Diastereoselective synthesis of tetrahydrofurans via mead reductive cyclization of keto-β-lactones derived from the tandem Mukaiyama aldol lactonization (TMAL) process

Article abstract of DOI:10.1021/jo7014246

(Chemical Equation Presented) The development of a diastereoselective, three-step strategy for the construction of substituted tetrahydrofurans from alkenyl aldehydes based on the tandem Mukaiyama aldol-lactonization process and Mead reductive cyclization of keto β-lactones is reported. Stereochemical outcomes of the TMAL process are consistent with models established for Lewis acid-mediated additions to α-benzyloxy and β-silyloxy aldehydes while reductions of the five-membered oxocarbenium ions are consistent with Woerpel's models. Further rationalization for observed high diastereoselectivity in reductions of α-silyloxy 5-membered oxocarbenium ions based on stereoelectronic effects are posited. A diagnostic trend for coupling constants of γ-benzyloxy β-lactones was observed that should enable assignment of the relative configuration of these systems.

Full text of DOI:10.1021/jo7014246

Diastereoselective Synthesis of Tetrahydrofurans via Mead
Reductive Cyclization of Keto-â-Lactones Derived from the Tandem
Mukaiyama Aldol Lactonization (TMAL) Process
T. Andrew Mitchell and Daniel Romo*
Department of Chemistry, P.O. Box 30012, Texas A&M UniVersity, College Station, Texas 77842-3012
romo@mail.chem.tamu.edu
ReceiVed June 30, 2007
The development of a diastereoselective, three-step strategy for the construction of substituted
tetrahydrofurans from alkenyl aldehydes based on the tandem Mukaiyama aldol-lactonization process
and Mead reductive cyclization of keto â-lactones is reported. Stereochemical outcomes of the TMAL
process are consistent with models established for Lewis acid-mediated additions to R-benzyloxy and
â-silyloxy aldehydes while reductions of the five-membered oxocarbenium ions are consistent with
Woerpel’s models. Further rationalization for observed high diastereoselectivity in reductions of R-silyloxy
5-membered oxocarbenium ions based on stereoelectronic effects are posited. A diagnostic trend for
coupling constants of γ-benzyloxy â-lactones was observed that should enable assignment of the relative
configuration of these systems.
Introduction
Tetrahydrofurans (THFs) are common heterocyclic motifs in
natural products, and thus, many routes have been developed
to access these moieties.1 These approaches can be divided into
three major synthetic strategies (Figure 1). In one strategy, an
oxygen nucleophile displaces, adds to, or opens an activated
group (G) such as a leaving group (e.g., mesylate),2 an olefin
(e.g., iodoetherification),3 or a strained ring (e.g., epoxide)4 to
form a new C-O bond (Type I). In another strategy, a
nucleophile adds to an oxocarbenium intermediate and a new
C-C or C-H bond is formed (Type II).5 Finally, several
miscellaneous strategies have been developed1 including ring
FIGURE 1. General Routes to Tetrahydrofurans.
contractions of various six-membered rings such as tetrahydro-
pyrans6 and δ-lactones.7
Some of the most elegant and efficient approaches to THFs
fall into the last category (Type III). Overman developed the
Prins-pinacol route to THFs8 that has been applied to trans-
kumausyne and other members of the Laurencia family of
marine natural products,9 as well as (-)-citreoviral10 and
(1) For reviews on the synthesis of THFs, see: (a) Kang, J. E.; Lee, E.
Chem. ReV. 2005, 105, 4348. (b) Norcross, R.; Paterson, I. Chem. ReV.
1995, 95, 2041. (c) Harmange, J.-C.; Figadere, B. Tetrahedron: Asymmetry
1993, 4, 1711. (d) Boivin, T. Tetrahedron 1987, 43, 3309.
(2) (a) Buchanan, J. G.; Dunn, A. D.; Edgar, A. R. J. Chem. Soc., Perkin
1 1974, 1943. (b) Buchanan, J. G.; Dunn, A. D.; Edgar, A. R. J. Chem.
Soc., Perkin 1 1975, 1191.
(3) Rychnovsky, S. D.; Bartlett, P. A. J. Am. Chem. Soc. 1981, 103,
3963.
(4) Chamberlin previously reported a similar route to THFs as Mead,
but utilizing epoxides instead of â-lactones: (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.
(6) Michael, P.; Ting, P. C.; Bartlett, P. A. J. Org. Chem. 1985, 50,
2416.
(7) Mantell, S. J.; Ford, P. S.; Watkin, D. J.; Fleet, G. W. J.; Brown, D.
Tetrahedron Lett. 1992, 33, 4503.
(8) For initial disclosure, see: Hopkins, M. H.; Overman, L. E. J. Am.
Chem. Soc. 1987, 109, 4748. For a Perspective, see: Pennington, L. D.;
Overman, L. E. J. Org. Chem. 2003, 68, 7143.
(5) Ogawa, T.; Pernet, A. G.; Hanessian, S. Tetrahedron Lett. 1973, 37,
3543.
