Oxidopyrylium-Alkene [5 + 2] Cycloaddition Conjugate Addition

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Oxidopyrylium-Alkene [5 + 2] Cycloaddition Conjugate Addition Cascade (C) Sequences: Scope, Limitation, and Computational Investigations 3

Riley H Kaufman, Chunyin Marshall Law, Justin A Simanis, Erica L Woodall, Christian R Zwick, Henry B Wedler, Paul Wendelboe, Christopher G Hamaker, John R Goodell, Dean J Tantillo, and T. Andrew Mitchell J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01322 • Publication Date (Web): 12 Jul 2018 Downloaded from http://pubs.acs.org on July 12, 2018

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The Journal of Organic Chemistry

Oxidopyrylium-Alkene [5 + 2] Cycloaddition Conjugate Addition Cascade (C3) Sequences: Scope, Limitation, and Computational Investigations Riley H. Kaufman,† Chunyin M. Law,† Justin A. Simanis,† Erica L. Woodall,† Christian R. Zwick III,† Henry B. Wedler,‡ Paul Wendelboe,‡ Christopher G. Hamaker,† John R. Goodell,† Dean J. Tantillo,*‡ and T. Andrew Mitchell*† †

Department of Chemistry, Illinois State University, Campus Box 4160, Normal, IL 61790-4160;

‡

Department of Chemistry, University of California, Davis, 1 Shields Avenue, Davis, CA 95616 †

[email protected]; ‡[email protected]

RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required according to the journal that you are submitting your paper to)

Abstract. Oxidopyrylium-alkene [5 + 2] cycloaddition conjugate addition cascade (C3) sequences are described. Intramolecular cycloadditions involving terminal alkenes, enals, and enones were investigated. Substrates with tethers of varying lengths delivered five- and sixmembered carbocycles and heterocycles thus demonstrating the scope and limitation of the cycloaddition-conjugate addition cascade. Several experiments and theoretical calculations provide evidence for the proposed mechanistic pathway.

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INTRODUCTION Cycloadditions are exceptional synthetic tools that provide efficient avenues toward the construction of many important ring systems.1 Whereas Diels–Alder [4 + 2] cycloadditions are ubiquitous among organic reactions,2 [5 + 2] cycloadditions are significantly less familiar (Figure 1).3 However, [5 + 2] cycloadditions provide efficient access to seven-membered rings, which represent challenging structural motifs common among many natural products.4 More specifically, oxidopyrylium-based [5 + 2] cycloadditions5 have been utilized toward the synthesis of bridged polycyclic ethers (i.e. D, Figure 2),6 either as end-game synthetic targets or as intermediates en route to highly functionalized seven-membered carbocycles.5 Building upon the seminal work of Hendrickson,7 Sammes,8 and Wender,9 recent examples in the literature illustrate the expanding utility of oxidopyrylium-based [5 + 2] cycloadditions.5a,10 Although several strategies toward the generation of oxidopyrylium intermediates (i.e. C) have been disclosed, conversion of acetoxypyranones7 (i.e. B) derived from oxidative Achmatowicz11 rearrangement12 of furfuryl alcohols (i.e. A) has endured as a practical and versatile route (Figure 2), particularly since the development of intramolecular variants by Sammes.8

Figure 1. Diels–Alder [4 + 2] versus Oxidopyrylium-Alkene [5 + 2] Cycloadditions

Figure 2. Activation of Acetoxypyranones to Oxidopyryliums en route to Bridged Ethers


