Reversal of the regiochemistry in the rhodium-catalyzed [4+3] cycloaddition between vinyldiazoacetates and dienes

Article abstract of DOI:10.1002/anie.201406440

A regio-, diastereo-, and enantioselective [4+3] cycloaddition between vinylcarbenes and dienes has been achieved using the dirhodium tetracarboxylate catalyst [Rh₂(SBTPCP)₄]. This methodology provides facile access to 1,4-cycloheptadienes that are regioisomers of those formed from the tandem cyclopropanation/Cope rearrangement reaction of vinylcarbenes with dienes.

Full text of DOI:10.1002/anie.201406440

Angewandte
Chemie
DOI: 10.1002/anie.201406440
Carbenoids
Reversal of the Regiochemistry in the Rhodium-Catalyzed [4+3]
Cycloaddition between Vinyldiazoacetates and Dienes**
Pablo E. Guzmꢀn, Yajing Lian, and Huw M. L. Davies*
Abstract: A regio-, diastereo-, and enantioselective [4+3]
cycloaddition between vinylcarbenes and dienes has been
achieved using the dirhodium tetracarboxylate catalyst [Rh2(S-
BTPCP)4]. This methodology provides facile access to 1,4-
cycloheptadienes that are regioisomers of those formed from
the tandem cyclopropanation/Cope rearrangement reaction of
vinylcarbenes with dienes.
defined regiocontrol is a great advantage for the predictable
use of the Diels–Alder reaction but it also presents a limi-
tation as the reverse regioisomer 4 is not readily accessed.
Limited methods have been developed to address this long-
standing problem but they involve multistep synthetic
sequences.[3] Relatedly, our laboratory has developed a rho-
dium-catalyzed formal [4+3] cycloaddition between vinyl-
diazoacetates and dienes (Scheme 1b).[4,5] This reaction is
also highly regioselective, as illustrated by the reaction of
1 with the rhodium vinylcarbene intermediate 5 to generate
the cycloheptadiene 6, because it proceeds by a tandem
cyclopropanation/Cope rearrangement (CPCR). Herein we
describe an alternative and mechanistically distinct [4+3]
cycloaddition caused by initial attack of the diene at the
vinylogous position of the vinylcarbene instead of at the
carbene center. In this way, we achieve a regiochemical switch
of the [4+3] cycloaddition, thus leading to the formation of
the cycloheptadiene 7.
Cycloaddition reactions play a pivotal role in the synthetic
design of complex natural products. The venerable Diels–
Alder reaction is a notable example of the synthetic utility of
cycloaddition strategies.[1] Excellent stereocontrol is routinely
achieved, and with appropriate electronic bias in the diene
1 and dienophile 2, high levels of regioselectivity are also
obtained to form the cyclohexene 3 (Scheme 1a).[2] The
A representative example of the regular formal [4+3]
cycloaddition of vinyldiazoacetates is the [Rh2(S-PTAD)4]-
catalyzed reaction of the 2-siloxyvinyldiazoacetate 9 with
various dienes (8; Scheme 2).[5a] Some of the most significant
chiral catalysts for the reactions of vinyldiazoacetates are
illustrated in Figure 1.[6] The [Rh2(S-PTAD)4]-catalyzed reac-
tion proceeds with high asymmetric induction and has been
used as a key reaction for the synthesis of several natural
products.[5a,b] In all of the published examples to date, the
Scheme 1. Different cycloaddition approaches.
Scheme 2. [Rh2(S-PTAD)4]-catalyzed tandem cyclopropanation/Cope
rearrangement. TBS=tert-butyldimethylsilyl.
[*] Dr. P. E. Guzmꢀn, Dr. Y. Lian, Prof. Dr. H. M. L. Davies
Department of Chemistry, Emory University
1515 Dickey Drive, Atlanta, GA 30322 (USA)
E-mail: hmdavie@emory.edu
Homepage: http://www.chemistry.emory.edu/faculty/davies/
[**] This work was supported by the National Institutes of Health (GM-
099142-02). We would like to thank Dr. John Bacsa, Emory
University, for the X-Ray crystallographic analysis and Changming
Qin for supplying [Rh2(S-BTPCP)4].
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201406440.
Figure 1. Representative chiral dirhodium catalysts.
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Table 2: Optimization studies for the formation of 13.
reactions are highly regioselective, thus proceeding by an
initial cyclopropanation of the electronically most favorable
and sterically most accessible double bond.
