Asymmetric Organocatalytic One-Pot, Two-Step Sequential Process to Synthesize Chiral Acetal-Containing Polycyclic Derivatives from Cyclic Hemiacetals and Enones

Article abstract of DOI:10.1021/acs.joc.7b01915

We have developed an efficient one-pot, two-step sequential process to synthesize biologically and synthetically important chiral acetal-containing polycyclic derivatives. This novel protocol had been proved to proceed via Michael-lactolization-oxocarbenium ion ring-closing sequence, which was initiated by a key reactive enamine intermediate and interrupted the previously established reaction pathway of two different enones used in this work, and generated the corresponding cycloadducts with excellent stereoselectivity bearing up to seven continuous stereocenters. Both chiral and racemic starting cyclic hemiacetals worked well in this strategy. The synthetic applications of the obtained polycyclic products have also been demonstrated.

Full text of DOI:10.1021/acs.joc.7b01915

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Article
Asymmetric Organocatalytic One-pot, Two-step Sequential
Process to Synthesize Chiral Acetal-Containing Polycyclic
Derivatives from Cyclic Hemiacetals and Enones
Chao Liu, and Yan-Kai Liu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01915 • Publication Date (Web): 15 Sep 2017
Downloaded from http://pubs.acs.org on September 15, 2017
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The Journal of Organic Chemistry
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Asymmetric Organocatalytic Oneꢀpot, Twoꢀstep Sequential Process to Synthesize Chiral
AcetalꢀContaining Polycyclic Derivatives from Cyclic Hemiacetals and Enones
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a
,a,b
Chao Liu , and YanꢀKai Liu*
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a
Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of
China, Qingdao 266003, China
b
Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology,
Qingdao 266003, China
Email: liuyankai@ouc.edu.cn
ABSTRACT
We have developed an efficient oneꢀpot, twoꢀstep sequential process to synthesize biologically and
synthetically important chiral acetalꢀcontaining polycyclic derivatives. This novel protocol had been proved
to proceed via Michaelꢀlactolizationꢀoxocarbenium ion ringꢀclosing sequence, which initiated by a key
reactive enamine intermediate and interrupted the previously established reaction pathway of two different
enones used in this work, and generated the corresponding cycloadducts with excellent stereoselectivity
bearing up to seven continuous stereocenters. Both chiral and racemic starting cyclic hemiacetals worked well
in this strategy. The synthetic applications of the obtained polycyclic products have also been demonstrated.
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INTRODUCTION
The densely functionalized chiral polycyclic frameworks, especially the ones containing acetal moiety, are
often found in many compounds which have broad applications in both synthetic organic chemistry and
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medicinal chemistry. Thus, the strategies that could effectively form chiral acetalꢀcontaining polycyclic
frameworks are clearly highly desirable but challenging goals, which attribute to the production of continuous
2
multiple chiral centers with high chemoꢀ, regioꢀ, and stereocontrol.
3
In the research field of asymmetric organocatalysis, the enamineꢀbased Michael reaction between
4
aldehydes and electronꢀdeficient alkenes has emerged as a highly valuable CꢀC bondꢀformation strategy,
providing versatile building blocks with high to excellent stereoselectivity for further useful transformations.
5
Meanwhile, the asymmetric organocatalytic oneꢀpot sequential processes, which could be performed under
operationally simple and environmentally friendly reaction conditions, have received considerable attention
due to their various synthetic utilities and extremely powerful synthetic efficiency for the construction of
chiral polycyclic frameworks with high structural and stereochemical complexity. Indeed, in the last decade,
remarkable progress has been described toward the asymmetric organocatalytic oneꢀpot sequential processes
initiated by the enamineꢀbased Michael reaction to access biologically and synthetically important
6
polycycles. However, expansion of this promising strategy to efficiently synthesize aforementioned chiral
7
acetalꢀcontaining polycyclic frameworks remains scarce.
Recently, we focused on the chemistry of cyclic hemiacetal which could be directly used to construct chiral
heterocycles with high stereoselectivities through the asymmetric organocatalytic oneꢀpot sequential
8
9
processes. In this work, we became interested in employing γꢀlactamꢀderived cyclic enone 1 and
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2ꢀarylideneindaneꢀ1,3ꢀdione 2 in an asymmetric organocatalytic oneꢀpot sequential process to react with
cyclic hemiacetal 3, respectively, in the presence of aminocatalyst (S)ꢀ4 (TMS = trimethylsilyl) providing
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densely functionalized chiral acetalꢀcontaining polycyclic molecules (Scheme 1, bottom). It should be noted
that this novel sequential process is challenging, since it potentially interrupted the previously established
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reaction pathway (Scheme 1, top), such as oxoꢀDielsꢀAlder process of enone 1 and [2+2+2] annulation
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process of enone 2, and thus is expected to proceed via a novel Michaelꢀlactolizationꢀoxocarbenium ion
ringꢀclosing sequence, which is initiated by the enamineꢀbased Michael reaction between cyclic hemiacetal 3
and activated enones 1 and 2, respectively. Herein, we report our initial findings in developing this oneꢀpot
sequential process.
Scheme 1. Designed Asymmetric Organocatalytic Oneꢀpot, Twoꢀstep Sequential Process
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RESULTS AND DISCUSSION
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We began the optimization studies with 1a and (S)ꢀ3a as the starting substrates and the commercially
available diphenylprolinol trimethylsilyl ether (S)ꢀ4 as the catalyst (for the full optimization studies, see the
Supporting Information, Table S1 and S2). As shown in Table 1, the first step of this oneꢀpot, twoꢀstep
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sequential process occurred by using pꢀNO
2
PhCOOH (pꢀNBA) as the coꢀcatalyst in the solvent of toluene at
o
o
2
5 C and was followed by BF
3
·Et
2
O catalyzed ring closure reaction at 0 C in CH
2
2
Cl , yielding the target
chiral acetalꢀcontaining polycyclic product 5a in 68% isolated yield with >99:1 diastereoselectivity bearing
four stereocenters (Table 1, entry 1). Further solvent screening revealed that solvents have a remarkable effect
on the reactivity of the first step but little effect on the final diastereoselectivity of this protocol (Table 1,
entries 2ꢀ6). To our delight, toluene is also a good choice for the second ring closure step, both reactivity and
stereoselectivity were maintained (Table 1, entry 7). Thus, the whole process of this oneꢀpot, twoꢀstep
sequence could be carried out in oneꢀpot conditions, thereby saving time, effort, and production costs.
3 2
Additionally, compared with BF ·Et O, neither PTSA nor TFA gave better results (Table 1, entries 8ꢀ9).
Unsurprisingly, when the reaction was catalyzed by the racemic catalyst (±)ꢀ4, compounds 5a and 5'a could
be isolated as an inseparable mixture of diastereoisomers (Table 1, entry 10, 5a:5'a = 50:50).
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Table 1. Optimization Studies for the Oneꢀpot, Twoꢀstep Sequential Process
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d
solvent
dr
b
c
entry
acid
t (h) yield (%)
step 1
toluene CH
CH Cl CH
EtOH CH
CH CN CH
DMF CH
THF CH
step 2
5a:5'a
>99:1
>99:1
97:3
1
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8
2
2
2
2
2
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
BF
BF
BF
BF
BF
BF
3
·Et
3
·Et
3
·Et
3
·Et
3
·Et
3
·Et
2
2
2
2
2
2
O
O
O
O
O
O
12
20
48
48
48
48
24
24
24
24
68
57
45
34
52
33
66
45
63
66
2
2
3
93:7
92:8
98:2
toluene toluene BF ·Et O
>99:1
97:3
3
2
toluene toluene
toluene toluene
PTSA
TFA
9
97:3
e
10
toluene toluene BF ·Et O
50:50
3
2
a
Unless otherwise noted, all reactions were carried out using 1a (0.20 mmol, 1.0 equiv) and (S)ꢀ3a (0.24 mmol, 1.2 equiv) in
o
solvent (0.2 mL) with (S)ꢀ4 (20 mol%) and pꢀNBA (20 mol%) at 25 C. After full conversion of the first step, the solvent was
then replaced by a new solvent (0.2 mL) for the second steps and the acid (0.40 mmol, 2.0 equiv) were added to the reaction
o
b
c
mixture slowly at 0 C, and then stirred at this temperature for another 24 h. Refers to the first step. Isolated yield of 5a.
d
e
Determined by chiral HPLC analysis of the isolated products. (±)ꢀ4 was used in the reaction. PTSA = pꢀtoluene sulfonic
acid. DMF = N,Nꢀdimethylformamide. THF = tetrahydrofuran. TFA = trifluoroacetic acid.
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Consequently, with the optimized conditions in hand (Table 1, entry 7), the scope and generality of this
highly stereocontrolled oneꢀpot, twoꢀstep sequential process was then studied by varying the substituents of
both cyclic enones 1 and cyclic hemiacetals (S)ꢀ3. The results are listed in Table 2. Enones 1 with
electronꢀdeficient, electronꢀrich, and heterocyclic substituents on the aromatic ring, as well as 2ꢀnaphthyl and
cinnamyl, were all well tolerated, affording the corresponding polycyclic products 5aꢀ5k in moderate to good
yield with excellent diastereoselectivity (Table 2, entries 1ꢀ11). Pleasingly, a series of aryl substituted cyclic
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hemiacetals (S)ꢀ3 and also the one containing a sixꢀmembered ring proved to be suitable for this sequence
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(
Table 2, entries 12ꢀ15). Additionally, both the reactivity and efficiency remained excellent when changing
the substituent on the N atom of enone 1 (Table 2, entries 16 and 17). To our delight, the reaction could be
performed on a 2 mmol scale (Table 2, entry 18), and the desired product 5a was obtained in slightly higher
yield with excellent diastereoselectivity.
