Lewis acid promoted Mukaiyama aldol-Prins (MAP) cyclizations of acetals, ketals, α-acetoxy ethers, and orthoformates

Article abstract of DOI:10.1055/s-2008-1032053

The Mukaiyama aldol-Prins (MAP) cyclization of acetals stereoselectively provided substituted tetrahydropyrans. The scope of the reaction has been expanded to include other electrophiles, including ketals and α-acetoxy ethers. Finally, a double MAP cycliz

Full text of DOI:10.1055/s-2008-1032053

LETTER
363
Lewis Acid Promoted Mukaiyama Aldol–Prins (MAP) Cyclizations of Acetals,
Ketals, a-Acetoxy Ethers, and Orthoformates
Lewis AcidPromoted
i
Mukaiy
c
ama
A
ldol
h
–Prins
C
ycliz
a
ations el R. Gesinski, Lori J. Van Orden, Scott D. Rychnovsky*
Department of Chemistry, 1102 Natural Sciences II, University of California, Irvine, CA 92697-2025, USA
Fax +1(949)8246379; E-mail: srychnov@uci.edu
Received 16 October 2007
Abstract: The Mukaiyama aldol–Prins (MAP) cyclization of ace-
tals stereoselectively provided substituted tetrahydropyrans. The
scope of the reaction has been expanded to include other electro-
philes, including ketals and a-acetoxy ethers. Finally, a double
MAP cyclization with orthoformates is described.
H
TiBr4/Ti(OiPr)4, 2,6-DBMP
CH2Cl2, –78 °C
+
O
O
R'
O
R''
2
1
Key words: tandem reactions, aldol reactions, annulations, acetals,
Br
carbocations
Br (eq/ax) 1.3:1
OH (S/R) 4.5:1
OH
O
O
R'
R''
3
The Prins reaction is a powerful transformation that gen-
erates a carbon–carbon bond through the coupling of an
activated aldehyde or ketone to an olefin.1 The carboca-
tion intermediate produced from this reaction has been
utilized in subsequent processes to develop elaborate
structures with high levels of stereoselectivity.2 The Mu-
kaiyama aldol–Prins reaction is an alternative tandem pro-
cess in which an oxocarbenium generated from the
Mukaiyama aldol addition of an aldehyde to a homoallylic
vinyl ether has been shown to undergo an intramolecular
Prins reaction. The carbenium ion intermediate is trapped
by addition of a nucleophile to generate cis-2,6-dialkyltet-
rahydropyrans (THP) stereoselectively.3 The scope of the
MAP reaction has been successfully extended to acetal-
type electrophiles, and the preliminary results are de-
scribed herein.
OMe
TiBr4, 2,6-DBMP
CH2Cl2, –78 °C
+
OMe
O
R'
O
R''
2
4
Br
Br (eq/ax) 8:1
OMe (S/R) 1:1
O
OMe O
R'
R''
5
Scheme 1 MAP cyclizations for leucascandrolide A
aldehydes with chelating groups.3 It has been hypothe-
sized that an oxocarbenium ion electrophile, which would
not be subject to chelation, might avoid this issue. When
dimethyl acetal 4 was employed as an electrophile the
equatorial bromide was obtained in 8:1 selectivity. Unfor-
tunately, the addition was not stereoselective at the meth-
oxy center, but because of the high selectivity obtained at
the bromide center, the MAP reaction with acetals war-
ranted further investigation.
Recently, the MAP reaction has been applied to the total
synthesis of the marine natural product leucascandrolide
A.4 The reaction of aldehyde 1 with vinyl ether 2 produced
THP 3 with high selectivity for the 1,3-anti product but
only modest equatorial/axial selectivity at the bromide
center (Scheme 1). The modest selectivity at the bromide
center is a known issue with MAP cyclizations utilizing
A proposed mechanism for the MAP reaction of acetals is
shown in Scheme 2.4 Initial coordination of titanium tet-
rabromide to dimethyl acetal 6 provides oxocarbenium
Br
R
OMe
O
MeOTiBr4
R
R
Br
OMe
TiBr4
10
R'
R'
O
R
R
OMe
OMe
– MeOTiBr4
OMe
MeOTiBr4
O
OMe
O
Br
R'
R'
R
6
7
8
9
OMe
O
11 R'
Scheme 2 Mechanism of the MAP reaction with acetals
SYNLETT 2008, No. 3, pp 0363–0366
x
x.
x
x.
