Soc. 1993, 115, 830.
(20) See the Supporting Information for details.
(21) Denmark, S. E.; Fu, J. Org. Lett. 2002, 4, 1951.
(22) Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226.
9546 J. Org. Chem. Vol. 73, No. 24, 2008

Cascade Synthesis of Tetrahydrofurans and -pyrans
TABLE 2. Three-Component Synthesis of THFs 19b-g from
r-Benzyloxy-γ-ketoaldehydes (()-9b-g
the relative amount of THF 19a, although furan 20a remained
the major product (entry 3). This was unexpected since the
TMAL process does not typically proceed below 23 °C, and
this may be due to the increased electrophilicity of the aldehyde
due to either inductive effects of the benzyloxy substituent or
bidentate chelation with the aldehyde.15b Increasing the ratio
of Lewis acid to ketene acetal had the most profound effect
and finally delivered THF 19a as the major product (entries 4
and 5). When these conditions were combined with a large
excess of Et3SiH at ambient temperature, crude 1H NMR
analysis indicated an improved ratio, but the isolated yield of
THF 19a did not improve (entry 6). Upon lowering the
temperature with a large excess of both ZnCl2 and Et3SiH, the
desired THF 19a could be isolated in 50% yield (entry 7). As
expected, if “precoordination” conditions were not used, the ratio
decreased dramatically (entry 8). Utilizing 8.0 equiv of ZnCl2
and 100 equiv of Et3SiH provided the best ratio but lower
isolated yield of THF 19a (entry 9). In several conditions
wherein an improved ratio (19a/20a) was obtained as determined
by crude 1H NMR analysis (i.e., entries 6 and 9), several minor
and unidentified byproducts were also produced. Finally, optimal
conditions were achieved by maintaining the reaction temper-
ature at 0 °C for 12 h to deliver THF 19a in 54% yield, and
this corresponds to an average of ∼86% yield per step over the
four steps involving aldol reaction, lactonization, reductive
cyclization, and DIBAlH reduction (entry 10).
Applying the cascade process to R-benzyloxy-γ-ketoalde-
hydes (()-9b-g and ketene acetal (E)-2c delivered THFs
19b-g with consistently high diastereoselectivity (>19:1) and
generally in moderate (42-54%) yields with one exception
(entry 4) accompanied by lesser amounts of furans 20b-g
(Table 2).26 In general, greater steric bulk of the ketone
substituent appears to inhibit the production of the desired THF
and increase formation of the furan. This observation is
consistent with increased steric interactions with Et3SiH during
the reduction step with larger substituents enabling presumed
elimination processes, which led to furan byproduct, to become
more competitive. In the case of the phenyl substituted ketoal-
dehyde (()-9e, the desired THF 19e was obtained in only 13%
yield along with 48% of furan 20e (entry 4). While steric
interactions may also lead to reduced yields in this case,
stabilization of the oxocarbenium intermediate and greater
conjugation achieved during elimination in route to furan 20e
likely also contribute to diminished yields.
a Determined by crude 1H NMR (300 MHz) analysis. b Isolated yield
over two steps including the cascade process and DIBAlH reduction.
Yields in parentheses correspond to estimated yields of volatile furans
20. c Not determined. d In this case, it was necessary to maintain the
DIBAlH reduction at -78 °C and slowly warm to -30 °C to prevent
cleavage of the PMB group.
SCHEME 5. Synthesis of THFs 19h,i from
ꢀ-Silyloxy-γ-ketoaldehydes (()-9h,i via the Cascade Process
Employing ꢀ-silyloxy-γ-ketoaldehydes (()-9 h,i as substrates
in the cascade process led to lower yields of THFs 19h,i and
isolation of new byproducts, THFs 21a,b (Scheme 5). Ketoal-
dehyde (()-9h and ketene acetal (E)-2c (E/Z, >19:1)27 under
slightly modified reaction conditions delivered the desired THF
19h in low yield but good diastereoselectivity (dr, 9:1) and THF
21a. When the bulky, R-oxygenated ketene acetal (Z)-2d (>19:
1) was utilized, only 5% yield of the desired THF 19i was
isolated along with 40% of THF 21b. These byproducts
presumably arise from self-condensation and reduction of the
ketoaldehyde substrates 9h,i without incorporation of ketene
acetals (E)-2c and (Z)-2d, respectively.