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Table 2. Substrate Scope of Cyclic Enones 1 and Cyclic Hemiacetals (S)ꢀ3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
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8
9
0
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7
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9
0
1
2
3
b
c
entry
1
5/n
R
R
R
yield
68
62
64
69
54
65
63
62
35
52
64
64
65
30
32
dr
5a/1 Ph
5b/1 Ph
5c/1 Ph
5d/1 Ph
5e/1 Ph
Ph
Bn
Bn
Bn
Bn
Bn
Bn
Bn
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
2
2
4ꢀNO Ph
3
4ꢀClPh
4ꢀMePh
2ꢀFPh
4
5
6
5f/1
Ph
3ꢀBrPh
3ꢀMePh
7
5g/1 Ph
5h/1 Ph
8
3ꢀMeOPh Bn
9
5i/1
5j/1
Ph
Ph
2ꢀthienyl
cinnamyl
Bn
Bn
10
11
12
5k/1 Ph
5l/1
2ꢀnaphthyl Bn
Bn
4ꢀBrPh Ph
13
14
15
16
17
18
5m/1 4ꢀClPh Ph
5n/1 4ꢀMePh Ph
Bn
Bn
Bn
5o/2 Ph
5p/1 Ph
5q/1 Ph
5a/1 Ph
Ph
Ph
Ph
Ph
2ꢀMeOBn 64
4ꢀFBn
Bn
60
70
d
a
Unless otherwise noted, all reactions were carried out using 1 (0.20 mmol, 1.0 equiv) and (S)ꢀ3 (0.24 mmol, 1.2 equiv) in
o
toluene (0.2 mL) with (S)ꢀ4 (20 mol%) and pꢀNBA (20 mol%) at 25 C. After full conversion of the first step, BF
3
—Et
2
O (0.40
o
b
mmol, 2.0 equiv) were added dropwise to the reaction mixture at 0 C, and then stirred for another 24 h. Isolated yield of 5.
c
1
d
Determined by H NMR spectroscopy on the isolated products. Reaction was performed on a 2 mmol scale.
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To understand the excellent diastereoselectivity observed in this oneꢀpot, twoꢀstep sequential process, we
investigated the effect of both starting cyclic hemiacetal 3 and catalyst 4 (Scheme 2). Starting from racemic
cyclic hemiacetal (±)ꢀ3a, polycyclic products 5a and 6 were formed as two readily separable epimers (1:1) at
Oꢀbenzyl position (Scheme 2, a) and each with excellent diastereoselectivity. This result indicates that it is
possible to explore this oneꢀpot, twoꢀstep sequential process with racemic cyclic hemiacetal 3 to deliver
products with high stereoselectivity and suggests that this process is highly atom economic pathway. As
expected, product 6 could be further formed with similar diastereoselectivity using cyclic hemiacetal (R)ꢀ3a
and catalyst (S)ꢀ4 (Scheme 2, b). Moreover, epimers 5'a and 6' were obtained, respectively, with excellent
diastereoselectivity regardless of the chirality of cyclic hemiacetals 3 and the catalyst (R)ꢀ4 (Scheme 2, c and
d). These results suggested that the chirality of (R)ꢀ and (S)ꢀ3 had no influence on both the diastereoselectivity
and reactivity, and thus this oneꢀpot sequential process is catalystꢀcontrolled rather than substrateꢀcontrolled
stereoselective reaction process.
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Scheme 2. The Chirality Match Relationship between Precursors, Catalyst and the Stereochemical Outcome
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With these results in hand, we next focused on the scope of the reaction between enones 2 and cyclic
hemiacetals (S)ꢀ3a under the same optimized conditions. As shown in Table 3, several substituted enones 2
containing electronꢀwithdrawing and electronꢀdonating groups on the aromatic ring as well as heteroaromatic
substituent generated polycyclic products 7aꢀ7h in acceptable yield with excellent diastereoselectivity.
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0
a
Table 3. Substrate Scope of Cyclic Enones 2 and Cyclic Hemiacetals (S)ꢀ3a
b
c
entry
7
R
yield
47
dr
1
2
3
4
5
6
7
8
7a
7b
7c
7d
7e
7f
Ph
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
2ꢀNO Ph
43
2
3ꢀBrPh
40
4ꢀClPh
45
2ꢀMeOPh
3ꢀMeOPh
4ꢀMePh
2ꢀthienyl
40
51
7g
7h
53
33
a
Unless otherwise noted, all reactions were carried out using 2 (0.20 mmol, 1.0 equiv) and (S)ꢀ3a (0.24 mmol, 1.2 equiv) in
o
toluene (0.2 mL) with (S)ꢀ4 (20 mol%) and pꢀNBA (20 mol%) at 25 C. After full conversion of the first step, BF
3
·Et
2
O (0.40
o
b
mmol, 2.0 equiv) were added dropwise to the reaction mixture at 0 C, and then stirred for another 24 h. Isolated yield of 7.
c
1
Determined by H NMR spectroscopy on the isolated products.
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2
3
In order to demonstrate the possible reaction pathway, several control experiments were conducted to
obtain more mechanistic details (Scheme 3). Generally, there are two possible intermediates 8 and 8' could be
involved in this oneꢀpot, twoꢀstep sequential process. Starting from the reactoin of cyclic hemiacetal (S)ꢀ3a
and enone 1a catalyzed by (S)ꢀ4, intermediate 8 was proposed to be formed via Michaelꢀlactolization
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
sequence, while intermediate 8' might be obtained by a Michaelꢀenolizationꢀlactolization sequence.
However, in the presence of BF ·Et O and Et SiH, the subsequent reduction reaction lead to 9 as the unique
product, and neither 10 nor 5a was obtained (Scheme 3, a). Moreover, no reaction occurred when compound
a was subjected to the same reduction conditions. Additionally, similar behavior was observed in the
3
2
3
5
reaction between (S)ꢀ3a and enone 2a, resulting in the formation of compound 11 as the only product by the
Michaelꢀlactolizationꢀreduction sequence (Scheme 3, b). All these results suggested that this novel oneꢀpot,
twoꢀstep sequential process proceeded via Michaelꢀlactolizationꢀoxocarbenium ion ringꢀclosing sequence.
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1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 3. Control Experiments
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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2
3
14
The relative and absolute configurations of 5a and 7a were unambiguously determined by Xꢀray analysis,
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
and the configuration of all the other examples were assigned by NOE experiments and analogy. To explain
the observed absolute stereochemical outcome, a proposed mechanism for the generation of 5a is rationalized
in Scheme 4. The asymmetric organocatalytic oneꢀpot, twoꢀstep sequential process is initiated by the
formation of the enamine intermediate between the catalyst (S)ꢀ4 and the cyclic hemiacetal (S)ꢀ3a, which
attacked the cyclic enone 1a from the Re face thus affording the Michael adduct 12 and followed by
intramolecular acetalization yielding the intermediate 8 containing a hemiacetal moiety in the structure. The
subsequent nucleophilic attack of the hydroxy group of the enol to the Si face of the oxocarbenium ion
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
intermediate, induced by BF ·Et O, offers the target chiral acetalꢀcontaining polycyclic product 5a in a
3
2
diastereomerically pure form. Accordingly, compound 7a is proposed to be formed via a similar
stereocontrolled pathway.
Scheme 4. Proposed Mechanism for the Asymmetric Organocatalytic Oneꢀpot, Twoꢀstep Sequential Process
Next, selected transformations were performed to illustrate the synthetic potential of the corresponding
chiral acetalꢀcontaining polycyclic products 5 and 7 (Scheme 5). Starting from 5a, the cyclic hemiacetal 13,
which was easily achieved by Pd/C catalyzed debenzylation, could be reduced to fused oxygenꢀcontaining
3 3 2
heterocycle 14 in the presence of Et SiH and BF ·Et O. Interestingly, 5a did not generate any product 9 in the
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1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
presence of Et
3
SiH and BF
3
·Et
2
O (Scheme 3, a), while the use of TiCl
4
, instead of BF
3
·Et
2
O, led to the
desired 9 in good yield with high diastereoselectivity. A reduction of 7a triggered by NaBH
4
in MeOH lead to
the polycycle 15, which subsequently underwent a threeꢀstep sequence involving one olefin hydrogenation
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
o
and two reductive debenzylation at 40 C to afford fully substituted pyran derivative 16 bearing five
continuous stereocenters, and the absolute configuration of the product 16 was assigned by a singleꢀcrystal
1
3
o
o
Xꢀray analysis. We also found that the reduction of 15 working at a lower temperature (25 C versus 40 C)
led to 17 with excellent diastereoselectivity containing six continuous stereocenters and a preserved hydroxy
3 3 2
group. Additionally, by treating 15 with Et SiH and BF ·Et O, the O,Oꢀacetal moiety could be
chemoselectively opened to afford the oxocarbenium ion intermediate, which was smoothly transformed to
enone 18 via a domino process involving reduction and dehydroxylation sequence. Moreover, compound 19,
which contained five continuous stereogenic centers, was easily accessed via simple reduction conditions at
o
2
5 C. Finally, tetracyclic 20, one of the epimers of 17, could be obtained in good isolated yield under mild
reduction conditions. It should be noted that cyclic compounds 9 and 13ꢀ20 were formed with multiple
stereogenic centers with good to excellent diastereoselectivities.