10.1021/jo7014246 CCC: $37.00 © 2007 American Chemical Society
Published on Web 11/01/2007
J. Org. Chem. 2007, 72, 9053-9059
9053

Mitchell and Romo
SCHEME 1. Tandem Mukaiyama Aldol-Lactonization
briarellin E.11 Roush and Micalizio12 refined and expanded the
[3+2] annulation of aldehydes and allylsilanes toward THFs
first reported by Panek.13 This strategy had been applied to
pectenotoxin II,14 amphidinolide F,15 asimicin,16 (+)-bullatacin,17
angelmicin B,18 and haterumalide ND.19 Lee developed a radical
cyclization approach to THFs20 and utilized this method in the
total synthesis of pamamycin 607,21 (+)-methyl nonactate,22
kumausallene,23 and kumausyne.24 Herein, we report a hybrid
of Type I and Type II strategies that involves a Mead reductive
cyclization of keto-â-lactones prepared by the tandem Mu-
kaiyama aldol-lactonization (TMAL) process.
(TMAL) Process
SCHEME 2. Mead Reductive Cyclization toward
Tetrahydrofurans
â-Lactones continue to gain prominence as versatile inter-
mediates in synthesis,25 to be found as integral components in
bioactive natural products,26 and to demonstrate their utility as
enzyme inhibitors with therapeutic potential.27 We previously
reported stereoselective routes to both cis28 and trans29 â-lac-
tones via tandem Mukaiyama aldol-lactonization (TMAL)
processes employing substrate control (Scheme 1).28,29 This
methodology was applied to total syntheses of (-)-panclicin
D,27a tetrahydrolipstatin/orlistat,27b okinonellin B,27c and brefel-
din A.27d Mead previously demonstrated the utility of simple
keto-â-lactones 8 for the synthesis of THFs 9 by a Lewis acid-
mediated, reductive cyclization process (Scheme 2).30 Building
on these precedents, we envisioned a highly diastereoselective
synthesis of substituted tetrahydrofurans by combining the
SCHEME 3. Three-Step Strategy toward Tetrahydrofurans
SCHEME 4. Synthesis of Aldehydes (()-10a-c
(9) (a) Brown, M. J.; Harrison, T.; Overman, L. E. J. Am. Chem. Soc.
1991, 113, 5378. (b) Grese, T. A.; Hutchinson, K. D.; Overman, L. E. J.
Org. Chem. 1993, 58, 2468.
(10) Hanaki, N.; Link, J. T.; MacMillan, D. W. C.; Overman, L. E.;
Trankle, W. G.; Wurster, J. A. Org. Lett. 2000, 2, 223.
(11) Corminboeuf, O.; Overman, L. E.; Pennington, L. D. J. Am. Chem.
Soc. 2003, 125, 6650.
(12) (a) Roush, W. R.; Pinchuk, A. N.; Micalizio, G. C. Tetrahedron
Lett. 2000, 41, 9413. (b) Micalizio, G. C.; Roush, W. R. Org. Lett. 2000,
2, 461.
(13) Panek, J. S.; Yang, M. J. Am. Chem. Soc. 1991, 113, 9868.
(14) Micalizio, G. C.; Roush, W. R. Org. Lett. 2001, 3, 1949.
(15) Shotwell, J. B.; Roush, W. R. Org. Lett. 2004, 6, 3865.
(16) Tinsley, J. M.; Roush, W. R. J. Am. Chem. Soc. 2005, 127, 10818.
(17) Tinsley, J. M.; Mertz, E.; Chong, P. Y.; Rarig, R-A. F.; Roush, W.
R. Org. Lett. 2005, 7, 4245.
(18) Lambert, W. T.; Roush, W. R. Org. Lett. 2005, 7, 5501.
(19) Hoye, T. R.; Wang, J. J. Am. Chem. Soc. 2005, 127, 6950.
(20) Lee, E.; Tae, J. S.; Lee, C.; Park, C. M. Tetrahedron Lett. 1993,
34, 4831.
(21) (a) Lee, E.; Jeong, E. J.; Kang, E. J.; Sung, L, T.; Hong, S. K. J.
Am. Chem. Soc. 2001, 123, 10131. (b) Jeong, E. J.; Kang, E. J.; Sung, L.
T.; Hong, S. K.; Lee, E. J. Am. Chem. Soc. 2002, 124, 14655.
(22) Lee, E.; Choi, S. J. Org. Lett. 1999, 1, 1127.
(23) Lee, E.; Yoo, S-K.; Choo, H.; Song, H. Y. Tetrahedron Lett. 1998,
39, 317.
TMAL process and Mead reductive cyclization of substituted
keto-â-lactones (Scheme 3).
Results and Discussion
Synthesis of Keto-â-Lactones 12a-f via the Tandem
Mukaiyama Aldol Lactonization. The required aldehydes (()-
10a-c, possessing both R- and â-oxygenation, were prepared
by standard procedures (Scheme 4).31 Application of the TMAL
process to R-benzyloxy aldehyde (()-10a employing propionate
ketene acetal 6a proceeded with high diastereoselectivity to give
â-lactone 11a based on chelation control (Table 1, entry 1).
