Domino Hydroalkoxylation-[4+2]-Cycloaddition for Stereoselective Synthesis of 1,4-Heterocycle-Fused Chromenes: Rapid Access to the [6-6-7-6] Tetracyclic Core of Cytorhizhins B–D

Article abstract of DOI:10.1002/ejoc.201901565

A substrate dependent regio- and stereoselective domino hydroalkoxylation-formal-[4+2] cycloaddition is described for the facile synthesis of linear as well as spirocyclic 1,4-heterocycle-fused chromene ketals. Enantiospecific synthesis of oxazepino chromene derivatives was successfully carried out using chiral pool amino alkynols. The developed hydroalkoxylation cascade offered rapid access to the spirocyclic [6-6-7-6] tetracyclic core of cytorhizhins B–D with correct relative configuration.

Full text of DOI:10.1002/ejoc.201901565

A Journal of
Accepted Article
Title: Domino Hydroalkoxylation-[4+2]-Cycloaddition for
Stereoselective Synthesis of 1,4-Heterocycle-Fused Chromenes:
Rapid Access to the [6-6-7-6] Tetracyclic Core of Cytorhizhins B-
D
Authors: Santosh J. Gharpure, Santosh Kumar Nanda, Dipak J
Fartade, and Dharmendra S Vishwakarma
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901565
Link to VoR: http://dx.doi.org/10.1002/ejoc.201901565
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10.1002/ejoc.201901565
European Journal of Organic Chemistry
COMMUNICATION
Domino Hydroalkoxylation-[4+2]-Cycloaddition for Stereoselective
Synthesis of 1,4-Heterocycle-Fused Chromenes: Rapid Access to
the [6-6-7-6] Tetracyclic Core of Cytorhizhins B-D
Santosh J. Gharpure,* Santosh K. Nanda, Dipak J. Fartade and Dharmendra S. Vishwakarma
Abstract: A substrate dependent regio- and stereoselective domino
hydroalkoxylation-formal-[4+2] cycloaddition is described for the facile
synthesis of linear as well as spirocyclic 1,4-heterocycle-fused
chromene ketals. Enantiospecific synthesis of oxazepino chromene
derivatives was successfully carried out using chiral pool amino
alkynols. The developed hydroalkoxylation cascade offered rapid
access to the spirocyclic [6-6-7-6] tetracyclic core of cytorhizhins B-D
with correct relative configuration.
While the intramolecular hydroalkoxylation of alkynes for the
synthesis of cyclic ethers is well-established, there are only
scattered reports on the synthesis of the biologically privileged
seven-membered [1,4]-heterocyclic motifs using gold, silver and
platinum catalyzed hydroalkoxylation.[3] The use of expensive
precious metal catalysts coupled with a lack of regioselectivity
with some of these methods leaves room for further
improvements
in
developing
strategies
relying
on
hydroalkoxylation of alkynes for the synthesis of seven membered
1,4-heterocycles. Further, the presence of 1,4-heterocyclic motifs
in wide range natural products, development of a regio- and
stereoselective method giving rapid access to these scaffolds are
highly desirable.[4] To address some of these problems, recently,
Introduction
Chroman framework is a part of several structurally diverse
natural products, which exhibit a wide range of significant
biological as well as pharmacological activity.[1] Strategies for the
synthesis of spirocyclic chromans have gained traction due to the
presence of this moiety in natural products such as berkelic acid
and g-rubromycin.[1d] Interestingly, corresponding spirocyclic
chromans with 1,4-heterocycle connection are very rare in nature
and their synthesis too is scarcely explored. Recently,
cytorhizhins A-D (1-4) bearing an unprecedented [6-6-5-6-7/8]
pentacyclic framework embedded with a spirocyclic chroman
moiety and 1,4-heterocycle connection, were isolated from the
endophytic fungus Cytospora rhizophorae (Figure 1).[1e]
we
have
disclosed
TMSOTf-mediated
intramolecular
hydroalkoxylation-reduction cascades for the regio- and
stereoselective synthesis of 1,4-oxazepanes.[5] Herein, we
disclose the first examples of Lewis acid promoted, substrate
controlled, 7-endo-dig and 7-exo-dig hydroalkoxylation-formal-
[4+2] cycloaddition of heteroatom substituted alkynols for the
regio- and stereoselective synthesis of 1,4-heterocycle-fused
linear and spiro chromenes, respectively. In particular, 7-exo-dig
hydroalkoxylation-formal-[4+2] cycloaddition cascade of phenol
tethered alkynol revealed an expeditious approach for the
synthesis of common [6-6-7-6] tetracyclic framework of
cytorhizhins B-D (2-4).