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2
3
Scheme 5. Useful Transformations
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
CONCLUSION
In conclusion, we have developed a novel asymmetric organocatalytic oneꢀpot, twoꢀstep sequential process to
synthesize biologically and synthetically important chiral acetalꢀcontaining polycyclic frameworks with
excellent stereoselectivities bearing multiple stereocenters. Based on some initial control experiments, this
oneꢀpot sequential process had been proved to be challengeable, as it interrupted the previously established
reaction pathway, such as oxoꢀDielsꢀAlder process of enone 1 and [2+2+2] annulation process of enone 2,
and proceeded via a Michaelꢀlactolizationꢀoxocarbenium ion ringꢀclosing sequence, which initiated by a key
reactive enamine intermediate. Moreover, selected transformations demonstrated that the results present
herein have a potential utility on the synthesis of related functionalized chiral heterocycles.
EXPERIMENTAL SECTION
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
13
1
13
General Methods. The H and C NMR spectra were recorded at 500 MHz for H and at 125 MHz for C,
1
13
respectively. The chemical shifts (δ) for H and C are given in ppm relative to residual signals of the
1
13
3
solvents (CDCl , δ = 7.26 ppm for H NMR, 77.16 ppm for C NMR). Coupling constants (J) are given in
Hz. The following abbreviations are used to indicate the multiplicity: s, singlet; brs, broad singlet; d, doublet;
t, triplet; q, quartet; m, multiplet. ESIꢀHRMS spectrometer was obtained from the Waters QꢀTof Ultima
Global. Xꢀray data were obtained from Zhongke chemical technology service center and collected on a
Bruker Smartꢀ1000 CCD diffractometer equipped with a graphiteꢀmonochromatized MoꢀKα radiation
20
D
(0.71073 Å) at 291(2) K. Optical rotations are reported as follows: [α]
(c in g per 100 mL, solvent). All the
reactions were set up under air and using freshly distilled solvents, without any precautions to exclude
moisture, unless otherwise noted, open air chemistry on the benchtop. Chromatographic purification of
products was accomplished using column chromatography on silica gel (300ꢀ400 mesh). For thin layer
chromatography (TLC) analysis throughout this work, Merck precoated TLC plates (silica gel 60 GF254,
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2
3
0
.25 mm) were used, using UV light as the visualizing agent and an acidic mixture of ceric ammonium
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
molybdate or basic aqueous potassium permanganate (KMnO ) as stain developing solutions. Organic
4
solutions were concentrated under reduced pressure on EYELA rotary evaporator. HPLC analysis on chiral
stationary phase were performed on a HITACHI Chromaster. Daicel Chiralpak IA, IB, IC or ODꢀH columns
with iꢀPrOH/nꢀhexane as the eluent were used. HPLC traces were compared to racemic samples prepared by
mixture of two enantiomeric final products obtained by using (S)ꢀand (R)ꢀcatalyst.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Materials. Commercial reagents and solvents were purchased from SigmaꢀAldrich, Fluka, and Alfa Aesar
used as received, without further purification. (S)ꢀ and (R)ꢀdiphenylprolinol silyl ether is commercially
15
available
from
Daicel
chiral
Technologies.
The
γꢀlactamꢀderived
cyclic
enone
1,
16
11
2
ꢀarylideneindaneꢀ1,3ꢀdione 2, and chiral hemiacetals 3, were prepared according to the literature
procedures.
General Procedure for the Synthesis of Chiral Cyclic Hemiacetal 3. In an ovenꢀdried, 100 mL roundꢀbottom
flask equipped with a magnetic stirring bar in a stream of nitrogen, (ꢀ)ꢀDIPꢀChloride (7.7 mmol) was
dissolved in THF (50 mL) at ꢀ25 °C. After the addition of the corresponding keto ester (7.0 mmol), the
solution was stirred for 2 h, and then the mixture was warmed to 0 °C before quenched by 2.2 equiv of
diethanolamine. This mixture was filtered through a silica gel and purified by flash chromatography affording
the pure hydroxy ester.
2 2
The hydroxy ester prepared as described above was dissolved in CH Cl (10 mL), and the solution was
cooled to 0 °C, followed by the addition of 4 drops of trifluoroacetic acid. Stirring for 6 h at room
temperature completed the lactonization, and the reaction mixture was worked up with aqueous sodium
bicarbonate. The organic layer was washed with water, dried (MgSO
without further purification.
4
), and concentrated to get the lactone
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1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
A solution of DIBALꢀH (1.5 M in toluene, 7.5 mmol) was added dropwise to a solution of the obtained
lactone (5.0mmol) in dry toluene (50 mL) maintained at ꢀ78 ºC over a period of 1.5 hours. The reaction
mixture was stirred for another 4.5 h at ꢀ78 ºC, then quenched by the dropwise addition of methanol (3.3 mL).
The mixture was allowed to warm to 0 ºC and diluted with water (8.8 mL). After mechanically stirring for 30
minutes, the brown slurry was filtered and washed thoroughly with distilled diethyl ether (5 × 100 mL). The
filtrate was concentrated at reduced pressure to afford crude product as a colorless oil that was purified by
flash column chromatography on silica gel to give the desired starting cyclic hemiacetal 3.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
General Procedure for Asymmetric Synthesis of 5. A glass vial equipped with a magnetic stirring bar was
charged with 1 (0.20 mmol, 1.0 equiv), and (S)ꢀ3 (0.24 mmol, 1.2 equiv) in toluene (0.4 mL) with (S)ꢀ4 (13.0
o
mg, 0.04 mmol) and pꢀNO
2
PhCOOH (6.7 mg, 0.04 mmol) at 25 C. After the Michael addition had been
.
o
completed, BF
3
Et
2
O (0.40 mmol, 2.0 equiv) was added dropwise at 0 C. The reaction was stirred at this
temperature for 24 h. The mixture was purified by column chromatography on silica gel to provide the
desired product 5.
(2S,3aR,4S,8aS)ꢀ6ꢀbenzylꢀ2,4ꢀdiphenylꢀ2,3,3a,5,6,8aꢀhexahydrofuro[3',2':5,6]pyrano[2,3ꢀc]pyrrolꢀ7(4H)ꢀone
1
(5a). White solid (57 mg, 68%); mp 210-211 ºC; H NMR (500 MHz, CDCl
3
) δ7.48 (d, J = 7.4 Hz, 2H),
7
.35 (dd, J = 13.0, 7.1 Hz, 4H), 7.29 (d, J = 6.7 Hz, 2H), 7.28 – 7.24 (m, 3H), 7.22 (d, J = 7.3 Hz, 2H), 7.15
(d, J = 7.3 Hz, 2H), 5.74 (d, J = 3.3 Hz, 1H), 5.16 (dd, J = 10.2, 6.1 Hz, 1H), 4.75 (d, J = 14.9 Hz, 1H), 4.48
d, J = 14.9 Hz, 1H), 3.61 (s, 1H), 3.53 (d, J = 2.4 Hz, 2H), 2.70 – 2.62 (m, 1H), 2.56 (dt, J = 12.4, 6.3 Hz,
(
13
1H), 1.83 (dd, J = 23.6, 12.1 Hz, 1H). C NMR (125 MHz, CDCl ) δ165.1, 147.0, 142.9, 142.8, 141.6, 137.0,
3
1
29.4, 128.8, 128.6, 128.3, 127.8, 127.7, 127.6, 127.2, 126.3, 118.5, 100.0, 83.0, 47.9, 47.8, 46.7, 40.1,38.3.
+
20
D
ESIꢀHRMS: [M+H] calcd. For C28
H
26NO
3
m/z: 424.1907; found: 424.1908. [α]
3
+12.4 (c = 0.12 in CHCl ).
1
The diastereomeric ratio was determined by H NMR analysis, dr >20:1.
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1
2
3
(2S,3aR,4S,8aS)ꢀ6ꢀbenzylꢀ4ꢀ(4ꢀnitrophenyl)ꢀ2ꢀphenylꢀ2,3,3a,5,6,8aꢀhexahydrofuro[3',2':5,6]pyrano[2,3ꢀc]pyr
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
rolꢀ7(4H)ꢀone (5b). White solid (58 mg, 62%); mp 139-140 ºC; H NMR (500 MHz, CDCl ) δ8.21 (d, J =
3
8
7
1
.7 Hz, 2H), 7.45 (d, J = 7.2 Hz, 2H), 7.35 (t, J = 9.0 Hz, 4H), 7.28 (ddd, J = 7.0, 5.5, 4.6 Hz, 4H), 7.23 –
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
.19 (m, 2H), 5.72 (d, J = 3.4 Hz, 1H), 5.18 (dd, J = 10.5, 5.5 Hz, 1H), 4.71 (d, J = 14.9 Hz, 1H), 4.52 (d, J =
13
4.9 Hz, 1H), 3.74 (s, 1H), 3.60 – 3.43 (m, 2H), 2.66 – 2.57 (m, 2H), 1.85 (dd, J = 22.0, 10.8 Hz, 1H). C
NMR (125 MHz, CDCl
3
) δ164.7, 149.9, 147.4, 143.7, 141.2, 136.7, 128.9, 128.9, 128.3, 128.2, 128.0, 127.9,
+
1
26.3, 124.7, 116.5, 99.7, 83.0, 47.6, 47.2, 46.8, 39.8, 38.1. ESIꢀHRMS: [M+H] calcd. For C28
H
N O
25 2 5
m/z:
20
D
1
4
69.1758; found: 469.1756. [α]
+10.4 (c = 0.60 in CHCl
3
). The diastereomeric ratio was determined by H
NMR analysis, dr >20:1.
