Stereoselective rhodium-catalyzed [(3+2)+2] carbocyclization reaction of trialkoxysilyl-substituted alkenylidenecyclopropanes with monosubstituted alkynes

Tetrahedron 69 (2013) 7826e7830

Contents lists available at SciVerse ScienceDirect

Tetrahedron journal homepage: www.elsevier.com/locate/tet

Stereoselective rhodium-catalyzed [(3þ2)þ2] carbocyclization reaction of trialkoxysilyl-substituted alkenylidenecyclopropanes with monosubstituted alkynes P. Andrew Evans a, *, Tomass Baikstis b, Phillip A. Inglesby b a b

Department of Chemistry, Queen’s University, 90 Bader Lane, Kingston, ON K7L 3N6, Canada Department of Chemistry, University of Liverpool, Crown Street, Liverpool L69 7ZD, United Kingdom

a r t i c l e i n f o

a b s t r a c t

Article history: Received 18 April 2013 Received in revised form 16 May 2013 Accepted 20 May 2013 Available online 24 May 2013

The highly regio- and diastereoselective rhodium-catalyzed [(3þ2)þ2] carbocyclization reaction of trialkoxysilyl-substituted alkenylidenecyclopropanes (ACPs) with monosubstituted alkynes is reported. This work represents the first example of a metal-catalyzed higher-order carbocyclization with a vinylsilane, which facilitates the regioselective insertion of the alkyne and the selective introduction of a secondary alcohol. For example, stereospecific Tamao oxidation of the allylsilane resulting from the stereoselective cycloaddition provides the corresponding C6 hydroxyl group that is present in an array of related sesquiterpene natural products. Ó 2013 Elsevier Ltd. All rights reserved.

Keywords: Carbocyclization Rhodium-catalyzed Stereoselective Vinylsilane

1. Introduction

A) Representative Natural Products H

O

Me OH H

Me

O

Me O H HO HO

Me

Transition metal-catalyzed higher-order carbocyclization reactions continue to evolve as an important method for the stereoselective construction of complex polycyclic systems.1 In this context, we recently reported the rhodium-catalyzed [(3þ2)þ2] carbocyclization of alkenylidenecyclopropanes (ACPs) with activated alkynes for the construction of cis-fused bicyclo[5.3.0]heptadiene systems, which provides the carbon framework present in a number of biologically interesting sesquiterpene natural products (Scheme 1A).2,3 Nevertheless, despite the inherent synthetic utility of this process, there are several significant limitations. For example, optimal regioselectivity with monosubstituted alkynes is only obtained with propargylic ketones (Scheme 1B) and the introduction of oxygenation at C6, as exemplified by the syn,antistereotriad in sesquiterpenes repin, lactarorufin A, and velleratretraol, requires an ACP with an enol ether or suitable surrogate.4 Although 1,1-disubstituted alkenes within the ACP component are excellent substrates for the construction of bridgehead quaternary carbon stereogenic centers, the corresponding 1,2-disubstituted alkenes undergo competitive ene-cycloisomerization reactions, which is particularly problematic for the Z-isomer.2,5 We

Scheme 1. Representative examples of sesquiterpene natural products and the rhodium-catalyzed [3þ2þ2] reactions with unsubstituted and triorganosilylsubstituted ACPs.

* Corresponding author. Tel.: þ1 613 533 6286; fax: þ1 613 533 6669; e-mail address: [email protected] (P.A. Evans).

envisioned that a vinylsilane-substituted ACP would ameliorate the challenging alkyne insertion by providing a traceless controller for alkyne insertion and a secondary alcohol following Tamao oxidation (Scheme 1C).6 Furthermore, vinylsilanes are significantly more

0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tet.2013.05.096

HO

O 6 O HO

O

Me Me

Repin O

H 6 HO

Me

O

Lactarorufin A

H 6 HO

O

OH

Velleratretraol

B) Previous Work cat. Rh(I)

X

R

H

H

Poor Regioselectivity

R + X

X H

R ≠ COMe

H

R2

C) This Work cat. Rh(I)

X

[Si] 1

2

R

H

H

Excellent Regioselectivity

R vs. X

X H [Si] 3

up to rs >19:1 ds >19:1

H R [Si] 4

P.A. Evans et al. / Tetrahedron 69 (2013) 7826e7830

stable than acyclic enol ethers and readily prepared from the corresponding monosubstituted alkyne.7,8 Herein, we now describe the first regio- and diastereoselective rhodium-catalyzed [(3þ2)þ 2] carbocyclization reactions of trialkoxysilyl-substituted ACPs with monosubstituted alkynes for the construction of trialkoxysilylsubstituted bicycloheptadienes (Scheme 1C), which provides a unified approach to controlling the alkyne insertion of monosubstituted alkynes and the introduction of oxygenation at C6. Scheme 2 outlines the proposed catalytic cycle, which delineates the origin of regiocontrol in this process. Oxidative addition of the metal into the distal bond of the cyclopropane, followed by rearrangement to the TMM species iii provides the resting state for this transformation.9 This is followed by rate-limiting stereospecific carbometallation of the alkene to afford iv as a single diastereoisomer.10 We envision that the steric bias of the triorganosilyl group [Si] will control the orientation of alkyne insertion to minimize steric interaction with the substituent on the alkyne (R), thereby favoring the formation of v (vs vi). Reductive elimination of the rhodium(III) intermediate v regenerates the active rhodium(I) species to afford the desired carbocycle 3 with excellent regio- and diastereoselectivity. Interestingly, we are unaware of any examples of higher-order carbocyclization reactions of this type with vinylsilanes.

