An unexpected reversal of diastereoselectivity in the [4+3]-cycloaddition reaction of nitrogen-stabilized oxyallyl cations with methyl 2-furoate

Article abstract of DOI:10.1055/s-2008-1042765

An unexpected reversal of diastereoselectivity in the [4+3] cycloaddition of methyl 2-fuorate with nitrogen-stabilized oxyallyl cations derived from epoxidation of chiral allenamides is described here. This intriguing reversal in favor of the endo-II cycloaddition pathway is likely a result of minimizing the dipole interaction between the oxyallyl cation and ester carbonyl of methyl 2-fuorate. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1042765

CLUSTER
739
An Unexpected Reversal of Diastereoselectivity in the [4+3]-Cycloaddition
Reaction of Nitrogen-Stabilized Oxyallyl Cations with Methyl 2-Furoate
[4+3]
C
yc
e
loaddition
R
n
e
action of
O
n
xyallyl Cati
i
ons
w
it
f
h
M
ethy
e
l
2-Furoater E. Antoline, Richard P. Hsung*
Division of Pharmaceutical Sciences and Department of Chemistry, University of Wisconsin–Madison,
777 Highland Avenue, Rennebohm Hall, Madison, WI 53705, USA
Fax +1(608)2625345; E-mail: rhsung@wisc.edu
Received 27 November 2007
can be further enhanced with a bidentate metal cation such
as Zn (2a-Zn) that can chelate to both the oxyallyl oxygen
atom and the oxazolidinone carbonyl oxygen. On the oth-
er hand, while a metal chelation is not possible in confor-
Abstract: An unexpected reversal of diastereoselectivity in the
[4+3] cycloaddition of methyl 2-fuorate with nitrogen-stabilized
oxyallyl cations derived from epoxidation of chiral allenamides is
described here. This intriguing reversal in favor of the endo-II cy-
cloaddition pathway is likely a result of minimizing the dipole inter- mation 2b, it possesses a minimized dipole interaction
action between the oxyallyl cation and ester carbonyl of methyl 2-
fuorate.
relative to 2a and is likely the source of minor endo-II cy-
cloadducts. This model has been in accord with the ob-
Key words: stereoselective [4+3] cycloadditions, allenamides, ni-
trogen-stabilized oxyallyl cations, endo-I versus endo-II selectivity,
dipole interaction
served endo-I:endo-II ratios in the presence and absence
of ZnCl2 (Scheme 1), and served as a foundation for our
approach to asymmetric [4+3] cycloadditions employing
achiral allenamides.18 However, when investigating re-
gioselectivity patterns in our [4+3] cycloaddition using
methyl 2-furoate, we encountered an unexpected reversal
of stereoselectivity favoring the endo-II pathway. We re-
port herein this intriguing observation and its implications
for our mechanistic model.
In the last twenty years, chemistry of heteroatom-substi-
tuted oxyallyl cations has played a significant role in the
advancement of [4+3] cycloadditions1–3 particularly in ad-
dressing the challenge of developing diastereoselective4
and asymmetric5,6 approaches. Our interest in the chemis-
try of allenamides7–10 has led to a unique variant of nitro-
As shown in Scheme 2, DMDO epoxidation of allena-
mide 1 and subsequent cycloaddition with methyl 2-fu-
roate led to the respective cycloadducts 4a and 4b19,20 in
good yields. While regiochemically, the methoxy carbon-
yl group and oxazolidinone ring could be readily assigned
as being syn2b,4e,f {or on the same side of the [3.2.1]oxa-
bicyclooctene} using proton NMR and COSY, the diaste-
reomeric ratio provoked our suspicion because they are
opposite from what we have been accustom to (see
Scheme 1): A lower dr (70:30) was obtained in the pres-
ence of ZnCl2 while a higher dr (≥95:5) was seen without
using ZnCl2. A closer inspection initially through NOSEY
gen-substituted
chiral
oxyallyl
cations.11
We
demonstrated that nitrogen-stabilized oxyallyl cation 2
derived from DMDO epoxidations12 of allenamide 1 can
undergo highly diastereoselective13–16 [4+3] cycloaddi-
tions (Scheme 1).