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In our previous work, we reported preliminary investigations of the formation and cycloaddition of oxidopyrylium intermediates13 toward a novel oxidopyrylium-alkene [5 + 2] cycloaddition conjugate addition cascade (C3) en route to caged polycyclic bis-ethers.14 Herein, we report the full account of these investigations that led to the following proposed reaction pathway (Scheme 1): A: acetoxypyranone I adopts a half-chair conformation II in which the αproton is coplanar with the π-system of the ketone; B: rate-limiting deprotonation affords the enol/enolate III; C: rapid elimination of the acetate delivers the oxidopyrylium IV; D: Oxidopyrylium-alkene [5 + 2] cycloaddition gives bridged tricyclic ether V that contains the crucial pendant nucleophile (i.e. aldehyde or ketone); E: reversible, n–π*-mediated, asynchronous concerted nucleophilic addition-conjugate addition provides caged tetracyclic ethers in which as many as 4 new bonds, 3 new rings, and 6 contiguous stereocenters are constructed as a single diastereomer. Toward this end, we conducted the following studies: (1) construction of acetoxypyranone-alkene starting materials via oxidative Achmatowicz rearrangement of furfuryl alcohols; (2) Grubbs–Hoveyda cross-metathesis toward functionalized acetoxypyranone-alkenes; (3) optimization of the amine base in the oxidopyrylium-alkene [5 + 2] cycloaddition; (4) scope and limitation of the oxidopyrylium-alkene [5 + 2] cycloaddition reaction (i.e. no subsequent conjugate addition); (5) scope and limitation of the oxidopyryliumalkene [5 + 2] cycloaddition conjugate addition cascade (C3); (6) exploration of the reaction pathway via synthetic experiments and theoretical calculations.


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SCHEME 1. Proposed Reaction Pathway of Oxidopyrylium-alkene [5 + 2] Cycloaddition Conjugate Addition Cascade (C3) Sequence 3 2 1

AcO R(O)C

[5+2] Cycloaddition Conjugate Addition

O

I

R = H, Me, Et

R3N: H

R'

2 3

O

4

O

5

1 2

O

E 3

2

4

2 1

AcO R(O)C

O

5

1 2

R

H

NR3

4

R1 O

5

C 2

H D

2

AcO H NR3

O 1

V

Oxidopyrylium-Alkene [5+2] Cycloaddtion Conjugate Addition Cascade

H

O

O

3 3

4

1

O

H

II

B (RDS)

O

R H H R' = H or alkyl; R = H, Me, Et VI

5 1

1

R'O

A: -proton coplanar with ketone -system B: rate-limiting deprotonation to enolate C: elimination of acetate to oxdiopyrylium D: diastereoselective [5+2] cycloaddition E: diastereoselective conjugate addition

A

4

O

R'OH, CH3CN (0.1 M), R3N, 60 °C 2

3

2

O

5

1

AcO

H

O

4

5

O H

1

O

H

2

IV

III

RESULTS AND DISCUSSION Construction of acetoxypyranone starting materials via oxidative Achmatowicz rearrangement of furfuryl alcohols. In order to synthesize acetoxypyranones with a variety of tethered olefins toward intramolecular oxidopyrylium-alkene [5 + 2] cycloadditions, we utilized the oxidative Achmatowicz rearrangement of furfuryl alcohols derived from the corresponding starting materials 1a-g (Scheme 2).15 Sammes demonstrated that acetoxypyranone 2a could be synthesized in three steps from furfural 1a (eq. 1); the resulting mixture of diastereomers could then be subjected to [5 + 2] cycloaddition.8 Our initial investigations were sparked by the relative