X

R

i

[Si] 3

RhLn

X

R [Si]

X

Rh(I)Ln

RhLn

RhLn

vs. X

X

[Si]

v

vi

[Si] 1

R

[Si] ii

R X

RhLn iv [Si]

X

RhLn [Si] iii

Scheme 2. Proposed catalytic cycle for the rhodium-catalyzed [(3þ2)þ2] carbocyclization reaction of triorganosilyl-substituted ACPs with monosubstituted alkynes.

2. Results and discussion Table 1 summarizes the examination of the rhodium-catalyzed [(3þ2)þ2] carbocyclization reaction of various ACPs with monosubstituted alkynes (Table 1). Preliminary studies focused on a series of alkyne substituents to determine the feasibility of this process with both activated and unactivated groups. Treatment of the ACP 1 (R1¼H) with the monosubstituted alkynes 2 in the presence of [Rh(cod)Cl]2 modified with triphenylphosphite, furnished the cisfused bicyclo[5.3.0]heptadienes 3/4 with excellent efficiency and diastereoselectivity, albeit with the exception of methyl propiolate that provides a modest yield (entries 1 vs 2e4). Nevertheless, regardless of the alkyne, the cycloaddition provides relatively poor selectivity for the alkyne insertion (entries 1e4). Additionally, phenylacetylene facilitates a reversal in the normal mode of regioselectivity, to furnish 4 as the major constitutional isomer, which is consistent with the insertion occurring with electronic control (entry 4).11 Although we had previously demonstrated that 1,2disubstituted alkenes (R1¼Me) dramatically improve the insertion step, the olefin geometry is critical, since the Z-isomer is particularly prone to competitive ene-cycloisomerization. In this context, we envisioned that the corresponding E-vinylsilane would promote selective alkyne insertion (vide supra), which would provide

7827

Table 1 Rhodium-catalyzed [(3þ2)þ2] carbocyclization reaction with monosubstituted alkynes (1, X¼C(CO2Me)2)a

Entry 1 2 3 4 5 6 7

ACP 1 R1¼

Alkyne 2 R2¼

3:4b

dsb

H H H H SiMe2Ph Si(OEt)3 OAc

CO2Me i Pr TMSd Ph CO2Me CO2Me CO2Me

2:1 1:1 1:1 1:4 19:1 19:1 19:1

19:1 19:1 19:1 19:1 19:1 19:1 19:1

Yield (%)c 50 80 75 78 53 63 27

Bold signifies optimal conditions. a All reactions were carried out on 0.20 mmol scale in toluene (0.1 M) at 100  C utilizing 5 mol% of [Rh(cod)Cl]2, 30 mol% P(OPh)3, and 5 equiv of the alkyne. b The regio- and diastereoselectivities were determined by 1H NMR on the crude reaction mixtures. c Isolated yield of 3/4. d An additional 5 equiv of alkyne was added after 6 h.

a traceless controller or alcohol surrogate. Gratifyingly, the dimethylphenylsilyl (R1¼SiMe2Ph) and triethoxylsilane (R1¼Si(OEt)3) groups provide excellent selectivity (entries 5 and 6), in which the latter was optimal in terms of overall efficiency for the formation of the bicyclo[5.3.0]heptadiene 3. In contrast, treatment of the enol acetate 1 (R1¼OAc), furnished the cycloadduct 3 with excellent selectivity, albeit in poor yield (entry 7). Hence, although the acyclic enol acetate directly provides the desired oxygenation for the construction of the aforementioned sesquiterpenes, the poor efficiency coupled with the challenges to prepare this motif in a selective manner makes the vinylsilane a much more attractive synthon for the installation of a secondary hydroxyl group at C6. Overall, this higher-order carbocyclization reaction generates two rings and three stereogenic centers in a single operation with complete regio- and diastereoselectivity. Table 2 outlines the application of the optimized reaction conditions (Table 1, entry 6) to carbon- and nitrogen-tethered ACPs with a variety of monosubstituted alkynes. The reaction of the ACP 1a (X¼C(CO2Me)2) with isopropylacetylene (2, R¼iPr) affords 3b/4b with 4:1 regioselectivity favoring 3b (entry 2),12 in which the silyl group provides only a modest increase in selectivity (cf. Table 1, entry 2). In contrast, methyl propiolale, trimethylsilylacetylene and phenylacetylene afford excellent regio- and diastereoselectivity for 3a, 3c, and 3d, respectively, albeit the latter requires a slightly elevated temperature (entries 1, 3, and 4). Interestingly, the cycloadducts from the reaction with trimethylsilylacetylene contain two different silyl moieties thereby making them particularly versatile intermediates, which can be further elaborated into an array of functional groups. For example, removal of the trimethylsilyl group in 3c constitutes the cycloaddition with acetylene. Additionally, the selectivity for the phenylacetylene cycloadduct is remarkable, since the triethoxysilane reverses the regioselectivity from 1:4 to 19:1 and thereby overriding the inherent electronic preference for alkyne insertion (cf. Table 1, entry 4). It is also noteworthy that depending on the ACP employed (H vs Si(OEt)3), the reaction displays either alkyne-electronic control or substrate-steric control for the alkyne insertion.13 The reaction is also somewhat general with respect to the ACP, with the sulfonamide-tethered 1b (X¼NTs) affording the corresponding cycloadducts 3eeh with similar yields and selectivities (entries 5e8), albeit with the exception of 3e.14 Finally, the conversion of the cycloadducts 3h and 3d to 8 and 9, respectively, illustrates the inherent synthetic utility and versatility of this strategy (Scheme 3). For example, treatment of 3h (X¼NTs)

7828 Table 2 Highly regio- and (Si¼Si(OEt)3).a,b,c

P.A. Evans et al. / Tetrahedron 69 (2013) 7826e7830

diastereoselective

[(3þ2)þ2]

carbocyclization

reaction

electronically and sterically controlled processes. Finally, these developments are likely to be employed in related [mþnþo] carbocyclization reactions as well as finding application in the total synthesis of complex polycyclic sesquiterpenes natural products. 4. Experimental 4.1. General