2
0
0
8
Advanced online publication: 16.01.2008
DOI: 10.1055/s-2008-1032053; Art ID: S08207ST
© Georg Thieme Verlag Stuttgart · New York

364
M. R. Gesinski et al.
LETTER
Table 1 Optimization of the MAP Reaction with Acetals
X
Br
O
Lewis acid
base
OMe
OMe
OMe
+
+
Ph
Ph
O
Ph
O
Ph
Ph
14 X = Br
15 X = Cl
12
13
16
Entry Lewis acida
Base (equiv)
–
Temp (°C) Solvent
Yield (%)
dr (X) eq/axb
86:14
82:18
92:8
dr (OMe)c
1
2d
3
4
5
6
7
8
TiBr4
TiBr4
TiBr4
TiBr4
–78
–78
–78
–78
–78
–78
0
CH2Cl2
CH2Cl2
CH2Cl2
43
29
67
44
50
44
0
55:45
55:45
55:45
55:45
53:47
57:43
–
i-Pr2NEt (1.5)
2,6-DBMP (1.5)
2,6-DBMP (1.5)
2,6-DBMP (1.5)
2,6-DBMP (1.5)
2,6-DBMP (1.5)
AlMe3 (0.3)
CH2Cl2–hexanes
CH2Cl2
93:7
e
TiBr4/Ti(Oi-Pr)4
TiCl4
91:9
CH2Cl2
90:10
–
TMSBr
CH2Cl2
f
AlBr3
–40
CH2Cl2
40
80:20
56:44
a Unless otherwise noted, 4 equiv of Lewis acid were used.
b Determined by integration of the crude 1H NMR spectra.
c Determined by GC analysis.
d THP 16 was also isolated in 17% yield.
e Formed by premixing an 8:1 solution of TiBr4 and Ti(Oi-Pr)4.
f 1.5 equiv of AlBr3.
ion 7, which is activated toward nucleophilic addition. study (entry 7).6 Finally, an aluminum tribromide–
Mukaiyama aldol addition of vinyl ether 2 produces bro- trimethylaluminum-mixed Lewis acid system had been
mo ether 8 which is then activated to form ion pair 9. Di- demonstrated to promote very demanding Diels–Alder re-
rect collapse of this intermediate produces an axial actions,7 but the elevated temperatures required for the
bromide 10 while solvolysis produces an equatorial bro- MAP acetal reaction with this catalyst furnished reduced
mide 11.5,6 The selectivity of this last, partitioning step is yields and unremarkable selectivities (entry 8). Ultimate-
not sensitive to the structure of the acetal and should pro- ly, the original conditions for the MAP cyclization of al-
vide high selectivities for the equatorial diastereomer. dehydes proved to be optimal for acetal substrates.
This variation of the MAP cyclization is expected to work
with a variety of oxocarbenium ions.
With an optimized procedure in hand, various acetals
were explored as possible coupling partners (Table 2). A
Initial efforts were undertaken to optimize the MAP cy- dibenzyl acetal was first employed to provide a benzyl
clization of dimethyl acetal 12 with homoallylic vinyl ether that could easily be deprotected. This reaction pro-
ether 13 (Table 1). The use of various bases to sequester ceeded with yields and selectivities comparable to the
adventitious protic acid were first explored. Without base, dimethyl acetal substrate (entry 1). Cyclic acetals were
a considerable amount of proton-mediated Prins cycliza- also employed as a possible method to control the newly
tion product 16 of vinyl ether 13 was observed (entry 1). formed ether stereocenter. Initial results with an achiral
Hünig’s base proved detrimental to the reaction due to co- five-membered cyclic acetal were discouraging (entry 2).