OH
6
OH
6
OH
OH
OH
OH
OH
6
OH
OH
Results and Discussion
6
6
6
6
6
6
Me
Me
5
5
5
Me
Me
O
O
O
In continuation of our group’s interest in developing strategies for
the Lewis acid mediated stereoselective synthesis of 1,4-
heterocycles and cyclic ethers,[6] we recently reported
hydroalkoxylation-formal-[4+2] cycloaddition cascade for the
stereoselective synthesis of heterocycle-fused chromene
ketals.[6g] We envisioned that 1,4-heterocycle-fused linear
chromenes 9-11 could be obtained via 7-endo-dig
O
O
O
7
8
7
O
O
O
Me
Me
Cl
Me
Me
Me
OH
cytorhizins A (1)
R
cytorhizins C (3): R = OMe
cytorhizins D (4): R = OAc
cytorhizins B (2)
Figure 1. Cytorhizhins A-D (1-4) having [6-6-5-6-7/8] pentacyclic framework with
embedded spirocyclic chroman with 1,4-heterocycle connection.
hydroalkoxylation-formal-[4+2]
cycloaddition
cascade
of
corresponding N/O/S-tethered aryl substituted alkynols 5-7 with
salicylaldehyde (8) (Scheme 1). On the other hand, N/O-tethered
alkynols 5-6 with H/TMS/alkyl substitution upon reaction with
salicylaldehyde (8) would form 1,4-heterocycle-fused spiro
chromenes 12-13 through 7-exo-dig hydroalkoxylation-formal-
Cascade functionalization of alkyne has gained substantial
attention over the past decade for the construction of complex
organic scaffolds. In this context, transition metal catalyzed
hydroalkoxylation of alkyne coupled with various cascades, such
as [1,3]-dipolar cycloaddition, [4+2]-cycloaddition and Prins
cyclization of the in situ generated cyclic enol ether has been
investigated for the synthesis of functionalized heterocycles.[2]
[4+2] cycloaddition cascade.
Substrate driven diverse modes of hydroalkoxylation-cycloaddition cascade
O
H
7-endo-dig
hydroalkoxylation
7-exo-dig
hydroalkoxylation
R1
HO
8
6
X
⋅
TMSOTf
CH2Cl2
TMSOTf
CH2Cl2
+
R1
[a]
Prof. Dr. S. J. Gharpure, Dr. S. K. Nanda, D. J. Fartade, D. S.
Vishwakarma
6
6
R2
⋅
⋅
O
R1 = Ar
n = 0
R1 = H, Alkyl
TMS
X
7
R2
( )n
O
O
O
⋅
Department of Chemistry
Ar
R3
OH
Indian Institute of Technology Bombay, Powai
Mumbai – 400076, India, Tel: +91-22-2576 7171
E-mail: sjgharpure@iitb.ac.in
R2
⋅
n = 1
X
R3
12-13
9-11
aliphatic tethered
dr >19:1
R3
5: X = NTs
6: X = O
7: X = S
aryl tethered
dr >19:1
Homepage: https://ether.chem.iitb.ac.in/~sjgharpure/index.html
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
Scheme 1. Proposed hydroalkoxylation-cycloaddition cascade.