1a X¼C(COMe2)2

1b X¼NTs

a All reaction were carried out on 0.20 mmol scale in toluene (0.1 M) at 100  C (unless otherwise stated) utilizing 5 mol % of [Rh(cod)Cl]2, 30 mol % P(OPh)3, and 5 equiv of alkyne. b Isolated yields. c Regio- and diastereoselectivities were determined by 1H NMR on the crude reaction mixtures. d Reaction performed at 120  C in p-xylene. e Reaction conversion was 50%.

with TBAF, furnished 8 in 86% yield as a single regio- and diastereoisomer (cf. Table 1, entry 4), which circumvents the problems usually associated with simple monosubstituted alkynes. Alternatively, Tamao oxidation of the triethoxysilyl group in 3d (X¼C(CO2Me)2) furnished the secondary alcohol 9 in 62% yield, which maps onto the stereotriad in the sesquiterpenes outlined in Scheme 1A.

Scheme 3. Removal and oxidation of the triethoxysilyl group in the trialkoxysilylsubstituted bicycloheptadienes.

3. Conclusions In conclusion, we have developed the first highly regio- and diastereoselective rhodium(I)-catalyzed [(3þ2)þ2] carbocyclization reaction of triethoxysilyl-substituted ACPs with monosubstituted alkynes. The vinylsilane dramatically improves the regioselective insertion of both activated and unactivated alkynes. Furthermore, the silane can either serve as a traceless controller or a secondary alcohol surrogate. Additionally, this study provides a deeper understanding of the reaction mechanism of the rhodium-catalyzed [(3þ2)þ2] carbocyclization reaction, in which alkyne insertion occurs via

All reactions were carried out under an atmosphere of argon in anhydrous solvent and commercially available reagents were used as received. All compounds were purified by flash chromatography using silica gel 60 (40e63 mm, FluoroChem) and gave spectroscopic data consistent with being 95% the assigned structure. Analytical thin layer chromatography (TLC) was performed on precoated 0.25 mm thick silica gel 60-F254 plates (Whatman PE SIL G/UV). IR spectra were recorded on a PerkineElmer FTIR Spectrum 100 (ATR) spectrometer; wavenumbers (n) are given in cm1; and the abbreviations w (weak, <25%), m (medium, 25e50%), s (strong, 51e75%), vs (very strong, >75%), and br (broad) are used to describe the relative intensities of the IR absorbance bands. Mass spectra were obtained through the Chemistry Department Mass Spectrometry Service, University of Liverpool. 1H NMR and 13C NMR spectra were recorded on a Bruker Avance DRX-500 spectrometer in CDCl3 at ambient temperature; chemical shifts (d) are given in parts per million and calibrated using the signal of residual undeuterated solvent as internal reference (dH¼7.26 ppm and dC¼77.16 ppm). 1H NMR data are reported as follows: chemical shift (multiplicity, first order spin system if available, coupling constant, integration). Coupling constants (J) are reported in Hertz and apparent splitting patterns are designated using the following abbreviations: s (singlet), d (doublet), t (triplet), q (quartet), quint. (quintet), sept. (septet), m (multiplet), br (broad), app (apparent), and combinations thereof. 13C NMR spectra with complete proton decoupling were described with the aid of an APT sequence, separating methylene and quaternary carbons (e, even), from methyl and methine (o, odd). 4.2. General alkyne-hydrosilylation procedure for the preparation of triethoxysilyl-substituted ACPs Tri-tert-butylphosphine (40.0 mL, 0.04 mmol; 1 M in toluene) was added to a solution of the Karstedt catalyst (893 mL, 0.04 mmol; w2% in xylene) in toluene (5 mL) at 0  C and stirred for ca. 5 min. The alkynyl-substituted ACP8 (4.00 mmol) and triethoxysilane (821 mg, 5.00 mmol) were added and the reaction was warmed to room temperature and stirred for ca. 12 h. The reaction was then concentrated in vacuo and purified by flash chromatography (silica gel, eluting with 5e20% diethyl ether/hexanes) to afford the triethoxysilyl-substituted ACP. 4.2.1. (E)-Dimethyl 2-(2-cyclopropylidenethyl)-2-(3-(triethoxysilyl) allyl)malonate, 1a. (X¼C(CO2Me)2, Si¼Si(OEt)3). 1H NMR (500 MHz, CDCl3) d 6.24 (dt, J¼18.6, 7.1 Hz, 1H), 5.62e5.57 (m, 1H), 5.50 (dt, J¼18.6, 1.3 Hz, 1H), 3.79 (q, J¼7.0 Hz, 6H), 3.70 (s, 6H), 2.78 (d, J¼7.4 Hz, 2H), 2.73 (dd, J¼7.1, 1.3 Hz, 2H), 1.21 (t, J¼7.0 Hz, 9H), 1.09e1.06 (m, 2H), 1.01e0.98 (m, 2H); 13C NMR (125 MHz, CDCl3) d 171.4 (e), 147.0 (o), 126.9 (e), 124.9 (o), 111.8 (o), 58.6 (e), 57.9 (e), 52.6 (o), 39.9 (e), 35.3 (e), 18.4 (o), 3.1 (e), 2.0 (e); IR (neat) 2975 (w), 2885 (w), 1735 (s), 1620 (w), 1438 (w), 1232 (m), 1099 (s), 1074 (s), 957 (m), 780 (m) cm1; HRMS (ESI, [MþNa]þ) calculated for C19H32O7SiNa 423.1815, found 423.1817. 4.2.2. (E)-N-(2-Cyclopropylidenethyl)-4-methyl-N-(3-(triethoxysilyl) allyl)benzenesulfonamide, 1b. (X¼NTs, Si¼Si(OEt)3). 1H NMR (500 MHz, CDCl3) d 7.70 (d, J¼8.3 Hz, 2H), 7.29 (d, J¼8.0 Hz, 2H), 6.18