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ease of separation of diastereomers (i.e. anti vs. syn), straightforward differentiation utilizing 1H NMR analysis (i.e. diagnostic protons α to ketone), and differing reactivity of each (vide infra).13 A similar sequence was followed with 2,5-disubstituted furan 1b16 to give acetoxypyranone 2b (eq. 2). Construction of substrates with heteroatom-containing tethers (i.e. oxygen 2c and nitrogen 2d) required alternative procedures. Treatment of aldehyde 1c17 with furyllithium followed by NBS-mediated Achmatowicz11 and acylation led to acetoxypyranone 2c (eq. 3). The nitrogen-tethered acetoxypyranone 2d required a much more involved synthetic sequence (eq. 4).18 Starting from commercially available 2-acetylfuran (i.e. 2-furyl methyl ketone, not shown), α-bromination and reduction with NaBH4 afforded bromohydrin 1d. Since the monobromide was inseparable from the 2-acetylfuran in the first step, ensuring complete conversion of starting material by TLC analysis allowed for straightforward separation from minor quantity of dibromide (not shown). Reduction of α-bromoacetylfuran with NaBH4 gave the corresponding alcohol 1d, which was determined to be highly unstable upon extraction and isolation. Even at slightly elevated temperatures reached during concentration, we observed that bromohydrin 1d was extremely sensitive. Consequently, the newly formed alcohol 1d was carried forward to the next step with minimal work-up and purification. Once protected with TBSCl and imidazole, the corresponding silyl ether (not shown) was stable to column chromatography. With these modified conditions, the reaction went from very low yield to nearly quantitative. Subsequent treatment with allylamine and K2CO3, protection of the resulting amine as the carbamate, and deprotection of the silyl ether with TBAF provided a suitable Achmatowicz precursor (not shown). Utilizing typical Achmatowicz work-up conditions of aqueous sodium thiosulfate (i.e. Na2S2O3) for the oxidative rearrangement resulted in poor yield thus we found that direct concentration and subjection to column chromatography gave a higher yield. Achmatowicz rearrangement of the furfuryl alcohol followed by acylation completed the synthesis of


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acetoxypyranone 2d in good yield over six steps (eq. 4). In contrast to the examples described thus far, acetoxypyranone-alkenes suitable for the synthesis of six-membered rings were explored. Acetoxypyranone 2e, the one-carbon homologue of acetoxypyranone 2a, was synthesized in similar fashion beginning from the homologous Grignard reagent derived from 6bromo-1-hexene (eq. 5). Introduction of an aromatic ring into the tether was achieved by treatment of known aldehyde 1f19 with furyllithium followed by Achmatowicz rearrangement and acylation to afford acetoxypyranone 2f (eq. 6). An identical sequence utilizing O-allyl salicylaldehyde 1g19 gave acetoxypyranone 2g (eq. 7). Acetoxypyranones 2a, b, e, and g could be separated or diastereomerically enriched for subsequent reactions (vide infra).


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SCHEME 2. Construction of Acetoxypyranone-Alkenes 2a-2g O O

H 1a

O

MgBr

1)

2) VO(acac)2, tBuOOH 3) acetyl chloride, py 37%

AcO

(1)

O

2a (dr 3.5:1) O

O

TBSO O

MgBr

1) H

1b

2) VO(acac)2, tBuOOH 3) Ac2O, py, DMAP 36% O 1)

O

AcO TBSO

O

2b (dr 7.7:1) O

Li THF, 78 °C AcO

O

H 1c

OH O

Br

2) NBS, THF, H2O 3) acetyl chloride, py 36%

(3)

O O

2c (dr 1.8:1)

1) TBSCl, imidazole 2) allylNH 2, K2CO3 75 °C 3) CH3OC(O)Cl, Et3N 4) 1.0 M TBAF, THF 5) VO(acac)2, tBuOOH 6) acetyl chloride, py 40%

1d

(2)

O AcO

(4)

O

OCH3

N 2d (dr 2.5:1)

O O

O O

H 1a

MgBr

1)

AcO 2) VO(acac)2, tBuOOH 3) acetyl chloride, py 25% O

O

1) H

1f

O 1g

O

Li THF, 78 °C AcO

1) H

2e (dr 2.3:1)

2) VO(acac)2, tBuOOH 3) acetyl chloride, py 29% O

O

(6)

O

2f (dr 3.5:1)

Li THF, 78 °C

O AcO

2) VO(acac)2, tBuOOH 3) acetyl chloride, py 41%

(5)

O

2g (dr 3.3:1)


(7)