Mechanistically, we have consistently rationalized that
the observed stereoselectivity is a result of furan ap-
proaching in a favorable endo manner17 from the less-hin-
dered bottom or endo-I face of the oxyallyl cation
assuming the preferred conformation 2a. This preference
shielding the top face
for endo-II or exo-II
a likely path
to endo-II
Ph
H
O
N
–78 °C or
–45 °C
DMDO
O
O
O
O
H
Cl
O
N
N
H
Zn]
O
Cl
O
O
Ph
O
•
Ph
2a [or 2a-Zn]
endo-I face
2b
1: chiral allenamide
O
H
H
O
H
O
O
O
Ph
Ph
O
O
O
N
with ZnCl2
endo-I:II ≥95:5
without ZnCl2
O
N
N
O
endo-I:II 75:25
O
O
Ph
3a: endo-I: favored
O
3b: endo-II
3b: endo-II
Scheme 1 Endo-I versus endo-II in the [4+3] cycloaddition
SYNLETT 2008, No. 5, pp 0739–0744
x
x.
x
x.
2
0
0
8
Advanced online publication: 26.02.2008
DOI: 10.1055/s-2008-1042765; Art ID: Y01607ST
© Georg Thieme Verlag Stuttgart · New York

740
J. E. Antoline, R. P. Hsung
CLUSTER
H
O
O
O
O
H
O
4.0 equiv DMDO
added via syringe pump
CO2Me
O
Ph
O
CO2Me
O
N
N
+
N
O
3.0 equiv
CO2Me
O
O
syn
•
Ph
Ph
4b: endo-II
CH2Cl2, –78 °C, 18 h
1
4a: endo-I
70
≥ 95
2.0 equiv ZnCl2 [63% yield]:
without ZnCl2 [60% yield]:
30
≤ 5
H
O
H
O
O
CO2Allyl
O
Ph
O
CO2Allyl
N
+
N
O
O
O
Ph
5b: endo-II
5a: endo-I
≤ 5
≥ 95
without ZnCl2 [40% yield]:
Scheme 2 An endo-II selective [4+3] cycloaddition
lectivity toward endo-I, endo-II is favored with or without
ZnCl2.
To be consistent with conformation 2a being preferred,
we initially proposed that 2-fuorate esters might have
switched from an endo-I approach to exo-I approach and
that endo-II 4b was derived from an epimerization from
the initial exo-I cycloadduct 4c (Scheme 3). However, this
assertion is likely not correct based on our deuterium la-
beling study. With or without ZnCl2, the cycloaddition us-
ing deuterated allenamide 1-D led to 4a-D and 4b-D with
the same respective endo-I/endo-II ratios with essentially
no loss of deuterium content. If an epimerization had tak-
en place to afford the endo-II cycloadduct, the deprotona-
tion–protonation process should have led to a significant
loss of deuterium labeling.
Figure 1 X-ray crystal structure of endo-II cycloadduct 4b
and ultimately via single-crystal X-ray structure
(Figure 1) revealed that the major isomer 4b is actually
the endo-II product. When employing allyl 2-furoate
without ZnCl2, the same outcome was attained for the re-
spective cycloadducts 5a and 5b.
Having effectively ruled out the exo-I pathway, we re-
evaluated endo-I and endo-II pathways. As shown in
Scheme 4, if the endo-II cycloadduct originates from the
oxyallyl cation assuming conformation 6b, its advantage
is a minimized dipole interaction, and its distinct disad-
vantage relative to conformer 6a [locked in a bidentate
manner] or 6a¢ (monocoordinated) is the A1,3-strain (in
blue) for which the severity would be dependent upon the
size of the W group. Support for this A1,3-strain is seen
with the high endo-I:endo-II ratio obtained from the cy-
cloaddition of allenamide 7 substituted with Sibi’s auxil-
This reversal of stereoselectivity in favor of endo-II sur-
prised us because based on our mechanistic model: With
or without ZnCl2, endo-I should dominate through the
preferred conformation 2a (or 2a-Zn) with the chelating
metal serving to further enhance the endo-I pathway.