P.A. Evans et al. / Tetrahedron 69 (2013) 7826e7830

(dt, J¼18.8, 5.6 Hz, 1H), 5.60e5.56 (m, 1H), 5.50 (dt, J¼18.8, 1.5 Hz, 1H), 3.93 (d, J¼6.8 Hz, 2H), 3.85 (dd, J¼5.5, 1.4 Hz, 2H), 3.77 (q, J¼7.0 Hz, 6H), 2.42 (s, 3H), 1.20 (t, J¼7.0 Hz, 9H), 1.06e1.03 (m, 2H), 0.99e0.96 (m, 2H); 13C NMR (125 MHz, CDCl3) d 146.8 (o), 143.3 (e), 137.7 (e), 129.8 (o), 127.7 (e), 127.3 (o), 123.2 (o), 112.7 (o), 58.6 (e), 51.4 (e), 48.8 (e), 21.7 (o), 18.4 (o), 2.6 (e), 2.0 (e); IR (neat) 2974 (w), 2885 (w), 1621 (w), 1343 (m), 1159 (s), 1076 (s), 960 (m), 782 (m), 717 (m) cm1; HRMS (ESI, [MþNa]þ) calculated for C21H33NO5SiSNa 462.1746, found 462.1762.

7829

1640 (w), 1435 (w), 1247 (s), 1165 (m), 1102 (s), 1078 (vs), 957 (m), 833 (s), 780 (m), 748 (m) cm1; HRMS (ESI, [MþNa]þ) calculated for C24H42O7Si2Na 521.2367, found 521.2379.

A solution of the ACP (0.20 mmol), alkyne (1.00 mmol), [Rh(cod) Cl]2 (0.01 mmol), and triphenylphosphite (0.06 mmol) in toluene (2 mL) was back-filled under vacuum with argon. The reaction vessel was placed in pre-heated oil bath (100  C) and stirred for ca. 16 h. The reaction was cooled to ambient temperature and concentrated in vacuo to afford the crude product. Purification by flash chromatography (silica gel, eluting with diethyl ether/hexanes) afforded the desired cycloadduct as an oil.

4.3.4. (3aS*,8S*,8aR*)-Dimethyl 4-methylene-6-phenyl-8-(triethoxysilyl)-3,3a,4,5,8,8a-hexahydroazulene-2,2(1H)-dicarboxylate, 3d. 1H NMR (500 MHz, CDCl3) d 7.33e7.28 (m, 4H), 7.23e7.20 (m, 1H), 5.97 (dd, J¼7.3, 2.0 Hz, 1H), 5.03 (s, 1H), 4.84 (s, 1H), 3.84 (q, J¼7.0 Hz, 6H), 3.74 (s, 3H), 3.73 (s, 3H), 3.48 (d, A of AB, JAB¼18.1 Hz, 1H), 3.31 (d, B of AB, JAB¼18.0 Hz, 1H), 3.07 (app. dt, J¼8.7, 5.3 Hz, 1H), 2.64-2.56 (m, 1H), 2.62 (dd, A of ABX, JAB¼14.5 Hz, JAX¼8.9 Hz, 1H), 2.45 (dd, J¼13.1, 5.7 Hz, 1H), 2.39 (dd, B of ABX, JAB¼14.6 Hz, JBX¼5.1 Hz, 1H), 2.08 (dd, J¼10.0, 7.5 Hz, 1H), 2.06 (app. t, J¼12.9 Hz, 1H), 1.22 (t, J¼7.0 Hz, 9H); 13C NMR (125 MHz, CDCl3) d 173.2 (e), 172.8 (e), 147.9 (e), 144.1 (e), 139.2 (e), 128.2 (o), 126.7 (o), 126.4 (o), 125.9 (o), 110.8 (e), 59.8 (e), 58.8 (e), 52.8 (o), 52.7 (o), 45.9 (o), 44.4 (o), 42.0 (e), 39.0 (e), 37.2 (e), 25.4 (o), 18.4 (o); IR (neat) 2974 (w), 2887 (w), 1732 (s), 1644 (w), 1435 (w), 1248 (m), 1164 (m), 1100 (s), 1074 (s), 957 (m), 777 (m), 756 (m), 697 (m) cm1; HRMS (ESI, [MþNa]þ) calculated for C27H38O7SiNa 525.2285, found 525.2291.

4.3.1. (3aS*,8S*,8aR*)-Trimethyl 4-methylene-8-(triethoxysilyl)-3,3a, 4,5,8,8a-hexahydroazulene-2,2,6(1H)-tricarboxylate, 3a. 1H NMR (500 MHz, CDCl3) d 7.03 (dd, J¼7.7, 1.6 Hz, 1H), 4.92 (s, 1H), 4.80 (s, 1H), 3.82 (q, J¼7.0 Hz, 6H), 3.73 (s, 3H), 3.72 (s, 3H), 3.72 (s, 3H), 3.32 (d, A of AB, JAB¼17.8 Hz, 1H), 3.17 (d, B of AB, JAB¼17.9 Hz, 1H), 3.02 (dt, J¼8.9, 5.5 Hz, 1H), 2.64 (dd, A of ABX, JAB¼14.5 Hz, JAX¼8.6 Hz, 1H), 2.58e2.51 (m, 1H), 2.32 (dd, J¼12.7, 5.6 Hz, 1H), 2.29 (dd, B of ABX, JAB¼14.5 Hz, JBX¼5.3 Hz, 1H), 2.14 (app. t, J¼7.7 Hz, 1H), 2.08 (app. t, J¼13.0 Hz, 1H), 1.21 (t, J¼7.0 Hz, 9H); 13C NMR (125 MHz, CDCl3) d 173.1 (e), 172.6 (e), 168.2 (e), 147.0 (e), 140.7 (o), 130.2 (e), 112.8 (e), 59.4 (e), 59.0 (e), 52.9 (o), 52.9 (o), 52.0 (o), 46.2 (o), 42.6 (o), 39.8 (e), 38.1 (e), 36.3 (e), 27.8 (o), 18.3 (o); IR (neat) 2975 (w), 2890 (w), 1733 (s), 1709 (s), 1642 (w), 1435 (m), 1258 (vs), 1164 (s), 1101 (s), 1080 (vs), 960 (m), 734 (m) cm1; HRMS (ESI, [MþNa]þ) calculated for C23H36O9SiNa 507.2026, found 507.2041.