The possibility of reversing the regiochemistry of the
CPCR [4+3] cycloaddition was discovered during a study of
the reaction of 9 with 2-tert-butyldimethylsiloxybutadiene
(11a) catalyzed by [Rh2(S-PTAD)4] (Table 1, entry 1). The
Table 1: First observation of [4+3] cycloadduct 13a.
Entry 11
R
Solvent
CH2Cl2
12/13/14[a] Yield [%][e] ee [%][c]
1
2
3
4
11a TBS
11a TBS
11b TMS n-pentane 14:18:68
11c TIPS n-pentane 5:95:trace
9:70:26
37,[b] 16[d]
23,[b] 42[d]
16,[b] 45[d]
59[c]
54
87
70
96
n-pentane 4:29:62
Entry Solvent
Catalyst
12a/13a[a] Yield [%] 13a
ee [%][d]
[a] Determined by 1H NMR analyis of the crude reaction mixture.
[b] Combined yield of 12 and 13. [c] Adduct 13. [d] Yield of isolated 14.
[e] Yield of isolated product. TIPS=triisopropylsilyl, TMS=trimethyl-
silyl.
1
2
3
4
n-pentane [Rh2(S-PTAD)4]
CH2Cl2 [Rh2(S-PTAD)4]
n-pentane [Rh2(S-DOSP)4]
CH2Cl2 [Rh2(S-DOSP)4]
94:6
87:13
79:21
30:70
55[b]
43[c]
62[c]
61[c]
ꢀ73
ꢀ71
33
5
[a] Determined by 1H NMR analysis of the crude reaction mixture.
[b] Yield of the isolated 12a. [c] Combined yield of 12a and 13a. [d] A
negative sign indicates the enantiomer of 13a.
(entries 1 and 2). The desired cycloadduct 13a was the
dominant product when dichloromethane was used as the
solvent (entry 1) but the enantioinduction (87% ee versus
54% ee) was higher when n-pentane was used as solvent
(entry 2). Further optimization studies revealed that the
siloxy group migration to form 14 was sensitive to the size of
the siloxy group on the diene. The OTMS derivative 11b gave
more of the alkynoate product 14b, but when the more
sterically demanding OTIPS derivative 11c was used, only
traces of the alkynoate 14c was observed. Furthermore, the
size of the siloxy group also influenced carbenoid versus
vinylogous reactivity, as the ratio of 12c to the desired
regioisomer 13c improved to 5:95. Furthermore, the bulkier
silyl groups resulted in improved levels of enantioselectivity
for the reaction (70% ee for the TMS derivative 13b, 87% ee
for the TBS derivative 13a, and 96% ee for the TIPS
derivative 13c).
major product was the typical CPCR cycloadduct 12a but
a small amount of the regiosiomeric [4+3] cycloadduct 13a
was also formed (12a/13a = 94:6). We rationalized that the
formation of the regioisomeric [4+3] cycloadduct 13a was
most likely caused by a competing reaction of the diene
occurring at the vinylogous position of the carbenoid, thus
generating a zwitterionic intermediate, which then cyclizes to
13a.[7–9] Previous studies have shown that vinylogous reac-
tivity is favored in polar solvents.[7] Indeed, when the reaction
was repeated using dichloromethane as the solvent, the ratio
of 12a to 13a improved to 87:13, and the regiosiomeric [4+3]
cycloadduct 13a was produced in 71% ee. Another major
chiral catalyst for vinyldiazoacetate reactions is the proline-
derived dirhodium catalyst [Rh2(S-DOSP)4] (see Figure 1).
Having established optimized reaction conditions for the
formation of the regiosiomeric [4+3] cycloadducts, we
explored the generality of this reaction with the representa-
tive 2-siloxydienes 15 (Table 3). Both 4-substituted and 3,4-
disubstituted 2-OTIPS-1,3-dienes afforded the [4+3] cyclo-
adducts 16 with good regiocontrol and moderate yields. In
general, the products 16 were formed in higher yields at
elevated temperatures with the diene as the limiting reagent
(38–50% yield versus 65–78% yield), but the levels of
asymmetric induction were generally higher at ambient
temperatures with the vinyldiazoacetate 9 as the limiting
agent (90–94% ee versus 82–95% ee). The [4+3] cyclo-
addition is restricted to moderately electron-rich dienes.