Use of the acetate ketene acetal 2e provided THF 19j in good
yield but with poor diastereoselectivity as expected.11c Related
to the strategy of Evans,28 a masked acetate aldol in the form
of thiophenyl ketene acetal (E)-2f (E/Z, 2:1) delivered THF 19k
in excellent diastereoselectivity but with diminished yield
(Scheme 6). The low yield in this case and also with several
other R-heteroatom substituted ketene acetals (i.e., R-SMe, OMe,
OTBS, OTBDPS) is likely due to rate-retardation of the TMAL
process enabling the side-reaction leading to production of
simple THFs (i.e., 21c) to be more competitive. Thus, we
observed an inverse relationship between the size of the
R-substituent of the ketene acetal and the yield of THF, which
is consistent with our previous studies of the TMAL process.11e
Allyltrimethylsilane was also studied as a nucleophile, and
under standard conditions, THF 19l was isolated as a single
Variations of the ketene acetal were also explored with a
desire to incorporate an acetate aldol into the cascade process.
(26) Due to difficulties arising from either volatility or purification of furans
20b-g, the yields are reported as estimates.
(27) Pure (E)-2c (>19:1) is required with ꢀ-silyloxy aldehydes in order to
obtain maximum diastereoselectivity in the TMAL; see refs 11a and 11b.
(28) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103,
2127.
J. Org. Chem. Vol. 73, No. 24, 2008 9547

Mitchell et al.
TABLE 3. Optimization of the Cascade, Three-Component
Process to Tetrahydropyrans
SCHEME 6. Variation of the the Ketene Acetal 2 with
Ketoaldehyde (()-9 in the Cascade Process
entry ZnCl2 (equiv) Et3SiH (equiv) ratio 22a/23a % yield of 22ab
1
2
3
4
5
4.0
1.5
1.5
2.0
2.0
50.0
0.0
1.5
2.0
10.0
4:1
NDc
34
3:1
20:1
>20:1
68d
75
∼75e
a Determined by crude 1H NMR (500 MHz) analysis. b Isolated yield
after flash column chromatography. c Not determined. d Combined yield
of 22a and 23. e Contaminated with minor inseparable byproduct.
SCHEME 7. Use of Allyltrimethylsilane as Nucleophile in
the Cascade Process Leading to Allyl THF 19l
SCHEME 9. Conversion of THP 22a to Methyl Ester 24
and p-Bromobenzoate 25
SCHEME 8. Synthesis of the Tetrahydrofuran Fragment
19m of Colopsinol B via the Cascade Process
Synthesis of Tetrahydropyrans via the Tandem Mukai-
yama Aldol-Lactonization/Mead Reductive Cyclization.
Brief studies with R-benzyloxy-δ-ketoaldehyde (()-10 indicate
that this cascade process is also applicable toward THP synthesis
and is, in fact, more efficient (Table 3). Minimal optimization
was required due to our previous extensive investigations toward
THFs (cf. Table 1). Application of optimal conditions identified
for THF synthesis gave a 4:1 ratio (entry 1) of THP 22a and a
dihydropyran (DHP) byproduct 23. A control experiment
without addition of Et3SiH produced the DHP 23 in 34% yield
(entry 2). Upon reducing the equivalents of ZnCl2 and Et3SiH,
low selectivity was again observed; however, the total yield of
the inseparable THP and DHP was 68% (entry 3). Optimal
conditions were eventually found and gave the desired THP
22a in 75% yield as the major product in a highly diastereo-
selective fashion (dr, 16:1) with minimal DHP 23 (entry 4).