However, in this case, although ZnCl2 does sway the se-
Ph
Ph
O
O
O
O
Ph
N
epimerization
O
O
O
N
N
4b
H
H
Zn
CO2Me
O
O
endo-II
2a-Zn
2a
OR
H
O
CO2Me
4c: exo-I
the reversal of stereoselectivity:
change of endo-I to exo-I approach
O
O
D
D
O
4.0 equiv DMDO
added via syringe pump
O
CO2Me
O
Ph
O
O
O
CO2Me
N
D
N
+
N
O
3.0 equiv
CO2Me
O
•
Ph
O
Ph
4a-D: endo-I
O
CH2Cl2, –78 °C, 18 h
1-D: 89% D
4b-D: endo-II
2.0 equiv ZnCl2 [20% yield]:
without ZnCl2 [25% yield]:
30
≤ 5
70 [82% D]
≥ 95 [94% D]
Scheme 3 Ruling out the exo-I approach with deuterium labeling
Synlett 2008, No. 5, 739–744 © Thieme Stuttgart · New York

CLUSTER
[4+3] Cycloaddition Reaction of Oxyallyl Cations with Methyl 2-Furoate
741
W
endo-II
W
O
O
N
O
A1,3
O
O
O
N
N
H
H
H
M
O
O
W
O
M
M
6a'
6b
6a
endo-I
M = Zn
endo-I
M = Na, Zn, or H
O
H
H
O
Ph
4.0 equiv DMDO
O
O
O
Ph
No ZnCl2
O
O
N
N
H
+
O
N
O
74% yield; endo-I:II 95:5
O
•
W
Ph
8a: endo-I
O
Ph
7: W = CHPh2
8b: endo-II
Scheme 4 Reevaluations of endo-I and endo-II pathways
iary.22 Even when ZnCl2 was not employed, the utility of unique in its preference to react through the endo-II path-
a more bulky diphenyl methyl group resulted in a greater way.
A1,3-strain in conformer 6b and precluded any formation
of the endo-II cycloadduct 8b.
Being intrigued with this phenomenon, we propose here a
kinetic model shown in Scheme 6 that accounts for the
The question became if we had underestimated the pres- significance of the dipole interaction in the oxyallyl cation
ence of conformer 6b in spite of the A1,3-strain. Toward conformers. Given the A1,3-strain present in conformer 2b,
that goal, we probed conditions that could be in its favor. conformer 2a would remain as the preferred conformer in
As shown in Scheme 5, we examined the cycloaddition of the oxyallyl cation equilibrium especially when coordi-
allenamide 1 with furan in CF3CH2OH because Walters11a nated in a bidentate fashion as shown in 2a-Zn. However,
observed a similar stereoselectivity change toward endo- conformer 2b (or 2b-Zn) is the more reactive conformer
II (and even exo) cycloadducts when CF3CH2OH was the when using methyl 2-furoate with kb > ka (or kb-Zn > ka-Zn
)
reaction solvent for their [4+3] cycloadditions. However, because the transition state involving 2b (or 2b-Zn) con-
we found that either in the presence or absence of ZnCl2, sists of the least number of aligned dipoles (see red ar-
the respective ratio shifted only slightly toward endo-II. In rows) when accounting for the ester carbonyl dipole of
addition, when using monodentate Lewis acid NaClO4, methyl 2-furoate.