O O

7


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Grubbs–Hoveyda cross-metathesis toward functionalized acetoxypyranone-alkenes. In order to study the oxidopyrylium-alkene [5 + 2] cycloaddition conjugate addition cascade (C3) sequence, terminal alkenes were subjected to cross-metathesis utilizing Grubbs–Hoveyda 2nd Generation catalyst20 with either crotonaldehyde or methyl vinyl ketone (Table 1). Prior results (entry 1) with diastereomerically pure anti-acetoxypyranone-alkene 2a (dr >19:1) provided good yield of both anti-acetoxypyranone-enal 3a (dr >19:1) and anti-acetoxypyranone-enone 4a (dr >19:1).13 More substituted acetoxypyranone 2b (dr 7.7:1) was subjected to metathesis to provide the corresponding anti-enal 3b (dr >19:1) and anti-enone 4b (dr >19:1) with enrichment of diastereomeric ratios observed during column chromatography (entry 2). Heteroatom-containing acetoxypyranones 2c (dr 1.8:1) and 2d (dr 2.5:1) also provided good yields of the desired C3 precursors as mixtures of diastereomers (entries 3-4). As opposed to the presumed antiacetoxypyranone enone 4e, only the anti-acetoxypyranone enal 3e (dr >19:1) was constructed (entry 5) due to the unsuccessful cycloadditions that resulted from this tether (vide infra). Crossmetathesis of both aromatic ring-containing acetoxypyranones 2f/2g afforded the desired enals 3f/3g and enones 4f/4g. The carbocyclic precursor 2f was used as a mixture of diastereomers (dr 3.5:1) to provide the corresponding α,β-unsaturated metathesis products 3f/4f (entry 6), whereas the allyl ether anti-2g (dr >19:1) was separable thus giving rise to anti-acetoxypyranone-enal 3g (dr >19:1) and anti-acetoxypyranone-enone 4g (dr >19:1) in moderate yields (entry 7).


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TABLE 1. Grubbs–Hoveyda Cross-Metathesis to Acetoxypyranone–Enals/Enones

acetoxypyranone-enal (3a-g)

% yield 3a (dr)b

% yield 4a (dr)b

entry

alkene (2)

1

anti-2a (>19:1)

81 (>19:1)

83 (>19:1)

2

anti-2b (7.7:1)

65 (>19:1)

49 (>19:1)

3

2c (dr 1.8:1)

47 (1.4:1)

64 (2.2:1)

4

2d (dr 2.5:1)

45 (2.5:1)

70 (2.5:1)

56 (>19:1)

NA

77 (3.8:1)

82 (3.7:1)

30 (>19:1)

51 (>19:1)

acetoxypyranone-enone (4a-g)

O 5

anti-2e (>19:1)

AcO OHC

O

anti-3e

6

2f (dr 3.5:1)

O 7

anti-2g (>19:1)

AcO OHC anti-3g

a

O O

b

Isolated yield. Determined by analysis of 1H NMR upon purification by chromatography.


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Optimization of the amine base in the oxidopyrylium-alkene [5 + 2] cycloaddition. Screening of amine bases at 60 °C in acetonitrile (0.1 M) for 6 h provided a range of conversions to cycloadduct 5a with N-methylpyrrolidine (NMP), 1,4-diazabicyclo[2.2.2]octane (DABCO), and quinuclidine affording complete consumption of both anti- and syn-acetoxypyranone 2a (Table 2). Overall, a clear trend of steric and electronic dependence of the base was observed in these conversion studies (entries 2-8), which was the initial clue that led to the broader demonstration of a qualitative rate difference between anti- and syn-acetoxypyranone (i.e. syn > anti) toward conversion to tricyclic ether 5a.13

TABLE 2. Amine Base Optimization of [5 + 2] Cycloaddition

entry base anti-2a/5aa 1 pyridine 88/0 2 N-methylmorpholine 89/5 3 N,N-diisopropylethyl amine 86/5 4 triethylamine 62/36 5 N-methylpiperidine 59/41 6 N-methylpyrrolidine 0/88 7 quinuclidine 0/90 8 1,4-diazabicyclo[2.2.2]octane 0/81 a Determined by 1H NMR analysis utilizing 1,3,5-trimethoxybenzene as the internal standard.