Increasing the amount of Et3SiH to 10 equiv did not improve
the yield further and led to trace amounts of inseparable
byproduct. Due to the efficiency of this process, it was possible
to isolate the initially formed TIPS esters in contrast to the THF
synthesis. While triisopropylsilyl esters are known to be stable
to silica gel,25 we found that rapid purification was necessary
to prevent desilylation. The TIPS ester 22a is readily converted
to the corresponding methyl ester 24 by standard Fisher
esterification (Scheme 9). In an attempt to further verify the
relative stereochemistry of THP 22a via X-ray crystallographic
analysis, DIBAlH reduction and acylation delivered the p-
bromobenzoate 25 in good yield. Unfortunately, this derivative
was not crystalline. Allyltrimethylsilane (10 equiv) was also
explored and gave a partially separable mixture of THP 22b
and DHP 23 (60%, combined yield) (Scheme 10).20 Use of
fewer equivalents of allyltrimethylsilane gave approximately
equimolar quantities of THP 22b to DHP 23, while alternative
allyl transfer reagents and nucleophiles including allyltriph-
diastereomer, albeit in reduced yield (Scheme 7). Greater
quantities of the typical side-product, furan 20a, are produced
and this likely reflects the slower addition of this nucleophile
to the oxocarbenium. However it is important to note that an
additional C-C bond is constructed with high stereocontrol of
the resulting quaternary center. TMSCN was also studied briefly
but gave a complex reaction mixture.
To highlight the utility of this methodology, we targeted the
THF fragment of the DNA polymerase inhibitor, colopsinol B,
isolated from the dinoflagellate Amphidinium and structurally
related to the amphidinolides (Scheme 8).29 To date, only the
relative stereochemistry of the THF and THP rings has been
determined by NOE and ROESY correlations and 1H-1H
coupling constants, and given that no previous synthetic studies
toward this natural product have been reported, this became an
interesting target for application of the cascade process. Under
typical conditions with ketene acetal 2e and R-benzyloxy-γ-
ketoaldehyde (()-9g, alcohols 19m were obtained following
DIBALH reduction as a mixture of diastereomers as observed
previously with ketene acetal 2e (Scheme 7). The major
diastereomer was separable and was isolated in 23% yield (two
steps). The relative stereochemistry was deduced from coupling
constant and NOE analysis and correlated well with THF 19j
(Scheme 6) and with data reported for colopsinol B.20
(29) Kubota, T.; Tsuda, M.; Takahashi, M.; Ishibashi, M.; Naoki, H.;
Kobayashi, J. J. Chem. Soc., Perkin Trans. 1 1999, 3483.
9548 J. Org. Chem. Vol. 73, No. 24, 2008

Cascade Synthesis of Tetrahydrofurans and -pyrans
TABLE 4. Representative NOE Enhancements and Coupling
Constants for Representative Tetrahydrofurans
SCHEME 10. Synthesis of Allyl Tetrahydropyran 22b via
the Cascade Process from Ketoaldehyde (()-10
SCHEME 11. Attempted Synthesis of an Oxepane from
Ketoaldehyde (()-26 via the Cascade Process
19a: mult
(J (Hz))a
19h: mult
(J (Hz))a
19l: mult
(J (Hz))a
proton(s)
A
B
C
C′
D
D′
E
d (6.0)
ddq (5.5, 6.0, 10.0) dq (6.5,6.5)
ddd (2.0, 5.5, 13.0) ddd (3.5, 6.5, 7.0) dd (4.5, 13.0)
ddd (7.0, 10.0, 13.0) NAb
dd (7.0, 13.0)
d (6.5)
s (NA)b
ddc (7.5, 13.5)
ddd (2.0, 4.0, 7.0)
ddd (7.0, 9.5, 13.0) ddd (4.5, 5.5, 7.0)
NAb
ddd (3.5, 6.5, 13.0) NAb
enylsilane, allyltributylstannane, and 1,3-dimethoxybenzene
produced complex reaction mixtures.