4.3.5. (3aS*,8R*,8aS*)-Methyl 4-methylene-2-tosyl-8-(triethoxysilyl)1,2,3,3a,4,5,8,8a-octahydrocyclohepta[c]-pyrrole-6-carboxylate, 3e. 1H NMR (500 MHz, CDCl3) d 7.72 (d, J¼8.2 Hz, 2H), 7.32 (d, J¼7.9 Hz, 2H), 6.92 (dd, J¼7.6, 1.8 Hz, 1H), 4.86 (s, 1H), 4.50 (s, 1H), 3.79 (q, J¼7.0 Hz, 6H), 3.70 (s, 3H), 3.55 (dd, J¼10.1, 7.4 Hz, 1H), 3.45 (dd, A of ABX, JAB¼10.5 Hz, JAX¼7.5 Hz, 1H), 3.33 (dd, B of ABX, JAB¼10.5 Hz, JBX¼2.2 Hz, 1H), 3.28 (d, J¼18.3 Hz, 1H), 2.97e2.92 (m, 3H), 2.49 (ddt, J¼10.4, 9.2, 7.5 Hz, 1H), 2.44 (s, 3H), 1.93 (app. t, J¼8.3 Hz, 1H), 1.20 (t, J¼7.0 Hz, 9H); 13C NMR (125 MHz, CDCl3) d 167.9 (e), 145.0 (e), 143.5 (e), 139.8 (o), 133.9 (e), 131.3 (e), 129.8 (o), 127.7 (o), 112.1 (e), 59.1 (e), 52.1 (e), 52.1 (o), 51.6 (e), 45.7 (o), 42.0 (o), 36.1 (e), 25.2 (o), 21.7 (o), 18.4 (o); IR (neat) 2975 (w), 2890 (w), 1709 (m), 1645 (w), 1598 (w), 1346 (m), 1259 (m), 1160 (s), 1074 (vs), 960 (m), 779 (m), 732 (m) cm1; HRMS (ESI, [MþNa]þ) calculated for C25H37NO7SiSNa 546.1958, found 546.1962.

4.3.2. (3aS*,8S*,8aR*)-Dimethyl 6-isopropyl-4-methylene-8-(triethoxysilyl)-3,3a,4,5,8,8a-hexahydroazulene-2,2(1H)-dicarboxylate, 3b. 1H NMR (500 MHz, CDCl3) d 5.43 (dd, J¼7.1, 1.6 Hz, 1H), 4.94 (s, 1H), 4.74 (s, 1H), 3.81 (q, J¼7.0 Hz, 6H), 3.73 (s, 3H), 3.72 (s, 3H), 3.02 (d, A of AB, JAB¼18.1 Hz, 1H), 2.90 (dt, J¼8.7, 4.9 Hz, 1H), 2.81 (d, B of AB, JAB¼18.1 Hz, 1H), 2.57 (dd, A of ABX, JAB¼14.7 Hz, JAX¼8.8 Hz, 1H), 2.51e2.44 (m, 1H), 2.40 (dd, J¼13.1, 5.7 Hz, 1H), 2.33 (dd, B of ABX, JAB¼14.8 Hz, JBX¼4.8 Hz, 1H), 2.19 (sept., J¼6.9 Hz, 1H), 1.96 (app. t, J¼12.8, 1H), 1.84 (dd, J¼10.8, 7.0 Hz, 1H), 1.21 (t, J¼7.0 Hz, 9H), 0.99 (d, J¼7.1 Hz, 3H), 0.97 (d, J¼7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) d 173.5 (e), 172.9 (e), 148.9 (e), 145.3 (e), 119.7 (o), 109.8 (e), 60.0 (e), 58.7 (e), 52.8 (o), 52.8 (o), 45.8 (o), 44.8 (o), 39.5 (e), 38.7 (e), 36.9 (e), 36.7 (o), 24.1 (o), 21.9 (o), 21.6 (o), 18.4 (o); IR (neat) 2971 (w), 2885 (w), 1734 (s), 1639 (w), 1435 (w), 1259 (m), 1165 (m), 1102 (s), 1078 (vs), 957 (m), 776 (m) cm1; HRMS (ESI, [MþNa]þ) calculated for C24H40O7SiNa 491.2441, found 491.2458.