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10.1002/ejoc.201901565
European Journal of Organic Chemistry
COMMUNICATION
R2
R1
X
To test the feasibility of the envisaged hydroalkoxylation-formal-
[4+2] cycloaddition cascade, the requisite enantiomerically pure
alkynols (5a-g) were prepared from the corresponding amino
acids.[7] Alkynol 5a upon reaction with salicylaldehyde (8a) using
2 equiv TMSOTf as Lewis acid in CH2Cl2 at 0 oC, afforded
corresponding enantiomerically enriched 3,7-disubstituted
oxazepino chromene ketal 9a in excellent yield (92%) and
diastereoselectivity (dr ³19:1) (Scheme 2). Interestingly, alkynols
5b-c bearing electron donating (OMe) as well as electron
withdrawing (NO2) substituents on aryl ring, led to the exclusive
formation of desired oxazepino chromene ketals 9b-c,
respectively. o-Vanillin (8b) also reacted with alkynol 5a to furnish
requisite oxazepino chromene ketal 9d in good yield (76%).
Various other chiral, enantiomerically pure N-tethered alkynols
5b-f were also subjected to reaction with salicylaldehyde
derivatives 8a-b to give oxazepino chromene ketals (9e-i),
respectively. It is noteworthy that L-proline derived alkynol 5g
having Lewis basic tert-amine group also participated in this
reaction uneventfully furnishing oxazepino chromene 9j in very
good yield as a single detectable diastereomer. In general, the
reaction was found to be highly diastereoselective giving rapid
and enantiospecific access to a range of 3,7-disubstituted
oxazepino chromene derivatives 9a-j. In all the cases a single
diastereomer was obtained and the ‘cis’ stereochemistry was
unambiguously assigned based on single crystal X-ray diffraction
studies on the chromene derivatives 9a, 9e and 9g.[8]
O
X
TMSOTf
(2 eqiuiv)
R3
R2
+
H
R3
O
H
CH2Cl2, 0 o
0.5-1.0 h
C
O
O
Ar
R1
HO
Ar
5h-m: X = NTs
6a-e: X = O
7a-c: X = S
9k-r: X = NTs, dr >19:1
10a-e: X = O, dr >19:1
11a-c: X = S
8a: R3 = H
8b-c: R3 = OMe
Ts
Ts
OMe
N
N
O
O
O
O
O
Ph
9k
71%
Ph
Me
Ts
Me
9l
79%
9k
Ts
Ts
N
N
N
O
p-(MeO)-C6H4
O
p-(O2N)-C6H4
O
p-(MeO)-C6H4
O
O
Cy
Me
Ts
Me
Ts
9m
49%
9n
79%
9o
91%
Ts
H
OMe
N
N
N
H
O
p-(MeO)-C6H4
O
p-(MeO)-C6H4
O
p-(MeO)-C6H4
O
O
O
O
Cy
Ph
H
H
9p
84%
9q
78%
9r
78%
O
O
Ph
Ph
O
O
p-(OMe)-C6H4
10b
98%
O
O
O
O
p-(Me)-C6H4
10a
89%
p-(NO2)-C6H4
10c
0%
O
S
O
H
Ph
O
O
O
O
p-(Me)-C6H4
10e
98%
O
O
Ph
p-(OMe)-C6H4
11a
46%
H
OMe
10d
79%
Ts
Ts
O
R1
TMSOTf
(2 eqiuiv)
N
S
S
N
R3
H
R1
+
R3
CH2Cl2, 0 o
0.5-1.0 h
C
O
O
O
3,5-(Me)2-C6H3
O
O
O
O
Ar
HO
p-(Me)-C6H4
11b
60%
H
5a-g
9a-j
dr >19:1
11c
53%
Ar
8
11b
Ts
Ts
Scheme 3. Diastereoselective synthesis of oxazepino/dioxepino/oxathiepino
chromene derivatives 9-11. In all the cases, dr was determined by 1H NMR of
the crude reaction mixture.
