Synthesis of 3-acyltetrahydrofurans from formaldehyde acetals of allylic diols

Article abstract of DOI:10.1016/S0040-4039(00)01571-9

3-Acyltetrahydrofurans having hydrogen substituents at C5 can be prepared with high stereocontrol and enantiopurity from alkoxymethyl or thioalkoxymethyl derivatives of allylic diols. (C) 2000 Published by Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01571-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9431–9435
Synthesis of 3-acyltetrahydrofurans from formaldehyde
acetals of allylic diols†
Catherine M. Gasparski,† Paul M. Herrinton,‡ Larry E. Overman* and John P. Wolfe
Department of Chemistry, 516 Rowland Hall, University of California, Irvine, CA 92697-2025, USA
Received 31 August 2000; revised 12 September 2000; accepted 14 September 2000
Abstract
3-Acyltetrahydrofurans having hydrogen substituents at C5 can be prepared with high stereocontrol
and enantiopurity from alkoxymethyl or thioalkoxymethyl derivatives of allylic diols. © 2000 Published
by Elsevier Science Ltd.
Substituted tetrahydrofuran rings are found in numerous natural products and various
medicinally useful agents. Not surprisingly, a wide variety of methods have been developed for
stereocontrolled construction of tetrahydrofurans.1 A common theme is to establish functional-
ity and stereochemistry in an acyclic fragment that is evolved to a substituted tetrahydrofuran
by an intramolecular etherification reaction. Less common are methods that construct tetra-
hydrofurans by C–C bond formation. A versatile method of this latter type is the assembly of
substituted 3-acyltetrahydrofurans from allylic diol and carbonyl components.2–5 As illustrated
in Scheme 1, this distinctive process stitches the carbonyl carbon of an aldehyde or ketone
between the alkene and alcohol termini of an allylic diol. High stereoselectivity is a signature
characteristic of this tetrahydrofuran synthesis and has allowed this reaction to serve as the
cornerstone of stereocontrolled total syntheses of various oxacyclic natural products.6–10
A
limitation of the method as constituted in Scheme 1 is the inability to prepare tetrahydrofurans
having two hydrogen substituents at C5. In this case, the 1,3-dioxolane 2 is extremely stable§ and
* Corresponding author. Fax: 949 8243866; e-mail: leoverma@uci.edu
†
We are delighted to dedicate this paper to Harry Wasserman on the occasion of his 80th birthday. His creative
scholarship and leadership have immeasurably enriched organic chemistry.
†
Catherine M. Gasparski, also known as Sr. Mary Albert Gasparski. Current address: St. Cecilia Motherhouse, 801
Dominican Drive, Nashville, TN 37228-1909, USA.
‡
Current address: Pharmacia & Upjohn, MS 1510-91-01, Kalamazoo, MI 49007-4910, USA.
4-Alkenyl-1,3-dioxolanes are likely intermediates in the direct condensation of 1 with aldehydes and ketones to form
§
4.
0040-4039/00/$ - see front matter © 2000 Published by Elsevier Science Ltd.
PII: S0040-4039(00)01571-9

