Stereoselective synthesis of highly substituted annulated dihydropyrans based onγ-lithiation and homoaldol reaction of an enantiopure α-silylated vinyl carbamate

Article abstract of DOI:10.1055/s-0029-1218596

The N,N-diisopropylcarbamate of (-)-myrtenol is converted into the corresponding [1-(trimethylsilyl)vinyl] carbamate. Its-lithiation by means of sec-butyllithium/TMEDA, titanation, and addition to aldehydes leads with high stereoselectivity to enantiopure anti-homoaldol products. These add, under the influence of boron trifluoride-diethyl ether complex, a second equivalent of aldehyde and form, in an intermolecular silyl-Prins reaction, the title compounds, again with essentially complete stereoselectivity. After desilylation, the reaction takes the regular course with formation of an annulated five-membered ring. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1218596

PAPER
329
Stereoselective Synthesis of Highly Substituted Annulated Dihydropyrans
Based on g-Lithiation and Homoaldol Reaction of an Enantiopure a-Silylated
Vinyl Carbamate
Stereoselective
h
S
ynthesis of
é
Highly
S
ub
r
stituted
è
A
nnulated
s
D
ihydropy
e
rans Hémery, Birgit Wibbeling,1 Roland Fröhlich,1 Dieter Hoppe*
Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstr. 40, 48149 Münster, Germany
Fax +49(251)8339772; E-mail: dhoppe@uni-muenster.de
Received 14 July 2009; revised 31 August 2009
Dedicated to Professor Wilhelm Flitsch on the occasion of his 85th birthday
alkene 12, which gave suitable crystals for X-ray analysis
Abstract: The N,N-diisopropylcarbamate of (–)-myrtenol is con-
verted into the corresponding [1-(trimethylsilyl)vinyl] carbamate.
Its g-lithiation by means of sec-butyllithium/TMEDA, titanation,
and addition to aldehydes leads with high stereoselectivity to enan-
tiopure anti-homoaldol products. These add, under the influence of
boron trifluoride–diethyl ether complex, a second equivalent of al-
dehyde and form, in an intermolecular silyl-Prins reaction, the title
compounds, again with essentially complete stereoselectivity. After
desilylation, the reaction takes the regular course with formation of
an annulated five-membered ring.
(Figure 1).10 We considered that the silyl group could
eventually be removed later in a suitable step.
BuLi, TMEDA
O
N
Li
O
N
H
O
N
O
N
OCb
Key words: chiral allyl carbamates, vinyl carbamates, diastereo-
selective g-lithiation, aldehyde addition, annulated dihydropyrans
1
2
R1
OH
The homoaldol reaction of metalated alk-2-enyl N,N-di-
isopropylcarbamates has become a valuable tool in enan-
tioselective synthesis.2 Chiral monoterpene derived
cyclohex-2-enyl N,N-diisopropylcarbamates such as 1,
undergo diastereoselective lithiodeprotonation reactions
to form lithium compounds 2 (Scheme 1).3 In particular
after lithium–titanium exchange,4 compound 3 can be
used as a versatile homoaldol reagent and with aldehydes
forms homoaldol products 4, often with high stereoselec-
tivity.3 Treated with a further equivalent of aldehyde (or
acetal or even ketone) leads to the formation, via interme-
diate oxocarbenium ion 5, of bicyclic tetrahydrofurans 7
as single diastereomers.5
H
ClTi(NEt2)3
R1CH=O
(Et2N)3Ti
OCb
OCb
4
3
R1
R2CH=O
BF3⋅OEt2
O
H
R2
OCb
5
R1
R1
O
H
H
(–)-Myrtenol (8) is another readily available monoter-
pene, which was converted into the carbamate 9
(Scheme 2).3 Lithiation by means of n-butyllithium/
N,N,N¢,N¢-tetramethylethylenediamine (TMEDA) result-
ed in the formation of two equilibrating lithium com-
pounds 10.6 Their homoaldol reaction (as well as
silylation) took place with poor diastereoselectivity. We
had experienced in previous work7 and verified by
calculations8 that homoaldol reactions of reagents, pre-
pared by g-lithiation of vinyl carbamates proceed with
very high stereoselectivity. Therefore, lithium intermedi-
ate 10 was converted, via titanation/hydrolysis, into vinyl
carbamate 11, which was found to be the pure (E)-alkene.
For removal of the most acidic vinylic proton, lithiation
and silylation proceeded well,9 furnishing the pure (Z)-
– Cb
O
R2
R2
OCb
O
7
6
Scheme 1 Stereoselective synthesis of hexahydroisobenzofuran-
4(1H)-ones3
Figure 1 X-ray crystal structure of 12
SYNTHESIS 2010, No. 2, pp 0329–0342
x
x
.
x
x
.2
0
0
9
Advanced online publication: 07.12.2009
DOI: 10.1055/s-0029-1218596; Art ID: T13809SS
© Georg Thieme Verlag Stuttgart · New York

330
T. Hémery et al.
PAPER
carbon atom took place as expected from the rear face of
14 (opposite to the isopropylidene bridge). Addition of 2-
methylpropanal (17a) to the solution of carbanion 14 gave
rise to two epimers, 18a (23%) and epi-18a (51%), differ-
ing in the relative configuration of the side chain. The ma-
jor diastereomer epi-18a provided suitable crystals for an
X-ray structure analysis12 (Figure 2) and confirmed its rel-
ative syn-configuration. The anti-configuration of the
diastereomer 18a was determined by NOE spectroscopy
and confirmed by X-ray crystal structure analysis13
(Figure 3).
CbCl
OH
O
N
pyridine, 90 °C
9
8
O
OCb
2. (i) Ti(Oi-Pr)4 (1.4 equiv)
(ii) MeOH
1. n-BuLi, TMEDA
Et2O, –78 °C
OCb
Et2O, –78 °C
Li⋅TMEDA
10
HS
HR
1. s-BuLi, TMEDA
2. ClSiMe3
OCb
OCb
Et2O, –78 °C
H
SiMe3
12 (93%)
11 (58%)
Scheme 2 Synthesis of alkene 12
Figure 2 Structure of epi-18a
The g-lithiation of vinyl carbamate 12 by a slight excess
of sec-butyllithium/TMEDA in diethyl ether at –78 °C
proceeded smoothly (2 h) by removal of the g-pro-S H to
form the a-lithio carbamate 14 (Scheme 3).11
N
N
sBu Li
H
HR
HS
O
Figure 3 Structure of 18a and NOE enhancements
H
s-BuLi, TMEDA
Et2O, –78 °C
N(i-Pr)2
OCb
SiMe3
O
This result excludes a pericyclic addition process of lithi-
um compound 14 onto aldehydes,14 and, thus, does not
permit a conclusion about the configuration of the react-
ing lithium species.15 However, metal exchange of lithium
for titanium(IV) in lithioallylic compounds ensures the
pericyclic process in carbonyl addition.7 Consequently,
before addition of the aldehyde 17, an excess of chloro-
tris(diethylamino)titanium was reacted with the lithium
compound 14 (Scheme 4). Aldehydes 17 furnished almost
exclusively the anti-configured homoaldol products 18
(Table 1).
Me3Si
12
TS-13
O
Li
O
O
N(i-Pr)2
O
N(i-Pr)2
1. Me2C=O
Me3Si Li
N
O
Me3Si
TS-15
N
14
1.
(17a)
O
2. H2O
2. H2O
H
H
1. R1CH=O 17
ClTi(NEt2)3
OH
14
Ti(NEt2)3
OCb
H
H
CbO
SiMe3
SiMe3
19
OH
OH
OCb
16
R1
OCb
H
CbO
R1
OH
SiMe3
epi-18a (51%)
SiMe3
18a (23%)
O
2. H2O
OCb
Ti
(NEt2)3
Me3Si
H
SiMe3
Scheme 3 Lithiation of 12 and reaction with acetone and 2-methyl-
propanal
TS-20
18
Scheme 4 Titanium-mediated homoaldol reaction of 12 via lithium
intermediate 14 (see Scheme 3)
The addition of acetone produced a single addition prod-
uct 16 in 33% yield besides starting material 12, as a result
of reprotonation of 14 by CH-acidic acetone. No a-addi-
tion product was found. Obviously, the attack onto the g-
The products have to arise from the a-(R)-titanium inter-
mediate 19, but it does not provide a solid conclusion on
the configuration of the dominating lithium compound.
Synthesis 2010, No. 2, 329–342 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of Highly Substituted Annulated Dihydropyrans
331
Although lithium–titanium exchange of lithiated allyl car- furans but the corresponding diastereomerically pure di-
bamates usually proceeds with inversion of configuration, hydropyrans 23aa–fc were obtained with good yields
steric repulsion may cause exceptions.3b
(Scheme 5, Table 2). The product 23ac gave suitable
crystals for X-ray analysis, which confirmed its structure
(Figure 4).17 The similarity in structure and configuration
of further dihydropyrans 23ba–fc was deduced from NOE
experiments (an example is shown in Figure 5).
The anti-homoallyl alcohols 18 reacted smoothly with
different aldehydes in the presence of BF3·OEt2 under the
conditions of the Krämer tetrahydrofuran synthesis.5 To
our great surprise, not the expected annulated tetrahydro-
Table 1 Homoaldol Reaction of 12 with Aldehydes 17a–ia
Entry Aldehyde
Product
Yield (%)
69
[a]D20 (CHCl3)b
drc
H
H
OH
1
2
17a
17b
2-methylpropanal
18a
–56.0
>99:1
OCb
SiMe3
cyclopropanecarbaldehyde
18b
18c
64
60
–2.6
>99:1
>99:1
OH
OCb
SiMe3
H
3
17c
benzaldehyde
–32.2
OH
OCb
SiMe3
Br
4
17d
4-bromobenzaldehyded
18d
62
–16.3
nde
H
OH
OCb
SiMe3
5
17e
naphthalene-2-carbaldehyde
18e
57
–17.9
nde
H
H
OH
OCb
SiMe3
OH
6
7
17f
prop-2-enal
18f
65
73
–2.7
>99:1
OCb
SiMe3
O
H
17g
furan-2-carbaldehyde
18g
–41.6
94:6
OH
OCb
SiMe3
Synthesis 2010, No. 2, 329–342 © Thieme Stuttgart · New York

332
T. Hémery et al.
Table 1 Homoaldol Reaction of 12 with Aldehydes 17a–ia (continued)
Entry Aldehyde Product
PAPER
Yield (%)
[a]D20 (CHCl3)b
drc
O
O
H
8
9
17h
2,3-O-isopropylidene-D-glyceraldehydef 18h
65g
–70.6
97:3
OH
OCb
SiMe3
H
17i
2,2-dimethylpropanal
18i
76
–87.5
>99:1
OH
OCb
SiMe3
a For reaction conditions, see Scheme 4.
b c 0.56–1.02.
c Determined by GC analysis of the crude product.
d 4.5 h lithiation.
e The products decomposed on GC.
f 4 h lithiation.
g Proposed relative configuration assuming a Felkin–Anh-type attack.16
Table 2 Cyclocondensation of 18a–i with Different Aldehydes 17a–ga
20
Entry Substrate Aldehyde
Reaction conditions
Product
Yield
(%)
[a]D
(CHCl3)b
H
0 °C, 1 h;
r.t., 2 h
O
1
2
18a
18b
17c
17c
benzaldehyde
benzaldehyde
23ac
65
+88.0
OCb
H
0 °C, 3 h
23bc
23cc
21c
+74.0
+80.5
O
OCb
H
3
18c
17c
benzaldehyde
0 °C, 1 h; r.t., 1 h
62
O
OCb
Br
4
18d
17c
benzaldehyde
0 °C, 1 h; r.t., 1.5 h
23dc
70
+57.0
H
O
OCb
Synthesis 2010, No. 2, 329–342 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of Highly Substituted Annulated Dihydropyrans
Table 2 Cyclocondensation of 18a–i with Different Aldehydes 17a–ga (continued)
Entry Substrate Aldehyde Reaction conditions Product
333
20
Yield
(%)
[a]D
(CHCl3)b
5
18e
17c
benzaldehyde
0 °C, 1 h; r.t., 45 min 23ec
52
+80.3
H
H
O
OCb
O
6
18f
17c
benzaldehyde
0 °C, 2 h; r.t., 2 h
23fc
48
+85.1
OCb
7
8
18g
18h
17c
17c
benzaldehyde
benzaldehyde
0 °C, 1 h; r.t. 2 h
–
–
decomp.
decomp.