Highly electron-rich dienes such as the triisopropylsilyl
variant of the Danishefskyꢀs diene results in the formation
of a complex mixture of products, whereas less electron-rich
dienes such as the p-nitro derivative of 15a fail to react. The
absolute configuration of 16a was determined by X-ray
crystallography of a derivative prepared by DIBAL reduction
and subsequent hydrolysis. The absolute configuration of the
other cycloadducts are tentatively assigned by analogy.[10]
The [Rh2(S-DOSP)4]-catalyzed reaction of
9 with 11a
increased the amount of 13a formed. In the reaction
conducted in n-pentane, the ratio of 12a to 13a was 79:21,
whereas when dichloromethane was used as solvent, the ratio
improved to 30:70 (Table 1, entries 3 and 4), but with poor
enantiocontrol (5% ee).
Recently, we discovered that the sterically crowded
tetrakis(triarylcyclopropanecarboxylate) dirhodium catalysts
are very effective at enhancing vinylogous reactivity of
rhodium vinylcarbenes.[8j] Therefore, we explored the effect
of [Rh2(S-BTPCP)4] on the reaction of 9 with the 2-
siloxydienes 11 (Table 2). The [Rh2(S-BTPCP)4]-catalyzed
reaction resulted in the formation of a third product, the
alkynoate 14a, in addition to 12a and 13a. Compounds
related to 14a had been observed in the reaction of vinyl-
carbenes with vinyl ethers and were shown to be derived from
vinylogous attack on the vinylcarbenoid and subsequent
siloxy-group transfer.[8c] The [Rh2(S-BTPCP)4]-catalyzed
reaction, however, was promising because the amount of
the standard cycloadduct 12a was considerably reduced
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Table 3: Reactions of the dienes 15 with 9.
Table 5: Diastereoselective formal [4+3] cycloaddition.
[a] 5 equiv of diene, n-pentane, RT. [b] 2 equiv of 9, hexanes, reflux. Yield
is that of the product isolated after silica gel chromatography.
[a] Yield is that of the isolated product after silica gel chromatography.
Enantiomeric excess was determined by HPLC using a chiral stationary
phase.
In general, vinylogous reactivity under rhodium(II) cat-
alysis is most common when the vinyl terminus of the
carbenoid is unsubstituted.[8] [Rh2(S-BTPCP)4], however, is
capable of inducing vinylogous reactivity on more highly
substituted vinylcarbenes.[8j] Therefore, the [Rh2(S-BTPCP)4]
reaction of the methyl-substituted vinyldiazoacetate 17 was
examined (Table 4). The mono- and bicyclic cycloadducts 18
Consequently, we were pleasantly surprised to find that the
cycloadducts 20 were produced as single diastereomers with
high levels of asymmetric induction (96% ee). The high
diastereoselectivity is presumably caused by preferred reac-
tion of the vinylcarbenoid with (Z,E)-19 rather than with
(E,E)-19.
A final reaction was conducted between 17 and 19a
(Scheme 3). Even though both 17 and 19a are composed of
Table 4: Diastereoselective formal [4+3] cycloaddition.
Scheme 3. Reaction of 17 with 19a.
[a] The ee value of the corresponding allylic alcohol. Yield refers to that of
product isolated after silica gel chromatography. Enantiomeric excess
was determined by HPLC using a chiral stationary phase.
mixtures of E/Z isomers, the [Rh2(S-BTPCP)4]-catalyzed
reaction smoothly formed the cycloadduct 21, containing
three new stereogenic centers, in 72% yield as a single
diastereomer. Analysis of 21 by HPLC using a chiral sta-
tionary phase was unsuccessful, but after treatment with
DIBAL, the resulting cycloheptene 22 was determined to
have an ee value of 85% (reduction yield is not optimized).
A reasonable mechanism for the [4+3] cycloadditions is
shown in Scheme 4. [Rh2(S-BTPCP)4] has been shown to be
a sterically hindered catalyst which blocks the re face of the
carbene,[6c] and preferentially reacts at the vinylogous position
when electron-rich trapping agents are used. The regioiso-
meric [4+3] cycloaddition involves initial attack at the
vinylogous position of the vinylcarbene, as illustrated in 23,
to generate the zwitterionic intermediate 24. A similar type of
zwitterionic intermediate has been proposed for the [3+2]
cycloaddition between vinylcarbenes and dienes.[8d] The high
diastereoselectivity of this reaction suggests that the subse-
containing stereogenic centers at C3 and C7 were formed with
high levels of enantiocontrol (92–99% ee). Furthermore, even
though 17 consists of a mixture of E,Z isomers, only the cis
diastereomers of 18 were formed. These results suggest that
only one geometrical isomer of the rhodium vinylcarbene is
capable of undergoing the [4+3] cycloaddition.