dd (4.0, 5.0)
m (NA)b
d (7.0)
ddd (5.0, 6.5, 9.5) dd (5.0, 5.5)
F
G
m (NA)b
d (7.0)
m (NA)b
d (7.5)
Finally, in efforts to define the limits of this cascade process,
we targeted a substrate (()-26 that would lead to an oxepane if
successful.30 As expected, even after gentle warming, oxepane
28 was not observed, however, the keto-ꢀ-lactone 27 could be
isolated in useful yields (70%) resulting from only the TMAL
portion of this cascade process (Scheme 11).
a Determined by 1H NMR (500 MHz) analysis. b Not applicable.
c Only one dd is provided here.20
TABLE 5. NOE Correlations and Coupling Constants for
Representative Tetrahydropyrans
Stereochemical Determination of Tetrahydrofurans and
Tetrahydropyrans Synthesized via the Tandem, Three-
Component Process. The stereochemical outcome of the
TMAL portion of this cascade process is in accord with previous
diastereoselectivities observed with R-benzyloxy and ꢀ-silyloxy
substrates,11 while that of the subsequent reductive cyclization15
sequence is in accord with that previously observed in our
stepwise THF synthesis11g and is consistent with established
and recent models for additions to cyclic oxocarbenium ions.17,18
Extensive NOE enhancements, coupling constant analysis, and
X-ray crystallography were used to assign the relative stereo-
chemistry of the tetrahydrofurans and tetrahydropyrans obtained
via the cascade process. Whereas THPs adopt readily predictable
low energy chair conformations simplifying coupling constant
analysis, the greater conformational mobility of THF rings
makes the most stable envelope conformation more challenging
to predict. Coupling constant analysis supports the relative
stereochemistry shown for representative THFs 19a, 19h, and
19l and NOE enhancements provided further evidence for the
assigned relative stereochemistry (Table 4).31 For example,
JHB,HC′ exhibited a diagnostic coupling constant (J ) 10 Hz) in
THF 19a corresponding to a 1,2-diaxial relationship as ex-
pected.32 However, as expected, the corresponding coupling
constant was not present in THF 19l, yet other relevant coupling
constants maintained a similar range. THF 19h showed a similar
coupling constant (JHD,HE ) 9.5 Hz), and the relative stereo-
chemistry was also supported by NOE enhancements. In
addition, single-crystal X-ray analysis of a p-bromobenzoate
derivative (not shown) derived from acylation of alcohol 19a
provided further evidence for the relative stereochemistry of
this THF.20 Finally, the relative stereochemistry also provides
evidence for the proposed mechanistic pathway (vide infra).
Coupling constant analysis provided evidence for the pro-
posed relative stereochemistry of THPs 22a, 24, and 22b and
22a: mult
(J (Hz))a
24: mult
(J (Hz))a
22b: mult
(J (Hz))a
proton(s)
A
B
C
C′
D
D′
E
F
G
H
d (6.0)
d (6.0)
s (NA)b
ddq (2.0, 6.0, 8.0) ddq (2.5,6.0,8.5)
ddc (8.5,13.5)
m
m
m
m
m
m
m
m
m
m
m
m
ddd (4.5, 9.3, 10.5) ddd (4.5, 9.0, 10.5) ddd (4.5, 9.5, 10.5)
dd (2.8, 9.3)
dq (2.8, 7.0)
d (7.0)
dd (5.0, 9.0)
dq (5.0, 7.5)
d (7.5)
dd (3.0, 9.5)
dq (3.0, 7.0)
d (7.0)
a Determined by 1H NMR (500 MHz) analysis. b Not applicable.
c Only one dd is provided here.20
NOE enhancements gave further confirmation (Table 5). For
example, typical 1,2-diaxial coupling constants were observed
for several key protons including JHB,HC′ (8.0 Hz) and JHD,HE′
,
JHE,HF (10.5 and 9.3 Hz, respectively), pointing to the expected
favored chair conformation adopted by THP 22a. A similar
coupling constant trend was observed for the methyl ester THP
24. Finally, the relative stereochemistry of THP 22b was also
confirmed by typical 1,2-diaxial coupling constants observed
for JHD,HE, JHE,HF (10.5 and 9.5 Hz, respectively) and also NOE
enhancements (HFfHB,B′). In the case of THPs, the newly
generated stereocenter external to the ring is assigned on the
basis of ample precedent from the TMAL and previous
syntheses of THFs.