syn-2a/5aa 90/2 68/14 68/14 6/80 7/89 0/91 0/95 0/88

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Scope and limitation of the oxidopyrylium-alkene [5 + 2] cycloaddition reaction (i.e. no subsequent conjugate addition). Prior to investigating the scope and limitation of the cascade sequence (vide infra), we subjected the acetoxypyranones to oxidopyrylium-alkene [5 + 2] cycloadditions (Table 3). Previous results with anti-acetoxypyranone 2a (entry 1) and synacetoxypyranone 2a (not shown) provided the cycloadduct 5a in good yield.13 The TBSOCH2appended variant 2b (dr 7.7:1) afforded cycloadduct 5b in 65% yield (entry 2). Excellent yields were observed for both tetrahydrofuran 5c and pyrrolidine 5d derived from acetoxypyranones 2c and 2d, respectively (entries 3-4). The simplest homologous variant (i.e. cyclohexane precursor 2e) could not be accessed (entry 5), presumably due to entropic factors. Increasing the rigidity of the tether (i.e. alkenes 2f and 2g) delivered very good yields of the desired six-membered rings contained within cycloadducts 5f and 5g (entries 6-7). All successful oxidopyrylium-alkene [5 + 2] cycloadditions proceeded with complete diastereoselectivity (>19:1 as determined by analysis of the

1

H NMR spectrum of the purified mixture) as expected. Whereas enal-derived

cycloadduct-aldehydes (cf. Scheme 1: V (R = H)) could not be isolated from the corresponding acetoxypyranone-enals (i.e. 3), enone-derived cycloadduct-ketones (i.e. 6) were readily accessed from the corresponding acetoxypyranone-enones 4 (Table 4). This was observed previously with conversion of enone 4a to ketone 6a in 87% yield (entry 1). More substituted acetoxypyranoneenone 4b gave ketone 6b in 63% yield (entry 2). Oxygen- and nitrogen-tethered enones 4c and 4d delivered the corresponding ketones 6c and 6d, respectively, in good yields (entries 3-4). Although the enone 4e corresponding to presumed cycloadduct 6e (entry 5) was not synthesized, more structurally rigid enones 4f and 4g afforded excellent yield of carbocycle 6f (entry 6) and good yield of benzopyran derivative 6g (entry 7), respectively. Several examples (entries 3, 4, 7) were isolated as diastereomeric mixtures with the minor epimer (α to ketone) tentatively assigned based on coupling constant (J) analysis of diagnostic bridgehead protons in the 1H NMR spectra.


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TABLE 3. Oxidopyrylium-alkene [5 + 2] Cycloadditions of Terminal Alkenes

entry

acetoxypyranone (dr)

1

2a (>19:1)

cycloadduct (5) O O 5a

2

% yielda

drb

-c

>19:1

65

>19:1

84

>19:1

H

2b (7.7:1)

O 3

2c (1.8:1)

O O 5c H

4

2d (2.5:1)

87

>19:1

5

2e (>19:1)

19:1

7

2g (>19:1)

83

>19:1

a

Isolated yield. b Determined by analysis of 1H NMR upon purification by chromatography. c See Table 2. d Not detected.


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TABLE 4. Oxidopyrylium-alkene [5 + 2] Cycloadditions of Enones

% yielda

drb

4a (>19:1)

87

>19:1

4b (>19:1)

63

>19:1

83

6.9:1d

entry

enone (dr)

1

2

cycloadduct (6)

O 3

4c (2.2:1)

O Me

O O

6c H H

4

4d (2.5:1)

80

8.7:1d

5

4e (NA)

NAc

-e

6

4f (3.7:1)

90

>19:1

7

4g (>19:1)

76

5.0:1d

a

Isolated yield. b Determined by analysis of 1H NMR upon purification by chromatography. c Not attempted. d Minor diastereomer is the presumed epimer (α to ketone) based on J values calculated from 1H NMR analysis. e Not applicable.