However, acetate ketene acetal 6b gave low diastereoselectivity
as expected with only a slight preference for the Felkin-Ahn-
derived â-lactone anti-11b (Table 1, entry 2). Both of these
TMAL reactions proceeded in comparable yield and diastereo-
selectivity at 0 °C under slightly prolonged reaction times. The
sterically demanding, oxygenated ketene acetal 6c delivered
moderate yield of anti-11c after prolonged reaction times and
proceeded with moderate diastereoselectivity (Table 1, entry 3).
In the case of â-silyloxy aldehydes (()-10b-c, â-lactones
11d-f were obtained with moderate diastereoselectivity and the
(24) Lee, E.; Yoo, S-K.; Cho, Y-S.; Cheon, H-S.; Chong, Y. H.
Tetrahedron Lett. 1997, 38, 7757.
(25) (a) Pommier, A.; Pons, J.-M. Synthesis 1995, 729. (b) Wang, Y.;
Tennyson, R. L.; Romo, D. Heterocycles 2004, 64, 605. For selected recent
examples, see: (c) Donohoe, T. J.; Sintim, H. O.; Sisangia, L.; Harling, J.
D. Angew. Chem. Int. Ed. 2004, 43, 2293. (d) Getzle, Y. D. Y. L.; Kundnani,
V.; Lobkovsky, E. B.; Coates, G. W. J. Am. Chem. Soc. 2004, 126, 6842.
(e) Calter, M. A.; Tretyak, O. A.; Flaschenriem, C. Org. Lett. 2005, 7, 1809.
(f) Mitchell, T. A.; Romo, D. Heterocycles 2005, 66, 627. (g) Shen, X.;
Wasmuth, A. S.; Zhao, J.; Zhu, C.; Nelson, S. G. J. Am. Chem. Soc. 2006,
128, 7438. (h) Henry-Riyad, H.; Lee, C.; Purohit, V. C.; Romo, D. Org.
Lett. 2006, 8, 4363. (i) Reddy, L. R.; Corey, E. J. Org. Lett. 2006, 8, 1717.
(26) Lowe, C.; Vederas, J. C. Org. Prep. Proced. Int. 1995, 27, 305.
(27) (a) Yang, H. W.; Zhao, C.; Romo, D. Tetrahedron 1997, 53, 16471.
(b) Ma, G.; Zancanella, M.; Oyola, Y.; Richardson, R. D.; Smith, J. W.;
Romo, D. Org. Lett. 2006, 8, 4497. (c) Schmitz, W. D.; Messerschmidt,
B.; Romo, D. J. Org. Chem. 1998, 63, 2058. (d) Wang, Y.; Romo, D. Org.
Lett. 2002, 4, 3231.
(28) Wang, Y.; Zhao, C.; Romo, D. Org. Lett. 1999, 1, 1197.
(29) Yang, H. W.; Romo, D.; J. Org. Chem. 1997, 62, 4.
(30) Mead, K. T.; Pillai, S. K. Tetrahedron Lett. 1993, 34, 6997.
(31) See Supporting Information for details.
9054 J. Org. Chem., Vol. 72, No. 24, 2007

Synthesis of Tetrahydrofurans
TABLE 1. Alkenyl â-Lactones 11a-f via the TMAL Process from
Aldehydes (()-10a-c
SCHEME 6. Synthesis of Keto-â-Lactones 12a-f via
Ozonolysis
TABLE 2. Stereochemical Assignment of γ-Benzyloxy-â-lactones
11a-c and 12a-c Based on Coupling Constants
a With the exception of syn-11c, only trans â-lactones were produced
and the major diastereomer is displayed. b Entries 1-2 proceeded efficiently
at 0 °C with increased reaction times and delivered comparable yield and
diastereoselectivity. c Refers to isolated, purified yield (SiO2) of both
diastereomers. d Refers to relative stereochemistry and was determined by
analysis of crude reaction mixture by 1H NMR (300 MHz). e Diastereomers
were separable by flash column chromatography. f This yield includes the
subsequent ozonolysis step. g The minor diastereomer is tentatively assigned
as a cis-â-lactone arising from chelation control based on coupling constant
analysis (see Table 2).
a Determined by analysis of chromatographically pure â-lactones by 1H
NMR (300 MHz). b Minor diastereomers were carried directly to ozonolysis
step and thus not fully characterized. c Not available. This keto-â-lactone
was not prepared.
(Scheme 6). The use of PPh3 to reduce the ozonides proved to
be more efficient, leading to fewer byproducts compared to
dimethyl sulfide and therefore simplified purification. Due to
some instability noted for keto-â-lactones 12, they were typically
rapidly purified and used immediately in subsequent Mead
reductive cyclizations.