A plausible mechanism for the synthesis of both THFs and
THPs can be rationalized based on the formation of silylated
ꢀ-lactone 11 from a boat-like transition state arrangement 29
derived from a chelation-controlled TMAL process (Scheme
12, enantiomeric series shown which simplifies drawing of
transition state arrangements).11c,d,g Upon invertive alkyl C-O
cleavage of the silylated ꢀ-lactone 11 by the pendant ketone,
oxocarbenium intermediate 12 is formed and adopts the favored
(30) R-Benzyloxy-ꢀ-ketoaldehyde (()-26 was prepared in an analogous
fashion as R-benzyloxy-δ-ketoaldehyde (()-10. See the Supporting Information
for details.
(31) The relative stereochemistry of other THFs reported herein followed
similar trends; see the Supporting Information for details.
(32) Calculations (MM2) lend support to the proposal that the envelope
conformations displayed in Table 4 are low energy conformations.
J. Org. Chem. Vol. 73, No. 24, 2008 9549

Mitchell et al.
SCHEME 12. Mechanistic Proposals for the Cascade, Three-Component Synthesis of Tetrahydrofurans and Tetrahydropyrans
envelope or half-chair conformation. In the case of THFs (n )
1), envelope conformation 12a is favored as a result of through-
space stabilization of the oxocarbenium by the pseudoaxial
benzyloxy substituent.17a,b THF 13a is obtained via inside attack
of Et3SiH on the favored envelope conformation 12a. In the
case of THPs (n ) 2), nucleophilic addition proceeds through
the stereoelectronically favored half-chair conformation 12b via
axial attack.18 Isolation of byproduct such as furan 30 or DHP
23 is rationalized by E1 elimination via R-deprotonation of the
oxocarbenium likely by the pyridyl moiety of ketene acetal (E)-
2c. Excess ZnCl2 would be expected to deactivate the pyridyl
nitrogen and thereby greatly lower the rate of elimination leading
to increased yields of THF 13a and THP 22a. Isolation of DHP
23 provides evidence for a corresponding dihydrofuran (not
isolated or shown), which undergoes further elimination, driven
by aromaticity, to provide furan 30.
Experimental Section
Representative Procedure for the Swern Oxidation of
Diols As Described for r-Benzyloxy-γ-ketoaldehyde (()-9a. To
a solution of oxalyl chloride (2.6 mL, 29.88 mmol) in CH2Cl2 (50
mL) was added DMSO (4.2 mL, 59.76 mmol) dropwise at -78
°C, and the mixture was stirred for 5 min. To this solution was
added diol 16a (1.57 g, 7.47 mmol) in CH2Cl2 (50 mL), and the
solution was stirred for 15 min, at which time Et3N (16.7 mL,
119.52 mmol) was added and the resulting solution stirred for 2 h
at -78 °C. The reaction was quenched with pH 7 buffer, and the
mixture was stirred vigorously for 30 min and allowed to warm to
23 °C. The mixture was diluted with ether (250 mL), separated
from the aqueous layer, washed with water (3 × 50 mL) and brine
(3 × 50 mL), dried over MgSO4, filtered, and concentrated under
reduced pressure. Purification by flash column chromatography
(hexanes/ethyl acetate 75:25) delivered ketoaldehyde (()-9a (1.28
g, 83%) as a pale yellow oil: Rf ) 0.46 (hexanes/ethyl acetate 30:
70); IR (thin film) 3029, 2719, 1715, 1111 cm-1; H NMR (300
1
MHz, CDCl3) δ 2.19 (s, 3H), 2.84 (dd, J ) 6.6, 17.4 Hz, 1H), 2.91
(dd, J ) 4.8, 17.4 Hz, 1H), 4.26 (ddd, J ) 0.9, 4.8, 6.6 Hz, 1H),
4.66 (d, J ) 11.7 Hz, 1H), 4.73 (d, J ) 11.7 Hz, 1H), 7.30-7.39
(m, 5H), 9.78 (d, J ) 0.9 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ
30.1, 44.3, 73.0, 79.3, 127.9 (2), 128.0, 128.4 (2), 137.1, 202.4,
204.5; ESI-HRMS calcd for C12H14O3Na [M + Na] 229.0841, found
229.0860.