4.3.6. (3aS*,8R*,8aS*)-6-Isopropyl-4-methylene-2-tosyl-8-(triethoxysilyl)-1,2,3,3a,4,5,8,8a-octahydrocyclohepta-[c]pyrrole, 3f. 1H NMR (500 MHz, CDCl3) d 7.72 (d, J¼8.2 Hz, 2H), 7.31 (d, J¼8.1 Hz, 2H), 5.34 (dd, J¼7.0, 2.0 Hz, 1H), 4.82 (s, 1H), 4.40 (s, 1H), 3.77 (q, J¼7.0 Hz, 6H), 3.58 (dd, J¼10.3, 7.2 Hz, 1H), 3.37 (d, J¼4.6 Hz, 2H), 2.90 (d, A of AB, JAB¼18.7 Hz, 1H), 2.85 (app. t, J¼10.5 Hz, 1H), 2.84e2.81 (m, 1H), 2.76 (d, B of AB, JAB¼18.6 Hz, 1H), 2.42 (s, 3H), 2.37 (app. tt, J¼11.0, 7.5 Hz, 1H), 2.16 (sept., J¼6.8 Hz, 1H), 1.66 (dd, J¼11.3, 7.1 Hz, 1H), 1.92 (t, J¼7.0 Hz, 9H), 0.94 (d, J¼6.9 Hz, 3H), 0.92 (d, J¼6.9 Hz, 3H); 13 C NMR (125 MHz, CDCl3) d 146.5 (e), 146.1 (e), 143.3 (e), 134.2 (e), 129.7 (o), 127.7 (o), 118.9 (o), 109.6 (e), 58.8 (e), 51.5 (e), 51.3 (e), 45.3 (o), 43.7 (o), 38.5 (e), 36.7 (o), 22.6 (o), 21.8 (o), 21.7 (o), 21.5 (o), 18.4 (o); IR (neat) 2972 (m), 2888 (w), 1640 (w), 1489 (w), 1347 (m), 1162 (s), 1102 (s), 1080 (vs), 959 (m), 812 (w), 776 (m) cm1; HRMS (ESI, [MþNa]þ) calculated for C26H41NO5SiSNa 530.2372, found 530.2375.

4.3.3. (3aS*,8S*,8aR*)-Dimethyl 4-methylene-8-(triethoxysilyl)-6(trimethylsilyl)-3,3a,4,5,8,8a-hexahydroazulene-2,2(1H)-dicarboxylate, 3c. 1H NMR (500 MHz, CDCl3) d 5.94 (app. dt, J¼6.9, 1.6 Hz, 1H), 4.85 (s, 1H), 4.72 (s, 1H), 3.81 (q, J¼7.0 Hz, 6H), 3.72 (s, 6H), 3.00 (d, J¼17.7 Hz, 1H), 2.97e2.93 (m, 1H), 2.93 (dt, J¼8.4, 5.0 Hz, 1H), 2.58 (dd, A of ABX, JAB¼14.6 Hz, JAX¼8.5 Hz, 1H), 2.51e2.44 (m, 1H), 2.37e2.31 (m, 2H), 2.05 (app. t, J¼12.8 Hz, 1H), 2.05e2.01 (m, 1H), 1.21 (t, J¼7.0 Hz, 9H), 0.04 (s, 9H); 13C NMR (125 MHz, CDCl3) d 173.5 (e), 172.9 (e), 149.3 (e), 140.6 (e), 135.8 (o), 110.0 (e), 59.7 (e), 58.8 (e), 52.8 (o), 52.8 (o), 46.5 (o), 43.4 (o), 39.4 (e), 39.2 (e), 37.6 (e), 27.8 (o), 18.4 (o), 1.8 (o); IR (neat) 2973 (w), 2888 (w), 1734 (s),

4.3.7. (3aS*,8S*,8aS*)-4-Methylene-2-tosyl-8-(triethoxysilyl)-6-(trimethylsilyl)-1,2,3,3a,4,5,8,8a-octahydrocyclo-hepta[c]pyrrole, 3g. 1H NMR (500 MHz, CDCl3) d 7.72 (d, J¼8.2 Hz, 2H), 7.31 (d, J¼8.0 Hz, 2H), 5.83 (dd, J¼6.8, 1.7 Hz, 1H), 4.74 (s, 1H), 4.45 (s, 1H), 3.77 (q, J¼7.0 Hz, 6H), 3.52 (dd, J¼10.1, 7.3 Hz, 1H), 3.42 (dd, A of ABX, JAB¼10.4 Hz, JAX¼7.4 Hz, 1H), 3.33 (dd, B of ABX, JAB¼10.4 Hz, JBX¼2.2 Hz, 1H), 2.93 (app. t, J¼10.3 Hz, 1H), 2.89e2.86 (m, 1H), 2.88 (d, A of AB, JAB¼17.3 Hz, 1H), 2.75 (d, B of AB, JAB¼17.9 Hz, 1H), 2.43 (s, 3H), 2.41 (app. tt, J¼10.0, 7.4 Hz, 1H), 1.86 (dd, J¼9.3, 6.5 Hz, 1H), 1.19 (t, J¼7.0 Hz, 9H), 0.00 (s, 9H); 13C NMR (125 MHz, CDCl3) d 147.0 (e), 143.3 (e), 141.2 (e), 134.8 (o), 134.1 (e), 129.8 (o), 127.7 (o), 110.1