–
–
–
–
0 °C, 1 h; r.t., 18 h
H
O
9
18i
17c
benzaldehyde
0 °C, 4 h; r.t., 12 h
26
65
–31.1
O
H
H
cyclopropanecarbalde-
hyde
O
10
11
12
18a
18a
18a
17b
17d
17f
0 °C, 1 h
23ab
23ad
23af
80
41
53
–21.6
+82.6
+67.7
OCb
O
4-bromobenzaldehyde
0 °C, 1 h; r.t., 3 h
OCb
Br
H
H
O
prop-2-enal
0 °C, 1 h; r.t., 1 h
OCb
O
13
14
18a
18a
17g
17i
furan-2-carbaldehyde
2,2-dimethylpropanal
0 °C, 1 h; r.t., 30 min 23ag
19c
+32.3
–
O
OCb
0 °C, 1 h; r.t., 36 h
–
decomp.
–
a For reaction conditions, see Scheme 5.
b c 0.24–1.23.
c As decomposition was observed by TLC, the reaction was stopped.
Synthesis 2010, No. 2, 329–342 © Thieme Stuttgart · New York

334
T. Hémery et al.
PAPER
Furthermore, TS-21 can also undergo a [3,3]-sigmatropic
oxa-Cope rearrangement,19 affording TS-21¢, also E-con-
figured. Nucleophilic attack of the trimethyl(vinyl)silane
in TS-21 or the more reactive allyltrimethylsilane TS-21¢
induces the formation of cis-23.
R1
R1
H
CbO
H
O
R2
R2CH=O
OH
BF3⋅OEt2
OCb
Me3Si
TS-21
H
CH2Cl2
SiMe3
18
We finally were faced with another surprise: when treat-
ing compound 18i with benzaldehyde and BF3·OEt2, the
reaction proceeded only very sluggishly and we isolated
the tetrahydrofuran 26 (Scheme 6). The structure of 26
was confirmed by a NOE investigation (Figure 6). Obvi-
ously the oxocarbenium salt 21ic is unable to undergo cy-
clization due to its high steric load. Instead 18i is
desilylated by fluoride, formed from BF3, to produce ho-
moaldol 24, which undergoes, via oxocarbenium ion TS-
25, the ‘usual’ cyclization.
oxa-Cope
R1
H
CbO
O
R1
O
R2
R2
Me3Si
H
Me3Si OCb
H
22
TS-21′
+ HX
– Me3SiF
R1
H
O
R2
H
H
OCb
BF3/HF
OH
OH
23
THF, r.t.
OCb
OCb
Scheme 5 Cyclocondensation of 18 with aldehydes
H
SiMe3
18i
24
H
H
PhCH=O
BF3⋅OEt2
– Cb
O
CbO
O
CH2Cl2, 0 °C
Ph
O=HC
H
Ph
TS-25
26
Scheme 6 Desilylation of 18i following by cyclization
Figure 4 Structure of 23ac
H
H
O
H
H
H
H
CH=O
H
OCb
H
Br
H
O
Figure 6 NOE enhancements for 26
H
Figure 5 NOE enhancements for 23ad
The reaction course was confirmed by the following con-
trol experiment: 18i was desilylated by means of tetrabu-
tylammonium fluoride and the resulting homoaldol
product 24 was treated with benzaldehyde/BF3·OEt2. In a
We assume that the origin of the six-membered-ring for- rapid reaction (0 °C, 90 min), the annulated tetrahydrofu-
mation is caused by the stabilization of the cationic inter- ran 26 was formed in 75% yield. It is evident from this re-
mediate 22 by the b-trimethylsilyl group, produced by the sult that even though the desilylation by BF3·OEt2-derived
cyclization of the oxocarbenium ion TS-21.18 From 22 (or fluoride is the slowest step, its rate overrides the dihydro-
even already during the cyclization step) the trimethylsilyl pyran cyclization of 18i. Nevertheless, the formation of
group is eliminated with formation of the unsaturated ring the five-membered ring was observed only in that partic-
23. Consequently, the reaction course resembles an in- ular case.
tramolecular silyl-mediated Prins-type reaction.19 The ob-
served cis-selectivity of the reaction can be explained by
the formation of the E-configured oxocarbenium ion TS-
In conclusion, it was demonstrated, with the example of (–)-
myrtenyl carbamate, that allyl carbamates with remote
stereogenic centers are easily isomerized to the corre-
sponding vinyl carbamates, capable of efficient diastereo-
selective g-lithiation, and homoaldol reaction. The silyl
group causes under the conditions of the Krämer tetrahy-
21, which adopts the energetically favored six-membered
chair conformation with both substituents (R1 and R2) in a
pseudoequatorial position.
Synthesis 2010, No. 2, 329–342 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of Highly Substituted Annulated Dihydropyrans
335
[(Z)-(1R,5S)-6,6-Dimethylbicyclo[3.1.1]hept-2-ylidene](tri-
methylsilyl)methyl N,N-Diisopropylcarbamate (12)
drofuran synthesis the formation of an annulated dihydro-
pyran ring. Four new stereocenters are formed with high
stereoselectivity. When the silyl group is removed from
the intermediates 18, the usual tetrahydrofuran annulation
takes place.
A 1.28 M soln of s-BuLi in hexanes (1.2 mL, 1.54 mmol, 1.6 equiv)
was added dropwise to a soln of 11 (274 mg, 0.98 mmol, 1.0 equiv)
and TMEDA (145 mg, 1.25 mmol, 1.3 equiv) in Et2O (4 mL) at –78
°C. After a lithiation time of 1.5 h, TMSCl (165 mg, 1.52 mmol, 1.6
equiv) was added slowly within 5 min. The mixture was stirred at
–78 °C for 2 h and it was quenched by the addition of sat. aq NH4Cl
(10 mL). After warming to r.t. and addition of Et2O (10 mL), the or-
ganic layer was removed. The aqueous phase was extracted with
Et2O (3 × 15 mL). The combined organic layers were dried
(MgSO4) and concentrated under reduced pressure. Purification by
column chromatography (Et2O–pentane) yielded 12 (321 mg, 93%)
as a colorless solid; mp 34–36; Rf = 0.63 (Et2O–pentane, 1:4).
All reactions were carried out under an argon atmosphere in flame-
dried flasks sealed by rubber septa. Unless otherwise specified, ma-
terials were obtained from commercial sources and used without
purification. All solvents were dried according to standard proce-
dures and purified by distillation prior to use. TMSCl and TMEDA
were distilled from powdered CaH2 and stored under argon. s-BuLi
was filtered through Celite before use and its concentration was de-
termined by titration against Ph2CHCO2H.20 ClTi(NEt2)3 was ob-
tained as described in the literature.4 Flash column chromatography
was performed on Merck 60 silica gel, 40–63 mm (pressure ~1 bar)
and monitored by TLC on Merck 60 F254 silica gel. Solvents for
chromatography were distilled prior to use. The IR spectra were re-
corded on a Varian 3100 Excalibur series spectrophotometer. Melt-
ing points are uncorrected and were measured on a MFB 595
melting point apparatus from Gallenkamp. The NMR spectra were
recorded in CDCl3 on a Bruker AV 400 or Varian Inova 500 MHz
with TMS as internal standard. Diastereotopic methylene protons
with different chemical shifts are abbreviated HA and HB. Optical
rotations were measured using a Perkin-Elmer polarimeter 341. El-
emental analyses were performed on an Elementar Analysensys-
teme Vario El III analyser at the Chemistry Department of the
University of Münster. HRMS (ESI) was carried out with a Quattro
LCZ with nanospray inlet. X-ray crystallographic data sets were
collected with a Nonius KappaCDD diffractometer.21
[a]D20 –1.9 (c 0.96, CHCl3).
IR (ATR): 2923, 2867, 1684, 1452, 1368, 1323, 1241, 1217, 1145,
1072, 1048, 839, 770, 755 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.12 [s, 9 H, Si(CH3)3], 0.80 (s, 3
H, CH3), 1.23 [m, 12 H, CH3(Cb)], 1.25 (s, 3 H, CH3), 1.41 (d, J =
9.9 Hz, 1 H, HA-CH2), 1.84 (m, 2 H, CH2), 1.96 (m, 1 H, CH), 2.37
(m, 3 H, CH2, HB-CH2), 2.70 (t, J = 5.4 Hz, 1 H, CH), 3.86, 4.04 [br
s each, 2 H, CH(Cb)].
13C NMR (100 MHz, CDCl3): d = 0.1 (CH3), 18.7 (CH2), 20.6
(CH3), 21.6 (CH3), 21.7 (CH3), 22.1 (CH3), 23.6 (CH2), 25.9 (CH2),
27.4 (CH3), 40.6 (CH), 40.6 (C), 45.5 (CH), 45.9 (CH), 46.1 (CH),
145.6 (C), 145.7 (C), 154.5 (C).
Anal. Calcd for C20H37NO2Si: C, 68.32; H, 10.61; N, 3.98. Found:
C, 68.34; H, 10.47; N, 3.78.
[(E)-(1R,3S,5R)-3-(1-Hydroxy-1-methylethyl)-6,6-dimethyl-
bicyclo[3.1.1]hept-2-ylidene](trimethylsilyl)methyl N,N-Diiso-
propylcarbamate (16)
[(E)-(1R,5S)-6,6-Dimethylbicyclo[3.1.1]hept-2-ylidene]methyl
N,N-Diisopropylcarbamate (11)
Carbamate 12 (98 mg, 0.28 mmol, 1.0 equiv), dissolved in Et2O (2
mL), was deprotonated with 1.28 M s-BuLi in hexanes (0.28 mL,
0.36 mmol, 1.3 equiv) in the presence of TMEDA (42 mg, 0.36
mmol, 1.3 equiv) at –78 °C for 2 h. Acetone (55 mg, 0.95 mmol, 3.4
equiv) was added dropwise and the soln was stirred at –78 °C for an
additional 5 h. The reaction was stopped by the addition of sat. aq
NH4Cl (5 mL) and warmed to r.t. After addition of Et2O (5 mL) and
separation of the organic phase, the aqueous layer was extracted
with Et2O (3 × 10 mL). The combined organic phases were dried
(MgSO4) and the solvent evaporated under reduced pressure. Puri-
fication of the crude product by column chromatography (Et2O–
pentane) afforded unreacted starting material (59 mg, 50%) and 16
(39 mg, 33%) as a colorless liquid; Rf = 0.34 (Et2O–pentane, 1:4).