Conclusions
The development of a diastereoselective, three-component
cascade sequence involving the TMAL process is described and
provides an expedient route to tetrahydrofurans and tetrahy-
dropyrans from simple ketoaldehydes, thiopyridyl ketene acetals,
and silyl nucleophiles. This complexity-building process pro-
vides further evidence for silylated ꢀ-lactone intermediates in
the TMAL process and provides further impetus to explore
different nucleophiles to trap this intermediate and access
additional products from these versatile intermediates. The
described process incorporates the TMAL process and Mead’s
reductive cyclization of isolated keto-ꢀ-lactones. The stereo-
chemical outcome of this process is consistent with observed
selectivities of the TMAL process and both established and
recently refined models for nucleophilic additions to 5- and
6-membered oxocarbenium ions. The utility of this method was
demonstrated by a single-step synthesis of the tetrahydrofuran
fragment of colopsinol B from a simple ketoaldehyde. This
methodology should find application in the total synthesis of
THF and THP-containing natural products and diversity-oriented
synthesis. Studies in this direction are ongoing in our laboratories
and will be reported in due course.
Representative Procedure for the Tandem, Three-
Component Synthesis of r-Benzyloxy-γ-ketoaldehydes, Thio-
pyridyl Ketene Acetals, and Silyl Nucleophiles As Described
for Tetrahydrofuran 19a. ZnCl2 (423 mg, 3.10 mmol) was freshly
fused at ∼0.5 mmHg and subsequently cooled to ambient temper-
ature. The ketene acetal (E)-2c (301 mg, 0.93 mmol) was added as
a solution in CH2Cl2 (5 mL) and stirred for 4 h at 23 °C. The
heterogeneous mixture was cooled to 0 °C, Et3SiH (6.3 mL, 38.80
mmol) and R-benzyloxy-γ-ketoaldehyde (()-9a (160 mg, 0.78
mmol) in CH2Cl2 (5 mL) were added sequentially, and the reaction
was stirred for 12 h at 0 °C. The reaction was quenched with pH
7 buffer, stirred vigorously for 30 min, poured over Celite with
1
additional CH2Cl2, and dried with Na2SO4. Crude H NMR (300
MHz) analysis revealed a 6.2:1 ratio of a single diastereomer (>19:
1) of THF to furan silyl esters. Upon concentration under reduced
pressure, the residue was dissolved in CH2Cl2 (20 mL). The
resulting solution was treated with DIBAlH (830 µL, 4.66 mmol)
at -78 °C, warmed to 0 °C quickly, and stirred for 6 h. The reaction
quenched with MeOH (5 mL) at 0 °C dropwise, treated with
9550 J. Org. Chem. Vol. 73, No. 24, 2008

Cascade Synthesis of Tetrahydrofurans and -pyrans
Rochelle’s salt (10 mL), and stirred vigorously for 12 h. The
resulting suspension was poured over Celite and washed with ether
(200 mL). The combined organic solution was washed with satd
aq NH4Cl (2 × 20 mL), water (2 × 20 mL), and brine (2 × 20
mL), dried over MgSO4, filtered, and concentrated under reduced
pressure. Purification by gradient flash column chromatography
(hexanes/ethyl acetate 85:15 to 80:20) delivered THF 19a (104 mg,
54%) as a colorless oil and furan 20a as a pale yellow oil.