N
N
Bn
Bn
O
O
O
O
p-(MeO)-C6H4
Ph
9a
92%
9b
81%
9a
Attention was next turned towards expanding the scope of this
reaction in the diastereoselective synthesis of 3,7-disubstituted
oxazepino chromene 9. In general, the reaction was found to
proceed efficiently and N-tethered alkynols 5h-m upon treatment
with salicylaldehyde (8a) and m-methoxy salicylaldehyde (8c)
furnished corresponding oxazepino chromene derivatives 9k-r in
good to excellent yield as single detectable diastereomers
(Scheme 3). On similar lines, the reaction of O-tethered alkynols
6a-b and 6e with salicylaldehyde (8a) gave corresponding
dioxepino chromene 10a-b and 10e, respectively, in excellent
yield and diastereoselectivity. While alkyne having electron
withdrawing para-NO2 substitution on aryl ring gave oxazepino
chromene 9c and 9m in moderate yield, O-tethered alkynol 6c
failed to furnish the expected dioxepino chromene derivative 10c.
This could be due to the low reactivity of electron deficient
alkynols towards hydroalkoxylation and competing decomposition
of the propargylic benzylic ether. Alkynol 6a upon reaction with o-
vanillin (8b) also led to the formation of dioxepino chromene
derivative 10d. Furthermore, S-tethered alkynols 7a-c too
participated in the hydroalkoxylation-formal-[4+2] cascade to
Ts
Ts
Ts
N
N
N
Bn
iPr
Bn
O
O
O
O
O
O
Ph
9d
p-(O2N)-C6H4
Ph
OMe
9c
9e
89%
78%
76%
Ts
Ts
Ts
N
N
iPr
iPr
O
O
O
O
Ph
9f
3,5-(Me)2-C6H3
9g
85%
OMe
9g
85%
Ts
N
N
N
iPr
Ph
O
O
O
O
O
O
p-(MeO)-C6H4
3,5-(Me)2-C6H3
p-(MeO)-C6H4
OMe
9j
9h
9i
88%
70%
76%
Scheme 2. Diastereoselective synthesis of oxazepino chromene derivatives 9.
In all the cases, dr was determined by 1H NMR of the crude reaction mixture.
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10.1002/ejoc.201901565
European Journal of Organic Chemistry
COMMUNICATION
furnish oxathiepino chromene derivatives 11a-c in good yield. In
all the cases, the stereochemistry of the chromene derivatives
was confirmed by NOE study. It was further ascertained by single
crystal X-ray diffraction studies on the chromenes 9k and 11b.[8]
TMS-deprotected spiro chromene 12a was obtained as the sole
product in excellent yield (Table 1, entry 1). The structure of the
spiro chromene 12a was confirmed unambiguously by X-ray
diffraction study (See, SI).[8] Interestingly, terminal alkynol 5o (R1
= H) and aliphatic alkynol 5p (R1 = nBu) also furnished the spiro
chromene derivatives 12a-b albeit in lower yields (Table 1, entry
2-3). When phenol derived alkynols 6f-g were reacted with
salicylaldehyde (8a), spiro chromene derivatives 13a-b were
obtained as the only detectable products (Table 1, entries 4-5).
TMS-alkynol 6h upon reaction with salicylaldehyde (8a) gave
TMS-bearing spiro chromene 13c as a minor product along with
spirocyclic chromene 13b as the major product (49%) (Table 1,
entry 6). Interestingly, p-methoxy phenol derived alkynol 6i gave
chromene 13d in excellent yield and diastereoselectivity (Table 1,
entry 7). It should be noted that the compound 13d contains the
common [6-6-7-6] tetracyclic core of cytorhizhins B-D (2-4)
(Figure 1).
Table 1. Diastereoselective synthesis of spiro chromene 12 and 13.