4.3. General procedure for the rhodium-catalyzed [(3D2)D2] carbocyclization reaction

7830

P.A. Evans et al. / Tetrahedron 69 (2013) 7826e7830

(e), 58.9 (e), 52.1 (e), 51.6 (e), 46.0 (o), 42.3 (o), 38.2 (e), 26.2 (o), 21.7 (o), 18.4 (o), 1.9 (o); IR (neat) 2974 (w), 2888 (w), 1642 (w), 1599 (w), 1348 (m), 1247 (w), 1163 (s), 1102 (s), 1080 (vs), 960 (w), 835 (m) cm1; HRMS (ESI, [MþNa]þ) calculated for C26H43NO5Si2SNa 560.2298, found 560.2286. 4.3.8. (3aS*,8R*,8aS*)-4-Methylene-6-phenyl-2-tosyl-8-(triethoxysilyl)-1,2,3,3a,4,5,8,8a-octahydrocyclohepta-[c]pyrrole, 3h. 1H NMR (500 MHz, CDCl3) d 7.75 (d, J¼8.1 Hz, 2H), 7.33 (d, J¼8.1 Hz, 2H), 7.30e7.20 (m, 5H), 5.86 (dd, J¼7.3, 2.1 Hz, 1H), 4.91 (s, 1H), 4.47 (s, 1H), 3.81 (q, J¼7.0 Hz, 6H), 3.64 (dd, J¼10.3, 7.3 Hz, 1H), 3.45 (dd, A of ABX, JAB¼10.5 Hz, JBX¼7.2 Hz, 1H), 3.40 (dd, B of ABX, JAB¼10.5 Hz, JBX¼2.0 Hz, 1H), 3.32 (d, A of AB, JAB¼18.7 Hz, 1H), 3.25 (d, B of AB, JAB¼18.5 Hz, 1H), 3.02 (dt, J¼7.4, 1.5 Hz, 1H), 2.94 (app. t, J¼10.5 Hz, 1H), 2.51 (app. tt, J¼10.7, 7.5 Hz, 1H), 2.44 (s, 3H), 1.90 (dd, J¼10.9, 7.4 Hz, 1H), 1.21 (t, J¼7.0 Hz, 9H); 13C NMR (125 MHz, CDCl3) d 145.9 (e), 143.7 (e), 143.4 (e), 140.0 (e), 133.9 (e), 129.8 (o), 128.3 (o), 127.7 (o), 127.0 (o), 125.9 (o), 125.5 (o), 110.6 (e), 59.0 (e), 51.7 (e), 51.4 (e), 45.5 (o), 43.4 (o), 41.1 (e), 23.7 (o), 21.7 (o), 18.5 (o); IR (neat) 2974 (w), 2887 (w), 1645 (w), 1597 (w), 1490 (m), 1346 (m), 1161 (s), 1077 (vs), 958 (s), 813 (m), 755 (m) cm1; HRMS (ESI, [MþNa]þ) calculated for C29H39NO5SiSNa 564.2216, found 564.2209.

crude product. Purification by flash chromatography (silica gel, eluting with 40e60% diethyl ether/petroleum ether) afforded 9 (15.1 mg, 62%) as a colorless oil: 1H NMR (500 MHz, CDCl3) d 7.38e7.36 (m, 2H), 7.33e7.30 (m, 2H), 7.27e7.24 (m, 1H), 5.95 (dt, J¼3.0, 1.4 Hz, 1H), 4.98 (s, 1H), 4.87 (s, 1H), 4.29e4.27 (m, 1H), 3.77 (s, 3H), 3.76 (s, 3H), 3.34 (d, A of AB, JAB¼16.7 Hz, 1H), 3.23 (d, B of AB, JAB¼16.3 Hz, 1H), 3.02e2.97 (m, 1H), 2.68 (dd, A of ABX, JAB¼13.9 Hz, JAX¼7.8 Hz, 1H), 2.56e2.50 (m, 1H), 2.48 (dd, A of ABX, JAB¼13.7 Hz, JAX¼5.8 Hz, 1H), 2.37 (d, J¼5.7 Hz, 1H), 2.33 (dd, B of ABX, JAB¼13.9 Hz, JBX¼7.0 Hz, 1H), 2.28 (dd, B of ABX, JAB¼13.8 Hz, JBX¼10.8 Hz, 1H); 13C NMR (125 MHz, CDCl3) d 173.6 (e), 172.7 (e), 145.8 (e), 142.7 (e), 138.0 (e), 133.2 (o), 128.5 (o), 127.3 (o), 126.0 (o), 112.4 (e), 69.6 (o), 58.9 (e), 53.2 (o), 53.1 (o), 49.2 (o), 46.5 (o), 40.9 (e), 37.5 (e), 37.1 (e); IR (neat) 3708 (w), 3681 (w), 3444 (w), 2952 (m), 2866 (w), 1727 (s), 1644 (w), 1435 (m), 1256 (vs), 1202 (m), 1052 (s), 1033 (s), 897 (m), 732 (m), 698 (m) cm1; HRMS (ESI, [MþNa]þ) calculated for C21H24O5Na 379.1521, found 379.1520. Acknowledgements We sincerely thank the EPSRC (EP/G010250) for financial support. We also acknowledge NSERC for a Canada Research Chair (PAE) and the Royal Society for a Wolfson Research Merit Award (PAE).