Characterization data for THF 19a: Rf ) 0.56 (hexanes/ethyl acetate
60:40); IR (thin film) 3443, 1096, 1058 cm-1; 1H NMR (500 MHz,
CDCl3) δ 0.94 (d, J ) 7.0 Hz, 3H), 1.27 (d, J ) 6.0 Hz, 3H), 1.54
(ddd, J ) 7.0, 10.0, 13.0 Hz, 1H), 1.95-2.03 (m, 1H), 2.11 (ddd,
J ) 2.0, 5.5, 13.0 Hz, 1H), 3.58 (dd, J ) 6.5, 11.0 Hz, 1H), 3.64
(dd, J ) 4.5, 11.0 Hz, 1H), 3.93 (dd, J ) 4.0, 4.5 Hz, 1H), 3.98
(ddd, J ) 2.0, 4.0, 7.0 Hz, 1H), 4.16 (ddq, J ) 5.5, 6.0, 10.0 Hz,
1H), 4.45 (d, J ) 12.0 Hz, 1H), 4.55 (d, J ) 12.0 Hz, 1H),
7.29-7.38 (m, 5H); 13C NMR (125 MHz, CDCl3) δ 12.4, 20.4,
37.8, 40.4, 66.6, 71.6, 74.5, 81.6, 87.9, 127.96 (3), 128.00 (2), 138.0;
ESI-HRMS calcd for C15H22O3Li [M + Li] 251.1647, found
251.1686. Partial characterization data for furan 20a: Rf ) 0.75
(hexanes/ethyl acetate 60:40); 1H NMR (300 MHz, CDCl3) δ 1.26
(d, J ) 6.9 Hz, 3H), 1.57-1.61 (m, 1H), 2.27 (d, J ) 0.9 Hz, 3H),
2.99 (app sext, J ) 6.6, 1H), 3.71 (dd, J ) 5.7, 6.3 Hz, 1H),
5.88-5.89 (m, 1H), 5.97-5.98 (m, 1H).
Representative Procedure for the Tandem, Three-Compo-
nent Synthesis of r-Benzyloxy-δ-ketoaldehydes, Thiopyridyl
Ketene Acetals, and Silyl Nucleophiles As Described for Tet-
rahydropyran 22a. ZnCl2 (203 mg, 1.49 mmol) was freshly fused
at ∼0.5 mmHg and subsequently cooled to ambient temperature.
The ketene acetal (E)-2c (289 mg, 0.89 mmol) was added as a
solution in CH2Cl2 (5 mL) and stirred for 4 h at 23 °C. The
heterogeneous mixture was cooled to 0 °C, Et3SiH (241 µL, 1.48
mmol) and R-benzyloxy-δ-ketoaldehyde (()-10 (164 mg, 0.74
mmol) in CH2Cl2 (5 mL) were added sequentially, and the reaction
mixture was subsequently warmed from 0 to 23 °C over 24 h. The
reaction was quenched with pH 7 buffer, stirred vigorously for 30
min, poured over Celite with additional CH2Cl2, and dried with
Na2SO4. Crude 1H NMR (500 MHz) analysis revealed a 20:1 ratio
of THP 22a (dr 16:1) to DHP 23 (dr >19:1). Purification by flash
column chromatography (hexanes/ethyl acetate 98:2) delivered THP
22a (243 mg, 75%) as a pale yellow oil: Rf ) 0.56 (hexanes/ethyl
acetate 90:10); IR (thin film) 3029, 1717, 1088, 745, 694 cm-1; 1H
NMR (500 MHz, CDCl3) δ 1.05 (d, J ) 7.0 Hz, 3H), 1.07 (d, J )
6.0 Hz, 3H), 1.09 (d, J ) 7.0 Hz, 9H), 1.10 (d, J ) 7.5 Hz, 9H),
1.20-1.32 (m, 1H), 1.31 (qq, J ) 7.0, 7.5 Hz, 1H), 1.42-1.52 (m,
1H), 1.68-1.74 (m, 1H), 2.26-2.32 (m, 1H), 3.00 (dq, J ) 2.8,
7.0 Hz, 1H), 3.24 (ddd, J ) 4.5, 9.3, 10.5 Hz, 1H), 3.43 (ddq, J )
2.0, 6.0, 8.0 Hz, 1H), 3.86 (dd, J ) 2.8, 9.3 Hz, 1H), 4.44 (d, J )
11.8 Hz, 1H), 4.66 (d, J ) 11.8 Hz, 1H), 7.28-7.39 (m, 5H); 13
C
NMR (125 MHz, CDCl3) δ 9.3, 12.2(3), 18.0(3), 18.1(3), 21.4,
29.3, 32.9, 41.4, 70.4, 73.76, 73.85, 81.1, 127.9, 128.1(2), 128.6(2),
138.5, 175.4; ESI-HRMS calcd for C25H42O4SiLi [M + Li]
441.3012, found 441.3014.