ordination to titanium (entry 2). Ultimately, the hindered Reduced selectivities were observed, possibly because the
pyridine base, 2,6-di-tert-butyl-4-methylpyridine (2,6- oxocarbenium ion of the cyclic acetal provided a manifold
DBMP), proved ideal to buffer the system (entry 3). As for chelation, which has been shown to decrease equatori-
expected, less polar solvent systems disfavored the pro- al selectivity.3a The C2-symmetric chiral cyclic acetals
posed charged transition states and diminished yields have shown enhanced selectivities for nucleophilic addi-
were observed (entry 4). Additionally, various Lewis acid tions.8 When coupled with a chiral vinyl ether, a 71%
systems were explored to further enhance yields and se- yield was obtained with 89:11 bromide selectivity and
lectivity. Both the attenuated Lewis acid system used for 70:30 selectivity for the alkoxy stereocenter in favor of
leucascandrolide A and titanium tetrachloride provided the expected diastereomer (entry 3).
comparable selectivities, but reduced yields (entries 5 and
6). Bromotrimethylsilane has been shown to provide high
selectivities for axial bromination in similar systems, but
led only to decomposition of the starting materials in this
Various other electrophiles were also employed as cou-
pling partners for the MAP cyclization. Ketals and a-ace-
toxy ethers were successful coupling partners, providing
Synlett 2008, No. 3, 363–366 © Thieme Stuttgart · New York

LETTER
Lewis Acid Promoted Mukaiyama Aldol–Prins Cyclizations
Table 2 Exploration of Various Electrophiles for the MAP Reaction
Entry Electrophile Homoallylic vinyl ether
365
Major product
Yield dr (Br)
dr (OR)
1:1
(%)
eq/axa
Br
OBn
OBn
1
2
64
>95:5
OBn
Ph
Ph
Ph
Ph
O
O
Ph
Ph
O
Ph
Ph
OH
Br
O
44
71
74:26
89:11
1:1
O
O
O
Br HO
3
7:3b,c
O
O
TBDPSO
O
Ph
O
TBDPSO
O
Ph
Br
MeO OMe
4
5
6
7
8
61
65
36
23
90
95:5
–
Ph
Ph
O
O
Ph
Ph
O
OMe
Br
OAc
OEt
88:12
82:18
80:20
92:8
1:1
1:1
1:1
7:3d
OEt
Ph
O
Ph
Br
O
O
OAc
Ph
Ph
Ph
O
O
O
Ph
Ph
Ph
O
O
Br
OAc
OAc
O
O
Br
TMS
Ph
O
O
O
TMS
Ph
a Ratios determined by integration of the crude 1H NMR spectra.
b Ratio determined by HPLC analysis of the crude material.
c Stereochemistry of the major isomer determined by removal of the chiral auxiliary and formation and analysis of both MPTA ester diaste-
reomers.
d Ratio of isolated products.
yields and selectivities similar to those observed for the proved successful, providing interesting pseudo-C2-sym-
acetals (entries 4 and 5).9 Cyclic a-acetoxy ethers were in- metric structures 18 and 19.13 Utilizing E-homoallylic vi-
triguing electrophiles since selective nucleophilic addi- nyl ether 20 as a nucleophile selectively produced bis-
tion has been demonstrated depending on substitution.10 THP 21 with two equatorial methyl groups, in agreement
Unfortunately, neither simple five- or six-membered a- with precedent.3c,14 Overall, six new stereocenters were
acetoxy ethers provided useful yields of THP products generated in this single reaction.
(entries 6 and 7).11 Finally, chiral a-(trimethylsilyl)benzyl
The MAP cyclization has proven to be a very effective
method for the formation of a variety of substituted tet-
rahydropyrans. Utilization of acetals, a-acetoxy ethers,
and orthoformates has expanded the scope and utility of
a-acetoxy ethers have been employed to enhance the se-
lectivity of aldol additions.12 When this chiral auxiliary
was utilized for the MAP cyclization, a 90% yield of the
expected THP was produced with 7:3 selectivity for the
the reaction. The use of various chiral auxiliaries led to
aldol addition (entry 8).
enhanced stereoselectivity in the aldol-addition step. The
Orthoesters were also examined as substrates for double expanded scope of the MAP cyclization will be a power-
MAP cyclizations (Scheme 3). Only orthoformates ful tool in natural product synthesis.