9432
R1
R2
R3
O
+
OH
OH
R6
R5
O
R4
EO
R3
R4
R1
R6
R5
R2 R1
1
R3
R4
Lewis or
R6
R5
O
Bronsted acid
R2
O
R1
3
4
R2
R3
+
[E = Lewis acid or H ]
O
O
R5
R6
R4
2
Scheme 1. Formation of 3-acyltetrahydrofurans from allylic diols and aldehydes or ketones
does not undergo ring-opening to generate the obligatory intermediate 3 under conditions mild
enough to avoid heterolytic cleavage of the allylic C–O bond.4,5 In this communication, we
report a modification of the sequence depicted in Scheme 1 that allows 5-unsubstituted
tetrahydrofurans 4 (R5=R6=H) to be prepared. Moreover, we report the best evidence to date
that this tetrahydrofuran synthesis takes place by a Prins cyclization–pinacol rearrangement
pathway.
Our approach for generating formaldehyde oxonium ions 3 (R5=R6=H) was to access these
intermediates from allylic diol precursors having the homoallylic alcohol protected as an
alkoxymethyl or thioalkoxymethyl ether. Initial scouting experiments showed that
methoxymethyl (MOM) and methylthiomethyl (MTM) derivatives functioned well, and that to
prevent 1,3-dioxolane formation the allylic alcohol was best protected with a tert-
butyldimethylsilyl (TBS) group. The cyclization substrates depicted in Table 1 were prepared in
41–81% overall yield from commercially available starting materials by reaction of a-alkoxyke-
tone intermediates¶ with alkenyl Grignard or lithium reagents followed by silylation (TBS-OTf,
2,6-lutidine) of the intermediate alcohols.** We initially surveyed a variety of Lewis acids for the
conversion of propenyl substrate 6 to acyltetrahydrofuran 17. Strong Lewis acids or reagents
that convert the methoxymethyl group to more labile halomethyl intermediates11 were required
(Table 1). For example, the conversion of 6“17 was realized within hours at −78°C in CH2Cl2
in the presence of 1 equiv. of TiCl4 or BCl3 (entries 1 and 3). While bromodimethylborane could
also be employed,12 this Lewis acid was not strong enough to promote ionization of the initially
produced bromomethyl derivative except at elevated temperatures; as a result yields of 17 were
improved by promoting this ionization at −78°C by adding AgBF4 (entry 2). A single
¶ (a) ( )-3-(Methoxymethoxy)-5-phenyl-2-pentanone was prepared in 58% overall yield from 2-methyl-5-phenyl-1-
penten-3-ol by the following sequence: (i) MOM-Cl, (i-Pr)2EtN, CH2Cl2, rt; (ii) cat. OsO4, NaIO4, dioxane–H2O, rt.
(b) (S)-2-(Methoxymethyl)-6-phenyl-3-hexanone was prepared in 52% overall yield from ethyl (S)-lactate by the
,
following sequence: (i) (MeO)2CH2, BF3·OEt2, 4 A molecular sieves, CH2Cl2, rt; (ii) Ph(CH2)3Li, Et2O, −100°C. (c)
( )-2-(Methoxymethoxy)cyclopentanone was prepared in 52% yield from 2-hydroxycyclopentanone by reaction with
MOM-Cl, (i-Pr)2EtN, CH2Cl2, rt. (d) ( )-2-[(Methylthio)methoxy]cyclopentanone was prepared in 54% yield from
2-hydroxycyclopentanone by reaction with MTM-Cl, AgNO3, 2,6-lutidine, toluene, 60°C.
1
** The stereochemistry of the cyclization precursors was confirmed by H NMR NOE experiments. The enantio-
purity of (S)-lactate-derived 10 was established by HPLC analysis using a Daicel OJ column.

9433
Table 1
Synthesis of 5-unsubstituted 3-acyltetrahydrofuransa

9434
1
tetrahydrofuran 17, whose stereochemistry was secured by H NMR NOE experiments, was
produced (dr >98:2) under all three reaction conditions. Attempted conversion of the congener of
6 lacking the TBS group to 17 under similar conditions provided only the corresponding
1,3-dioxolane. Since the yield of 17 from 6 was highest with BCl3, this Lewis acid was chosen
for subsequent experiments.
The scope of this synthesis of 3-acyl-5-unsubstituted tetrahydrofurans is summarized in Table
1. The nucleophilicity and stereochemistry of the alkene component can be varied widely (entries
3–6), which allows substituents to be introduced with high stereocontrol at carbons 2, 3 and 4 of
the tetrahydrofuran ring. With the exception of entry 6, a single tetrahydrofuran stereoisomer
was produced.†† The minor trans isomer formed in the rearrangement of 10 likely arises by
epimerization of 20 subsequent to its formation, since the amount of 21 produced varied from
run to run. Significantly, there was no detectable loss of enantiopurity in the conversion of
10“20.†† Entries 7 and 9 show that cis-hexahydrobenzofuranones can be prepared in useful
yields from cyclization precursors derived from trans-1-alkenylcyclopentane-1,2-diols. Moreover,
entry 9 illustrates that this tetrahydrofuran synthesis can be carried out under milder, more selec-
tive conditions by using dimethyl(methylthio)sulfonium tetrafluoroborate to activate the MTM
precursor.13 This entry also shows that when the 1,3-dioxolane derived from the rearrangement
substrate has some degree of strain, protecting the allylic hydroxyl group is not essential. The
major product produced from exposure of cis-1-alkenylcyclopentane-1,2-diol-derived precursor
13 to BCl3 was the corresponding 1,3-dioxabicyclo[3.3.0]octane (1,3-dioxolane formation).
As we have discussed in some detail previously,4 two possible mechanisms for the formation
of 3-acyltetrahydrofurans from allylic diol and carbonyl precursors are Prins cyclization14
followed by pinacol rearrangement,15 and 2-oxonia[3,3]-sigmatropic rearrangement followed by
aldol-type cyclization. These possibilities are illustrated in Scheme 2 for the conversion of 10“20.
OTBS
O
pinacol
+
rearrangement
R
R
O
–TBSCl
O
Prins
cyclization
25
20
retention
OTBS
OTBS
OTBS
R
R
OTBS
[3,3]
C–C rotation
BCl3
R
R
O
O
O
OMOM
+
+
+
H
10
24
26
ent-26
aldol
aldol
–TBSCl
–TBSCl
O
O
and
R
R
O
20
O
ent-20
racemization
Scheme 2. Mechanistic possibilities (R=CH2CH2CH2Ph)
1
†† Stereochemical assignments were made by H NMR NOE experiments. Enantiopurity of 20 was established by
HPLC analysis using a Daicel OD column.