SCHEME 5. Reversal of Relative Stereochemistry of
Alkenyl-â-Lactone 11b via the TMAL Process with
Thiophenyl Ketene Acetal 18
Stereochemical Assignment of â-Lactones 11-12. With the
exception of â-lactones 11c, bearing a bulky TBDPS group,
stereochemical assignment of â-lactones 11a-f obtained via
the TMAL process corresponded to previous reports and were
subsequently confirmed by NOE analysis of the corresponding
THFs 13a-f (Vide infra).31 However, the γ-benzyloxy-â-
lactones 11a-c and 12a-c displayed a significant trend in
coupling constants that may be a predictive tool for assignment
of relative (i.e., syn vs anti) stereochemistry of these systems
(Table 2). It is well-established that the internal stereochemistry
(i.e., cis vs trans) of â-lactones can be assigned based on
coupling constant analysis, and this is observed for â-lactones
11-12 (cis: J3,4 ) 5.7-6.0 Hz; trans: J3,4 ) 3.3-4.5 Hz).34
stereochemical outcome is consistent with Evans’ model32 and
our previous studies27 (Table 1, entries 4 and 6). Once again,
acetate ketene acetal 6b gave low diastereoselectivity as
expected (Table 1, entry 5). Our previous studies suggested that
use of thiophenyl acetate ketene acetal 18 with R-benzyloxy
aldehyde (()-10a may lead to a reversal of selectivity toward
the chelation controlled adduct, which could be attributed to
greater possibility for chelation control due to the monodentate
thiophenyl ligand.33 Indeed, this reversal was observed for
R-unsubstituted-â-lactones 11b, albeit in diminished ratio
(Scheme 5).
(33) Zhao, C. Ph.D. Thesis, Texas A&M University, 1999.
Ozonolysis of alkenyl-â-lactones 11 proceeded smoothly to
deliver the required keto-â-lactones 12 for reductive cyclization
(32) Evans, D. A.; Dart, M. J.; Duffy, J. L.; Yang, M. G. J. Am. Chem.
Soc. 1996, 118, 4322.
(34) Abraham, R. J. J. Chem. Soc. B 1968, 173.
J. Org. Chem, Vol. 72, No. 24, 2007 9055

Mitchell and Romo
TABLE 3. Optimization of the Reductive Cyclization of
Keto-â-Lactone syn-12a
TABLE 4. Mead Reductive Cyclization of Keto-â-Lactones 12
toward Tetrahydrofurans 13a-f
ratio THF
Lewis
Acid
conc.
Et3SiH
13a/
%
entry
(M)a methodb (equiv) furan 19c
yieldd
1
2
3
4
5
6
TiCl4
0.05
0.05
0.05
0.01
0.01
0.01
A
B
B
C
C
C
1.2
1.2
1.2
1.2
20.0
0
1/5
1/1
2/1
10/1
68/1
0/1
ND
ND
60
BF3‚OEt2
TESOTf
TESOTf
TESOTf
TESOTf
68
67
28 (98)e
a Refers to the final concentration of keto-â-lactone in CH2Cl2. b Lewis
acid (1.2 equiv) was added to a solution of keto-â-lactone and Et3SiH in
CH2Cl2 at -78 °C. Method A: TiCl4 in CH2Cl2 (1.0 M) was added down
the side of the flask and stirred for 4 h at -78 °C. Method B: Neat Lewis
acid was added dropwise at -78 °C, quickly warmed to 0 °C, and stirred
for 4 h. Method C: Lewis acid in CH2Cl2 (0.03 M) was added down the
side of the flask and allowed to warm to 0 °C over 6 h. c Ratio determined
by crude 1H NMR (500 MHz). d Refers to isolated yield of inseparable
mixture of THF and furan. e Significant loss of the furan occurred during
purification leading to diminished yields. However, estimated yield based
on crude weight and 1H NMR analysis indicated nearly quantitative
conversion.
However, to the best of our knowledge, the determination of
relative stereochemistry of these systems has not previously been
based solely on coupling constant analysis. In the case of
γ-benzyloxy-â-lactones 11a-c and 12a-c, the coupling con-
stants for syn (J4,5 ) 4.5-6.0 Hz) and anti (J4,5 ) 2.7-3.6 Hz)
diastereomers followed a clear trend that is also consistent with
our previous studies.27 This is likely due to the conformational
rigidity of these systems resulting from torsional strain.35
Although subsequent NOE data for stereochemical assignment
of THF 13c was inconclusive, a tentative assignment of the
precursor â-lactones anti-11c and anti-12c based on this
diagnostic coupling constant trend is plausible.
a Isolated yields of the mixture of diastereomers. b Determined by analysis
1
of crude reaction mixtures by H NMR (500 MHz). c TESOTf in CH2Cl2
(0.03 M solution) was added to a solution of keto-â-lactone and Et3SiH
(20 equiv) in CH2Cl2 at -78 °C and allowed to warm to 0 °C over 5 h.
d BF3•OEt2 in CH2Cl2 (0.03 M solution) was added to a solution of keto-
â-lactone and Et3SiH (20 equiv) in CH2Cl2 at -78 °C and allowed to warm
to 0 °C over 5 h. This reaction was then stirred for 3 days at 0-10 °C.
e TiCl4 in CH2Cl2 (1.0 M) was added to a solution of keto-â-lactone and
Et3SiH (20 equiv) in CH2Cl2 for 4 h at -78 °C. f Yield in parentheses refers
to recovered keto-â-lactone 12c.
Optimization of Mead Reductive Cyclization. Initial studies
of the reductive cyclization of keto-â-lactone syn-12a employing
conditions reported by Mead with TiCl4 or BF3•OEt2 as Lewis
acid led to the desired THF 13a along with significant quantities
of an unexpected byproduct, furan 19 (Table 3, entries 1-2).