A soln of 9 (1.456 g, 5.20 mmol, 1.0 equiv) and TMEDA (798 mg,
6.86 mmol, 1.3 equiv) in Et2O (15 mL) was cooled to –78 °C. 1.6 M
n-BuLi in n-hexane (3.75 mL, 6.00 mmol, 1.2 equiv) was added
slowly and the soln was stirred for 2 h. A soln of Ti(Oi-Pr)4 (2.143
g, 7.54 mmol, 1.45 equiv) in Et2O (3 mL) was added slowly over
10–15 min. After transmetalation at –78 °C for 4 h, MeOH (5 mL)
was added dropwise to the mixture. After 10 min, 2 M HCl (15 mL)
was added and the soln was warmed to r.t. Additional Et2O (15 mL)
was added and the organic phase was removed. The aqueous phase
was extracted with Et2O (3 × 25 mL each). The combined organic
layers were neutralized by washing with sat. aq NaHCO3 (50 mL)
and dried (MgSO4). After concentration under vacuum, purification
of the residue by column chromatography (Et2O–pentane) furnished
11 as a colorless solid (850 mg, 58%); mp 36–38 °C; Rf = 0.58
(Et2O–pentane, 1:4).
[a]D20 +18.5 (c 0.37, CHCl3).
IR (ATR): 3502, 2972, 2987, 1709, 1693, 1427, 1370, 1315, 1245,
1140, 1042, 1005, 840, 764 cm–1.
[a]D20 –28.8 (c 1.20, CHCl3).
1H NMR (500 MHz, CDCl3): d = 0.14 [s, 9 H, Si(CH3)3], 0.81 (s, 3
H, CH3), 1.21 [m, 9 H, C(CH3)2, CH3(Cb)], 1.27 [s, 3 H, C(CH3)2],
1.31 [m, 9 H, CH3, CH3(Cb)], 1.78 (m, 2 H, HA-CH2, HA-CH2), 1.90
(m, 1 H, CH), 2.01 (dtd, J = 14.1, 10.4, 2.0 Hz, 1 H, HB-CH2), 2.26
(m, 1 H, HB-CH2), 2.75 (t, J = 5.6 Hz, 1 H, CH), 2.90 (dd, J = 2.7
Hz, 1 H, CH), 3.20 (br s, 1 H, OH), 3.61, 4.18 [br s each, 2 H,
CH(Cb)].
13C NMR (100 MHz, CDCl3): d = 0.6 (CH3), 20.5 (CH3), 20.9
(CH3), 21.2 (CH3), 21.8 (CH3), 25.4 (CH2), 25.5 (CH3), 27.9 (CH2),
28.7 (CH3), 30.7 (CH3), 40.6 (CH), 42.3 (CH), 43.2 (C), 45.3 (CH),
46.6 (CH), 47.2 (CH), 74.0 (C), 144.5 (C), 149.7 (C), 153.0 (C).
IR (ATR): 2920, 2870, 1701, 1431, 1368, 1330, 1309, 1283, 1214,
1189, 1132, 1094, 1044, 897, 761 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.76 (s, 3 H, CH3), 1.22 [m, 15 H,
CH3, CH3(Cb)], 1.35 (dt, J = 9.9, 3.3 Hz, 1 H, HA-CH2), 1.89 (m, 2
H, CH2), 1.97 (m, 1 H, CH), 2.37 (m, 2 H, CH, HB-CH2), 2.48 (m,
2 H, CH2), 3.77, 4.14 [br s each, 2 H, CH(Cb)], 6.76 (m, 1 H, CH).
13C NMR (100 MHz, CDCl3): d = 17.8 (CH2), 20.4 (CH3), 21.5
(CH3), 22.1 (CH3), 23.4 (CH2), 25.9 (CH3), 28.1 (CH2), 40.7 (C),
40.8 (CH), 45.3 (CH), 46.5 (CH), 46.7 (CH3), 125.1 (C), 128.1
(CH), 153.3 (C).
Anal. Calcd for C17H29NO2: C, 73.07; H, 10.46; N, 5.01. Found: C,
72.97; H, 10.41; N, 4.81.
Anal. Calcd for C23H43NO3Si: C, 67.43; H, 10.58; N, 3.42. Found:
C, 67.25; H, 10.63; N, 3.30.
Synthesis 2010, No. 2, 329–342 © Thieme Stuttgart · New York

336
T. Hémery et al.
PAPER
{(E)-(1R,3S,5R)-3-[(R)-1-Hydroxy-2-methylpropyl]-6,6-di-
methylbicyclo[3.1.1]hept-2-ylidene}(trimethylsilyl)methyl
N,N-Diisopropylcarbamate (18a) and {(E)-(1R,3S,5R)-3-[(S)-1-
Hydroxy-2-methylpropyl]-6,6-dimethylbicyclo[3.1.1]hept-2-
ylidene}(trimethylsilyl)methyl N,N-Diisopropylcarbamate
(epi-18a)
Carbamate 12 (100 mg, 0.28 mmol, 1.0 equiv), dissolved in Et2O (2
mL), was deprotonated with 1.28 M s-BuLi in hexanes (0.28 mL,
0.36 mmol, 1.3 equiv) in the presence of TMEDA (45 mg, 0.38
mmol, 1.3 equiv) at –78 °C for 2 h. 2-Methylpropanal (65 mg, 0.90
mmol, 3.2 equiv) was added dropwise and the soln was stirred at
–78 °C for an additional 4 h. The reaction was quenched by the ad-
dition of sat. aq NH4Cl (5 mL) and warmed to r.t. After dilution with
Et2O (5 mL), the organic layer was separated and the aqueous phase
was extracted with Et2O (3 × 10 mL). The combined organic layers
were dried (MgSO4) and the solvent evaporated under vacuum. Pu-
rification of the crude product by column chromatography (Et2O–
pentane) yielded 18a (29 mg, 23%) and epi-18a (61 mg, 51%) as
two colorless solids.
Titanium-Mediated Homoaldol Reaction of 12; General Proce-
dure
Carbamate 12 (1.0 equiv) and TMEDA (1.3 equiv) were dissolved
in Et2O (6 mL/mmol) and cooled to –78 °C under argon. 1.6 M s-
BuLi in hexanes (1.3 equiv) was added dropwise. The mixture was
stirred for 2 h and a soln of ClTi(NEt2)3 (3.0 equiv) in Et2O (1 mL/
mmol) was slowly added. After 4 h transmetalation, the aldehyde
(3.0 equiv) was added [solid aldehydes were dissolved in Et2O (1
mL/mmol) before addition] and the soln was stirred for an addition-
al 3 h. 2 M HCl (15 mL/mmol) was added at –78 °C and the reaction
was warmed to r.t. After dilution with t-BuOMe (10 mL/mmol), the
layers were separated. The aqueous phase was extracted with t-
BuOMe (3 × 15 mL/mmol). The combined organic extracts were
washed with sat. aq NaHCO3 (20 mL/mmol) and dried (MgSO4).
After evaporation under vacuum of the solvent, the crude product
was purified by column chromatography (Et2O–pentane) to furnish
the homoaldol products 18.
18a
According to the general procedure, 12 (250 mg, 0.71 mmol, 1.0
equiv) and 17a (162 mg, 2.25 mmol, 3.2 equiv) yielded 18a (207
mg, 69%) as a colorless solid. For analytical data, see above.
Carbamate 18a
Mp 71–73 °C; Rf = 0.50 (Et2O–pentane, 1:1).
[a]D20 –56.0 (c 0.56, CHCl3).
{(E)-(1R,3S,5R)-3-[(R)-1-Cyclopropyl-1-hydroxymethyl]-6,6-
dimethylbicyclo[3.1.1]hept-2-ylidene}(trimethylsilyl)methyl
N,N-Diisopropylcarbamate (18b)
IR (ATR): 3400, 2961, 2904, 2873, 1671, 1457, 1431, 1381, 1327,
1366, 1248, 1139, 1061, 1043, 1009, 984, 837, 768, 615 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.13 [s, 9 H, Si(CH3)3], 0.77 (s, 3
H, CH3), 0.93 [dd, J = 8.0, 6.8 Hz, 6 H, CH(CH3)2], 1.21 [m, 6 H,
CH3(Cb)], 1.28 [m, 9 H, CH3, CH3(Cb)], 1.55 [m, 2 H, HA-CH2,
CH(CH3)2], 1.69 (m, 1 H, HA-CH2), 1.94 (m, 1 H, CH), 2.04 (dd, J =
13.7, 8.8 Hz, 1 H, HB-CH2), 2.32 (m, 1 H, HB-CH2), 2.72 (t, J = 5.4
Hz, 1 H, CH), 2.91 (m, 1 H, CH), 3.04 [dt, J = 9.7, 6.8 Hz, 1 H,
CH(OH)], 3.32 (m, 1 H, OH), 3.68, 4.15 [m each, 2 H, CH(Cb)].
According to the general procedure, 12 (176 mg, 0.50 mmol, 1.0
equiv) and 17b (103 mg, 1.47 mmol, 2.9 equiv) yielded 18b (134
mg, 64%) as a yellowish oil; Rf = 0.13 (Et2O–pentane, 1:4).
[a]D20 –2.6 (c 0.69, CHCl3).
IR (ATR): 3458, 2969, 2808, 2872, 1681, 1430, 1369, 1323, 1247,
1218, 1146, 1070, 1045, 1021, 839, 754, 625 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.12 [s, 9 H, Si(CH3)3], 0.27 [m,
1 H, CH(CH2)2], 0.44 [m, 2 H, CH(CH2)2], 0.57 [m, 1 H,
CH(CH2)2], 0.80 (s, 3 H, CH3), 0.92 [m, 1 H, CH(CH2)2], 1.25 [m,
16 H, HA-CH2, CH3, CH3(Cb)], 1.69 (d, J = 10.2 Hz, 1 H, HA-CH2),
1.96 (m, 3 H, CH, HB-CH2, HB-CH2), 2.31 (m, 1 H, OH), 2.71 (t, J =
5.4 Hz, 1 H, CH), 3.11 [m, 2 H, CH, CH(OH)], 3.76, 4.07 [m each,
2 H, CH(Cb)].
13C NMR (100 MHz, CDCl3): d = 0.2 (CH3), 2.8 (CH2), 3.4 (CH2),
16.6 (CH), 20.4 (CH3), 20.5 (CH3), 21.2 (CH3), 21.5 (CH3), 21.6
(CH3), 25.6 (CH3), 25.9 (CH2), 27.1 (CH2), 38.0 (CH), 40.6 (CH),
42.3 (C), 45.7 (CH), 45.9 (CH), 46.6 (CH), 79.6 (CH), 144.7 (C),
148.7 (C), 154.3 (C).
13C NMR (100 MHz, CDCl3): d = 0.3 (CH3), 14.1 (CH3), 19.9
(CH3), 20.4 (CH3), 21.2 (CH3), 21.3 (CH3), 21.5 (CH3), 25.6 (CH3),
25.6 (CH2), 31.6 (CH2), 35.0 (CH), 35.7 (CH), 40.6 (CH), 42.2 (C),
45.6 (CH), 45.9 (CH), 47.0 (CH), 83.9 (CH), 147.2 (C), 148.0 (C),
155.1 (C).
Anal. Calcd for C24H45NO3Si: C, 68.03; H, 10.70; N, 3.31. Found:
C, 67.80; H, 10.64; N, 3.21.
Carbmate epi-18a
Mp 125–128 °C; Rf = 0.28 (Et2O–pentane, 1:1).
[a]D20 +2.3 (c 0.59, CHCl3).
IR (ATR): 3476, 2955, 2871, 1677, 1455, 1432, 1368, 1322, 1248,
1219, 1138, 1069, 1041, 995, 839, 766 cm–1.
Anal. Calcd for C24H43NO3Si: C, 68.36; H, 10.28; N, 3.32. Found:
C, 68.60; H, 10.56; N, 3.11.