the ratio again remained essentially the same as not using
The observed ratios could begin to make intuitive sense
ZnCl2. It is noteworthy that the polarity of the reaction sol-
on the basis of this proposed model. In the absence of
vent does not exhibit any real impact on the endo-I:II ra-
ZnCl2, if the cycloaddition of methyl 2-furoate would pro-
ceed through conformer 2b at a faster rate than 2a [kb >
tio, and this was true in our previous study as well.13
Overall, for furan, the endo-I pathway dominates under all
ka], one could envision the endo-II cycloadduct 4b pre-
conditions. In contrast, the reaction for methyl 2-furoate
vailing. In addition, the endo-I:endo-II ratio of 75:25 from
the cycloaddition of furan (in brackets) implies the pres-
ence of a substantial amount of conformer 2b, assuming
using NaClO4 led to the endo-II cycloadduct 4b as the dis-
tinct major diastereomer. Methyl 2-furoate appears to be
furan reacts at a comparable rate through 2a and 2b. Al-
H
O
N
H
O
4.0 equiv DMDO
O
O
Ph
O
added via syringe pump
O
O
N
+
H
N
O
3.0 equiv
O
•
O
Ph
Ph
3a: endo-I
O
1
in CF3CH2OH, –40 °C, 18 h:
2.0 equiv ZnCl2 [41% yield]:
without ZnCl2 [40% yield]:
3b: endo-II
17 [≤5]
83 [≥95 in CH2Cl2]
71 [75 in CH2Cl2]
29 [25]
in acetone, – 78 °C, 18 h:
3.4 equiv NaClO4 [73% yield]:
78
22
H
H
O
4.0 equiv DMDO
O
CO2Me
Ph
O
added via syringe pump
O
O
CO2Me
N
+
N
O
3.0 equiv
CO2Me
O
O
Ph
O
in acetone, –78 °C, 18 h:
3.4 equiv NaClO4 [78% yield]:
4a: endo-I
4b: endo-II
8
92
Scheme 5 Preference for 2-furoate to proceed via the endo-II pathway
Synlett 2008, No. 5, 739–744 © Thieme Stuttgart · New York

742
J. E. Antoline, R. P. Hsung
CLUSTER
O
OMe
O
Ph
H
Ph
H
O
O
O
O
O
O
N
N
N
H
Zn
O
O
O
Zn]
2b [or 2b-Zn] 2a-Zn
2a
Ph
endo-I
endo-I
with no Zn2+
ka: slow
O
O
kb or kb-Zn
:
with Zn2+
:
OMe
OMe
:
faster
O
O
ka-Zn: slow
H
H
H
O
O
O
CO2Me
O
CO2Me
O
Ph
O
O
CO2Me
70 : 30
[with furan: ≤ 5 : ≥ 95]
N
N
N
≤ 5 : ≥ 95
[with furan: 75 : 25]
O
O
O
O
Ph
Ph
O
4a: endo-I: Not found
4b: endo-II
4a: endo-I: Leaking thru
Scheme 6 A dipole-minimized endo-II cycloaddition pathway
H
O
H
O
O
4.0 equiv DMDO
R
Ph
O
added via syringe pump
O
O
R
N
+
N
H
O
O
N
3.0 equiv
R
O
•
Ph
O
Ph
O
CH2Cl2, – 78 °C, 18 h
For R = CN:
1
9a: endo-I
9b: endo-II
2.0 equiv ZnCl2 [47% yield]:
17
83
For R = Me:
2.0 equiv ZnCl2 [47% yield]:
without ZnCl2 [54% yield]:
10a: endo-I
≥ 95
10b: endo-II
≤ 5
25
75
Scheme 7 Support for the dipole-minimized endo-II pathway
though the equilibrium ratio of 2a:2b may not be critical Secondly, we carried out the reaction of 2-cyanofuran
in a kinetic model, with the presence of conformer 2b pos- with chiral allenamide 1 in the presence of ZnCl2
sibly being substantial, one could then predict a complete (Scheme 7).23 The observed endo-I:endo-II ratio suggests
domination of the endo-II pathway when using methyl 2- that given the strong CN dipole, the cycloaddition again
furoate based on the premise of kb being greater than ka. prefers the transition state that presents the least amount
This is what we observed.
of dipole interaction, leading to the endo-II product 9b as
the major diastereomer. Moreover, since there is only one
conformation for the CN group relative to the furan ring,
the dipole model proposed in Scheme 6 for methyl 2-fu-
roate is applicable for a range of conformations that the
ester carbonyl group can assume during the cycloaddition
and not specific to the one shown.
On the other hand, in the presence of ZnCl2, for the cy-
cloaddition of methyl 2-furoate to proceed through con-
former 2b-Zn in a kinetically favored manner, it will have
to siphon slowly away from the predominant conformer
2a-Zn in the equilibrium. This would serve to disfavor the
endo-II pathway and allow the cycloaddition to proceed
via (or leaking through) 2a-Zn, leading to a ratio with de- Lastly, because we were unsuccessful in attempting the
creased preference for the endo-II cycloadduct 4b than the reaction of 2-methoxyfuran due to competing epoxidation
reaction without ZnCl2. It is noteworthy that with the and/or decompostions under the Lewis acidic condi-
equilibrium being heavily in favor of conformer 2a-Zn, tions,20 we examined reactions of 2-methylfuran. The ste-
the final endo-I:endo-II ratio of 30:70 suggests that the as- reochemical outcome in cycloadducts 10a,b returned to
sessment of kb-Zn being greater than ka-Zn for the cycload- normal in favor of the endo-I isomer both in the presence
dition of methyl 2-furoate is appropriate.
and absence of ZnCl2. These results firmly rule out any
steric factors that could play a role in the stereoselectivity
reversal, and suggest that alleviating the aligned dipole in-
teraction in the transition state for the reaction of methyl
2-furoate took place at the expense of endo-I cycloaddi-
tion pathway.