R1
O
TMSOTf
2 equiv
CH2Cl2, 0 o
0.1-0.2 h
O
R2
X
+
H
C
OH
O
X
R2
R1
HO
R3
R3
12a-b: X = NTs
13a-f: X = O
5n-p: X = NTs
6f-i: X = O
8a
Entry
Alkynols
Spiro chromenes
Yield (%), dra
TMS
O
Ts
Ts
Ts
N
1
93, 13:1
OH
O
H
12a
N
5n
5o
5p
6f
Ts
Me
Me
H
Ph
8a
TMSOTf
8a
TMSOTf
O
O
Ts
N
O
N
8
X
2
3
4
5
6
40, 13:1
55, ≥ 19:1
75, ≥ 19:1
72, 3.3:1
22, ≥ 19:1
CH2Cl2
CH2Cl2
OH
O
0 o
C
0 o
C
O
H
12a
OH
N
O
O
Ph
13e
X = O
Ph
X = NTs
Ref[6g]
Me
Ts
Me
Me
Me
Me
5q: X = NTs
6j: X = O
9s
86%, >19:1
C4H9
O
Ar
Ph
O
O
8a
8a
TMSOTf
N
Ts
H
H
TMSOTf
CH2Cl2
0 o
X = NTs
OH
N
O
O
O
N
8
X
H
CH2Cl2
0 o
C
X = O
C4H9
12bb
Ts
Me
C
O
Ph
Me
H
H
HO
H
H
C4H9
14a: Ar = Ph
O
78%, dr >19:1
14b: Ar = p-(Me)-C6H4
13f
71%, >19:1
5r-s: X = NTs
6k: X = O
O
56%, dr >19:1
OH
O
O
O
O
C4H9
13a
Me
Me
Scheme 4. Diversity oriented cascade [4+2]-cycloaddition.
H
O
O
In order to check if the oxygen tethered aryl substituted alkynol 6j
can give 8-endo-dig cyclization, it was subjected to reaction with
salicylaldehyde (8a) (Scheme 4).[6g] The reaction gave rise to
exclusive formation of spiro chromenes 13e in good yield (ORTEP
diagram, Figure 2).[8] This was in contrast to the behaviour of
nitrogen tethered aryl substituted alkynol 5q, which indeed had
given the linearly fused oxazocine chromene 9s via 8-endo-dig
hydroalkoxylation-formal-[4+2] cycloaddition.[6g] The reaction
following 7-exo-dig hydroalkoxylation-formal-[4+2] cycloaddition
path in the case of alkynol 6j is clearly the outcome of the aryl
oxygen substitution stabilising benzylic vinyl cation much more
than the aryl vinyl cation. To study the effect of conformation on
the hydroalkoxylation step, the trans-disubstituted oxygen
tethered cyclohexyl alkynol 6k was reacted with salicylaldehyde
(8a), which exclusively furnished spiro chromene 13f.
Interestingly, when corresponding nitrogen-tethered alkynols 5r-s
were treated with salicylaldehyde (8a) using TMSOTf, 8-
membered dibenzo[b,e]chromeno[3,4-g][1,4]oxazocines 14a-b
were formed as the sole products in good yield and excellent
diastereoselectivity.
OH
O
H
13b
6g
Me
Me
TMS
O
O
OH
O
TMS
6h
Me
13cc
Me
OMe
C4H9
C4H9
6
7
MeO
7
91, ≥ 19:1
6
O
OH
6
O
O
O
6i
Me
13d
Me
[a] In all the cases, dr was determined by 1H NMR of the crude reaction mixture.
[b] At 0 oC no conversion was detected, thus allowed to be stirred at rt for 2 h.
[c] TMS-deprotected spiro-chromene 13b was obtained as the major product
(49%).