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Scope and limitation of the oxidopyrylium-alkene [5 + 2] cycloaddition conjugate addition cascade. Attempted reactions utilizing acetoxypyranone-enals that were analogous to acetoxypyranone-enones did not undergo clean conversion, although evidence suggested the presence of trace quantities of desired cycloadduct-aldehydes. In fact, the detection of lactol 7a (Table 5) without addition of water led to discovery of the C3.13 Although separation of terminal alkene diastereomers (i.e. anti and syn) provided access to pure anti- and syn-acetoxypyranone enals, it was found that the mixture 3a (dr 3.5:1) could just as easily be treated with NMP in CH3CN:H2O (95:5) to deliver the bridged-ether lactol 7a in 63% yield (entry 1). Utilizing the same reaction conditions, the more highly substituted acetoxypyranone-enal 3b gave the corresponding lactol 7b, albeit in poor yield (entry 2). Incorporation of an oxygen into the tether (i.e. 3c) delivered the bis-ether lactol 7c in 70% yield (entry 3). However, incorporating nitrogen into the tether (i.e. 3d) gave mixed results (entry 4). Although, the pyrrolidine-lactol 7d could be synthesized, the desired product was always accompanied by the presumed aldehyde precursor (not shown) of the lactol. Unfortunately, tethers leading to six-membered rings were less effective (entries 5-7) with the best result giving 25% yield of carbocycle-lactol 7f (entry 6). Although the yields were poor to moderate for these reactions, the excellent diastereoselectivity reinforces our proposed reaction pathway (vide infra). Mixed results were obtained with acetoxypyranone-enones as C3 precursors (Table 6). While separation of terminal alkene diastereomers (i.e. anti and syn) once again provided access to anti-acetoxypyranone-enone 4a, subsequent annulations required more forcing conditions relative to enals (cf. Table 5). As such, treatment with NMP in CH3CN:H2O (50:50) and heat delivered the bridged-ether lactol 8a in 75% yield (entry 1) along with trace (6%) ketone 6a.14 Lactols 8b and 8d were inaccessible (entries 2, 4), but bis-ether lactol 8c was isolated in good yield (entry 3). Six-membered rings


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were again less effective (entries 5-7) with 35% yield of carbocycle 8f representing the only moderate result (entry 6).


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TABLE 5. Oxidopyrylium-alkene [5 + 2] Cycloaddition Conjugate Addition Cascade (C3) of Acetoxypyranone-Enals

% yielda

drb

3a (3.5:1)

63

>19:1

3b (>19:1)

32

>19:1

70

>19:1

entry

enal (dr)

1

2

lactol (7)

H 3

O

3c (1.4:1) HO

O O O

7c H H

4

3d (2.5:1)

48

>19:1

5

3e (>19:1)

19:1

7

3g (>19:1)

19:1

2

4b (>19:1)

19:1

4

4d (2.5:1)

19:1

7

4g (>19:1)

7

>19:1

entry

enone (dr)

1

lactol (8)

a

Isolated yield. b Determined by analysis of 1H NMR upon purification by chromatography. Not detected. d Not applicable. e Not attempted.


c

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Upon replacement of water as the nucleophile with a variety of functionalized alcohols, a mixture of diastereomers (~2:1) of acetoxypyranone-enal 3a gave moderate yields (20-63%) of the corresponding acetals 9a-f (Table 7).14 Importantly, excellent diastereoselectivity (dr >19:1) of the caged acetal 9 was observed in all cases. Similar to examples with H2O, 5% methanol was added with inclusion of 3Å molecular sieves to exclude water; this effectively provided the desired acetal 9a in 63% yield. Two equivalents of primary alcohols afforded the corresponding acetals 9b-d in good yields and isopropyl alcohol delivered the more sterically hindered acetal 9e in 53% yield. Although the yield of acetal 9f was low, an aryl group was introduced.