The study was then extended to the reaction of 9 with the
1,4-disubstituted diene 19, which would be expected to
generate the [4+3] cycloadducts 20 containing stereogenic
centers at C4 and C7 (Table 5). The additional terminal
substituent on the diene was expected to be a challenge to the
[4+3] cycloaddition because it would add steric interference
at the position of initial bond formation and the dienes 19
consisted of about a 9:1 mixture of Z,E to E,E isomers.
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vents. By an appropriate choice of diene and vinyldiazoace-
tate, cycloheptadienes with up to three new stereogenic
centers can be generated with excellent stereocontrol.
Experimental Section
Representative procedure for the synthesis of 13c: (E)-Triisopro-
pyl(penta-1,3-dien-2-yloxy)silane (1.51 mmol, 5.00 equiv), n-pentane
(3.5 mL), and [Rh2(S-BTPCP)4] (5.3 mg, 0.0030 mmol, 0.010 equiv)
were added to a round-bottom flask. A solution of methyl 3-[(tert-
butyldimethylsilyl)oxy]-2-diazobut-3-enoate (77.0 mg, 0.30 mmol,
1.00 equiv) in n-pentane (3.5 mL) was added by syringe pump over
1 h. Once the addition was complete, the reaction was stirred at 238C
for 0.5 h. The reaction was stopped by concentration under reduced
pressure and purified by flash chromatography on silica gel (n-
pentane/diethyl ether 98:2) to provide pure products.
Received: June 28, 2014
Revised: August 2, 2014
Published online: September 29, 2014
Keywords: carbenoids · cycloaddition · diazo compounds ·
.
rhodium · synthetic methods
Scheme 4. Proposed mechanism for the [4+3] cycloaddition: a) Gen-
eral model. b) Model of the reaction of the unsubstituted vinyldiazo-
acetate 9 with dienes 15a–c. c) Explanation for high diastereocontrol
when the diene or vinyldiazoacetates are not pure geometrical iso-
mers.
[1] O. Diels, K. Alder, Justus Liebigs Ann. Chem. 1928, 460, 98.
[2] For selected review of intermolecular and intramolecular Diels–
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Synthesis, Vol. 5 (Eds.: B. M. Trost, I. Fleming), Pergamon, New
York, 1991, pp. 315 – 399; b) W. R. Roush in Comprehensive
Organic Synthesis, Vol. 5 (Eds.: B. M. Trost, I. Fleming),
Pergamon, New York, 1991, pp. 513 – 550; c) E. J. Corey,
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[3] a) K. J. Shea, J. Staab, K. S. Zandi, Tetrahedron Lett. 1991, 32,
2715; b) G. M. Sammis, E. M. Flamme, H. Xie, D. M. Ho, E. J.
Sorenson, J. Am. Chem. Soc. 2005, 127, 8612.
[4] a) H. M. L. Davies, D. M. Clark, T. K. Smith, Tetrahedron Lett.
1985, 26, 5659; b) H. M. L. Davies, G. Ahmed, M. R. Churchill, J.
Am. Chem. Soc. 1996, 118, 10774; c) H. M. L. Davies, D. G.
Stafford, B. D. Doan, J. H. Houser, J. Am. Chem. Soc. 1998, 120,
3326; d) for an early review on the tandem cyclopropanation/
Cope rearrangement, see: H. M. L. Davies, Tetrahedron 1993,
49, 5203.
[5] For recent examples of the use of the tandem cyclopropanation/
Cope rearrangement in total synthesis, see: a) B. D. Schwartz,
J. R. Denton, Y. Lian, H. M. L. Davies, C. M. Williams, J. Am.
Chem. Soc. 2009, 131, 8329; b) Y. Lian, L. C. Miller, S. Born, R.
Sarpong, H. M. L. Davies, J. Am. Chem. Soc. 2010, 132, 12422;
c) J. P. Olson, H. M. L. Davies, Org. Lett. 2008, 10, 573; d) K. L.
Jackson, J. A. Henderson, H. Motoyoshi, A. J. Phillips, Angew.
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12, 3708.
[6] a) H. M. L. Davies, R. Bruzinski, D. K. Hutcheson, M. Fall, J.