Feasibility
of
proposed,
hitherto
unknown
7-exo-dig
hydroalkoxylation-formal-[4+2] cycloaddition cascade for the
stereoselective synthesis of 1,4-heterocycle-fused spiro
chromenes 12-13 was studied next.[9] When aniline-tethered
alkynol 5n (R1 = TMS) was reacted with salicylaldehyde (8a),
The formation of an 8-membered heterocycle- fused chromene
14a-b occurred through initial oxonium ion formation, followed by
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10.1002/ejoc.201901565
European Journal of Organic Chemistry
COMMUNICATION
Ar
explained on the basis of different transition state structures TS-
3-5 (Scheme 6). Thus, during the intermolecular cycloaddition,
the diene Int-C (in situ generated o-quinone methide) can
approach the dienophile Int-A either in an endo or exo manner.
However, during the endo-approach, both the transition state
structures (TS-3 and TS-4) were disfavoured due to steric
repulsion between Ha proton and aryl ring (1,3-diaxial interaction).
On the other hand, during exo-approach, TS-6 will be favoured
over TS-5 because of absence of 1,3-diaxal interactions in the
former, leading to the formation of the cyclo-adduct F, which on
subsequent elimination will furnish the chromene derivatives 9-10.
Ar
O
Ar
H
Ts
H
[4+2]
8a
O
N
H
N
N
8
TMSOTf
Ts
O
O
H
H
Ts HO
5r-s
H
14a-b
Int A
H
Ts
H
Ts
Ar
N
Ar
O
H
N
O
OH
Ha
H
Ha
HO
disfavoured
TS-1
favoured
TS-2
Reaction pathway for the formation of linear-chromenes
O
H
R2
X
Scheme 5. Plausible reaction pathway and origin of diastereoselectivity for the
formation of dibenzo[b,e]chromeno[3,4-g][1,4]oxazocines (14a-b).
X
8
R2
R1
X
R2
TMSOTf
OH
R1
O
H
Intermolecular
formal [4+2]
cycloaddition
O
O
O
Ar
Ar
R1
Ar
Int-A
7-endo-dig
hydroalkoxylation
5a-m: X = NTs
6a-e: X = O
7a-c: X = S
9a-r: X = NTs
10a-e: X = O
11a-c: X = S
intramolecular formal [4+2] cycloaddition, which is reminiscent of
alkyne Prins-type reaction (Scheme 5). The exclusive formation
of cis-diastereomer can presumably be explained on the basis of
transition state structures TS-1 and TS-2, which go through more
stable boat-chair conformation.[10] The TS-1 is disfavoured due to
the steric repulsion (1,3-diaxial interaction) between Ha and aryl
ring of salicylaldehyde. On the other hand, absence of this
interaction in the case of TS-2 makes it lower energy transition
Origin of diastereoselectivity
H
RO
Ar
X
OR
X
R
exo-
approach
X
H
R
O
+
H
H
O
Ha
H
O
R
RO
Ar
O
O
Ar
Ha
TS-5
H
O
H
1,3-diaxial
interactions
TS-6
favoured
Int-C
Int-A
disfavoured
state
structure, leading
to
the
formation
14a-b.
of cis-
endo-approach
disfavoured
dibenzo[b,e]chromeno[3,4-g][1,4]oxazocines
This
OR
H
intriguing reversal in reactivity may be an outcome of inability of
tosyl substituted nitrogen to stabilize the benzylic vinyl cation as
well as the associated conformational constrain, which facilitates
competitive oxonium ion formation over 7/8-exo/endo-dig
hydroalkoxylation.
X
RO
H
H
O
R
X
Ar
O
R
O
Ar
H
O
RO
Ha
cyclo-adduct F
Ha
X
H
H
O
-TMSOR
-TfOH
R
O
X
Ha
Ar
H
R
1,3-diaxial
interactions
TS-3
O
Ar
9-10
O
TS-4
Scheme 6. Reaction pathway and origin of diastereoselectivity for the formation
of linear chromenes 9-11.