1H NMR (400 MHz, CDCl3): d = 0.12 [s, 9 H, Si(CH3)3], 0.82 (s, 3
H, CH3), 0.86 [d, J = 6.7 Hz, 3 H, CH(CH3)2], 1.01 [d, J = 6.4 Hz, 3
H, CH(CH3)2], 1.22 [dd, J = 6.8, 2.9 Hz, 6 H, CH3(Cb)], 1.27 (s, 3
H, CH3), 1.32 [d, 6 H, CH3(Cb)], 1.71 (d, J = 9.6 Hz, 1 H, HA-CH2),
1.77 [m, 1 H, CH(CH3)2], 1.90 (m, 2 H, CH, HA-CH2), 1.99 (m, 1 H,
HB-CH2), 2.27 (m, 1 H, HB-CH2), 2.34 (br s, 1 H, OH), 2.68 (t, J =
5.6 Hz, 1 H, CH), 3.02 (dt, J = 10.2, 3.8 Hz, 1 H, CH), 3.56 [m, 1
H, CH(OH)], 3.64, 4.24 [m each, 2 H, CH(Cb)].
{(E)-(1R,3S,5R)-3-[(S)-1-Hydroxy-1-phenylmethyl]-6,6-di-
methylbicyclo[3.1.1]hept-2-ylidene}(trimethylsilyl)methyl
N,N-Diisopropylcarbamate (18c)
According to the general procedure, 12 (104 mg, 0.30 mmol, 1
equiv) and 17c (103 mg, 0.97 mmol, 3.2 equiv) yielded 18c (81 mg,
60%) as a yellowish oil; Rf = 0.19 (Et2O–pentane, 1:1).
[a]D20 –32.2 (c 0.96, CHCl3).
13C NMR (100 MHz, CDCl3): d = 0.2 (CH3), 19.2 (CH3), 20.8
(CH3), 20.6 (CH3), 20.6 (CH3), 21.2 (CH3), 21.8 (CH3), 24.9 (CH2),
25.7 (CH3), 27.4 (CH2), 31.1 (CH), 35.4 (CH), 39.9 (CH), 40.5 (C),
45.4 (CH), 46.5 (CH), 47.0 (CH), 77.2 (CH), 146.5 (C), 147.5 (C),
154.4 (C).
IR (ATR): 3472, 3063, 2968, 2871, 1681, 1477, 1454, 1431, 1369,
1322, 1247, 1217, 1156, 1135, 1068, 1044, 898, 840, 754, 701 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.18 [s, 9 H, Si(CH3)3], 0.79 (s, 3
H, CH3), 0.95 (d, J = 10.4 Hz, 1 H, HA-CH2), 1.28 [m, 15 H, CH3,
CH3(Cb)], 1.70 (m, 1 H, HA-CH2), 1.82 (m, 2 H, CH, HB-CH2), 2.15
(m, 1 H, HB-CH2), 2.72 (t, J = 5.5 Hz, 1 H, CH), 3.13 (d, J = 3.1 Hz,
1 H, OH), 3.33 (m, 1 H, CH), 4.16, 3.79 [m each, 2 H, CH(Cb)],
4.80 [dd, J = 8.1 Hz, 1 H, CH(OH)], 7.31 (m, 5 H, HAr).
Anal. Calcd for C24H45NO3Si: C, 68.03; H, 10.70; N, 3.31. Found:
C, 67.88; H, 10.85; N, 3.17.
13C NMR (100 MHz, CDCl3): d = 0.4 (CH3), 20.5 (CH3), 20.6
(CH3), 21.2 (CH3), 21.4 (CH3), 21.5 (CH3), 25.3 (CH2), 25.4 (CH3),
Synthesis 2010, No. 2, 329–342 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of Highly Substituted Annulated Dihydropyrans
337
26.4 (CH2), 38.7 (CH), 40.5 (CH), 42.4 (C), 45.8 (CH), 46.1 (CH),
46.7 (CH), 78.2 (CH), 127.3 (CH), 127.5 (CH), 128.1 (CH), 143.9
(C), 144.0 (C), 149.8 (C), 154.4 (C).
{(E)-(1R,3S,5R)-3-[(R)-1-Hydroxyprop-2-enyl]-6,6-dimethyl-
bicyclo[3.1.1]hept-2-ylidene}(trimethylsilyl)methyl N,N-Diiso-
propylcarbamate (18f)
According to the general procedure, 12 (179 mg, 0.51 mmol, 1.0
equiv) and 17f (87 mg, 1.55 mmol, 3.0 equiv) yielded 18f (133 mg,
65%) as a colorless oil; Rf = 0.16 (Et2O–pentane, 1:4).
Anal. Calcd for C27H43NO3Si: C, 70.85; H, 9.47; N, 3.06. Found: C,
70.73; H, 9.60; N, 2.81.
{(E)-(1R,3S,5R)-3-[(S)-(4-Bromophenyl)hydroxymethyl]-6,6-
dimethylbicyclo[3.1.1]hept-2-ylidene}(trimethylsilyl)methyl
N,N-Diisopropylcarbamate (18d)
According to the general procedure, 12 (350 mg, 0.99 mmol, 1.0
equiv) was deprotonated for 4.5 h, and after transmetalation was re-
acted with 17d (585 mg, 3.16 mmol, 3.2 equiv) for 18 h to give 18d
(329 mg, 62%) as a yellowish solid; mp 65–68 °C; Rf = 0.22 (Et2O–
pentane, 1:4).
[a]D20 –2.7 (c 0.82, CHCl3).
IR (ATR): 3445, 2969, 1696, 1430, 1378, 1320, 1247, 1218, 1135,
1070, 1045, 1010, 989, 839, 756 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.14 [s, 9 H, Si(CH3)3], 0.79 (s, 3
H, CH3), 1.25 [m, 15 H, CH3, CH3(Cb)], 1.56 (d, J = 10.4 Hz, 1 H,
HA-CH2), 1.69 (ddd, J = 13.9, 4.2, 1.8 Hz, 1 H, HA-CH2), 1.94 (m,
2 H, CH, HB-CH2), 2.32 (m, 1 H, HB-CH2), 2.74 (t, J = 5.8 Hz, 1 H,
CH), 2.91 (m, 2 H, CH, OH), 3.78, 4.07 [m each, 3 H, CH(OH),
CH(Cb)], 5.12 (m, 1 H, CH=CH2), 5.25 (m, 1 H, CH=CH2), 5.82
(m, 1 H, CH=CH2).
13C NMR (100 MHz, CDCl3): d = 0.3 (CH3), 20.5 (CH3), 20.5
(CH3), 21.2 (CH3), 21.5 (CH3), 21.6 (CH3), 25.5 (CH3), 25.8 (CH2),
27.1 (CH2), 37.2 (CH), 40.6 (CH), 42.3 (C), 45.8 (CH), 46.0 (CH),
46.6 (CH), 77.8 (CH), 115.2 (CH2), 140.5 (CH), 143.7 (C), 149.8
(C), 154.3 (C).
[a]D20 –16.3 (c 1.01, CHCl3).
IR (ATR): 3473, 2969, 2871, 1691, 1680, 1483, 1432, 1368, 1322,
1303, 1247, 1157, 1135, 1070, 1044, 1011, 839, 769, 755, 686 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.17 [s, 9 H, Si(CH3)3], 0.78 (s, 3
H, CH3), 0.91 (d, J = 10.4 Hz, 1 H, HA-CH2), 1.27 [m, 15 H, CH3,
CH3(Cb)], 1.66 (m, 1 H, HA-CH2), 1.83 (m, 2 H, HB-CH2, CH), 2.16
(m, 1 H, HB-CH2), 2.71 (t, J = 5.5 Hz, 1 H, CH), 3.13 (d, J = 3.4 Hz,
1 H, OH), 3.28 (m, 1 H, CH), 3.80, 4.12 [br s each, 2 H, CH(Cb)],
4.75 [dd, J = 8.0 Hz, 1 H, CH(OH)], 7.32 (d, J = 8.5 Hz, 2 H, HAr),
7.43 (d, 2 H, HAr).
Anal. Calcd for C23H41NO3Si: C, 67.76; H, 10.14; N, 3.44. Found:
C, 67.95; H, 10.39; N, 3.26.
13C NMR (100 MHz, CDCl3): d = 0.3 (CH3), 20.5 (CH3), 20.6
(CH3), 21.2 (CH3), 21.4 (CH3), 21.6 (CH3), 25.4 (CH3), 25.4 (CH2),
26.4 (CH2), 38.7 (CH), 40.4 (CH), 42.4 (C), 45.9 (CH), 46.0 (CH),
46.7 (CH), 77.4 (CH), 121.1 (CH), 129.2 (CH), 131.1 (CH), 143.0
(C), 143.6 (C), 150.1 (C), 154.5 (C).
{(E)-(1R,3S,5R)-3-[(S)-(Furan-2-yl)hydroxymethyl]-6,6-di-
methylbicyclo[3.1.1]hept-2-ylidene}(trimethylsilyl)methyl
N,N-Diisopropylcarbamate (18g)
According to the general procedure, 12 (178 mg, 0.51 mmol, 1.0
equiv) and 17g (145 mg, 1.51 mmol, 3.0 equiv) yielded 18g (165
mg, 73%) as a yellowish oil; Rf = 0.16 (Et2O–pentane, 1:4).
Anal. Calcd for C27H42BrNO3Si: C, 60.43; H, 7.89; N, 2.61. Found:
C, 60.61; H, 7.82; N, 2.50.
[a]D20 –41.6 (c 0.89, CHCl3).
IR (ATR): 3441, 2969, 2872, 1695, 1506, 1457, 1379, 1322, 1248,
1217, 1148, 1070, 1045, 1010, 841, 756 cm–1.
{(E)-(1R,3S,5R)-3-[(S)-Hydroxy(naphthalen-2-yl)methyl]-6,6-
dimethylbicyclo[3.1.1]hept-2-ylidene}(trimethylsilyl)methyl
N,N-Diisopropylcarbamate (18e)
According to the general procedure, 12 (104 mg, 0.30 mmol, 1.0
equiv) and 17e (147 mg, 0.94 mmol, 3.1 equiv) yielded 18e (87 mg,
57%) as a yellowish solid; mp 50–57 °C; Rf = 0.19 (Et2O–pentane,
1:4).
1H NMR (400 MHz, CDCl3): d = 0.16 [s, 9 H, Si(CH3)3], 0.81 (s, 3
H, CH3), 1.25 [m, 16 H, HA-CH2, CH3, CH3(Cb)], 1.62 (dd, J = 14.7,
3.6 Hz, 1 H, HA-CH2), 1.94 (m, 2 H, HB-CH2, CH) 2.30 (m, 1 H, HB-
CH2), 2.76 (t, J = 5.4 Hz, 1 H, CH), 3.37 (t, J = 8.5 Hz, 1 H, CH),
3.48 (m, 1 H, OH), 3.76, 4.08 [m each, 2 H, CH(Cb)], 4.66 [dd, J =
5.9 Hz, 1 H, CH(OH)], 6.25 (d, J = 3.0 Hz, 1 H, C=CH), 6.30 [dd,
J = 1.8 Hz, 1 H, CH=CH(O)], 7.34 [s, 1 H, CH=CH(O)].
[a]D20 –17.9 (c 1.02, CHCl3).
IR (ATR): 3472, 3056, 2955, 2871, 1684, 1457, 1368, 1321, 1305,
1247, 1157, 1135, 1069, 1044, 839, 750, 690 cm–1.
13C NMR (100 MHz, CDCl3): d = 0.3 (CH3), 20.5 (CH3), 20.5
(CH3), 21.1 (CH3), 21.2 (CH3), 21.6 (CH3), 25.5 (CH3), 25.5 (CH2),
27.7 (CH2), 36.3 (CH), 40.6 (CH), 42.4 (C), 45.7 (CH), 46.1 (CH),
46.8 (CH), 73.2 (CH), 107.0 (CH), 110.0 (CH), 141.6 (CH), 143.7
(C), 150.0 (C), 154.1 (C), 156.4 (C).