Synlett 2008, No. 3, 363–366 © Thieme Stuttgart · New York

366
M. R. Gesinski et al.
LETTER
and 2,2-dimethoxypropane (0.022 mL, 0.25 mmol) in
TiBr4, 2,6-DBMP
CH2Cl2, –78 °C
RO OR
CH2Cl2 (2.5 mL) was cooled to –78 °C. Titanium
tetrabromide (0.32 M in CH2Cl2, 3.1 mL, 1.0 mmol) was
then added dropwise over 10 min. After 2 h, a 1:1 mixture of
MeOH and Et3N (5 mL) was added and the reaction mixture
was allowed to warm to r.t. Then, sat. aq NaHCO3 (10 mL)
was added and the mixture was extracted with Et2O (2 × 10
mL). The combined organic layers were washed with brine
(1 × 10 mL), dried over MgSO4, and concentrated under
reduced pressure. Purification by flash chromatography
(15:1 hexanes–Et2O) yielded 54 mg (61%) of the expected
THP as a colorless oil; Rf = 0.31 (hexanes–Et2O, 9:1). 1H
NMR (500 MHz, CDCl3): d = 7.29 (t, J = 7.9 Hz, 2 H), 7.19
(t, J = 7.4 Hz, 3 H), 4.15 (tt, J = 12.0, 4.5 Hz, 1 H), 3.55–3.49
(m, 1 H), 3.32–3.26 (m, 1 H), 3.29 (s, 3 H), 2.83–2.77 (m, 1
H), 2.68–2.58 (m, 1 H), 2.24–2.16 (m, 2 H), 1.93–1.60 (m, 6
H), 1.26 (s, 3 H), 1.22 (s, 3 H). 13C NMR (125 MHz, CDCl3):
d = 142.0, 128.53, 128.49, 126.0, 76.5, 74.3, 74.1, 49.3, 47.0,
45.9, 44.6, 43.4, 37.7, 32.0, 26.2, 25.3. IR (neat): 2925,
2860, 1603, 1454, 1080 cm–1. HRMS (ES/MeOH): m/z calcd
for C18H27BrO2 [M + Na]+: 377.1092; found: 377.1088.
(10) (a) Larsen, C. H.; Ridgway, B. H.; Shaw, J. T.; Woerpel, K.
A. J. Am. Chem. Soc. 1999, 121, 12208. (b) Ayala, L.;
Lucero, C. G.; Romero, J. A. C.; Tabacco, S. A.; Woerpel,
K. A. J. Am. Chem. Soc. 2003, 125, 15521. (c) Lewis, M.
D.; Cha, J. K.; Kishi, Y. J. Am. Chem. Soc. 1982, 104, 4976.
(11) Cyclic a-methoxy ethers and more complicated sugar
moieties provided no THP products when employed as
electrophiles.
+
H
OR
TBDPSO
O
R = Me; 57% (dr 86:14)
R = Et; 54% (dr 85:15)
17
Br
Br
OR
TBDPSO
O
O
OTBDPS
18 R = Me
19 R = Et
TiBr4, 2,6-DBMP
CH2Cl2, –78 °C
EtO OEt
+
H
OEt
Ph
O
52% (dr >95:5)
Br
20
Br
OEt
Ph
O
O
Ph
21
Scheme 3 MAP reaction of orthoformates
Acknowledgment
This work was supported by the National Cancer Institute (CA-
081635) and a generous gift from Schering-Plough Research Insti-
tute.
(12) Rychnovsky, S. D.; Cossrow, J. Org. Lett. 2003, 5, 2367.
(13) Neither orthoacetates nor orthocarbonates were reactive
towards nucleophilic addition.
(14) Synthesis of bis-THP (21)
References and Notes
A solution of 2,6-di-tert-butyl-4-methylpyridine (35 mg,
0.58 mmol), homoallylic vinyl ether 20 (48 mg, 0.22 mmol),
and triethyl orthoformate (0.018 mL, 0.11 mmol) in CH2Cl2
(1.1 mL) was cooled to –78 °C. Titanium tetrabromide (0.32
M in CH2Cl2, 1.4 mL, 0.44 mmol) was then added dropwise
over 10 min. After 2 h, a 1:1 mixture of MeOH and Et3N (5
mL) was added and the reaction mixture was allowed to
warm to r.t. Then, sat. aq NaHCO3 (5 mL) was added and the
mixture was extracted with Et2O (2 × 5 mL). The combined
organic layers were washed with brine (1 × 5 mL), dried
over MgSO4, and concentrated under reduced pressure.