In the case of alkynols 5n-p and 6f-k, the stability of the vinyl
cation at the benzylic carbon led to the 7-exo-dig
hydroalkoxylation and resulted in the formation of exo-cyclic enol-
ether Int-B (Scheme 7). The enol-ether Int-B upon subsequent
intermolecular formal [4+2]-cycloaddition with salicylaldehyde
(8a) afforded corresponding spiro-chromene derivatives 12-13,
respectively. The origin of diastereoselectivity can be rationalized
based on the transition state structures TS-7 and TS-8. The
dienophile Int-C can approach the diene Int-B both in an endo as
well as in an exo-fashion. The exo-approach (TS-7) is disfavoured
due to the steric repulsion between the axial hydrogen (Ha) and
the aromatic ring of salicylaldehyde. In the case of endo-approach
(TS-8), absence of such type of interaction and presence of
secondary p-p interactions made it favourable, leading to the
formation of cyclo-adduct G. The cyclo-adduct G upon elimination
gave spiro-chromene derivatives 12-13.
Figure 2: ORTEP diagrams of 13e.
The formation of linear chromenes can be explained as follows.
In the case of alkynols 5a-m, 6a-e and 7a-c the stability of the aryl
vinyl cation facilitated the intramolecular hydroalkoxylation in a 7-
endo-dig manner to form endo-cyclic enol-ether Int-A. The cyclic
enol ether Int-A reacted with salicylaldehydes (8) in a formal [4+2]
cycloaddition fashion to furnish linear chromenes 9-11,
respectively. The diastereoselectivity of the cascade
hydroalkoxylation-formal[4+2]-cycloaddition process can be
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10.1002/ejoc.201901565
European Journal of Organic Chemistry
COMMUNICATION
Reaction pathway for the formation of spiro-chromenes
O
O
H
O
O
R1
O
R1
H
S
O
8
S
HO
O
8a
R2
TMSOTf
OH
OH
O
X
O
H
TMSOTf
(2 eqiuiv)
CH2Cl2
0 oC, 1 h
R3
Intermolecular
formal [4+2]
cycloaddition
O
O
O
X
p-(Me)-C6H4
R2
p-(Me)-C6H4
R1
X
R3
R2
R3
11d
81%
7d
Int-B
7-exo-dig
hydroalkoxylation
5n-p: X = NTs
6f-j: X = O
12a-c: X = NTs
13a-f: X = O
Scheme 9. Synthesis of sulfone tethered chromene.
Origin of diastereoselectivity
OR
RO
RO
H
R1
H
H
O
Ha
R1
Conclusions
O
Ha
O
Int-C
O
R1
X
O
X
R3
X
R3
O
In conclusion, Lewis acid promoted 7-endo and 7-exo-mode of
hydroalkoxylation-formal-[4+2] cycloaddition cascade was
developed for the stereoselective synthesis of 1,4-heterocycle-
R3
secondary
π-π interactions
Int-B
exo-approach
TS-7
endo-appraoch
TS-8
disfavoured
favoured
fused
linear/spiro
chromenes.
The
hydroalkoxylation
regioselectivity (7-exo-dig v/s 8-endo-dig) was dictated by the
substitution on the alkyne moiety. Further, conformationally
locked alkynols displayed unexpected reactivity to form 8-
membered heterocycle-fused chromenes via alkyne Prins-type
reaction. In addition, adjacent bis-dioxepino chromenes could be
successfully synthesized in an enantiospecific manner using the
developed hydroalkoxylation cascade.
O
-TMSOR
-TfOH
O
X
X
O
O
OR
R1
R1
R3
R3
cyclo-adduct G
12-13
Scheme 7. Reaction pathway and origin of diastereoselectivity for the formation
of spiro chromenes 12-13.
Experimental Section
Adjacent polycyclic ethers are present in many bioactive natural
products.[11] We envisioned that the developed cascade process
can be employed to gain rapid access to such types of motifs. The
bis-alkynol 15, prepared from (+)-diethyl L-tartrate, when treated
with 2 equiv of salicylaldehyde (8a), gave the adjacent bis-
dioxepino chromene 16 in 68% yield as a single diastereomer
(Scheme 8).