Keto-ꢀ-lactone 27 was prepared according to the representative
procedure for the tandem, three-component synthesis of THPs using
ZnCl2 (136 mg, 0.50 mmol), ketene acetal (E)-2c (194 mg, 0.60
mmol), Et3SiH (162 µL, 1.00 mmol), and R-benzyloxy-ꢀ-ketoal-
dehyde (()-26 (117 mg, 0.45 mmol) in CH2Cl2 (10 mL) and
1
warmed from 0 to 23 °C over 18 h. Aliquot H NMR (500 MHz)
analysis revealed keto-ꢀ-lactone 27 (>19:1) as the only detectable
product. The reaction was gently warmed to 40 °C for 8 h, but no
further reaction was observed. Representative workup and crude
1H NMR (500 MHz) analysis also revealed keto-ꢀ-lactone 27 (>19:
1) as the only detectable product. Purification by flash column
chromatography (hexanes/ethyl acetate 80:20) delivered keto-ꢀ-
lactone 27 (102 mg, 70%) as a pale yellow oil: Rf ) 0.46 (hexanes/
ethyl acetate 60:40); IR (thin film) 3029, 1826, 1714, 1119, 739,
1
697 cm-1; H NMR (500 MHz, CDCl3) δ 1.40 (d, J ) 7.5 Hz,
3H), 1.45-1.80 (m, 4H), 2.44 (t, J ) 7.0 Hz, 2H), 3.38 (dq, J )
4.0, 7.5 Hz, 1H), 3.58 (ddd, J ) 4.5, 6.5, 7.5 Hz, 1H), 4.22 (dd, J
) 4.0, 6.5 Hz, 1H), 4.63 (d, J ) 11.5 Hz, 1H), 4.74 (d, J ) 11.5
Hz, 1H), 7.29-7.38 (m, 5H); 13C NMR (125 MHz, CDCl3) δ 12.3,
19.3, 29.6, 30.0, 43.1, 48.2, 72.9, 78.5, 81.2, 127.9, 128.0(2),
128.5(2), 138.0, 171.4, 208.4; ESI-HRMS calcd for C17H24O4Li
[M + Li] 297.1678, found 297.1683.
Acknowledgment. We thank the NIH (GM-069784) and the
Robert A. Welch Foundation (A-1280) for generous support of
this work. We thank Kay Morris and Dr. Ziad Moussa, as well
as Profs. Dan Singleton and Brian Connell, for helpful discussions.
Supporting Information Available: Experimental details and
characterization data for thiopyridyl ketene acetal 2b, ꢀ-chlo-
rosilyl ester 4b, R-benzyloxy-γ-ketoaldehydes (()-9, 10, and
(()-26, tetrahydrofurans 19a-m and 21b,c, furans 20a-g,
tetrahydropyrans 22a, b, dihydropyran 23, methyl ester 24,
p-bromobenzoate 25, and keto-ꢀ-lactone 27. Key NOE enhance-
ments for selected tetrahydrofurans and single-crystal X-ray data
for the p-bromobenzoate derived from THF 19a. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO801604K
J. Org. Chem. Vol. 73, No. 24, 2008 9551