To support this model, we pursued the following experi-
ments. First, when we ran the reaction of methyl 2-furoate
in the presence of 7.0 equivalents of ZnCl2, the reaction
did not provide any cycloadducts but led to decomposi-
tions. This implies that methyl 2-furoate reacts extremely
slowly through conformer 2a-Zn, and its reaction could We have described here an unexpected reversal of stereo-
be essentially shut down when the equilibrium is shifted selectivity in the [4+3] cycloadditions of methyl 2-fuorate
almost exclusively toward 2a-Zn with excess ZnCl2.
with nitrogen-stabilized oxyallyl cations derived from ep-
oxidation of chiral allenamides. Although further studies
Synlett 2008, No. 5, 739–744 © Thieme Stuttgart · New York

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[4+3] Cycloaddition Reaction of Oxyallyl Cations with Methyl 2-Furoate
743
(8) For reviews on the chemistry and synthesis of allenamides,
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2005, Chap. 21.4.
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versal in favor of the endo-II cycloaddition pathway ap-
pears to be related to minimizing the dipole interaction
between the oxyallyl cation and the ester carbonyl in the
transition state of cycloaddition.
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Acknowledgment
Authors thank NIH-NIGMS [GM066055] and UW-Madison for fi-
nancial support.
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Lett. 1997, 38, 3353. (j) Harmata, M.; Jones, D. E. J. Org.
Chem. 1997, 62, 4885.
(5) Harmata, M.; Ghosh, S. K.; Hong, X.; Wacharasindu, S.;
Kirchhoefer, P. J. Am. Chem. Soc. 2003, 125, 2058.
(6) For a recent account that constitutes an enantioselective
formal [4+3] cycloaddition, see: Dai, X.; Davies, H. M. L.
Adv. Synth. Catal. 2006, 348, 2449.
(7) For a compendium on the chemistry of allenes, see: Krause,
N.; Hashmi, A. S. K. Modern Allene Chemistry, Vol. 1 and
2; Wiley-VCH: Weinheim, 2004.
(14) Antoline, J. E.; Hsung, R. P.; Huang, J.; Song, Z.; Li, G. Org.
Lett. 2007, 9, 1275.
(15) Xiong, H.; Huang, J.; Ghosh, S. K.; Hsung, R. P. J. Am.
Chem. Soc. 2003, 125, 12694.
(16) (a) Rameshkumar, C.; Hsung, R. P. Angew. Chem. Int. Ed.
2004, 43, 615. For a very recent account on intramolecular
[4+3] cycloadditions of allenyl dienes employing PtCl2 as a
catalyst, see: (b) Trillo, B.; López, F.; Gulías, M.; Castedo,
L.; Mascareñas, J. L. Angew. Chem. Int. Ed. 2008, 47, 951.
(17) For a review, see: (a) Hoffmann, H. M. R. Angew. Chem.,
Int. Ed. Engl. 1973, 12, 819; Angew. Chem. 1973, 85, 877.
(b) Also see: Hoffmann, H. M. R.; Joy, D. R. J. Chem. Soc.
B 1968, 1182.
(18) Huang, J.; Hsung, R. P. J. Am. Chem. Soc. 2005, 127, 50.
(19) General Procedure for the [4+3] Cycloaddition
To a solution of the allenamide in CH2Cl2 [0.10 M] was
added the appropriate furan (3.0–6.0 equiv) and 4 Å
pulverized MS (0.50 g). The reaction solution was cooled to
–78 °C, and ZnCl2 (2.0 equiv, 1.0 M in Et2O) was added.
Then, DMDO in acetone (4.0–6.0 equiv) was added as a
chilled solution (at –78 °C) via syringe pump over 3–4 h.