1H NMR (500 MHz, CDCl3): d = 0.22 [s, 9 H, Si(CH3)3], 0.81 (s, 3
H, CH3), 0.89 (t, J = 7.1 Hz, 1 H, HA-CH2), 1.03 (d, J = 10.4 Hz, 1
H, HA-CH2), 1.29 [m, 16 H, HB-CH2, CH3, CH3(Cb)], 1.80 (m, 1 H,
CH), 2.16 (dt, J = 6.0 Hz, 1 H, HB-CH2), 2.76 (t, 1 H, CH), 3.30 (s,
1 H, OH), 3.44 (m, 1 H, CH), 3.80, 4.19 [br s each, 2 H, CH(Cb)],
4.96 [d, J = 8.6 Hz, 1 H, CH(OH)], 7.45 (m, 2 H, HAr), 7.61 (m, 1
H, HAr), 7.82 (m, 4 H, HAr).
13C NMR (100 MHz, CDCl3): d = 0.4 (CH3), 20.5 (CH3), 20.6
(CH3), 21.2 (CH3), 21.5 (CH3), 21.6 (CH3), 25.4 (CH3), 25.5 (CH2),
26.6 (CH2), 38.6 (CH), 40.5 (CH), 42.4 (C), 45.8 (CH), 46.1 (CH),
46.8 (CH), 78.5 (CH), 125.5 (CH), 125.6 (CH), 125.9 (CH), 126.5
(CH), 127.6 (CH), 127.8 (CH), 128.0 (CH), 132.9 (C), 133.1 (C),
141.2 (C), 143.9 (C), 149.9 (C), 153.4 (C).
Anal. Calcd for C25H41NO4Si: C, 67.07; H, 9.23; N, 3.13. Found: C,
66.90; H, 9.56; N, 2.97.
[(E)-(1R,3S,5R)-3-{(1S)-[(2R)-2,2-Dimethyl-1,3-dioxolan-4-
yl]hydroxymethyl}-6,6-dimethylbicyclo[3.1.1]hept-2-
ylidene](trimethylsilyl)methyl N,N-Diisopropylcarbamate
(18h)
According to the general procedure, 12 (350 mg, 0.99 mmol, 1
equiv) was deprotonated for 4 h, and after transmetalation reacted
with 17h (546 mg, 4.20 mmol, 4.2 equiv) for 18 h. The reaction was
quenched by addition of sat. aq sodium potassium tartrate soln (10
mL) and warmed to r.t. After stirring for 1 h and addition of Et2O
(15 mL), the organic phase was separated. The aqueous layer was
extracted with Et2O (3 × 20 mL) and the combined organic phases
were dried (Na2SO4). Purification by column chromatography
(Et2O–pentane) gave 18h (313 mg, 65%) as a colorless oil; Rf = 0.56
(Et2O–pentane, 1:1).
Anal. Calcd for C31H45NO3Si: C, 73.33; H, 8.93; N, 2.76. Found: C,
73.08; H, 8.94; N, 2.65.
[a]D20 –70.6 (c 0.98, CHCl3).
Synthesis 2010, No. 2, 329–342 © Thieme Stuttgart · New York

338
T. Hémery et al.
PAPER
IR (ATR): 3398, 2952, 2874, 1671, 1457, 1434, 1369, 1327, 1308,
1248, 1214, 1155, 1064, 1045, 981, 898, 840, 770 cm–1.
13C NMR (100 MHz, CDCl3): d = 20.7 (CH3), 21.6 (CH2), 25.5
(CH3), 25.6 (CH2), 26.3 (CH3), 32.1 (CH), 32.2 (CH2), 36.7 (C),
41.0 (CH), 42.1 (C), 45.6 (CH), 46.7 (CH), 47.0 (CH), 84.7 (CH),
127.6 (C), 132.7 (CH), 152.8 (C).
1H NMR (400 MHz, CDCl3): d = 0.12 [s, 9 H, Si(CH3)3], 0.75 (s, 3
H, CH3), 1.27 (m, 15 H, CH3, CH3(Cb)], 1.32 [s, 3 H, OC(CH3)2O],
1.40 [s, 3 H, OC(CH3)2O], 1.63 (d, J = 10.4 Hz, 1 H, HA-CH2), 1.78
(dd, J = 14.0, 4.8 Hz, 1 H, HA-CH2), 1.94 (dd, J = 9.8 Hz, 1 H, CH),
2.16 (dd, 1 H, HB-CH2), 2.34 (ddt, J = 5.8 Hz, 1 H, HB-CH2), 2.69
(t, 1 H, CH), 3.16 (dd, J = 8.2 Hz, 1 H, CH), 3.34 [m, 1 H, CH(OH)],
3.73 [m, 3 H, CHOC(CH3)2O, CH(Cb), OH], 3.93 (dd, J = 8.7, 5.7
Hz, 1 H, CH2 °C(CH3)2O], 4.03 (dd, 1 H, CH2OC(CH3)2O), 4.20 [m,
1 H, CH(Cb)].
13C NMR (100 MHz, CDCl3): d = 0.2 (CH3), 20.4 (CH3), 20.5
(CH3), 21.2 (CH3), 21.3 (CH3), 21.5 (CH3), 25.4 (CH3), 25.6 (CH3),
25.6 (CH2), 26.6 (CH2), 32.4 (CH2), 35.0 (CH), 40.3 (CH), 42.3 (C),
45.7 (CH), 45.7 (CH), 47.1 (CH), 68.3 (CH2), 80.6 (CH), 81.0 (CH),
109.0 (C), 146.8 (C), 148.2 (C), 155.7 (C).
Cyclocondensation of Homoaldol Adducts 18 and 24; General
Procedure
A soln of homoaldol product 18 or 24 (1.0 equiv) and the corre-
sponding aldehyde 17a–i in CH2Cl2 was cooled to 0 °C. BF3·OEt2
(1.1–1.3 equiv) was added in a dropwise fashion and the soln was
stirred for the specified time at 0 °C. In most the cases the soln was
warmed up to r.t. and stirred for the specified additional time (see
Table 2). A soln of sat. aq NaCl (15 mL/mmol) was added followed
by CH2Cl2 (10 mL/mmol). The organic phase was removed and the
aqueous layer was extracted with Et2O (3 × 15 mL/mmol). The
combined organic layers were dried (Na2SO4) and the solvent was
removed under reduced pressure. Purification of the crude material
by column chromatography (Et2O–pentane) yielded the pure dihy-
dropyrans 23aa–he or the tetrahydrofuran 26, respectively.
Anal. Calcd for C26H47NO5Si: C, 64.82; H, 9.83; N, 2.91. Found: C,
64.85; H, 10.12; N, 2.88.
(1R,4S,6R,7S,9R)-3-(N,N-Diisopropylcarbamoyloxy)-6-isopro-
pyl-10,10-dimethyl-4-phenyl-5-oxatricyclo[7.1.1.02,7]undec-2-
ene (23ac)
{(E)-(1R,3S,5R)-3-[(R)-1-Hydroxy-2,2-dimethylpropyl]-6,6-
dimethylbicyclo[3.1.1]hept-2-ylidene}(trimethylsilyl)methyl
N,N-Diisopropylcarbamate (18i)
According to the general procedure, 18a (128 mg, 0.30 mmol, 1.0
equiv), 17c (37 mg, 0.35 mmol, 1.2 equiv), and BF3·OEt2 (0.04 mL,
0.32 mmol, 1.1 equiv) in CH2Cl2 (2.5 mL) yielded 23ac (86 mg,
65%) as a colorless solid; mp 50–57 °C; Rf = 0.46 (Et2O–pentane,
1:4).
According to the general procedure, 12 (102 mg, 0.29 mmol, 1
equiv) and 17i (79 mg, 0.92 mmol, 3.2 equiv) yielded 18i (96 mg,
76%) as a colorless solid; mp 101–106 °C; Rf = 0.38 (Et2O–pentane,
1:1).
[a]D20 –87.5 (c 0.78, CHCl3).
[a]D20+88.0 (c 0.48, CHCl3).
IR (ATR): 3491, 2948, 2904, 2871, 1674, 1478, 1457, 1434, 1368,
1329, 1249, 1143, 1071, 1049, 1016, 838, 755 cm–1.
IR (ATR): 3030, 2866, 2932, 2873, 1710, 1454, 1430, 1319, 1302,
1290, 1218, 1152, 1136, 1112, 1090, 1069, 1043, 749, 698 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.13 [s, 9 H, Si(CH3)3], 0.76 (s, 3
H, CH3), 0.91 [s, 9 H, C(CH3)3], 1.20 [m, 6 H, CH3(Cb)], 1.28 [m,
9 H, CH3, CH3(Cb)], 1.64 (dd, J = 13.6, 4.7 Hz, 1 H, HA-CH2), 1.76
(d, J = 10.3 Hz, 1 H, HA-CH2), 1.97 (m, 2 H, CH, HB-CH2), 2.30 (dt,
J = 5.8 Hz, 1 H, HB-CH2), 2.77 (t, 1 H, CH), 3.00 (t, J = 7.3 Hz, 1
H, CH), 3.21 [m, 2 H, CH(OH)], 3.65, 4.14 [br s each, 2 H, CH
(Cb)].
13C NMR (100 MHz, CDCl3): d = 0.8 (CH3), 20.4 (CH3), 20.4
(CH3), 21.0 (CH3), 21.1 (CH3), 21.4 (CH3), 24.8 (CH2), 25.3 (CH3),
26.5 (CH3), 32.4 (CH2), 32.6 (CH), 37.2 (C), 41.0 (CH), 42.4 (C),
45.7 (CH), 46.3 (CH), 47.0 (CH), 85.7 (CH), 146.6 (C), 148.8 (C),
155.2 (C).
1H NMR (400 MHz, CDCl3): d = 0.81 [d, J = 6.5 Hz, 3 H, CH3(Cb)],
6.96 [m, 6 H, CH(CH3)2, CH3(Cb)], 1.08 [d, J = 6.9 Hz, 3 H,
CH(CH3)2], 1.09 (m, 4 H, HA-CH2, CH3), 1.19 [d, 3 H, CH3(Cb)],
1.24 [d, 3 H, CH3(Cb)], 1.26 (s, 3 H, CH3), 1.54 (ddd, J = 13.0, 7.4
Hz, 1 H, HA-CH2), 1.96 [m, 1 H, CH(CH3)2], 2.08 (m, 2 H, HB-CH2,
CH), 2.53 (m, 1 H, HB-CH2), 2.68 (t, J = 5.7 Hz, 1 H, CH), 3.06 (m,
1 H, CH), 3.47 (dd, J = 9.5, 1.9 Hz, 1 H, CHCHO), 3.66, 6.79 [m
each, 2 H, CH(Cb)], 5.30 (d, J = 3.4 Hz, 1 H, CCHO), 7.29 (m, 5 H,
HAr).
13C NMR (100 MHz, CDCl3): d = 14.8 (CH3), 20.2 (CH3), 20.4
(CH3), 20.5 (CH3), 20.7 (CH3), 21.0 (CH3), 23.0 (CH3), 27.3 (CH3),
28.1 (CH), 28.5 (CH2), 33.0 (CH), 35.1 (CH2), 38.6 (C), 41.4 (CH),
43.7 (CH), 46.0 (CH), 46.1 (CH), 77.8 (CH), 84.0 (CH), 127.6
(CH), 128.0 (CH), 128.12 (CH), 130.8 (C), 138.2 (C), 141.2 (C),
152.5 (C).
Anal. Calcd for C25H47NO3Si: C, 68.60; H, 10.82; N, 3.20. Found:
C, 68.49; H, 10.88; N, 3.17.