Mead found that silyl triflates also promoted cyclization of keto
â-lactones to THFs.36 When triethylsilyl triflate (TESOTf) was
added dropwise at -78 °C and then warmed quickly to 0 °C,
the ratio of THF to furan did not improve significantly, but this
provided the desired THF 13a as the major product (Table 3,
entry 3). After extensive experimentation, we found that when
TESOTf was added down the side of the flask at -78 °C
(“precooled”) as a dilute solution in CH2Cl2, and the reaction
was allowed to warm to 0 °C slowly over 6 h; this provided
the desired THF 13a in 68% yield with only 6% of furan 19
(Table 3, entry 4). Further improvements resulted when a large
excess of Et3SiH (20.0 equiv) was employed and THF 13a was
isolated in 68% yield as a single diastereomer with only trace
amounts of furan 19 (Table 3, entry 5). Finally, a control
experiment revealed that furan 19 was the only product formed
in the absence of Et3SiH (Table 3, entry 6). Indeed, furan
byproducts have been observed previously during reductions
of 5-membered oxocarbenium ions.37
Scope of Mead Reductive Cyclization. Using the optimized
conditions, various γ-benzyloxy-keto-â-lactones 12 were con-
verted to THFs 13 with efficient transfer of stereochemistry and
only trace quantities of furan were observed (Table 4, entries
1-2). A possible stereoreinforcing effect is operative with anti-
and syn-â-lactones 12b (dr, 14:1 vs 19:1, respectively), which
may be due to a developing 1,3-diaxial interaction of the
oxocarbenium intermediate (cf. 24, Scheme 7) leading to greater
selectivity for “inside attack.” In the case of keto-â-lactone 12c,
TESOTf delivered a complex mixture of products, whereas
BF3•OEt2 provided a cleaner, albeit slower, reaction to provide
THF 13c (Table 4, entry 3). In the case of δ-silyloxy-keto-â-
lactones 12d-f, there was less concern of furan formation based
on our proposed mechanism (Vide infra). Thus, the strong Lewis
(37) In the course of the total synthesis of (-)-azaspiracid, a similar
byproduct was observed: Evans, D. A.; Kvaerno, L.; Mulder, J. A.; Raymer,
B.; Dunn, T. B.; Beauchemin, A.; Olhava, E.; Juhl, M.; Kagechika, K.
Angew. Chem., Int. Ed. 2007, 46, 4693. Similar furans were obtained from
the corresponding dihydrofurans: Katagiri, N.; Tabei, N.; Atsuumi, S.;
Haneda, T.; Kato, T. Chem. Pharm. Bull. 1985, 33, 102.
(35) Analysis of molecular models for these γ-benzyloxy-â-lactones
suggests that there should be a conformational preference due to unfavorable
gauche interactions and cancellation of dipoles.
(36) White, D.; Zemribo, R.; Mead, K. T. Tetrahedron Lett. 1997, 38,
2223.
9056 J. Org. Chem., Vol. 72, No. 24, 2007

Synthesis of Tetrahydrofurans
SCHEME 7. Model for Diastereoselectivity in Reductive Cyclization with γ-Benzyloxy-â-Lactones Based on Woerpel’s Model
and a Proposed Mechanism for Formation of Furan 21
SCHEME 8. Model for Diastereoselectivity in Reductive
Cyclization with δ-Silyloxy-â-lactones Based on Woerpel’s
Model
acid TiCl4 previously utilized by Mead promoted the reductive
cyclization in moderate to good yields with excellent levels of
stereochemical transfer using only 1.2 equiv of Et3SiH (Table
4, entries 4-6). The relative stereochemistry of all ring
stereocenters of THFs 13a-f was confirmed by NOE analysis
observed for multiple protons of the THF rings,31 which also
confirmed invertive ring cleavage during cyclization. The
relative stereochemistry between the R-stereocenter and the THF
rings is premised on stereochemical invertive cyclization of the
trans-substituted (vs cis) â-lactones, which in turn is based on
coupling constants. An exception was THF 13c for which NOE
data were inconclusive, and thus, relative stereochemistry was
tentatively assigned based on coupling constants (cf. Table 2).
Thus, the stereochemical outcome in each case is consistent with
stereochemical invertive alkyl C-O ring cleavage by the
pendant ketone followed by reduction of the oxocarbenium to
the tetrahydrofuran as predicted by the Woerpel model.38
Mechanistic Rationale for Mead Reductive Cyclization.