General procedure for the preparation of 1,4-heterocycle-fused
chromenes:
To a stirred solution of alkynol 5-7 (1 equiv) and salicylaldehyde (8a-c) (1
equiv) in dry CH2Cl2 (8 mL/mmol) was added TMSOTf (2 equiv) dropwise
at 0 oC and stirred at the same temperature. The reaction was monitored
by TLC, quenched with saturated aq. solution of NaOH upon completion,
extracted with CH2Cl2 (3 × 5 mL) and dried over anhydrous Na2SO4.
Evaporation of the solvent and purification of the residue over a silica gel
column using ethyl acetate-petroleum ether (3:97) as eluent furnished 1,4-
heterocycle-fused chromenes 9-14 and 16.
O
p-(Me)-C6H4
H
OH
8a (2 equiv)
O
O
O
O
OH
OH
Acknowledgments
O
O
TMSOTf
O
O
CH2Cl2, 0 o
C
p-(Me)-C6H4
p-(Me)-C6H4
68% (≥19:1)
15
p-(Me)-C6H4
16
We thank SERB, New Delhi for financial support. We thank Mr.
Darshan Mhatre of the X-ray facility of the Department of Chemistry, IIT
Bombay for collecting the crystallographic data and IRCC, IIT Bombay for
funding central facilities. We are grateful for the award of research
fellowship to S.K.N. and D.J.F. (CSIR, New Delhi), and D.S.V. (UGC, New
Delhi).
Scheme 8. Enantiospecific synthesis of adjacent bis-dioxepino chromene 15.
Further, to test the functional group compatibility, sulfone tethered
alkynol 7d was reacted with salicylaldehyde (8a), which furnished
the desired 1,4-heterocycle-fused chromene 11d in excellent
yield (Scheme 9). The structure of the product 11d was
unambiguously confirmed by X-ray diffraction study.[8]
Keywords: 1,4-heterocycles• hydroalkoxylation• linear/spiro
chromene• polycyclic ether• Lewis acids
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10.1002/ejoc.201901565
European Journal of Organic Chemistry
COMMUNICATION
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Entry for the Table of Contents (Please choose one layout)
COMMUNICATION
O
O
Santosh J. Gharpure,* Santosh K. Nanda,
Dipak J. Fartade and Dharmendra S.
Vishwakarma
MeO
R1
OH
6
OH
OH
R1
H
H
X
6
⋅
6
6
R2
5
R2
6
6
( )n
HO
HO
Me
⋅
⋅
⋅
O
O
TMSOTf
CH2Cl2, 0 o
OH
TMSOTf
CH2Cl2, 0 o
7
X
O
O
R1
X
⋅
O
O
R3
C
C
7
cytorhizins
B-D
O
Page No. – Page No.
R3
X = NTs
O, S
Me
Me
R2
7-endo-dig
hydroalkoxylation
7-exo-dig
hydroalkoxylation
aliphatic tethered
dr >19:1
aryl tethered
dr >19:1
R3
R
Title
⧫ Transtion metal free ⧫ Strereoselective ⧫ Regioselective ⧫ Broad substrate scpoe
A substrate dependent regio- and stereoselective domino hydroalkoxylation-formal
cycloaddition is described for the facile synthesis of linear as well as spirocyclic 1,4-
heterocycle-fused chromenes. The developed hydroalkoxylation cascade offered a
quick access to the [6-6-7-6] tetracyclic framework of cytorhizhins B-D.
Domino
Cycloaddition
Synthesis of 1,4-Heterocycle-Fused
Chromenes: Rapid Access to the [6-6-
7-6] Tetracyclic Core of Cytorhizhins B-
D
Hydroalkoxylation-[4+2]-
for Stereoselective
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