{(Z)-(1R,3S,5R)-3-[(S)-1-Hydroxy-2,2-dimethylpropyl]-6,6-
dimethylbicyclo[3.1.1]hept-2-ylidene}methyl N,N-Diisopropyl-
carbamate (24)
HRMS (ESI, EM): m/z [M + Na]+ calcd for C28H41NNaO3:
462.2979; found: 462.2978.
Compound 18i (117 mg, 0.27 mmol, 1.0 equiv) was dissolved in
THF (2 mL) and 1.0 M TBAF in THF (0.8 mL, 0.8 mmol, 3.0 equiv)
was added. The soln was stirred at r.t. for 2 h (TLC) and stopped by
addition of sat. aq NH4Cl (5 mL) and additional Et2O (5 mL). The
organic phase was removed and the aqueous layer was extracted
with Et2O (3 × 10 mL), the combined organic phases were dried
(MgSO4), and the solvent was evaporated under reduced pressure.
The residue (92 mg, 92%) was not purified and a partial analysis
was done before further reaction of the crude product; Rf = 0.26
(Et2O–pentane, 1:4).
1H NMR (400 MHz, CDCl3): d = 0.74 (s, 3 H, CH3), 0.96 [s, 9 H,
C(CH3)3], 1.22 [m, 15 H, CH3, CH3(Cb)], 1.55 (d, J = 10.2 Hz, 1 H,
HA-CH2), 1.19 (dd, J = 13.7, 4.5 Hz, 1 H, HA-CH2), 1.99 (m, 2 H,
CH, HB-CH2), 2.30 (m, 1 H, HB-CH2), 2.40 (t, J = 5.5 Hz, 1 H, CH),
2.52 (d, J = 5.6 Hz, 1 H, OH), 2.90 (t, J = 8.0 Hz, 1 H, CH), 3.19
[dd, 1 H, CH(OH)], 3.61, 4.22 [br s each, 2 H, CH(Cb)], 6.61 (d, J =
1.1 Hz, 1 H, CH).
(1R,4S,6R,7S,9R)-6-Cyclopropyl-3-(N,N-diisopropylcarbamoyl-
oxy)-10,10-dimethyl-4-phenyl-5-oxatricyclo[7.1.1.02,7]undec-2-
ene (23bc)
According to the general procedure, 18b (120 mg, 0.28 mmol, 1.0
equiv), 17c (37 mg, 0.35 mmol, 1.3 equiv), and BF3·OEt2 (0.04 mL,
0.32 mmol, 1.1 equiv) in CH2Cl2 (2.5 mL) yielded 23bc (24 mg,
21%) as a yellowish oil; Rf = 0.29 (Et2O–pentane, 1:4).
[a]D20 +74.0 (c 0.39, CHCl3).
IR (ATR): 3086, 2967, 2930, 2871, 1709, 1454, 1430, 1368, 1320,
1301, 1290, 1217, 1151, 1070, 1043, 1026, 894, 756, 698 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.43 [m, 3 H, CH(CH2)2], 0.61 [m,
1 H, CH(CH2)2], 0.75 [d, J = 6.2 Hz, 3 H, CH3(Cb)], 0.89 [m, 4 H,
CH(CH2)2, CH3(Cb)], 1.62 (d, J = 9.8 Hz, 1 H, HA-CH2), 1.12 (s, 3
H, CH3), 1.20 [m, 6 H, CH3(Cb)], 1.28 (s, 3 H, CH3), 1.78 (ddd, J =
13.7, 7.4 Hz, 1 H, HA-CH2), 2.06 (m, 1 H, CH), 2.28 (m, 1 H, HB-
Synthesis 2010, No. 2, 329–342 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of Highly Substituted Annulated Dihydropyrans
339
CH2), 2.54 (m, 1 H, HB-CH2), 2.79 (t, J = 5.7 Hz, 1 H, CH), 2.93 (t,
J = 8.8 Hz, 1 H, CHCHO), 3.18 (m, 1 H, CH), 3.58, 3.79 [br s each,
2 H, CH(Cb)], 5.30 (d, J = 3.4 Hz, 1 H, CCHO), 7.26 (m, 3 H, HAr),
7.36 (m, 2 H, HAr).
13C NMR (100 MHz, CDCl3): d = 1.3 (CH3), 3.9 (CH3), 13.9 (CH),
20.3 (CH3), 20.4 (CH3), 20.6 (CH3), 21.0 (CH3), 23.1 (CH3), 27.34
(CH3), 28.8 (CH2), 35.2 (CH2), 37.4 (CH), 38.5 (C), 41.5 (CH),
43.67 (CH), 46.0 (CH), 46.1 (CH), 78.2 (CH), 84.9 (CH), 127.9
(CH), 128.2 (CH), 128.5 (CH), 130.9 (C), 138.2 (C), 140.3 (C),
152.5 (C).
78.6 (CH), 83.0 (CH), 121.8 (C), 128.1 (CH), 128.2 (CH), 128.4
(CH), 129.3 (CH), 131.0 (C), 131.4 (CH), 138.1 (C), 139.0 (C),
139.9 (C), 152.5 (C).
Anal. Calcd C31H38BrNO3: C, 67.39; H, 6.93; N, 2.53. Found: C,
67.76; H, 7.13; N, 2.25.
(1R,4S,6S,7S,9R)-3-(N,N-Diisopropylcarbamoyloxy)-10,10-
dimethyl-6-(naphthalen-2-yl)-4-phenyl-5-oxatricyclo-
[7.1.1.02,7]undec-2-ene (23ec)
According to the general procedure, 18e (106 mg, 0.21 mmol, 1.0
equiv), 17c (28 mg, 0.26 mmol, 1.2 equiv), and BF3·OEt2 (0.03 mL,
0.24 mmol, 1.1 equiv) in CH2Cl2 (1 mL) yielded 23ec (58 mg, 52%)
as a colorless solid; mp 88–96 °C; Rf = 0.18 (Et2O–pentane, 1:4).
HRMS (ESI, EM): m/z [M + Na]+ calcd for C28H39NNaO3:
460.2822; found: 460.2818.
(1R,4S,6S,7S,9R)-3-(N,N-Diisopropylcarbamoyloxy)-10,10-
dimethyl-4,6-diphenyl-5-oxatricyclo[7.1.1.02,7]undec-2-ene
(23cc)
According to the general procedure, 18c (180 mg, 0.39 mmol, 1.0
equiv), 17c (50 mg, 0.47 mmol, 1.2 equiv), and BF3·OEt2 (0.055
mL, 0.43 mmol, 1.1 equiv) in CH2Cl2 (3.3 mL) yielded 23cc (115
mg, 62%) as a colorless solid; mp 62–63 °C; Rf = 0.22 (Et2O–pen-
tane, 1:4).
[a]D20 +80.3 (c 0.36, CHCl3).
IR (ATR): 3059, 2966, 2932, 2870, 1708, 1473, 1430, 1369, 1319,
1302, 1291, 1256, 1149, 1126, 1069, 1042, 893, 818, 752, 698 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.82 [br s, 3 H, CH3(Cb)], 1.00 [br
s, 3 H, CH3(Cb)], 1.09 (s, 3 H, CH3), 1.23 [m, 7 H, HA-CH2,
CH3(Cb)], 1.27 (s, 3 H, CH3), 1.51 (m, 1 H, HA-CH2), 1.67 (m, 1 H,
HB-CH2), 1.96 (m, 1 H, CH), 2.60 (m, 1 H, HB-CH2), 2.79 (t, J = 5.7
Hz, 1 H, CH), 3.46 (m, 1 H, CH), 3.66, 3.86 [br s each, 2 H,
CH(Cb)], 4.72 (d, J = 9.4 Hz, 1 H, CHCHO), 5.56 (d, J = 3.3 Hz, 1
H, CCHO), 7.32 (m, 3 H, HAr), 7.45 (m, 4 H, HAr), 7.59 (m, 1 H,
HAr), 7.82 (m, 4 H, HAr).
[a]D20 +80.5 (c 0.96, CHCl3).
IR (ATR): 3031, 2968, 2933, 2870, 1709, 1454, 1430, 1369, 1302,
1291, 1217, 1149, 1086, 1068, 1042, 1030, 741, 697, 668 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.81 [d, J = 6.1 Hz, 3 H, CH3(Cb)],
0.99 [d, 3 H, CH3(Cb)], 1.08 (s, 3 H, CH3), 1.22 [m, 10 H, HA-CH2,
CH3, CH3(Cb)], 1.46 (ddd, J = 13.8, 7.3, 2.1 Hz, 1 H, HA-CH2), 1.70
(m, 1 H, HB-CH2), 1.96 (m, 1 H, CH), 2.58 (m, 1 H, HB-CH2), 2.76
(t, J = 5.7 Hz, 1 H, CH), 3.35 (m, 1 H, CH), 3.65, 3.83 [br s each, 2
H, CH(Cb)], 4.55 (d, 1 H, CHCHO), 5.50 (d, 1 H, CCHO), 7.30 (m,
6 H, HAr), 7.43 (m, 4 H, HAr).
13C NMR (100 MHz, CDCl3): d = 20.4 (CH3), 20.45 (CH3), 20.7
(CH3) 21.1 (CH3), 23.1 (CH3), 27.2 (CH3), 28.9 (CH2), 35.0 (CH2),
37.2 (CH), 38.8 (C), 41.3 (CH), 43.9 (CH), 46.1 (CH), 46.2 (CH),
78.6 (CH), 83.8 (CH), 125.3 (CH), 125.8 (CH), 125.9 (CH), 126.9
(CH), 127.6 (CH), 128.0 (CH), 128.1 (CH), 128.2 (CH), 128.2
(CH), 128.5 (CH), 131.2 (C), 133.2 (C), 133.3 (C), 137.4 (C), 138.2
(C), 140.1 (C), 152.5 (C).
13C NMR (100 MHz, CDCl3): d = 20.4 (CH3), 20.5 (CH3), 20.7
(CH3), 21.1 (CH3), 23.1 (CH3), 27.2 (CH3), 28.8 (CH2), 35.0 (CH2),
37.2 (CH), 38.8 (C), 41.4 (CH), 43.8 (CH), 46.1 (CH), 46.2 (CH),
78.6 (CH), 83.7 (CH), 127.7 (CH), 127.9 (CH), 127.94 (CH), 128.1
(CH), 128.3 (CH), 128.4 (CH), 131.08 (C), 138.1 (C), 139.9 (C),
140.2 (C), 152.5 (C).
Anal. Calcd C35H41NO3: C, 80.27; H, 7.89; N, 2.67. Found: C,
79.98; H, 7.95; N, 2.44.
(1R,4S,6R,7S,9R)-3-(N,N-Diisopropylcarbamoyloxy)-10,10-
dimethyl-4-phenyl-6-vinyl-5-oxatricyclo[7.1.1.02,7]undec-2-ene
(23fc)
According to the general procedure, 18f (95 mg, 0.23 mmol, 1.0
equiv), 17c (28 mg, 0.26 mmol, 1.1 equiv), and BF3·OEt2 (0.035
mL, 0.28 mmol, 1.2 equiv) in CH2Cl2 (2 mL) yielded 23fc (46 mg,
48%) as a yellow oil; Rf = 0.27 (Et2O–pentane, 1:4).
Anal. Calcd C31H39NO3: C, 78.61; H, 8.30; N, 2.96. Found: C,
78.61; H, 8.32; N, 2.74.