4.4. Derivatization of cycloadducts 3h and 3d Supplementary data 4.4.1. (3aS*,8aS*)-4-Methylene-6-phenyl-2-tosyl-1,2,3,3a,4,5,8,8aoctahydrocyclohepta[c]pyrrole, 8. TBAF (0.37 mL, 0.370 mmol, 1 M in THF) was added to a stirred solution of 3h (40.0 mg, 0.074 mmol) in anhydrous THF (1.4 mL) at room temperature. The reaction mixture was stirred for ca. 45 min and then partitioned between water and diethyl ether. The combined organic phases were washed with saturated NaCl solution, dried (Na2SO4) and concentrated in vacuo to afford the crude product. Purification by flash column chromatography (silica gel, eluting with 30% diethyl ether/ hexanes) afforded 8 (24.0 mg, 86%) as a colorless oil: 1H NMR (500 MHz, CDCl3) d 7.75 (d, J¼8.2 Hz, 2H), 7.34 (d, J¼8.2 Hz, 2H), 7.31e7.22 (m, 5H), 5.84 (dd, J¼7.0, 6.1 Hz, 1H), 4.92 (s, 1H), 4.67 (s, 1H), 3.56 (dd, A of ABX, JAB¼10.0 Hz, JAX¼8.0 Hz, 1H), 3.49 (dd, A of ABX, JAB¼9.9 Hz, JAX¼7.0 Hz, 1H), 3.31 (dd, B of ABX, JAB¼10.0 Hz, JBX¼8.0 Hz, 1H), 3.25 (d, A of AB, JAB¼17.8 Hz, 1H), 3.21 (d, B of AB, JAB¼17.6 Hz, 1H), 3.06 (app. q, J¼7.8 Hz, 1H), 3.03 (dd, B of ABX, JAB¼10.0 Hz, JBX¼4.9 Hz, 1H), 2.57 (dddt, J¼11.0, 7.6, 4.5, 3.1 Hz, 1H), 2.45 (s, 3H), 2.17 (ddd, A of ABMX, JAB¼15.9 Hz, JAM¼10.9 Hz, JAX¼5.1 Hz, 1H), 2.03 (ddd, B of ABMX, JAB¼15.4 Hz, JBM¼7.8 Hz, JBX¼3.1 Hz, 1H); 13C NMR (125 MHz, CDCl3) d 144.4 (e), 143.6 (e), 143.2 (e), 140.4 (e), 133.4 (e), 129.8 (o), 128.4 (o), 127.8 (o), 127.1 (o), 125.8 (o), 125.6 (o), 113.2 (e), 53.7 (e), 50.5 (e), 47.6 (o), 41.0 (o), 39.6 (e), 28.4 (e), 21.7 (o); IR (neat) 3028 (w), 2937 (w), 1645 (w), 1481 (w), 1341 (s), 1161 (s), 1092 (m), 1045 (m), 904 (m), 815 (m), 663 (s) cm1; HRMS (ESI, [MþNa]þ) calculated for C23H25NO2SNa 402.1504, found 402.1493. 4.4.2. (3aS*,8S*,8aR*)-Dimethyl 8-hydroxy-4-methylene-6-phenyl3,3a,4,5,8,8a-hexahydroazulene-2,2(1H)-dicarboxylate, 9. mCPBA (13.0 mg, 0.074 mmol) was added to a stirred solution of 3d (34.0 mg, 0.068 mmol) and KHF2 (106.0 mg, 1.353 mmol) in anhydrous DMF (0.7 mL) at room temperature. The reaction mixture was stirred for ca. 6 h (TLC control) and then partitioned between water and diethyl ether. The combined organic phases were washed with saturated NaHCO3 solution, water, saturated NaCl solution, dried (Na2SO4), and concentrated in vacuo to afford the

Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.tet.2013.05.096. References and notes 1. For selected reviews on [mþ2þ2] carbocyclization reactions, see: (a) Inglesby, P. A.; Evans, P. A. Chem. Soc. Rev. 2010, 39, 2791; (b) Aubert, C.; Malacria, M.; Ollivier, C. In Science of Synthesis; De Vries, J. G., Molander, G. A., Evans, P. A., Eds.; Thieme: Stuttgart, Germany, 2011; Vol. 3, p 145; and pertinent references cited therein. 2. Evans, P. A.; Inglesby, P. A. J. Am. Chem. Soc. 2008, 130, 12838. 3. Evans, P. A.; Inglesby, P. A.; Kilbride, K. Org. Lett. 2013, 15, 1798. 4. For comprehensive reviews on sesquiterpene total syntheses, see: (a) Heathcock, C. H.; Graham, S. L.; Pirrung, M. C.; Plavac, F.; White, C. T. In Total Synthesis of Natural Products; ApSimon, J., Ed.; John Wiley & Sons: Hoboken, USA, 2007; Vol. 5; (b) Total Synthesis of Natural Products In A Sesquidecade of Sesquiterpenes: Total Synthesis of Natural Products 1980e1994, Part B: Bicyclic and Tricyclic Sesquiterpenes; Goldsmith, D., Pirrung, M. C., Morehead, A. T., Young, B. G., Eds.; John Wiley & Sons: Hoboken, USA, 2007. 5. Evans, P. A.; Inglesby, P. A. J. Am. Chem. Soc. 2012, 134, 3635. 6. For a review on the oxidation of carbonesilicon bonds, see: Jones, G. R. Tetrahedron 1996, 52, 7599. 7. For a review on alkyne hydrosilylation, see: Marciniec, B.; Maciejewski, H.; Pietraszuk, C.; Pawlu c, P. In Hydrosilylation A Comprehensive Review on Recent Advances; Marciniec, B., Ed.; Springer Science: 2009. € n, J.; de Meijere, A. 8. For the preparation of alkynyl ACPs, see: (a) Stolle, A.; Salau € n, J.; de Meijere, Tetrahedron Lett. 1990, 31, 4593; (b) Stolle, A.; Becker, H.; Salau A. Tetrahedron Lett. 1994, 35, 3517. 9. Mazumder, S.; Shang, D.; Negru, D. E.; Baik, M.-H.; Evans, P. A. J. Am. Chem. Soc. 2012, 134, 20569. 10. For the isolation and characterization of the desilylated rhodacycle, see: Inglesby, P. A; Bacsa, J.; Evans, P. A., submitted for publication. 11. The regioselectivity of this process is consistent with an electronic influence during alkyne insertion. For example, the reversal in regioselectivity between R¼CO2Me and Ph is attributed the direction of polarization. For a recent example of alkyne electronics influencing regioselectivity, see: Friedman, R. K.; Rovis, T. J. Am. Chem. Soc. 2009, 131, 10775. 12. Although 1a reacts with 1-hexyne with similar efficiency and selectivity (rs¼4:1), the cycloadduct was accompanied by an unidentified byproduct, which was not separable by flash chromatography from the cycloadduct. 13. For a review on steric and electronic effects during alkyne insertion into rhodacycles, see: Liu, P.; Houk, K. N. Inorg. Chim. Acta 2011, 369, 2. 14. The structure of 3g was confirmed via X-ray analysis (CCDC 937137). All other cycloadducts were assigned by analogy using 1H NMR and NOE.