Am. Chem. Soc. 1996, 118, 6897; b) R. P. Reddy, G. H. Lee,
H. M. L. Davies, Org. Lett. 2006, 8, 3437; c) C. Qin, V.
Boyarskikh, J. H. Hansen, K. I. Hardcastle, D. G. Musaev,
H. M. L. Davies, J. Am. Chem. Soc. 2011, 133, 19198.
quent cyclization to the cycloheptadiene 25 is faster than bond
rotation. Zwitterionic intermediates have been shown to be
likely in several types of stereoselective reactions of rhodium
vinylcarbenes,[8] so the concept of rapid cyclization of
zwitterionic intermediates without epimerization is well
established. Both the diene and the vinylcarbenoid would
need to react through an s-cis conformation for ring closure to
occur without bond rotation. Rhodium 2-siloxyvinylcarbenes
have been shown to preferentially adopt an s-cis conforma-
tion[11] and the 2-siloxy group would likely favor the s-cis
conformation of the diene. The face selectivity of attack of the
diene on the rhodium carbene determines the absolute
configuration of the final product, even when no stereocen-
ters are present in the zwitterionic intermediate 27, as
illustrated in the conversion sequence 26!27!28. This
situation would be the case for the examples shown in
Table 3. Even though the exact trajectory of approach of the
dienes is not known, the proposed mechanism can be used to
rationalize why highly diastereoselective reactions are possi-
ble even when the vinylcarbene and the diene are mixtures of
geometrical isomers. An E,E diene would have R1 in an
unfavorable position pointing towards the vinylcarbene (see
structure 29), whereas a Z vinylcarbene would unlikely form
because R3 would be pointing towards the catalyst surface
(see structure 30).
In summary, an asymmetric [4+3] cycloaddition between
rhodium vinylcarbenes and dienes has been developed. The
reaction proceeds with the opposite regiochemistry to the
traditional tandem cyclopropanation/Cope rearrangement.
An efficient asymmetric cycloaddition was achieved when
[Rh2(S-BTPCP)4] was used as catalyst in hydrocarbon sol-
[7] For early examples of vinylogous reactivity of rhodium vinyl-
carbenes, see: a) H. M. L. Davies, E. Saikali, T. J. Clark, E. H.
Chee, Tetrahedron Lett. 1990, 31, 6299; b) H. M. L. Davies, B.
Hu, E. Saikali, P. R. Bruzinski, J. Org. Chem. 1994, 59, 4535.
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[8] For recent applications of vinylogous reactivity of rhodium
vinylcarbenes in synthesis, see: a) Y. Lian, H. M. L. Davies, Org.
Lett. 2010, 12, 924; b) Y. Lian, H. M. L. Davies, Org. Lett. 2012,
14, 1934; c) D. Valette, Y. Lian, J. P. Haydek, K. I. Hardcastle,
H. M. L. Davies, Angew. Chem. Int. Ed. 2012, 51, 8636; Angew.
Chem. 2012, 124, 8764; d) A. G. Smith, H. M. L. Davies, J. Am.
Chem. Soc. 2012, 134, 18241; e) X. Wang, X. Xu, P. Y. Zavalji,
M. P. Doyle, J. Am. Chem. Soc. 2011, 133, 16402; f) X. Xu, P. Y.
Zavalij, W. Hu, M. P. Doyle, J. Org. Chem. 2013, 78, 1583; g) Y.
Qian, P. J. Zavalij, W. Hu, M. P. Doyle, Org. Lett. 2013, 15, 1564;
h) X. Wang, Q. M. Abrahams, P. Y. Zavalij, M. P. Doyle, Angew.
Chem. Int. Ed. 2012, 51, 5907; Angew. Chem. 2012, 124, 6009;
i) Y. Qian, X. Xu, X. Wang, P. J. Zavalij, W. Hu, M. P. Doyle,
Angew. Chem. Int. Ed. 2012, 51, 5900; Angew. Chem. 2012, 124,
6002; j) C. Qin, H. M. L. Davies, J. Am. Chem. Soc. 2013, 135,
14516.
[9] For a recent review on the vinylogous transformations of 9, see:
X. Xu, M. P. Doyle, Acc. Chem. Res. 2014, 47, 1396.
[10] For X-ray crystallographic data for the derivative of 16a, see the
Supporting Information. CCDC 979611 contains the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[11] J. H. Hansen, T. M. Gregg, S. R. Ovalles, Y. Lian, J. Autschbach,
H. M. L. Davies, J. Am. Chem. Soc. 2011, 133, 5076.
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