9435
A cyclization–pinacol sequence must proceed with retention of configuration at the homoallylic
stereogenic center.15 In contrast, a [3,3]-sigmatropic rearrangement–aldol process would yield
racemic products if the rearranged oxonium ion (26 in the example illustrated in Scheme 2)
contained no stereogenic centers and the barrier for aldol cyclization was higher than that of
C–C single bond rotation.§§ The complete preservation of enantiomeric purity in the conversion
of 10“20 is consistent with a cyclization–pinacol pathway. This result constitutes a more
convincing mechanistic proof than the one reported earlier,4 since the weakly nucleophilic
terminal vinyl group of 10 provides no bias towards Prins cyclization.
In summary, 3-acyl-5-unsubstituted tetrahydrofurans can be prepared with high stereocontrol
and enantiopurity from methoxymethyl or (methylthio)methyl derivatives of allylic diols. These
transformations, and related reactions reported earlier,3–10 most likely proceed by Prins cycliza-
tion–pinacol rearrangement pathways.
Acknowledgements
This research was supported by a Javits Neuroscience Investigator Award from NIH NINDS
(NS-12389) and by NIH NRSA postdoctoral fellowships to C.M.G. (GM-14524) and J.P.W.
(GM-20140). Merck, Pfizer and Roche Biosciences provided additional support. NMR and mass
spectra were determined at UC Irvine using instrumentation acquired with the assistance of NSF
and NIH Shared Instrumentation programs.
References
1. Elliott, M. C. J. Chem. Soc., Perkin Trans. 1 2000, 1291–1318 and earlier reviews in this series.
2. For brief reviews see: (a) Overman, L. E. Acc. Chem. Res. 1992, 25, 352–359. (b) Overman, L. E. Aldrichim. Acta
1995, 28, 107–120.
3. Martinet, P.; Mousset, G. Bull. Soc. Chim. Fr. 1970, 1071–1076.
4. Hopkins, M. H.; Overman, L. E.; Rishton, G. M. J. Am. Chem. Soc. 1991, 113, 5354–5365.
5. Brown, M. J.; Harrison, T.; Herrinton, P. M.; Hopkins, M. H.; Hutchinson, K. D.; Mishra, P.; Overman, L. E.
J. Am. Chem. Soc. 1991, 113, 5365–5378.
6. Brown, M. J.; Harrison, T.; Overman, L. E. J. Am. Chem. Soc. 1991, 113, 5378–5384.
7. Grese, T. A.; Hutchinson, K. D.; Overman, L. E. J. Org. Chem. 1993, 58, 2468–2477.
8. MacMillan, D. W. C.; Overman, L. E. J. Am. Chem. Soc. 1995, 117, 10391–10392.
9. Hanaki, N.; Link, J. T.; MacMillan, D. W. C.; Overman, L. E.; Trankle, W. G.; Wurster, J. A. Org. Lett. 2000,
2, 223–226.
10. Overman, L. E.; Pennington, L. D. Org. Lett. 2000, 2, 2683–2686.
11. Berger, D.; Overman, L. E.; Renhowe, P. A. J. Am. Chem. Soc. 1997, 119, 2446–2452.
12. Guindon, Y.; Yoakim, C.; Morton, H. E. Tetrahedron Lett. 1983, 24, 2969–2972.
13. Trost, B. M.; Shibata, T.; Martin, S. J. J. Am. Chem. Soc. 1982, 104, 3228–3229.
14. Snider, B. B. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon Press: Oxford, 1991;
Vol. 2, pp. 527–562.
15. Rickborn, B. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon Press: Oxford, 1991;
Vol. 3, pp. 721–732.
16. Eliel, E. L.; Allinger, N. L.; Angyal, S. J.; Morrison, G. A. Conformational Analysis; American Chemical Society:
Washington, DC, 1965; Chapters 2 and 3.
§§ A reasonable assumption considering the low barriers of CꢀC single bond rotations.16