The syringe pump was cooled by dry ice the entire addition
time. After the addition the reaction mixture was stirred for
another 14 h. The reaction was then quenched with sat. aq
NaHCO3, filtered through Celite®, concentrated in vacuo,
Synlett 2008, No. 5, 739–744 © Thieme Stuttgart · New York

744
J. E. Antoline, R. P. Hsung
CLUSTER
23
partitioned with CH2Cl2, extracted [4 × 20 mL], dried over
Na2SO4, and concentrated in vacuo. The crude residue was
purified via silica gel column chromatography (gradient
eluent: 10–75% EtOAc in hexane).
Compound 5b: Rf = 0.23 (50% EtOAc in hexane); [a]D
–72.8 (c 6.4, CH2Cl2). 1H NMR (400 MHz, CDCl3): d = 2.51
(d, 1 H, J = 16.0 Hz), 2.84 (dd, 1 H, J = 16.4, 6.0 Hz), 4.00
(s, 1 H), 4.17 (t, 1 H, J = 8.8 Hz), 4.39 (ddt, 1 H, J = 13.2,
5.6, 1.3 Hz), 4.66 (t, 1 H J = 8.4 Hz), 4.69 (m, 1 H), 4.83 (t,
1 H, J = 8.4 Hz), 5.07 (dd, 1 H, J = 5.6, 1.9 Hz), 5.27 (ddd,
1 H, J = 10.4, 2.5, 1.3 Hz) 5.34 (ddd, 1 H, J = 17.2, 3.0, 1.4
Hz) 5.84 (ddt, 1 H, J = 6.0, 11.6, 16.4), 6.28 (dd, 1 H,
J = 6.0, 2.0 Hz), 6.72 (d, 1 H, 6.0 Hz), 7.28–7.41 (m, 5 H).
13C NMR (125 MHz, CDCl3): d = 45.4, 64.4, 66.7, 68.6,
70.6, 79.1, 89.3, 119.6, 128.5, 129.5, 129.9, 131.3, 132.8,
133.7, 136.5, 158.2, 166.8, 199.5. IR (thin film): 3629 (w),
3445 (w), 3065 (w), 1764 (s), 1726 (s) cm–1. MS (APCI):
m/e (%) = 370.1 (100) [M + H]+.
(20) In our intermolecular nitrogen stabilized oxyallyl cation
[4+3] cycloadditions, for electron-rich furans, while some of
the low-yielding reactions are due to decomposition of the
epoxidized starting allenamide, most are due to noticeable
competing epoxidation of the respective electron-rich furan.
This issue can be circumvented using 6–10 equiv of furan,
leading to higher yields (see references 13 and 18). For
electron-deficient furans, the competing furan-epoxidation
is not a problem, and thus, we can employ a much lower
loading. However, we have found that reactions with
electron-deficient furans such as those shown in this study
are overall slower and more sluggish. This is consistent with
the fact that oxyallyl cation based [4+3] cycloadditions
proceed in an electrophilic manner.
23
Compound 9b: Rf = 0.13 (50% EtOAc in hexane); [a]D
–78.5 (c 2.0, CH2Cl2). 1H NMR (500 MHz, CDCl3): d = 2.52
(d, 1 H, J = 16.5 Hz), 2.79 (dd, 1 H, J = 17.0, 5.5 Hz), 3.84
(s, 1 H), 4.26 (dd, 1 H, J = 9.0, 7.0 Hz), 4.77 (t, 1 H, J = 8.5
Hz), 5.08 (d, 1 H, J = 4.0 Hz), 5.16 (t, 1 H, J = 8.0 Hz) 6.34
(br d, 1 H, J = 4.5 Hz), 6.37 (dd, 0.5 H, J = 6.0, 2.0 Hz), 6.61
(d, 0.5 H, J = 6.0 Hz), 7.41–7.48 (m, 5 H). 13C NMR (125
MHz, CDCl3): d = 29.6, 44.8, 45.3, 65.1, 71.4, 79.3, 79.7,
128.2, 128.8, 129.9, 130.2, 130.6, 132.8, 135.7, 197.2. IR
(thin film): 3509 (w), 3110 (w), 2897 (w), 1755 (s), 1729 (s)
cm–1. MS (APCI): m/e (%) = 311.1 (10) [M + H]+.