(
2S,3aR,4S,8aS)ꢀ6ꢀbenzylꢀ4ꢀ(4ꢀchlorophenyl)ꢀ2ꢀphenylꢀ2,3,3a,5,6,8aꢀhexahydrofuro[3',2':5,6]pyrano[2,3ꢀc]p
1
yrrolꢀ7(4H)ꢀone (5c). White solid (57 mg, 64%); mp 225-226 ºC; H NMR (500 MHz, CDCl
3
) δ7.46 (d, J =
7
.3 Hz, 2H), 7.35 (t, J = 7.6 Hz, 2H), 7.33 – 7.30 (m, 3H), 7.29 – 7.23 (m, 3H), 7.21 (d, J = 6.8 Hz, 2H), 7.08
(t, J = 5.5 Hz, 2H), 5.71 (d, J = 3.6 Hz, 1H), 5.17 (dd, J = 10.4, 6.0 Hz, 1H), 4.73 (d, J = 14.9 Hz, 1H), 4.50
d, J = 14.9 Hz, 1H), 3.59 (s, 1H), 3.53 (s, 1H), 3.50 (s, 1H), 2.61 (ddd, J = 13.0, 6.6, 3.8 Hz, 1H), 2.58 – 2.52
(
13
(m, 1H), 1.81 (dd, J = 24.0, 11.2 Hz, 1H). C NMR (125 MHz, CDCl
3
) δ164.9, 143.1, 141.4, 141.2, 136.9,
1
33.5, 129.6, 128.9, 128.6, 128.5, 128.3, 127.9, 127.8, 126.3, 117.9, 99.9, 83.0, 47.8, 47.7, 46.8, 39.5, 38.2.
+
20
D
ESIꢀHRMS: [M+H] calcd. For C28
H
25ClNO
3
m/z: 458.1517; found: 458.1518. [α]
+9.1 (c = 0.25 in
1
CHCl
3
). The diastereomeric ratio was determined by H NMR analysis, dr >20:1.
(2S,3aR,4S,8aS)ꢀ6ꢀbenzylꢀ2ꢀphenylꢀ4ꢀ(pꢀtolyl)ꢀ2,3,3a,5,6,8aꢀhexahydrofuro[3',2':5,6]pyrano[2,3ꢀc]pyrrolꢀ7(4
1
H)ꢀone (5d). White solid (60 mg, 69%); mp 203-204 ºC; H NMR (500 MHz, CDCl
3
) δ7.47 (d, J = 7.4 Hz,
2H), 7.36 (t, J = 7.5 Hz, 2H), 7.33 – 7.24 (m, 4H), 7.21 (d, J = 7.0 Hz, 2H), 7.15 (d, J = 7.8 Hz, 2H), 7.03 (d,
J = 7.9 Hz, 2H), 5.73 (d, J = 3.5 Hz, 1H), 5.16 (dd, J = 10.3, 6.1 Hz, 1H), 4.74 (d, J = 14.9 Hz, 1H), 4.49 (d, J
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=
14.9 Hz, 1H), 3.57 (s, 1H), 3.52 (d, J = 11.2 Hz, 2H), 2.67 – 2.59 (m, 1H), 2.54 (dt, J = 12.4, 6.3 Hz, 1H),
13
2
1
3
0
.33 (s, 3H), 1.81 (dd, J = 23.6, 12.2 Hz, 1H). C NMR (125 MHz, CDCl
3
) δ165.2, 142.7, 141.6, 139.8,
37.3, 137.0, 130.0, 128.8, 128.6, 128.3, 127.8, 127.7, 127.0, 126.4, 118.8, 100.1, 82.9, 48.1, 47.8, 46.8, 39.7,
0
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
20
8.3, 21.1. ESIꢀHRMS: [M+H] calcd. For C H NO m/z: 438.2064; found: 438.2066. [α]
D
+28.8 (c =
29
28
3
1
3
.44 in CHCl ). The diastereomeric ratio was determined by H NMR analysis, dr >20:1.
(2S,3aR,4R,8aS)ꢀ6ꢀbenzylꢀ4ꢀ(2ꢀfluorophenyl)ꢀ2ꢀphenylꢀ2,3,3a,5,6,8aꢀhexahydrofuro[3',2':5,6]pyrano[2,3ꢀc]p
1
yrrolꢀ7(4H)ꢀone (5e). White solid (48 mg, 54%); mp 216-217 ºC; H NMR (500 MHz, CDCl ) δ7.47 (d, J =
3
7
.4 Hz, 2H), 7.36 (t, J = 7.5 Hz, 2H), 7.33 – 7.20 (m, 7H), 7.15 – 7.03 (m, 3H), 5.70 (d, J = 3.5 Hz, 1H), 5.19
(dd, J = 10.3, 6.1 Hz, 1H), 4.74 (d, J = 14.9 Hz, 1H), 4.52 (d, J = 14.9 Hz, 1H), 4.00 (s, 1H), 3.57 (s, 2H),
13
2
.72 – 2.64 (m, 1H), 2.60 (dt, J = 12.5, 6.3 Hz, 1H), 1.83 (d, J = 11.3 Hz, 1H). C NMR (125 MHz, CDCl
3
)
δ165.0, 161.2, 159.2, 143.7, 141.5, 136.9, 129.3, 129.2, 128.9, 128.7, 128.3, 127.9, 127.8, 126.3, 125.0, 124.9,
+
117.0, 116.1, 115.9, 100.0, 83.1, 47.8, 46.8, 38.1, 32.3. ESIꢀHRMS: [M+H] calcd. For C28
H25FNO
3
m/z:
2
D
0
1
442.1813; found: 442.1814. [α]
+10.1 (c = 0.80 in CHCl
3
). The diastereomeric ratio was determined by H
NMR analysis, dr >20:1.
(2S,3aR,4S,8aS)ꢀ6ꢀbenzylꢀ4ꢀ(3ꢀbromophenyl)ꢀ2ꢀphenylꢀ2,3,3a,5,6,8aꢀhexahydrofuro[3',2':5,6]pyrano[2,3ꢀc]p
1
yrrolꢀ7(4H)ꢀone (5f). White solid (65 mg, 65%); mp 210-212 ºC; H NMR (500 MHz, CDCl
3
) δ7.46 (d, J =
7.3 Hz, 2H), 7.41 (d, J = 7.9 Hz, 1H), 7.36 (t, J = 7.6 Hz, 2H), 7.33 – 7.29 (m, 3H), 7.28 – 7.25 (m, 2H), 7.22
t, J = 7.4 Hz, 3H), 7.08 (d, J = 7.7 Hz, 1H), 5.72 (d, J = 3.6 Hz, 1H), 5.17 (dd, J = 10.3, 6.1 Hz, 1H), 4.75 (d,
(
J = 15.0 Hz, 1H), 4.50 (d, J = 14.9 Hz, 1H), 3.57 (s, 1H), 3.53 (d, J = 5.7 Hz, 2H), 2.63 (dd, J = 14.4, 4.9 Hz,
13
1
H), 2.55 (dt, J = 12.5, 6.3 Hz, 1H), 1.81 (dd, J = 23.5, 12.2 Hz, 1H). C NMR (125 MHz, CDCl
3
) δ164.9,
145.0, 143.3, 141.4, 136.9, 131.0, 130.8, 130.4, 128.9, 128.7, 128.3, 127.9, 127.8, 126.3, 125.8, 123.5, 117.5,
+
9
9.8, 83.0, 47.7, 47.6, 46.8, 39.7, 38.2. ESIꢀHRMS: [M+H] calcd. For C28
H
25BrNO
3
m/z: 502.1012; found:
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D
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5
02.1013. [α]
3
+14.3 (c = 0.46 in CHCl ). The diastereomeric ratio was determined by H NMR analysis,
4
5
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8
9
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5
5
5
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5
5
6
dr >20:1.
(2S,3aR,4S,8aS)ꢀ6ꢀbenzylꢀ2ꢀphenylꢀ4ꢀ(mꢀtolyl)ꢀ2,3,3a,5,6,8aꢀhexahydrofuro[3',2':5,6]pyrano[2,3ꢀc]pyrrolꢀ7(
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
4
2
1
2
H)ꢀone (5g). White solid (55 mg, 63%); mp 204-205 ºC; H NMR (500 MHz, CDCl
3
) δ7.47 (d, J = 7.4 Hz,
H), 7.36 (t, J = 7.5 Hz, 2H), 7.33 – 7.18 (m, 7H), 7.08 (d, J = 7.5 Hz, 1H), 6.94 (s, 2H), 5.74 (d, J = 3.5 Hz,
H), 5.16 (dd, J = 10.3, 6.1 Hz, 1H), 4.75 (d, J = 14.9 Hz, 1H), 4.49 (d, J = 14.9 Hz, 1H), 3.57 (s, 1H), 3.53 (s,
13
H), 2.69 – 2.60 (m, 1H), 2.55 (dt, J = 12.4, 6.3 Hz, 1H), 2.34 (s, 3H), 1.82 (dd, J = 23.6, 12.2 Hz, 1H). C
NMR (125 MHz, CDCl
3
) δ165.2, 142.8, 142.8, 141.6, 139.2, 137.0, 129.3, 128.8, 128.6, 128.3, 128.3, 127.8,
+
1
27.8, 127.7, 126.4, 124.2, 118.7, 100.1, 83.0, 47.9, 47.8, 46.8, 40.0, 38.3, 21.6. ESIꢀHRMS: [M+H] calcd.