Regarding the mechanism of this process for benzyloxy-
substituted systems, the reductive cyclization leading to THF
20 and furan 21 is presented as an example (Scheme 7). Ketone
cleavage of a silyl activated â-lactone intermediate 22 via alkyl
C-O scission in an SN2 fashion delivers the oxocarbenium 23
in line with previous proposals by Mead.30 The stereoelectroni-
cally favored envelope conformation 24 places the benzyloxy
substituent in the pseudoaxial orientation as proposed by
Woerpel and reduction occurs via “inside attack” of Et3SiH.38
Alternatively, a competing pathway leading to furan 21 could
involve elimination leading to enol ether 25 which then
undergoes acid-mediated elimination of benzyl alcohol to
provide oxocarbenium 26. This is followed by rapid aromati-
zation to furan 21 by loss of a second proton, which may occur
upon reaction workup.
of the reduction was >19:1 since the diastereomeric ratio of
the THFs 13d-f matched well with the diastereomeric ratio of
the substrate â-lactones 12d-f, respectively. There appear to
be several factors governing this increase in selectivity. Woerpel
has shown that hydrogen atoms prefer to reside in the pseudo-
axial position adjacent to an oxocarbenium in both five and six-
membered rings for favorable hyperconjugation between the
C-H bond and the 2p orbital of the oxocarbenium.38b,39 Less
studied by Woerpel were the effects of R-silyloxy oxocarbeni-
ums and both steric and electronic effects could influence the
stereochemical outcome. The decreased electron density of the
oxygen due to the silyloxy moiety40 leads to lower electron
donation compared to a benzyloxy substituent. Thus, compared
to the hydrogen atom, the pseudequatorial orientation of the
silyloxy substituent is preferred to a greater extent. Steric
considerations would also dictate that the more bulky silyloxy
group reside in the pseudoequatorial position to a greater degree
than a benzyloxy substituent. Additionally, developing gauche
interactions between the C5 methyl and the pseudoequatorial
silyloxy substituent also favors “inside attack” of Et3SiH (cf.
28, Scheme 8). These effects combine with the preferred “inside
In the case of δ-silyloxy-keto-â-lactones 12d-f, based on
Woerpel’s findings with related benzyloxy systems which
provided diastereomeric ratios of 5-6:1, we expected only
moderate selectivity for the reduction of oxocarbeniums 28
(Scheme 8).38b However, we found that the diastereoselectivity
(39) Ayala, L.; Lucero, C. G.; Romero, J. A. C.; Tabacco, S. A.; Woerpel,
K. A. J. Am. Chem. Soc. 2003, 125, 15521.
(40) (a) Keck, G. E.; Boden, E. P. Tetrahedron Lett. 1984, 25, 265. (b)
Kahn, S. D.; Keck, G. E.; Henre, W. J. Tetrahedron Lett. 1987, 28, 279.
(c) Keck, G. E.; Castellino, S. Tetrahedron Lett. 1987, 28, 281. (d)
Shambayati, S.; Blake, J.; Wierschke, S. G.; Jorgensen, W. L.; Schreiber,
S. L. J. Am. Chem. Soc. 1990, 112, 697.
(38) Larsen, C. H.; Ridgway, B. H.; Shaw, J. T.; Woerpel, K. A. J. Am.
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J. Org. Chem, Vol. 72, No. 24, 2007 9057

Mitchell and Romo
deliver crude THF 13a as a single diastereomer (>19:1) with only
trace amounts of furan 19 (68:1) as judged by analysis of crude 1H
NMR (500 MHz). Gradient flash column chromatography (hexanes/
ethyl acetate 80:20 to 60:40) delivered THF 13a (178 mg, 67%) as
a colorless oil. A center fraction from the column was used for
characterization: Rf ) 0.46 (60:40 hexanes/ethyl acetate); IR (thin
film) 3500-2300, 1708, 1091 cm-1; 1H NMR (500 MHz, CDCl3)
δ 1.23 (d, J ) 7.0 Hz, 3H), 1.29 (d, J ) 6.0 Hz, 3H), 1.54 (ddd,
J ) 6.5, 10.5, 13.5 Hz, 1H), 2.11 (ddd, J ) 1.0, 5.0, 13.5 Hz, 1H),
2.68 (dq, J ) 6.0, 7.0 Hz, 1H), 4.01 (ddd, J ) 1.0, 3.0, 6.5 Hz,
1H), 4.12 (dd, J ) 3.0, 6.0 Hz, 1H), 4.21-4.28 (m, 1H), 4.49 (d,
J ) 11.5 Hz, 1H), 4.52 (d, J ) 11.5 Hz, 1H), 7.27-7.37 (m, 5H);
13C NMR (125 MHz, CDCl3) δ 12.8, 20.5, 40.1, 42.8, 71.4, 75.3,
81.9, 85.4, 127.88(2), 127.95, 128.6(2), 138.1, 178.7; ESI-HRMS
calcd for C15H19O4 [M - H] 263.1283, found 263.1271.
attack” leading to high diastereoselectivity for R-silyloxy
substituted-oxocarbenium ions.
In summary, we developed a three-step strategy for the
diastereoselective synthesis of THFs from alkenyl aldehydes
proceeding through â-lactone intermediates. The strategy in-
volves the TMAL process and Mead’s reductive cyclization of
keto-â-lactones. The stereoselectivity of the latter process is
rationalized by Woerpel’s model for “inside attack” of oxocar-
beniums. An increase in selectivity for certain R-silyloxy
oxocarbenium ions was observed and is rationalized based on
stereoelectronic effects building on Woerpel’s findings. The
stereoselectivity of the TMAL process for R-benzyloxy and
â-silyloxy aldehydes with several thiopyridyl ketene acetals was
defined including a reversal in selectivity when a thiophenyl
ketene acetal was employed. A correlation between relative
stereochemistry and coupling constants was observed that
provides a predictive method for the stereochemical assignment
of γ-benzyloxy-â-lactones. This strategy should prove useful
for the synthesis of tetrahydrofurans found in natural products
and the results of these studies will be reported in due course.