(1R,4S,6S,7S,9R)-6-(4-Bromophenyl)-3-(N,N-diisopropylcarb-
amoyloxy)-10,10-dimethyl-4-phenyl-5-oxatricyclo[7.1.1.02,7]un-
dec-2-ene (23dc)
According to the general procedure, 18d (48 mg, 0.09 mmol, 1.0
equiv), 17c (13 mg, 0.12 mmol, 1.3 equiv), and BF3·OEt2 (0.015
mL, 0.12 mmol, 1.3 equiv) in CH2Cl2 (0.5 mL) yielded 23dc (35
mg, 70%) as a colorless solid; mp 69–72 °C; Rf = 0.25 (Et2O–pen-
tane, 1:4).
[a]D20 +85.1 (c 0.41, CHCl3).
IR (ATR): 3030, 2968, 2933, 2871, 1708, 1474, 1455, 1429, 1368,
1319, 1302, 1290, 1216, 1151, 1069, 1042, 990, 756, 699 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.77 [d, J = 6.2 Hz, 3 H, CH3(Cb)],
0.96 [d, 3 H, CH3(Cb)], 1.09 (s, 3 H, CH3), 1.12 (d, J = 9.9 Hz, 1 H,
HA-CH2), 1.18 [m, 6 H, CH3(Cb)], 1.28 (s, 3 H, CH3), 1.55 (m, 1 H,
HA-CH2), 2.05 (m, 2 H, CH, HB-CH2), 2.56 (m, 1 H, HB-CH2), 2.72
(t, J = 5.6 Hz, 1 H, CH), 3.03 (m, 1 H, CH), 3.60, 3.82 [br s each, 2
H, CH(Cb)], 4.03 (dd, J = 8.1, 8.7 Hz, 1 H, CHCHO), 5.22 (dd, J =
10.4, 1.4 Hz, 1 H, CH=CH2), 5.37 (dm, J = 17.6 Hz, 1 H, CH=CH2),
5.40 (d, 1 H, CCHO), 5.87 (ddd, 1 H, CH=CH2), 7.27 (m, 3 H, HAr),
7.38 (m, 2 H, HAr).
13C NMR (100 MHz, CDCl3): d = 20.3 (CH3), 20.4 (CH3), 20.6
(CH3), 21.1 (CH), 23.0 (CH3), 27.3 (CH3), 28.7 (CH2), 35.0 (CH2),
35.6 (CH), 38.7 (C), 41.4 (CH), 43.8 (CH), 46.0 (CH), 46.2 (CH),
77.8 (CH), 82.6 (CH), 118.1 (CH2), 128.0 (CH), 128.2 (CH), 128.5
(CH), 130.7 (C), 136.5 (CH), 138.0 (C), 139.9 (C), 152.4 (C).
[a]D20 +57.0 (c 0.24, CHCl3).
IR (ATR): 3064, 2969, 2931, 1700, 1489, 1455, 1432, 1369, 1321,
1302, 1216, 1149, 1071, 1030, 1011, 819, 751, 698 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.82 [d, J = 5.9 Hz, 3 H, CH3(Cb)],
0.99 [d, 3 H, CH3(Cb)], 1.08 (s, 3 H, CH3), 1.24 [m, 7 H, HA-CH2,
CH3(Cb)], 1.27 (s, 3 H, CH3), 1.44 (m, 1 H, HA-CH2), 1.69 (m, 1 H,
HB-CH2), 1.98 (m, 1 H, CH), 2.58 (ddd, J = 10.2, 6.2, 3.1 Hz, 1 H,
HB-CH2), 2.75 (t, 1 H, CH), 3.28 (m, 1 H, H), 3.64, 3.84 [m each, 2
H, CH(Cb)], 4.51 (d, J = 9.4 Hz, 1 H, CHCHO), 5.49 (d, J = 3.3 Hz,
1 H, CCHO), 7.31 (m, 5 H, HAr), 7.44 (m, 4 H, HAr).
13C NMR (100 MHz, CDCl3): d = 20.4 (CH3), 20.5 (CH3), 20.7
(CH3), 21.1 (CH3), 23.1 (CH3), 27.2 (CH3), 28.8 (CH2), 35.0 (CH2),
37.3 (CH), 38.8 (C), 41.3 (CH), 43.8 (CH), 46.1 (CH), 46.2 (CH),
HRMS (ESI, EM): m/z [M + Na]+ calcd for C27H37NNaO3:
446.2666; found: 446.2663.
Synthesis 2010, No. 2, 329–342 © Thieme Stuttgart · New York

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T. Hémery et al.
PAPER
(1R,4S,6R,7S,9R)-4-Cyclopropyl-3-(N,N-diisopropylcarbamoyl-
oxy)-6-isopropyl-10,10-dimethyl-5-oxatricyclo[7.1.1.02,7]undec-
2-ene (23ab)
According to the general procedure, 18a (129 mg, 0.30 mmol, 1.0
equiv), 17b (28 mg, 0.39 mmol, 1.3 equiv), and BF3·OEt2 (0.05 mL,
0.39 mmol, 1.3 equiv) in CH2Cl2 (2.5 mL) yielded 23ab (95 mg,
80%) as a yellowish oil; Rf = 0.56 (Et2O–pentane, 1:4).
IR (ATR): 2968, 2932, 2874, 1711, 1467, 1430, 1369, 1321, 1303,
1290, 1218, 1136, 1088, 1042, 922, 667, 632, 605 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.92 [d, J = 6.9 Hz, 3 H,
CH(CH3)2], 1.03 [m, 7 H, HA-CH2, CH3, CH(CH3)2], 1.22 [m, 12 H,
CH3(Cb)], 1.26 (s, 3 H, CH3), 1.48 (m, 1 H, HA-CH2), 1.92 [m, 1 H,
CH(CH3)2], 2.02 (m, 2 H, HB-CH2, CH), 2.49 (m, 1 H, HB-CH2),
2.66 (t, J = 5.7 Hz, 1 H, CH), 2.86 (m, 1 H, CH), 3.28 (dd, J = 9.5,
1.9 Hz, 1 H, CHCHO), 3.89 [br s, 2 H, CH(Cb)], 4.70 (dd, J = 6.2,
4.3 Hz, 1 H, CCHO), 5.16 (ddd, J = 10.2, 1.9, 1.0 Hz, 1 H,
CH=CH2), 5.30 (ddd, J = 17.2, 1.2 Hz, 1 H, CH=CH2), 5.83 (ddd, 1
H, CH=CH2).
13C NMR (100 MHz, CDCl3): d = 14.8 (CH3), 20.2 (CH3), 20.4
(CH3), 20.5 (CH3), 22.9 (CH3), 27.3 (CH3), 28.1 (CH), 28.4 (CH2),
32.7 (CH), 34.9 (CH2), 38.6 (C), 41.4 (CH), 43.8 (CH), 46.2 (CH),
76.8 (CH), 83.5 (CH), 116.9 (CH2), 131.0 (C), 136.9 (C), 137.2
(CH), 152.7 (C).
[a]D20 –21.6 (c 0.82, CHCl3).
IR (ATR): 3083, 2968, 2931, 2874, 1710, 1467, 1430, 1368, 1304,
1291, 1218, 1136, 1083, 1043, 1019, 897, 756, 666, 627 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.34 [m, 2 H, CH(CH2)2], 0.42 [m,
2 H, CH(CH2)2], 0.90 [d, J = 6.9 Hz, 3 H, CH(CH3)2], 0.95 [m, 1 H,
CH(CH2)2], 0.99 [m, 4 H, HA-CH2, CH(CH3)2], 1.04 (s, 3 H, CH3),
1.25 [m, 15 H, CH3, CH3(Cb)], 1.45 (dd, J = 12.0, 7.9 Hz, 1 H, HA-
CH2), 1.87 [m, 1 H, CH(CH3)2], 2.00 (m, 2 H, CH, HB-CH2), 2.48
(m, 1 H, HB-CH2), 2.69 (t, J = 5.6 Hz, 1 H, CH), 2.84 (m, 1 H, CH),
3.16 [dd, J = 9.5, 2.0 Hz, 1 H, CHCHO], 3.69 (dd, J = 7.6, 3.4 Hz,
1 H, CCHO), 3.84, 4.02 [br s each, 2 H, CH(Cb)].
Anal. Calcd C24H39NO3: C, 73.99; H, 10.09; N, 3.60. Found: C,
73.86; H, 10.46; N, 3.40.
13C NMR (100 MHz, CDCl3): d = 1.1 (CH2), 2.1 (CH2), 14.0 (CH),
14.9 (CH2), 20.1 (CH2), 20.4 (CH3), 20.5 (CH3), 21.4 (CH3), 23.0
(CH3), 27.4 (CH3), 28.2 (CH), 28.4 (CH2), 32.9 (CH), 35.1 (CH2),
38.6 (C), 41.4 (CH), 43.8 (CH), 46.0 (CH), 46.3 (CH), 77.9 (CH),
83.4 (CH), 130.5 (C), 138.9 (C), 152.8 (C).
(1R,4S,6R,7S,9R)-3-(N,N-Diisopropylcarbamoyloxy)-4-(furan-
2-yl)-6-isopropyl-10,10-dimethyl-5-oxatricyclo[7.1.1.02,7]un-
dec-2-ene (23ag)
According to the general procedure, 18a (130 mg, 0.31 mmol, 1.0
equiv), 17g (38 mg, 0.40 mmol, 1.3 equiv), and BF3·OEt2 (0.04 mL,
0.32 mmol, 1.1 equiv) in CH2Cl2 (2.5 mL) yielded 23ag (26 mg,
19%) as an orange oil; Rf = 0.44 (Et2O–pentane, 1:4).
Anal. Calcd C25H41NO3: C, 74.40; H, 10.24; N, 3.47. Found: C,
74.62; H, 10.61; N, 3.26.
[a]D20 +32.3 (c 0.31, CHCl3).
(1R,4S,6R,7S,9R)-4-(4-Bromophenyl)-3-(N,N-diisopropylcarb-
amoyloxy)-6-isopropyl-10,10-dimethyl-5-oxatricyclo-
[7.1.1.02,7]undec-2-ene (23ad)
IR (ATR): 2966, 2932, 2874, 1709, 1467, 1430, 1368, 1302, 1289,
1218, 1151, 1136, 1073, 1042, 1009, 757, 734 cm–1.
According to the general procedure, 18a (85 mg, 0.201 mmol, 1.0
equiv), 17d (40 mg, 0.22 mmol, 1.1 equiv), and BF3·OEt2 (0.03 mL,
0.24 mmol, 1.2 equiv) in CH2Cl2 (1 mL) yielded 23ad (43 mg, 41%)
as a colorless oil; Rf = 0.61 (Et2O–pentane, 1:4).
1H NMR (400 MHz, CDCl3): d = 0.90 [d, J = 6.9 Hz, 3 H,
CH(CH3)2], 0.93 [br s, 3 H, CH3(Cb)], 1.03 [d, J = 7.0 Hz, 3 H,
CH(CH3)2], 1.07 [m, 7 H, HA-CH2, CH3, CH3(Cb)], 1.21 [br s, 6 H,
CH3(Cb)], 1.27 (s, 3 H, CH3), 1.52 (m, 1 H, HA-CH2), 1.93 [dtd, J =
8.8, 1.9 Hz, 1 H, CH(CH3)2], 2.07 (m, 2 H, HB-CH2, CH), 2.53 (m,
1 H, HB-CH2), 2.73 (t, J = 5.7 Hz, 1 H, CH), 3.00 (m, 1 H, CH), 3.41
(dd, J = 2.0 Hz, 1 H, CHCHO), 3.70, 3.87 [br s each, 2 H, CH(Cb)],
5.38 (d, J = 3.3 Hz, 1 H, CCHO), 6.30 (d, J = 1.3 Hz, 2 H, CH=CH),
7.36 (t, 1 H, CH=CHO).