20
D
For C29
H28NO
3
m/z: 438.2064; found: 438.2065. [α]
3
+16.2 (c = 1.67 in CHCl ). The diastereomeric ratio
1
was determined by H NMR analysis, dr >20:1.
(2S,3aR,4S,8aS)ꢀ6ꢀbenzylꢀ4ꢀ(3ꢀmethoxyphenyl)ꢀ2ꢀphenylꢀ2,3,3a,5,6,8aꢀhexahydrofuro[3',2':5,6]pyrano[2,3ꢀc
1
]pyrrolꢀ7(4H)ꢀone (5h). White solid (56 mg, 62%); mp 187-188 ºC; H NMR (500 MHz, CDCl
3
) δ7.46 (d, J
=
7.4 Hz, 2H), 7.34 (t, J = 7.5 Hz, 2H), 7.27 (dt, J = 7.9, 7.3 Hz, 5H), 7.21 (d, J = 7.2 Hz, 2H), 6.80 (d, J =
9.6 Hz, 1H), 6.73 (d, J = 7.5 Hz, 1H), 6.67 (s, 1H), 5.73 (d, J = 3.3 Hz, 1H), 5.15 (dd, J = 10.2, 6.1 Hz, 1H),
.73 (d, J = 14.9 Hz, 1H), 4.49 (d, J = 14.9 Hz, 1H), 3.78 (s, 3H), 3.58 (s, 1H), 3.54 (s, 2H), 2.69 – 2.61 (m,
4
1
3
1H), 2.55 (dt, J = 12.3, 6.3 Hz, 1H), 1.81 (dd, J = 23.6, 12.1 Hz, 1H). C NMR (125 MHz, CDCl
3
) δ165.1,
1
60.3, 144.3, 142.8, 141.6, 136.9, 130.4, 128.8, 128.6, 128.2, 127.8, 127.7, 126.3, 119.4, 118.5, 113.1, 112.5,
+
100.0, 82.9, 55.4, 47.8, 47.7, 46.7, 40.0, 38.2. ESIꢀHRMS: [M+H] calcd. For C H NO m/z: 454.2013;
2
9
28
4
20
1
found: 454.2014. [α]
D
3
+9.1 (c = 0.27 in CHCl ). The diastereomeric ratio was determined by H NMR
analysis, dr >20:1.
(2S,3aR,4R,8aS)ꢀ6ꢀbenzylꢀ2ꢀphenylꢀ4ꢀ(thiophenꢀ2ꢀyl)ꢀ2,3,3a,5,6,8aꢀhexahydrofuro[3',2':5,6]pyrano[2,3ꢀc]py
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5
5
5
6
1
rrolꢀ7(4H)ꢀone (5i). White solid (29 mg, 35%); mp 215-216 ºC; H NMR (500 MHz, CDCl
3
) δ7.47 (d, J =
7
3
4
.4 Hz, 2H), 7.37 (d, J = 7.4 Hz, 1H), 7.34 (s, 1H), 7.33 – 7.28 (m, 2H), 7.28 – 7.24 (m, 2H), 7.25 – 7.16 (m,
H), 6.97 – 6.91 (m, 1H), 6.82 (d, J = 2.3 Hz, 1H), 5.78 (d, J = 3.1 Hz, 1H), 5.20 (dd, J = 10.1, 6.3 Hz, 1H),
.73 (d, J = 15.0 Hz, 1H), 4.52 (d, J = 14.9 Hz, 1H), 3.91 (s, 1H), 3.68 (d, J = 17.8 Hz, 1H), 3.57 (d, J = 17.8
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
Hz, 1H), 2.79 – 2.73 (m, 1H), 2.55 (dt, J = 12.3, 6.3 Hz, 1H), 1.79 (dd, J = 23.8, 12.1 Hz, 1H). C NMR (125
MHz, CDCl
3
) δ165.0, 146.4, 142.3, 141.5, 136.9, 128.9, 128.7, 128.3, 127.9, 127.8, 127.4, 126.3, 124.9,
+
1
24.5, 118.2, 100.1, 83.3, 48.3, 47.7, 46.8, 37.6, 34.8. ESIꢀHRMS: [M+H] calcd. For C26
H
23NO
3
S m/z:
20
D
1
4
30.1471; found: 430.1474. [α]
+37.2 (c = 0.50 in CHCl
3
). The diastereomeric ratio was determined by H
NMR analysis, dr >20:1.
(
2S,3aR,4R,8aS)ꢀ6ꢀbenzylꢀ2ꢀphenylꢀ4ꢀ((E)ꢀstyryl)ꢀ2,3,3a,5,6,8aꢀhexahydrofuro[3',2':5,6]pyrano[2,3ꢀc]pyrrolꢀ
1
7(4H)ꢀone (5j). White solid (47 mg, 52%); mp 199-200 ºC; H NMR (500 MHz, CDCl
3
) δ7.47 (d, J = 7.4
Hz, 2H), 7.37 (d, J = 7.4 Hz, 1H), 7.35 – 7.29 (m, 5H), 7.30 – 7.23 (m, 4H), 6.38 (d, J = 15.7 Hz, 1H), 6.15
(dd, J = 15.7, 8.3 Hz, 1H), 5.73 (d, J = 3.5 Hz, 1H), 5.55 (s, 1H), 5.21 (dd, J = 10.3, 6.2 Hz, 1H), 4.70 (d, J =
1
4.9 Hz, 1H), 4.57 (d, J = 14.9 Hz, 1H), 3.74 (d, J = 17.9 Hz, 1H), 3.57 (d, J = 17.9 Hz, 1H), 3.21 (d, J = 8.2
13
Hz, 1H), 2.70 – 2.59 (m, 1H), 2.48 (dt, J = 12.4, 6.4 Hz, 1H), 1.76 (dd, J = 23.4, 12.4 Hz, 1H). C NMR (125
MHz, CDCl
3
) δ165.1, 142.3, 141.6, 137.0, 136.2, 131.4, 130.1, 128.9, 128.8, 128.6, 128.3, 128.1, 127.8,
+
127.8, 126.4, 126.3, 118.2, 100.0, 83.1, 47.8, 46.8, 45.5, 37.4, 37.0. ESIꢀHRMS: [M+H] calcd. For
20
D
C
30
H
28NO
3
m/z: 450.2064; found: 450.2065. [α]
3
+8.5 (c = 0.27 in CHCl ). The diastereomeric ratio was
1
determined by H NMR analysis, dr >20:1.
(
2S,3aR,4S,8aS)ꢀ6ꢀbenzylꢀ4ꢀ(naphthalenꢀ2ꢀyl)ꢀ2ꢀphenylꢀ2,3,3a,5,6,8aꢀhexahydrofuro[3',2':5,6]pyrano[2,3ꢀc]
1
pyrrolꢀ7(4H)ꢀone (5k). White solid (60 mg, 64%); mp 230-231 ºC; H NMR (500 MHz, CDCl
3
) δ7.85 (t, J =
7
.6 Hz, 2H), 7.79 (d, J = 7.5 Hz, 1H), 7.57 (s, 1H), 7.50 (t, J = 7.4 Hz, 4H), 7.37 (t, J = 7.6 Hz, 2H), 7.33 –
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.25 (m, 4H), 7.23 (dd, J = 6.5, 5.3 Hz, 2H), 5.81 (d, J = 3.6 Hz, 1H), 5.18 (dd, J = 10.3, 6.1 Hz, 1H), 4.77 (d,
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
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3
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4
4
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4
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5
5
5
5
5
5
5
6
J = 14.9 Hz, 1H), 4.49 (d, J = 14.9 Hz, 1H), 3.79 (s, 1H), 3.57 (q, J = 18.0 Hz, 2H), 2.77 – 2.70 (m, 1H), 2.61
13
(
dt, J = 12.4, 6.4 Hz, 1H), 1.89 (dd, J = 23.6, 12.3 Hz, 1H). C NMR (125 MHz, CDCl
3
) δ165.1, 142.98,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
1
4
41.6, 140.0, 136.9, 133.6, 132.6, 129.4, 128.8, 128.6, 128.2, 127.8, 127.8, 127.8, 127.7, 126.8, 126.3, 126.3,
+
25.7, 125.2, 118.6, 100.1, 83.0, 47.8, 46.7, 40.1, 38.3. ESIꢀHRMS: [M+H] calcd. For C32
H
28NO
3
m/z:
2
D
0
1
74.2064; found: 474.2065. [α]
+9.9 (c = 0.27 in CHCl
3
). The diastereomeric ratio was determined by H
NMR analysis, dr >20:1.