Purification by flash chromatography (hexanes–Et2O, 20:1
to 15:1) yielded 37 mg (52%) of the title compound as a
colorless oil; [a]D24 +1.1 (c 1.9, CHCl3); Rf = 0.33 (hexanes–
Et2O, 9:1). 1H NMR (500 MHz, CDCl3): d = 7.32–7.06 (m,
10 H), 4.07–3.99 (m, 1 H), 3.93 (td, J = 11.6, 4.6 Hz, 1 H),
3.84 (td, J = 11.3, 4.5 Hz, 1 H), 3.75–3.65 (m, 1 H), 3.55–
3.43 (m, 1 H), 3.38–3.29 (m, 2 H), 3.21 (t, J = 9.1 Hz, 1 H),
3.04 (t, J = 9.5 Hz, 1 H), 2.85–2.60 (m, 4 H), 2.35–2.22 (m,
2 H), 2.00–1.58 (m, 12 H), 1.23 (t, J = 6.9 Hz, 3 H), 1.13 (d,
J = 6.5 Hz, 3 H), 1.10 (d, J = 6.4 Hz, 3 H). 13C NMR (125
MHz, CDCl3): d = 141.9, 128.8, 128.5, 126.0, 79.3, 78.4,
76.4, 75.8, 72.3, 64.9, 57.7, 57.2, 45.8, 45.6, 44.6, 44.5, 39.2,
38.8, 37.5, 32.1, 31.5, 16.4, 15.8. IR (neat): 2927, 2854,
1456, 1086 cm–1. HRMS (ES/MeOH): m/z calcd for
C33H46Br2O3 [M + Na]+: 671.1711; found: 671.1719.
(1) (a) Arundale, E.; Mikeska, L. A. Chem. Rev. 1952, 52, 505.
(b) Adams, D. R.; Bhatnagar, S. P. Synthesis 1977, 661.
(c) Snider, B. B. In The Prins Reaction and Carbonyl Ene
Reactions, Vol. 2; Trost, B. M.; Fleming, I.; Heathcock, C.
H., Eds.; Pergamon Press: New York, 1991, 527–561.
(d) Pastor, I. M.; Yus, M. Curr. Org. Chem. 2007, 11, 925.
(2) (a) Overman, L. E.; Pennington, L. D. J. Org. Chem. 2003,
68, 7143. (b) Miles, B.; Davis, C. H.; Coates, R. M. J. Org.
Chem. 2006, 71, 1493.
(3) (a) Kopecky, D. J.; Rychnovsky, S. D. J. Am. Chem. Soc.
2001, 123, 8420. (b) Patterson, B.; Marumoto, S.;
Rychnovsky, S. D. Org. Lett. 2003, 5, 3163. (c) Patterson,
B.; Rychnovsky, S. D. Synlett 2004, 543.
(4) Van Orden, L. J.; Patterson, B.; Rychnovsky, S. D. J. Org
Chem. 2007, 72, 5784.
(5) Alder, R. W.; Harvey, J. N.; Oakley, M. T. J. Am. Chem. Soc.
2002, 124, 4960.
(6) Jasti, R.; Vitale, J.; Rychnovsky, S. D. J. Am. Chem. Soc.
2004, 126, 9904.
(7) Jung, M. E.; Ho, D.; Chu, H. V. Org. Lett. 2005, 7, 1649.
(8) Johnson, W. S.; Edington, C.; Elliott, J. D.; Silverman, I. R.
J. Am. Chem. Soc. 1984, 106, 7588.
(9) Representative Experimental (Table 2, Entry 4)
A solution of 2,6-di-tert-butyl-4-methylpyridine (77 mg,
0.38 mmol), homoallylic vinyl ether 13 (50 mg, 0.25 mmol),
Synlett 2008, No. 3, 363–366 © Thieme Stuttgart · New York

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