13C NMR (100 MHz, CDCl3): d = 14.7 (CH3), 20.2 (CH3), 20.4
(CH3), 20.8 (CH3), 21.0 (CH3), 23.0 (CH3), 27.3 (CH3), 28.2 (CH),
28.4 (CH2), 32.6 (CH), 34.9 (CH2), 38.6 (C), 41.4 (CH), 43.8 (CH),
45.9 (CH), 46.1 (CH), 71.1 (CH), 84.4 (CH), 108.4 (CH), 110.0
(CH), 132.12 (C), 135.4 (C), 142.1 (CH), 152.7 (C), 153.4 (C).
[a]D20 +82.6 (c 1.23, CHCl3).
IR (ATR): 2965, 2931, 2873, 1710, 1487, 1463, 1430, 1368, 1302,
1289, 1217, 1151, 1136, 1109, 1083, 1042, 1011, 819, 756, 767
cm–1.
1H NMR (500 MHz, CDCl3): d = 0.86 [br s, 3 H, CH3(Cb)], 0.93 [d,
J = 6.9 Hz, 3 H, CH(CH3)2], 1.02 [d, 3 H, CH(CH3)2], 1.02 [br s, 3
H, CH3(Cb)], 1.07 (s, 3 H, CH3), 1.21 [br s, 6 H, CH3(Cb)], 1.25 (m,
1 H, HA-CH2), 1.26 (s, 3 H, CH3), 1.54 (m, 1 H, HA-CH2), 1.95 [m,
1 H, CH(CH3)2], 2.04 (m, 1 H, CH), 2.10 (m, 1 H, HB-CH2), 2.52
(m, 1 H, HB-CH2), 2.66 (t, J = 5.7 Hz, 1 H, CH), 3.03 (m, 1 H, CH),
3.45 (dd, J = 9.5, 1.9 Hz, 1 H, CHCHO), 3.68, 3.79 [br s each, 2 H,
CH(Cb)], 5.25 (d, J = 3.4 Hz, 1 H, CCHO), 7.22 (m, 2 H, HAr), 7.42
(m, 2 H, HAr).
HRMS (ESI, EM): m/z [M + Na]+ calcd for C26H39NNaO4:
452.2771; found: 452.2769.
(1R,2S,3S,5S,6S,8S)-5-tert-Butyl-9,9-dimethyl-3-phenyl-4-oxa-
tricyclo[6.1.1.02,6]decane-2-carbaldehyde (26)
From 18i: According to the general procedure, 18i (89 mg, 0.20
mmol, 1.0 equiv), 17c (26 mg, 0.25 mmol, 1.3 equiv), and BF3·OEt2
(0.03 mL, 0.24 mmol, 1.2 equiv) in CH2Cl2 (1.8 mL) yielded 26 (42
mg, 65%) as a colorless solid.
13C NMR (100 MHz, CDCl3): d = 14.7 (CH3), 20.16 (CH3), 20.3
(CH3), 20.5 (CH3), 20.8 (CH3) 21.1 (CH3), 23.0 (CH3), 27.3 (CH3),
28.1 (CH), 28.4 (CH2), 32.9 (CH), 35.0 (CH2), 38.6 (C), 41.4 (CH),
43.8 (CH), 46.1 (CH), 77.2 (CH), 84.1 (CH), 121.5 (C), 129.9 (CH),
131.1 (CH), 131.3 (C), 137.7 (C), 140.2 (C), 152.4 (C).
Anal. Calcd C28H40BrNO3: C, 64.86; H, 7.78; N, 2.70. Found: C,
64.98; H, 7.81; N, 2.53.
From 24: According to the general procedure, unpurified 24 (92
mg, 0.25 mmol, 1.0 equiv), 17c (36 mg, 0.34 mmol, 1.3 equiv), and
BF3·OEt2 (0.035 mL, 0.28 mmol, 1.1 equiv) in CH2Cl2 (1 mL) yield-
ed 23fc (62 mg, 76%).as a colorless solid.
(1R,4S,6R,7S,9R)-3-(N,N-Diisopropylcarbamoyloxy)-6-isopro-
pyl-10,10-dimethyl-4-vinyl-5-oxatricyclo[7.1.1.02,7]undec-2-ene
(23af)
According to the general procedure, 18a (127 mg, 0.30 mmol, 1.0
equiv), 17f (21 mg, 0.37 mmol, 1.2 equiv), and BF3·OEt2 (0.05 mL,
0.39 mmol, 1.3 equiv) in CH2Cl2 (2.5 mL) yielded 23af (61 mg,
53%) as a yellow oil; Rf = 0.50 (Et2O–pentane, 1:4).
Mp 84–94 °C; Rf = 0.62 (Et2O–pentane, 1:4).
[a]D20 –31.1 (c 0.80, CHCl3).
IR (ATR): 3033, 2957, 2906, 2807, 2705, 1722, 1474, 1454, 1396,
1363, 1220, 1194, 1082, 1066, 1027, 993, 748, 696, 647 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.60 (s, 3 H, CH3), 1.10 [s, 9 H,
C(CH3)3], 1.27 (s, 3 H, CH3), 1.71 (m, 2 H, HA-CH2, HA-CH2), 1.95
[a]D20 +67.7 (c 0.92, CHCl3).
Synthesis 2010, No. 2, 329–342 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of Highly Substituted Annulated Dihydropyrans
341
(m, 1 H, CH), 2.09 (m, 1 H, HB-CH2), 2.47 (m, 1 H, HB-CH2), 2.54
(dd, J = 6.3, 4.9 Hz, 1 H, CH), 2.97 (ddd, J = 10.3, 9.0, 3.0 Hz, 1 H,
CH), 3.53 (d, 1 H, CHCHO), 4.96 (s, 1 H, CCHO), 7.22 (m, 3 H,
HAr), 7.29 (m, 2 H, HAr), 8.87 [s, 1 H, CH(O)].
13C NMR (100 MHz, CDCl3): d = 23.0 (CH3), 26.5 (CH3), 26.5
(CH3), 26.9 (CH2), 32.0 (CH2), 33.9 (CH), 34.5 (C), 38.3 (C), 40.6
(CH), 43.8 (CH), 65.7 (C), 85.3 (CH), 96.6 (CH), 126.3 (CH), 127.9
(CH), 128.3 (CH), 136.7 (C), 205.7 (C).
(–0.16) e Å–3, hydrogen atoms calculated and refined as
riding atoms.
(11) Formula 14 depicts the a-(S)-epimer, which is assumed to be
the preliminary formed epimer by removal of the pro-S-H
(from the rear face). However its configurational stability is
unknown, it may be in equilibration with the a-(R)-epimer
(not shown).
(12) X-ray crystal structure analysis for epi-18a: formula
C24H45NO3Si, M = 423.70, colorless crystal 0.35 × 0.25 ×
0.07 mm, a = 10.8529 (5), b = 13.0316 (6), c = 18.5002 (8)
Å, V = 2616.5 (2) Å3, rcalc = 1.076 g cm–3, m = 0.954 mm–1,
empirical absorption correction (0.731 £ T £ 0.936), Z = 4,
orthorhombic, space group P212121 (No. 19), l = 1.54178 Å,
T = 223 K, w and j scans, 14181 reflections collected ( h,
k, l), [(sinq)/l] = 0.60 Å–1, 4588 independent (Rint = 0.050)
and 4348 observed reflections [I ≥ 2 s(I)], 274 refined
parameters, R = 0.044, wR2 = 0.114, Flack parameter –0.01
(3), max. residual electron density 0.21 (–0.17) e Å–3,
hydrogen atoms calculated and refined as riding atoms.
(13) X-ray crystal structure analysis for 18a: formula
C24H45NO3Si, M = 423.70, colorless crystal 0.40 × 0.15 ×
0.10 mm, a = 10.9427 (4), b = 13.3514 (5), c = 18.4110 (7)
Å, V = 2689.9 (2) Å3, rcalc = 1.046 g cm–3, m = 0.928 mm–1,
empirical absorption correction (0.708 £ T 0.913), Z = 4,
orthorhombic, space group P212121 (No. 19), l = 1.54178 Å,
T = 223 K, w and j scans, 14774 reflections collected ( h,
k, l), [(sinq)/l] = 0.60 Å–1, 4669 independent (Rint = 0.042)
and 4327 observed reflections [I ≥ 2 s(I)], 274 refined
parameters, R = 0.043, wR2 = 0.111, Flack parameter 0.01
(3), max. residual electron density 0.19 (–0.18) e Å–3,
hydrogen atoms calculated and refined as riding atoms.
(14) A six-membered Zimmerman–Traxler transition state of an
(E)-allylmetal leads to the anti-diastereomer.15
Anal. Calcd C22H30O2: C, 80.94; H, 9.26. Found: C, 80.64; H, 9.52.
Acknowledgment
This work was supported by the Deutsche Forschungsgemeinschaft
(SFB 424) and the Fonds der Chemischen Industrie. We would like
to thank Dr. Klaus Bergander for measuring plenty of NOE’s.
Thérèse Hémery would like to thank Sabine Kollmann for ge-
nerously providing ‘glyceraldehyde’.
References
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C28H41NO3, M = 439.62, colorless crystal 0.25 × 0.20 × 0.15
mm, a = 9.1840 (2), b = 12.7732 (3), c = 11.7279 (5) Å, b =
102.293 (2)°, V = 1343.67 (5) Å3, rcalc = 1.087 g cm–3, m =
0.540 mm–1, empirical absorption correction (0.877 £ T £
0.923), Z = 2, monoclinic, space group P21 (No. 4), l =
1.54178 Å, T = 223 K, w and j scans, 7668 reflections
collected ( h, k, l), [(sinq)/l] = 0.60 Å–1, 4270
independent (Rint = 0.038) and 4151 observed reflections
[I ≥ 2 sI)], 297 refined parameters, R = 0.040, wR2 = 0.112,
Flack parameter 0.1 (2), max. residual electron density 0.16
(–0.18) e Å–3, hydrogen atoms calculated and refined as
riding atoms.
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C20H37NO2Si, M = 351.60, colorless crystal 0.40 × 0.10 ×
0.07 mm, a = 10.6208 (3), b = 7.4155 (2), c = 14.7983 (5) Å,
b = 108.749 (2)°, V = 1103.65 (6) Å3, rcalc = 1.058 g cm–3,
m = 1.010 mm–1, empirical absorption correction (0.688 £
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1.54178 Å, T = 223 K, w and j scans, 6133 reflections
collected ( h, k, l), [(sinq)/l] = 0.60 Å–1, 2594
independent (Rint = 0.041) and 2497 observed reflections [I
≥ 2 s(I)], 226 refined parameters, R = 0.044, wR2 = 0.123,
Flack parameter 0.01 (4), max. residual electron density 0.16
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(21) Data sets were collected with a Nonius KappaCDD
diffractometer. Programs used: data collection COLLECT
(Nonius B.V., 1998), data reduction Denzo-SMN,22
Synthesis 2010, No. 2, 329–342 © Thieme Stuttgart · New York

342
T. Hémery et al.
PAPER
absorption correction Denzo23 structure solution SHELXS-
97,24 structure refinement SHELXL-97,25 graphics
SCHAKAL26 and DIAMOND.27 CCDC 739288–739291
contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge at
www.ccdc.cam.ac.uk/conts/retrieving.html [or from the
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 (1223)336033, E-mail:
deposit@ccdc.cam.ac.uk].
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2008, 64, 112.
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1997.
(27) DIAMOND: Bergerhoff, G.; Berndt, M.; Brandenburg, K.
J. Res. Natl. Inst. Stand. Technol. 1996, 101, 221.
(22) Denzo-SMN: Otwinowski, Z.; Minor, W. Methods Enzymol.
1997, 276, 307.
Synthesis 2010, No. 2, 329–342 © Thieme Stuttgart · New York