(2S,3aR,4S,8aS)ꢀ6ꢀbenzylꢀ2ꢀ(4ꢀbromophenyl)ꢀ4ꢀphenylꢀ2,3,3a,5,6,8aꢀhexahydrofuro[3',2':5,6]pyrano[2,3ꢀc]p
1
yrrolꢀ7(4H)ꢀone (5l). White solid (64 mg, 64%); mp 149-150 ºC; H NMR (500 MHz, CDCl
3
) δ7.48 (d, J =
8
.2 Hz, 2H), 7.38 – 7.31 (m, 4H), 7.31 – 7.24 (m, 4H), 7.21 (d, J = 7.3 Hz, 2H), 7.13 (d, J = 7.4 Hz, 2H), 5.72
(d, J = 3.5 Hz, 1H), 5.12 (dd, J = 10.2, 6.2 Hz, 1H), 4.75 (d, J = 14.9 Hz, 1H), 4.47 (d, J = 14.9 Hz, 1H), 3.60
s, 1H), 3.53 (d, J = 2.6 Hz, 2H), 2.65 (dt, J = 13.0, 5.0 Hz, 1H), 2.56 (dt, J = 12.4, 6.4 Hz, 1H), 1.76 (dd, J =
(
13
23.5, 12.1 Hz, 1H). C NMR (125 MHz, CDCl
3
) δ165.0, 142.8, 142.6, 140.8, 136.9, 131.7, 129.4, 128.9,
+
1
28.3, 128.1, 127.8, 127.7, 127.2, 121.7, 118.6, 100.0, 82.3, 47.9, 47.8, 46.8, 40.1, 38.2. ESIꢀHRMS: [M+H]
2
D
0
calcd. For C28
H
25BrNO
3
m/z: 502.1012; found: 502.1013. [α]
3
+35.1 (c = 0.65 in CHCl ). The
1
diastereomeric ratio was determined by H NMR analysis, dr >20:1.
(2S,3aR,4S,8aS)ꢀ6ꢀbenzylꢀ2ꢀ(4ꢀchlorophenyl)ꢀ4ꢀphenylꢀ2,3,3a,5,6,8aꢀhexahydrofuro[3',2':5,6]pyrano[2,3ꢀc]p
1
yrrolꢀ7(4H)ꢀone (5m). White solid (59 mg, 65%); mp 218-219 ºC; H NMR (500 MHz, CDCl
3
) δ7.40 (d, J =
8.4 Hz, 2H), 7.38 – 7.24 (m, 8H), 7.21 (d, J = 7.0 Hz, 2H), 7.14 (d, J = 7.2 Hz, 2H), 5.72 (d, J = 3.5 Hz, 1H),
.13 (dd, J = 10.2, 6.2 Hz, 1H), 4.74 (d, J = 14.9 Hz, 1H), 4.48 (d, J = 14.9 Hz, 1H), 3.61 (s, 1H), 3.54 (d, J =
5
13
3.6 Hz, 2H), 2.70 – 2.51 (m, 2H), 1.76 (dd, J = 23.4, 12.3 Hz, 1H). C NMR (125 MHz, CDCl
3
) δ165.0,
1
42.8, 142.6, 140.3, 136.9, 133.5, 129.4, 128.9, 128.8, 128.3, 127.8, 127.7, 127.6, 127.1, 118.6, 100.0, 82.2,
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5
5
5
5
5
5
5
5
6
+
4
7.9, 47.8, 46.8, 40.0, 38.2. ESIꢀHRMS: [M+H] calcd. For C28
H
25ClNO
3
m/z: 458.1517; found: 458.1516.
2
D
0
1
[
α]
3
+12.5 (c = 0.34 in CHCl ). The diastereomeric ratio was determined by H NMR analysis, dr >20:1.
(
2S,3aR,4S,8aS)ꢀ6ꢀbenzylꢀ4ꢀphenylꢀ2ꢀ(pꢀtolyl)ꢀ2,3,3a,5,6,8aꢀhexahydrofuro[3',2':5,6]pyrano[2,3ꢀc]pyrrolꢀ7(4
0
1
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8
9
0
1
2
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4
5
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7
8
9
0
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0
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0
1
H)ꢀone (5n). White solid (26 mg, 30%); mp 171-172 ºC; H NMR (500 MHz, CDCl
3
) δ7.43 – 7.31 (m, 4H),
7
.29 (d, J = 7.5 Hz, 2H), 7.27 – 7.24 (m, 2H), 7.21 (d, J = 7.3 Hz, 2H), 7.15 (dd, J = 11.5, 7.9 Hz, 4H), 5.73
(
d, J = 3.3 Hz, 1H), 5.13 (dd, J = 10.2, 6.1 Hz, 1H), 4.75 (d, J = 14.9 Hz, 1H), 4.48 (d, J = 14.9 Hz, 1H), 3.60
(
s, 1H), 3.53 (d, J = 2.3 Hz, 2H), 2.68 – 2.61 (m, 1H), 2.53 (dt, J = 12.3, 6.3 Hz, 1H), 2.34 (s, 3H), 1.81 (dd, J
13
=
23.6, 12.2 Hz, 1H). C NMR (125 MHz, CDCl
3
) δ165.2, 142.9, 142.8, 138.6, 137.54, 137.0, 129.4, 129.3,
1
28.9, 128.3, 127.8, 127.6, 127.2, 126.4, 118.5, 100.0, 82.9, 77.2, 47.9, 47.8, 46.8, 40.1, 38.3, 21.3. HRMS:
+
20
D
[
M+H] calcd. For C29
H
28NO
3
m/z: 438.2064; found: 438.2065. [α]
3
+10.4 (c = 0.45 in CHCl ). The
1
diastereomeric ratio was determined by H NMR analysis, dr >20:1.
(
2S,4aR,5S,9aS)ꢀ7ꢀbenzylꢀ2,5ꢀdiphenylꢀ3,4,4a,6,7,9aꢀhexahydroꢀ2Hꢀpyrano[3',2':5,6]pyrano[2,3ꢀc]pyrrolꢀ8(
1
5H)ꢀone (5o). White solid (28 mg, 32%); mp 196-197 ºC; H NMR (500 MHz, CDCl
3
) δ7.34 (d, J = 7.4 Hz,
3
H), 7.32 (d, J = 5.8 Hz, 4H), 7.28 (d, J = 10.8 Hz, 3H), 7.27 – 7.21 (m, 3H), 7.14 (d, J = 7.4 Hz, 2H), 5.54 (s,
1H), 5.12 (d, J = 11.6 Hz, 1H), 4.83 (d, J = 14.9 Hz, 1H), 4.51 (d, J = 14.9 Hz, 1H), 3.68 (d, J = 17.9 Hz, 1H),
.59 (d, J = 18.0 Hz, 1H), 3.39 (s, 1H), 2.14 (t, J = 7.7 Hz, 1H), 1.97 (dd, J = 13.1, 2.2 Hz, 1H), 1.87 (dd, J =
3
1
3
9.2, 7.1 Hz, 2H), 1.77 (dd, J = 19.6, 11.7 Hz, 1H). C NMR (125 MHz, CDCl
3
) δ165.1, 144.7, 142.8, 141.7,
1
37.1, 129.2, 128.9, 128.4, 128.3, 127.8, 127.6, 127.5, 127.4, 126.2, 119.3, 96.5, 72.6, 48.0, 46.8, 44.9, 41.7,
+
20
D
33.4, 25.7. ESIꢀHRMS: [M+H] calcd. For C H NO m/z: 438.2064; found: 438.2063. [α] +9.3 (c = 0.53
29
28
3
1
3
in CHCl ). The diastereomeric ratio was determined by H NMR analysis, dr >20:1.
(2S,3aR,4S,8aS)ꢀ6ꢀ(2ꢀmethoxybenzyl)ꢀ2,4ꢀdiphenylꢀ2,3,3a,5,6,8aꢀhexahydrofuro[3',2':5,6]pyrano[2,3ꢀc]pyrro
1
lꢀ7(4H)ꢀone (5p). White solid (58 mg, 64%); mp 184-184 ºC; H NMR (500 MHz, CDCl ) δ7.47 (d, J = 7.3
3
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Hz, 2H), 7.35 (t, J = 6.5 Hz, 4H), 7.27 (dd, J = 11.4, 3.7 Hz, 2H), 7.22 (dd, J = 17.5, 8.6 Hz, 2H), 7.16 (d, J =
.2 Hz, 2H), 6.89 (t, J = 7.4 Hz, 1H), 6.83 (d, J = 8.2 Hz, 1H), 5.72 (d, J = 3.5 Hz, 1H), 5.15 (dd, J = 10.3, 6.1
Hz, 1H), 4.73 (d, J = 14.9 Hz, 1H), 4.57 (d, J = 14.9 Hz, 1H), 3.77 (s, 3H), 3.62 (s, 1H), 3.58 (s, 2H), 2.69 –
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
7
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
2
.61 (m, 1H), 2.55 (dt, J = 12.4, 6.3 Hz, 1H), 1.82 (dd, J = 23.6, 12.2 Hz, 1H). C NMR (125 MHz, CDCl )
3
δ165.1, 157.5, 143.0, 141.7, 130.2, 129.3, 129.0, 128.6, 127.8, 127.5, 127.2, 126.4, 125.1, 120.8, 118.2, 110.5,
+
9
9.9, 83.0, 55.4, 48.3, 47.9, 41.4, 40.0, 38.3. ESIꢀHRMS: [M+H] calcd. For C29
H28NO
4
m/z: 454.2013;
20
D
1
found: 454.2012. [α]
analysis, dr >20:1.