Representative Procedure for Mead Reductive Cyclization
of γ-Benzyloxy-keto-â-lactones as Described for THF 13c
(Procedure B). To a solution of γ-benzyloxy-keto-â-lactone 12c
(199 mg, 0.40 mmol) in CH2Cl2 (20 mL) was added Et3SiH (1.3
mL, 8.00 mmol) slowly at -78 °C followed by BF3•OEt2 (61 µL,
0.48 mmol in 16 mL CH2Cl2) down the side of the flask at -78 °C
over 10 min to ensure cooling. Upon addition of 10 mL of CH2Cl2
to rinse down any remaining BF3•OEt2, the solution was allowed
to warm to 0 °C slowly over 5 h and then stirred at 0-10 °C for
3 days. The reaction was quenched with pH 4 buffer (50 mL) and
warmed to 23 °C with vigorous stirring. The layers were separated,
and the aqueous layer was extracted with CH2Cl2 (3 × 50 mL).
The combined organic extracts were dried over MgSO4, filtered,
and concentrated under reduced pressure to deliver crude THF 13c
as a mixture of diastereomers (∼18:1, ∼50% conversion) as judged
Experimental Section
Representative Procedure for the TMAL Reaction as De-
scribed for γ-Benzyloxy-alkenyl-â-lactone syn-11a. ZnCl2 (273
mg, 2.00 mmol) was freshly fused at ∼0.5 mmHg and subsequently
cooled to ambient temperature. Ketene acetal 6a (384 mg, 1.20
mmol) and then aldehyde (()-10a (204 mg, 1.00 mmol) were each
added as a solution in 5 mL of CH2Cl2 (final concentration of
aldehyde in CH2Cl2 ∼0.1 M). This suspension was stirred for 14 h
at 23 °C and then quenched with pH 7 buffer, stirred vigorously
for 30 min, and poured over Celite with additional CH2Cl2. After
concentration under reduced pressure, the residue was redissolved
in CH2Cl2 (final concentration of â-lactone in CH2Cl2 ∼0.15 M)
and treated with CuBr2 (357 mg, 1.60 mmol). After stirring for 2.5
h, the crude â-lactone syn-11a was again poured over Celite and
washed with ether (200 mL). The combined organic layers were
washed with 10% aq K2CO3 (3 × 50 mL), H2O (2 × 50 mL), and
brine (2 × 50 mL), dried over MgSO4, filtered, and concentrated
under reduced pressure to deliver crude â-lactone syn-11a as a
single diastereomer (>19:1) as judged by analysis of crude 1H NMR
(300 MHz). Purification by flash column chromatography (hexanes/
ethyl acetate 95:5) delivered pure syn-11a (216 mg, 83%) as a
colorless oil: Rf ) 0.42 (80:20 hexanes/ethyl acetate); IR (thin film)
3071, 3031, 1827, 1119 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.38
(d, J ) 7.5 Hz, 3H), 1.78 (dd, J ) 0.9, 1.2 Hz, 3H), 2.25 (ddd, J
) 0.9, 6.3, 14.1 Hz, 1H), 2.40 (ddd, J ) 1.2, 6.9, 14.1 Hz, 1H),
3.43 (dq, J ) 4.2, 7.5 Hz, 1H), 3.74 (ddd, J ) 6.0, 6.3, 6.9 Hz,
1H), 4.22 (dd, J ) 4.2, 6.0 Hz, 1H), 4.66 (d, J ) 12.0 Hz, 1H),
4.70 (d, J ) 12.0 Hz, 1H), 4.83-4.86 (m, 1H), 4.88-4.91 (m,
1H), 7.29-7.37 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 12.2, 22.7,
38.7, 47.5, 72.5, 76.8, 80.5, 114.2, 127.78, 127.82(2), 128.4(2),
137.9, 140.9, 171.5; ESI-HRMS calcd for C16H20O3Li [M + Li]
267.1572, found 267.1591.
Representative Procedure for Mead Reductive Cyclization
of γ-Benzyloxy-keto-â-lactones as Described for THF 13a
(Procedure A). To a solution of γ-benzyloxy-keto-â-lactone syn-
12a (262 mg, 1.00 mmol) in CH2Cl2 (50 mL) was added Et3SiH
(3.2 mL, 20.0 mmol) slowly at -78 °C followed by TESOTf (274
µL, 1.20 mmol in 40 mL CH2Cl2) down the side of the flask at
-78 °C over 10 min to ensure cooling. Upon addition of 10 mL of
CH2Cl2 to rinse down any remaining TESOTf, the solution was
allowed to warm to 0 °C slowly over 5 h, quenched with pH 4
buffer (50 mL), and warmed to 23 °C with vigorous stirring. The
layers were separated and the aqueous layer was extracted with
CH2Cl2 (3 × 50 mL). The combined organic extracts were dried
over MgSO4, filtered, and concentrated under reduced pressure to
1
by analysis of crude H NMR (500 MHz). Gradient flash column
chromatography (hexanes/ethyl acetate 90:10 to 60:40) delivered
recovered 12c (70 mg, 35%, dr 18:1) as a pale-yellow oil and THF
13c (102 mg, 51%, dr 18:1) as a pale yellow oil. A center fraction
of THF 13c from the column was used for characterization.