(21) Analytical Data
23
Compound 4b: Rf = 0.10 (50% EtOAc in hexane); [a]D
–86.2 (c 0.10, CH2Cl2). 1H NMR (500 MHz, CDCl3): d =
2.53 (d, 1 H, J = 16.2 Hz), 2.83 (dd, 1 H, J = 5.4, 16.0 Hz),
3.67 (s, 3 H), 3.96 (s, 1 H), 4.18 (t, 1 H, J = 8.1 Hz), 4.66 (t,
1 H, J = 8.0 Hz), 4.82 (t, 1 H, J = 9.2 Hz), 5.06 (dd, 1 H,
J = 5.2, 1.6 Hz), 6.28 (dd, 1 H, J = 6.0, 2.0 Hz), 7.15 (d, 1 H,
J = 6.4 Hz), 7.28–7.46 (m, 5 H). 13C NMR (75 MHz,
CDCl3): d = 14.5, 21.3, 45.4, 53.1, 64.4, 68.6, 70.6, 79.1,
89.3, 128.4, 129.5, 129.4, 140.2, 167.4, 171.4, 199.4 cm–1.
IR (thin film): 3280 (w), 2911 (w), 1766 (s) cm–1. MS
(APCI): m/e (%) = 344.1 (90) [M + H]+.
Compounds 10a,b: Rf = 0.31 (50% EtOAc in hexane). 1H
NMR (400 MHz, CDCl3): d = 1.31 (s, 3 H), 1.43 (s, 3 H),
2.43 (d, 1 H, J = 16.5 Hz), 2.49 (d, 1 H, J = 15.5 Hz), 2.65
(d, 1 H, J = 15.5 Hz), 2.75–2.82 (br, 1 H), 4.08 (dd, 1 H,
J = 8.0, 4.4 Hz), 4.19 (dd, 1 H, J = 8.4, 8.4 Hz), 4.74 (t, 2 H,
J = 8.8 Hz), 4.82 (dd, 1 H, J = 9.2, 4.4 Hz), 4.87 (dd, 2 H,
J = 8.4, 4.8 Hz), 4.92 (d, 2 H, J = 4.4 Hz), 4.99 (dd, 1 H,
J = 5.6, 0.8 Hz), 5.92 (d, 1 H, J = 6.0 Hz), 6.06 (br, 1.8 H),
6.13 (dd, 0.50 H, J = 6.4, 2.0 Hz), 6.45 (d, 0.20 H, J = 5.6
Hz), 6.48 (dd, 0.50 H, J = 4.4, 1.0 Hz), 7.27–7.44 (m, 10 H).
IR (thin film): 3425 (w), 2927 (m), 1751 (s), 1719 (s) cm–1.
MS (APCI): m/e (%) = 300.1 (100) [M + H]+.
23
Compound 4b-D: Rf = 0.10 (50% EtOAc in hexane); [a]D
–132.6 (c 0.30, CH2Cl2). 1H NMR (400 MHz, CDCl3): d =
2.52 (d, 1 H, J = 16.8 Hz), 2.84 (dd, 1 H, J = 5.2, 16.4 Hz),
3.65 (s, 3 H), 3.96 (s, 0.35 H), 4.20 (dd, 1 H, J = 8.8, 6.8 Hz),
4.74 (t, 1 H, J = 8.4 Hz), 4.96 (t, 1 H, J = 7.6 Hz), 5.05 (m, 1
H) 6.28 (dd, 1 H, J = 1.6, 5.6 Hz), 7.11 (d, 1 H, J = 6.0 Hz),
7.23–7.44 (m, 5 H). 13C NMR (125 MHz, CDCl3): d = 29.5,
45.4, 53.0, 64.3, 70.5, 79.1, 89.2, 128.4, 129.5, 129.9, 132.6,
133.6, 136.4, 158.3, 167.3, 199.4. IR (thin film): 3300 (w),
2910 (w), 1748 (s) cm–1. MS (APCI): m/e (%) = 345.1 (60)
[M + H]+.
(22) Sibi, M. P.; Porter, N. A. Acc. Chem. Res. 1999, 32, 163.
(23) When the reaction was carried out in the absence of ZnCl2,
it was very sluggish and inconclusive.
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