+32.6 (c = 0.62 in CHCl
3
). The diastereomeric ratio was determined by H NMR
(2S,3aR,4S,8aS)ꢀ6ꢀ(4ꢀfluorobenzyl)ꢀ2,4ꢀdiphenylꢀ2,3,3a,5,6,8aꢀhexahydrofuro[3',2':5,6]pyrano[2,3ꢀc]pyrrolꢀ
1
7
3
(4H)ꢀone (5q). White solid (53 mg, 60%); mp 208-209 ºC; H NMR (500 MHz, CDCl ) δ7.46 (d, J = 7.5 Hz,
2H), 7.35 (t, J = 7.5 Hz, 4H), 7.31 – 7.24 (m, 2H), 7.23 – 7.16 (m, 2H), 7.14 (d, J = 7.4 Hz, 2H), 6.97 (t, J =
.5 Hz, 2H), 5.73 (d, J = 3.4 Hz, 1H), 5.16 (dd, J = 10.2, 6.1 Hz, 1H), 4.69 (d, J = 14.9 Hz, 1H), 4.44 (d, J =
8
15.0 Hz, 1H), 3.62 (s, 1H), 3.52 (d, J = 5.4 Hz, 2H), 2.69 – 2.62 (m, 1H), 2.56 (dt, J = 12.4, 6.3 Hz, 1H), 1.84
13
–
1.77 (m, 1H). C NMR (125 MHz, CDCl ) δ165.1, 163.4, 161.4, 142.8, 142.7, 141.60, 132.8, 129.9, 129.9,
3
129.4, 128.6, 127.8, 127.6, 127.1, 126.3, 118.6, 115.8, 115.6, 100.1, 83.0, 47.9, 47.7, 46.0, 40.1, 38.3.
+
20
D
ESIꢀHRMS: [M+H] calcd. For C28
H25FNO
3
m/z: 442.1813; found: 442.1815. [α]
+12.7 (c = 0.22 in
1
CHCl
3
). The diastereomeric ratio was determined by H NMR analysis, dr >20:1.
General Procedure for Asymmetric Synthesis of 5'a. A glass vial equipped with a magnetic stirring bar was
charged with 1 (0.20 mmol, 1.0 equiv), and (S)ꢀ3a (0.24 mmol, 1.2 equiv) in toluene (0.4 mL) with (R)ꢀ4
o
(13.0 mg, 0.04 mmol) and pꢀNO
2
PhCOOH (6.7 mg, 0.04 mmol) and at 25 C. After the Michael addition had
.
o
been completed, BF
3
Et
2
O (0.40 mmol, 2.0 equiv) was added dropwise at 0 C. The reaction was stirred at this
temperature for 24 h. The mixture was purified by column chromatography on silica gel to provide the
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1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
desired product 5'a.
(2S,3aS,4R,8aR)ꢀ6ꢀbenzylꢀ2,4ꢀdiphenylꢀ2,3,3a,5,6,8aꢀhexahydrofuro[3',2':5,6]pyrano[2,3ꢀc]pyrrolꢀ7(4H)ꢀon
1
e (5'a). White solid (53 mg, 62%); mp 114-115 ºC; H NMR (500 MHz, CDCl
3
) δ7.34 (d, J = 7.2 Hz, 1H),
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7
.31 (d, J = 7.1 Hz, 3H), 7.29 – 7.25 (m, 3H), 7.24 (d, J = 7.8 Hz, 2H), 7.12 (d, J = 7.3 Hz, 1H), 5.84 (d, J =
.4 Hz, 1H), 5.48 (dd, J = 9.2, 2.1 Hz, 1H), 4.80 (d, J = 14.8 Hz, 1H), 4.47 (d, J = 14.9 Hz, 1H), 3.66 – 3.47
3
1
3
(m, 2H), 2.62 (ddd, J = 11.6, 8.4, 3.1 Hz, 1H), 2.34 (dd, J = 21.7, 12.1 Hz, 1H), 2.24 – 2.12 (m, 1H). C
NMR (125 MHz, CDCl
3
) δ165.1, 143.8, 142.7, 142.5, 137.0, 129.4, 128.9, 128.6, 128.3, 127.8, 127.7, 127.6,
+
1
27.3, 125.6, 118.3, 100.6, 80.0, 77.2, 47.9, 46.8, 45.6, 40.1, 36.7. ESIꢀHRMS: [M+H] calcd. For
2
0
C H NO m/z: 424.1907; found: 424.1908. [α]
ꢀ20.4 (c = 1.0 in CHCl ). The diastereomeric ratio was
3
28 26
3
D
1
determined by H NMR analysis, dr >20:1.
General Procedure for Asymmetric Synthesis of 6. A glass vial equipped with a magnetic stirring bar was
charged with 1 (0.20 mmol, 1.0 equiv), and (R)ꢀ3a (0.24 mmol, 1.2 equiv) in toluene (0.4 mL) with (S)ꢀ4
o
(13.0 mg, 0.04 mmol) and pꢀNO
2
PhCOOH (6.7 mg, 0.04 mmol) and at 25 C. After the Michael addition had
.
o
been completed, BF Et O (0.40 mmol, 2.0 equiv) was added dropwise at 0 C. The reaction was stirred at this
3
2
temperature for 24 h. The mixture was purified by column chromatography on silica gel to provide the
desired product 6.
(2R,3aR,4S,8aS)ꢀ6ꢀbenzylꢀ2,4ꢀdiphenylꢀ2,3,3a,5,6,8aꢀhexahydrofuro[3',2':5,6]pyrano[2,3ꢀc]pyrrolꢀ7(4H)ꢀon
1
e (6). White solid (52 mg, 63%); mp 105-106 ºC; H NMR (500 MHz, CDCl
3
) δ7.33 (d, J = 7.2 Hz, 2H), 7.30
(d, J = 7.2 Hz, 3H), 7.26 (d, J = 7.4 Hz, 3H), 7.23 (d, J = 7.6 Hz, 2H), 7.11 (d, J = 7.4 Hz, 2H), 5.84 (d, J =
.3 Hz, 1H), 5.47 (d, J = 10.6 Hz, 1H), 4.80 (d, J = 14.9 Hz, 1H), 4.47 (d, J = 14.9 Hz, 1H), 3.69 – 3.41 (m,
3
13
3H), 2.72 – 2.54 (m, 1H), 2.34 (dd, J = 21.7, 12.0 Hz, 1H), 2.19 (dd, J = 14.2, 5.4 Hz, 1H). C NMR (125
MHz, CDCl
3
) δ165.1, 143.8, 142.7, 142.5, 137.0, 129.4, 128.9, 128.6, 128.3, 127.8, 127.7, 127.6, 127.3,
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3
+
1
4
25.6, 118.3, 100.6, 80.0, 77.2, 47.9, 46.8, 45.6, 40.1, 36.7. ESIꢀHRMS: [M+H] calcd. For C28
H
26NO
3
m/z:
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
D
0
1
24.1907; found: 424.1912. [α]
+29.7 (c = 1.0 in CHCl
3
). The diastereomeric ratio was determined by H
NMR analysis, dr >20:1.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
General Procedure for Asymmetric Synthesis of 6'. A glass vial equipped with a magnetic stirring bar was
charged with 1 (0.20 mmol, 1.0 equiv), and (R)ꢀ3a (0.24 mmol, 1.2 equiv) in toluene (0.4 mL) with (R)ꢀ4
o
(13.0 mg, 0.04 mmol) and pꢀNO
2
PhCOOH (6.7 mg, 0.04 mmol) and at 25 C. After the Michael addition had
.
o
been completed, BF
3
Et
2
O (0.40 mmol, 2.0 equiv) was added dropwise at 0 C. The reaction was stirred at this
temperature for 24 h. The mixture was purified by column chromatography on silica gel to provide the
desired product 6'.
(
2R,3aS,4R,8aR)ꢀ6ꢀbenzylꢀ2,4ꢀdiphenylꢀ2,3,3a,5,6,8aꢀhexahydrofuro[3',2':5,6]pyrano[2,3ꢀc]pyrrolꢀ7(4H)ꢀon
1
e (6'). White solid (55 mg, 65%); mp 215-216 ºC; H NMR (500 MHz, CDCl
3
) δ7.47 (d, J = 7.5 Hz, 2H),
7
.35 (dd, J = 14.4, 7.3 Hz, 3H), 7.32 – 7.24 (m, 4H), 7.21 (d, J = 7.1 Hz, 2H), 7.15 (d, J = 7.3 Hz, 2H), 5.74
(d, J = 3.5 Hz, 1H), 5.16 (dd, J = 10.3, 6.1 Hz, 1H), 4.75 (d, J = 14.9 Hz, 1H), 4.48 (d, J = 14.9 Hz, 1H), 3.61
s, 1H), 3.53 (d, J = 2.3 Hz, 2H), 2.70 – 2.61 (m, 1H), 2.56 (dt, J = 12.4, 6.3 Hz, 1H), 1.83 (dd, J = 23.6, 12.1
(
13
Hz, 1H). C NMR (125 MHz, CDCl
3
) δ165.2, 142.9, 142.8, 141.6, 136.9, 129.4, 128.9, 128.6, 128.3, 127.8,
+
1
27.8, 127.6, 127.2, 126.3, 118.6, 100.0, 83.0, 77.2, 47.9, 47.8, 46.8, 40.1, 38.3. ESIꢀHRMS: [M+H] calcd.