Characterization data for the major (anti) diastereomer 13c: Rf )
0.30 (70:30 hexanes/ethyl acetate); IR (thin film) 3437-2404, 1731,
1
1108 cm-1; H NMR (500 MHz, CDCl3) δ 1.12 (s, 9H), 1.27 (d,
J ) 6.0 Hz, 3H), 1.48 (ddd, J ) 6.5, 11.0, 13.5 Hz, 1H), 2.03 (dd,
J ) 5.0, 13.5 Hz, 1H), 4.07 (dd, J ) 2.5, 6.5 Hz, 1H), 4.16 (dd, J
) 2.5, 4.5 Hz, 1H), 4.18-4.24 (m, 1H), 4.32 (s, 2H), 4.43 (d, J )
4.5 Hz, 1H), 7.23-7.70 (m, 15H); 13C NMR (125 MHz, CDCl3) δ
19.7, 20.0, 27.2(3), 40.3, 71.5, 72.8, 75.8, 81.0, 86.1, 127.8(2),
127.9, 128.00(2), 128.04(2), 128.6(2), 130.36, 130.40, 132.3, 132.8,
136.0(2), 136.2(2), 138.1, 173.0; ESI-HRMS calcd for C30H35O5Si
[M - H] 503.2254, found 503.2241.
Representative Procedure for Mead Reductive Cyclization
of δ-Silyloxy-keto-â-lactones as Described for THF 13d (Pro-
cedure C). To a solution of δ-silyloxy-keto-â-lactone 12d (202
mg, 0.71 mmol) in CH2Cl2 (15 mL) was added Et3SiH (137 µL,
0.85 mmol) dropwise at -78 °C followed by TiCl4 (846 µL, 1.0
M in CH2Cl2) down the side of the flask at -78 °C over 5 min to
ensure cooling. Upon addition of 5 mL of CH2Cl2 to rinse down
any remaining TiCl4, the solution was stirred at -78 °C for 3 h,
quenched with pH 7 buffer (50 mL), and warmed to 23 °C with
vigorous stirring. The layers were separated and the aqueous layer
was extracted with CH2Cl2 (3 × 50 mL). The combined organic
extracts were dried over MgSO4, filtered, concentrated under
reduced pressure to deliver crude THF 13d as a mixture of
1
diastereomers (9:1) as judged by analysis of crude H NMR (500
MHz). Gradient flash column chromatography (hexanes/ethyl
acetate 90:10 to 60:40) delivered THF 13d (170 mg, 84%, dr 9:1)
as a pale-yellow oil: Characterization data for the major (syn)
diastereomer 13d: Rf 0.49 (hexanes/ethyl acetate 60:40); IR (thin
film) 3475-2460, 1707, 1250 cm-1; 1H NMR (500 MHz, C6D6) δ
-0.04 (s, 6H), 0.90 (s, 9H), 1.07 (d, J ) 6.5 Hz, 3H), 1.14 (d, J )
7.0 Hz, 3H), 1.74 (ddd, J ) 6.5, 8.5, 13.0 Hz, 1H), 1.78 (ddd, J )
3.5, 6.5, 13.0 Hz, 1H), 2.47 (dq, J ) 7.0, 7.0 Hz, 1H), 3.67 (ddd,
J ) 3.5, 4.0, 6.5 Hz, 1H), 3.79 (dq, J ) 4.0, 6.5 1H), 4.24 (ddd, J
9058 J. Org. Chem., Vol. 72, No. 24, 2007

Synthesis of Tetrahydrofurans
) 3.5, 7.0, 8.5 Hz, 1H); 13C NMR (125 MHz, C6D6) δ -4.8, -4.6,
13.3, 18.1, 19.1, 25.9(3), 39.0, 45.0, 78.3, 78.7, 82.5, 180.6; ESI-
HRMS calcd for C14H27O4Si [M- H] 287.1679, found 287.1611.
Research (TAMU) for acquiring mass spectral data and helpful
discussions.
Supporting Information Available: Experimental details and
characterization data (including 1H and 13C NMR spectra) for
aldehydes (()-10a-c and their precursors, alkenyl-â-lactones 11a-
b, 11d, and 11f, keto-â-lactones 12a-f, tetrahydrofurans 13a-f
(with NOE data), and furan 19. A comparison of key coupling
constants for THFs 13a-c. This material is available free of charge
via the Internet at http://pubs.acs.org.
Acknowledgment. We thank the NIH (GM-069784) and the
Welch Foundation (A-1280) for generous support of this work.
We thank Dr. Ziad Moussa (TAMU) for helpful discussions
and Dr. Shane Tichy of the Laboratory for Biological Mass
Spectrometry supported by the Office of the Vice President for
JO7014246
J. Org. Chem, Vol. 72, No. 24, 2007 9059