2
D
0
For C28
H
26NO
3
m/z: 424.1907; found: 424.1908. [α]
3
ꢀ22.4 (c = 1.20 in CHCl ). The diastereomeric ratio
1
was determined by H NMR analysis, dr >20:1.
General Procedure for the Synthesis of 7. A glass vial equipped with a magnetic stirring bar was charged
with 2 (0.20 mmol, 1.0 equiv), and (S)ꢀ3a (0.24 mmol, 1.2 equiv) in toluene (0.4 mL) with (S)ꢀ4 (13.0 mg,
o
0.04 mmol) and pꢀNO
2
PhCOOH (6.7 mg, 0.04 mmol) at 25 C. After the Michael addition had been
.
o
completed, BF
3
Et
2
O (0.40 mmol, 2.0 equiv) was added dropwise at 0 C. The reaction was stirred at this
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1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
temperature for 24 h. The mixture was purified by column chromatography on silica gel to provide the
desired product 7.
(2S,3aR,4S,10aS)ꢀ2,4ꢀdiphenylꢀ2,3,3a,10aꢀtetrahydrofuro[2,3ꢀb]indeno[2,1ꢀe]pyranꢀ5(4H)ꢀone (7a). Yellow
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
solid (36 mg, 47%); mp 155-156 ºC; H NMR (500 MHz, CDCl
3
) δ7.40 (t, J = 6.9 Hz, 4H), 7.37 – 7.31 (m,
6
H), 7.29 (d, J = 7.6 Hz, 3H), 7.25 (dd, J = 10.3, 3.6 Hz, 1H), 5.93 (d, J = 3.7 Hz, 1H), 5.26 (dd, J = 10.4, 6.3
Hz, 1H), 3.97 (s, 1H), 2.87 – 2.80 (m, 1H), 2.63 (dt, J = 12.8, 6.5 Hz, 1H), 1.87 (dd, J = 23.6, 12.9 Hz, 1H).
1
3
C NMR (125 MHz, CDCl
3
) δ192.8, 171.6, 142.9, 141.2, 137.7, 133.5, 132.3, 130.4, 129.1, 128.7, 128.1,
+
1
27.2, 126.1, 121.4, 118.3, 105.9, 102.8, 83.8, 47.6, 37.3, 35.3. ESIꢀHRMS: [M+H] calcd. For C26
H O
21 3
m/z:
20
1
3
81.1485; found: 381.1486. [α]D ꢀ33.9 (c = 0.30 in CHCl ). The diastereomeric ratio was determined by H
3
NMR analysis, dr >20:1.
(2S,3aR,4S,10aS)ꢀ4ꢀ(2ꢀnitrophenyl)ꢀ2ꢀphenylꢀ2,3,3a,10aꢀtetrahydrofuro[2,3ꢀb]indeno[2,1ꢀe]pyranꢀ5(4H)ꢀone
1
(
7b). Yellow solid (37 mg, 43%); mp 160-161 ºC; H NMR (500 MHz, CDCl ) δ8.10 (d, J = 8.1 Hz, 1H),
3
7.56 (t, J = 7.5 Hz, 1H), 7.44 (dd, J = 10.8, 6.8 Hz, 4H), 7.41 – 7.38 (m, 3H), 7.35 (t, J = 7.5 Hz, 4H), 7.31 –
.26 (m, 1H), 5.83 (d, J = 3.4 Hz, 1H), 5.30 (dd, J = 10.4, 5.9 Hz, 1H), 4.55 (s, 1H), 2.96 – 2.90 (m, 1H), 2.87
7
1
3
(dd, J = 12.5, 6.2 Hz, 1H), 1.88 (dd, J = 22.6, 11.8 Hz, 1H). C NMR (125 MHz, CDCl
3
) δ192.3, 173.1,
1
48.4, 141.1, 138.1, 137.5, 134.0, 133.3, 132.6, 130.8, 129.4, 128.7, 128.4, 128.1, 126.2, 126.0, 121.6, 118.6,
+
104.4, 102.7, 83.9, 47.2, 37.1, 31.3. ESIꢀHRMS: [M+H] calcd. For C26
H
20NO
5
m/z: 426.1336; found:
20
D
1
4
26.1335. [α]
ꢀ34.3 (c = 0.23 in CHCl
3
). The diastereomeric ratio was determined by H NMR analysis,
dr >20:1.
(2S,3aR,4S,10aS)ꢀ4ꢀ(3ꢀbromophenyl)ꢀ2ꢀphenylꢀ2,3,3a,10aꢀtetrahydrofuro[2,3ꢀb]indeno[2,1ꢀe]pyranꢀ5(4H)ꢀo
1
ne (7c). Yellow solid (37 mg, 40%); mp 77-79 ºC; H NMR (500 MHz, CDCl
3
) δ7.45 – 7.37 (m, 6H), 7.34
(dd, J = 8.5, 4.4 Hz, 4H), 7.29 (d, J = 7.2 Hz, 1H), 7.21 (d, J = 6.7 Hz, 2H), 5.90 (d, J = 3.7 Hz, 1H), 5.26 (dd,
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3
J = 10.4, 6.3 Hz, 1H), 3.94 (s, 1H), 2.83 – 2.75 (m, 1H), 2.63 (dt, J = 12.9, 6.6 Hz, 1H), 1.86 (dd, J = 23.5,
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
3
1
2.9 Hz, 1H). C NMR (125 MHz, CDCl
3
) δ192.6, 171.9, 145.3, 141.1, 137.5, 137.5, 133.4, 132.5, 130.7,
1
30.6, 130.5, 130.4, 128.7, 128.1, 126.2, 126.0, 121.5, 118.5, 105.1, 102.6, 83.8, 47.4, 37.3, 35.1. ESIꢀHRMS:
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
20
D
[
M+H] calcd. For C H BrO m/z: 459.0590; found: 459.0591. [α]
ꢀ45.4 (c = 1.27 in CHCl ). The
3
2
6
20
3
1
diastereomeric ratio was determined by H NMR analysis, dr >20:1.
(
2S,3aR,4S,10aS)ꢀ4ꢀ(4ꢀchlorophenyl)ꢀ2ꢀphenylꢀ2,3,3a,10aꢀtetrahydrofuro[2,3ꢀb]indeno[2,1ꢀe]pyranꢀ5(4H)ꢀo
1
ne (7d). Yellow solid (37 mg, 45%); mp 83-84 ºC; H NMR (500 MHz, CDCl ) δ7.43 – 7.37 (m, 4H), 7.34 (t,
3
J = 7.4 Hz, 4H), 7.30 (t, J = 8.8 Hz, 3H), 7.23 (d, J = 8.4 Hz, 2H), 5.89 (d, J = 3.7 Hz, 1H), 5.26 (dd, J = 10.4,
13
6
.3 Hz, 1H), 3.94 (s, 1H), 2.82 – 2.75 (m, 1H), 2.63 (dt, J = 12.9, 6.6 Hz, 1H), 1.90 – 1.81 (m, 1H). C NMR
(
125 MHz, CDCl
3
) δ192.7, 171.7, 141.5, 141.1, 137.6, 133.4, 133.1, 132.4, 130.6, 129.2, 128.7, 128.6, 128.1,
+
126.2, 121.5, 118.5, 105.4, 102.7, 83.8, 47.5, 37.3, 34.8. ESIꢀHRMS: [M+H] calcd. For C26
H20ClO
3
m/z:
20
1
4
15.1095; found: 415.1093. [α]
D
ꢀ98.7 (c = 0.80 in CHCl
3
). The diastereomeric ratio was determined by H
NMR analysis, dr >20:1.
(
2S,3aR,4S,10aS)ꢀ4ꢀ(2ꢀmethoxyphenyl)ꢀ2ꢀphenylꢀ2,3,3a,10aꢀtetrahydrofuro[2,3ꢀb]indeno[2,1ꢀe]pyranꢀ5(4H)ꢀ
1
one (7e). Yellow solid (33 mg, 40%); mp 85-86 ºC; H NMR (500 MHz, CDCl
3
) δ7.47 – 7.39 (m, 4H), 7.34
(
dd, J = 11.3, 6.2 Hz, 4H), 7.29 (d, J = 7.2 Hz, 1H), 7.23 (d, J = 7.6 Hz, 1H), 7.08 (d, J = 7.3 Hz, 1H), 6.93 (d,
J = 8.1 Hz, 1H), 6.88 (t, J = 7.4 Hz, 1H), 5.78 (d, J = 3.1 Hz, 1H), 5.27 (dd, J = 10.1, 6.5 Hz, 1H), 4.32 (s,
1
H), 3.92 (s, 3H), 2.84 (d, J = 4.8 Hz, 1H), 2.66 (dt, J = 12.7, 6.4 Hz, 1H), 1.86 (dd, J = 23.9, 12.5 Hz, 1H).
1
3
C NMR (125 MHz, CDCl ) δ192.9, 172.6, 156.7, 141.5, 137.9, 133.6, 132.2, 130.6, 130.3, 128.6, 128.3,
3
1
27.9, 127.7, 126.2, 121.3, 120.7, 118.1, 110.8, 105.4, 103.2, 83.9, 55.6, 46.3, 37.2, 27.0. ESIꢀHRMS:
+
20
D
[M+H] calcd. For C27
H
23
O
4
m/z: 411.1591; found: 411.1592. [α]
3
ꢀ29.3 (c = 1.16 in CHCl ). The
1
diastereomeric ratio was determined by H NMR analysis, dr >20:1.
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