TABLE 7. Oxidopyrylium-alkene [5 + 2] Cycloaddition Conjugate Addition Cascade (C3) of Acetoxypyranone-Enal 3a with Alcohols H

O DABCO, M.S., 60 °C AcO OHC

O

ROH, CH3CN,1-6 h

O

H H H 9a-f (dr >19:1)b

3a (dr ~2:1) O

O

H

O

O

O

H3CO

O

O H

H

H H 9a (63%)

H

O

O H

O

O H3CO

H H 9c (57%)

H

H

H H 9d (62%)

H O

O

O

O

O

O

O

H H 9b (53%)

H

O

O

O O

O H

a

O

RO

20-63%a

H

O

H H 9e (53%)

H

H H 9f (20%)

Isolated yield. b Determined by analysis of 1H NMR upon purification by chromatography.


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Investigation of the reaction pathway via synthetic experiments and computational investigations utilizing M06-2X/6‐‐31+G(d,p). In order to investigate the reaction pathway, several experiments were designed that fall into three major sections: 1) Kinetic Isotope Effect (KIE) studies elucidating the rate-determining step (RDS) toward the formation of the oxidopyrylium intermediate; 2) probing of the conjugate addition shedding light on the high diastereoselectivity; and 3) theoretical calculations confirming many aspects of the proposed reaction pathway. 2H-labeled acetoxypyranones 2h and 2i (Schemes 3-4) were synthesized15 from deuterated furfural derivatives21 and separated (i.e. anti & syn) similar to the procedure for acetoxypyranone 2a.15 Pairwise experiments (i.e. anti-2a with anti-2h & syn-2a with syn-2h) revealed primary KIEs for both diastereomers (Scheme 3) indicating that deprotonation by the amine base is involved in the RDS en route to the oxidopyrylium intermediate (vide infra). Furthermore, large secondary KIEs were not observed upon deuterium labeling at the acetal carbon15 providing evidence that leaving of the acetoxy group is not involved in the RDS (Scheme 4). SCHEME 3. Primary Kinetic Isotope Effect (KIE) Studies

SCHEME 4. Secondary Kinetic Isotope Effect (KIE) Studies


19


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KIEs obtained via deuterium labeling and preliminary ground-state conformational analysis14 provided a glimpse into the initial steps of the reaction pathway (Scheme 5).13 Assuming conformational equilibrium, both anti- and syn-acetoxypyranones I adopt productive half-chair conformations (step A) in which the α-proton is coplanar with the π-system of the ketone.13,22 We proposed that rate-determining deprotonation (step B) affords the enol/enolate III as a transient (due to the imminent aromaticity of IV) mixture of enantiomers, which undergoes rapid release (step C) of the acetoxy moiety to form the oxidopyrylium intermediate IV. Intermediate IV then engages in the [5 + 2]/conjugate addition cascade (steps D-E).

SCHEME 5. Formation of Oxidopyrylium Reaction Pathway


20

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Generation of the oxidopyrylium intermediate (IV) was examined using M06-2X/631+G(d,p) calculations (see Computational Methods section for details) for the system shown in Figure 3 (2a). An E1CB-type elimination is predicted to occur wherein deprotonation occurs first yielding an oxyanion. This is followed by departure of acetate. Note that the same oxidopyrylium is produced from syn and anti starting materials once deprotonation and acetate departure occur. The computed energy profile for reaction of the syn reactant is shown in Figure 3 (similar energetics were found for the anti system; see Supporting Information for details). Note that TSSs for departure of acetate without complexation by the NMP–H+ led to higher barriers for acetate loss. Assuming that the [5 + 2] cycloaddition does not involve a high barrier (vide infra), our pathway is consistent with rate-limiting deprotonation. To further validate our computation results, we computed KIEs for the proton transfer step (see Computational Methods section for details). The predicted H/D KIE for the lowest energy proton transfer TSS for the syn-2a/h (Figure 3) ranges from 3.29-3.30, depending on how tunneling is treated, in excellent agreement with experiment (see Scheme 3). The predicted H/D KIE for the TSSs located for the potential TSSs located for the anti system (anti-2a/h) ranges from ~3-5, suggesting that either we have not yet found the lowest energy TSS or our methods are predicting that proton transfer occurs later than indicated by experiment (see Supporting Information for additional details).


21


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Figure 3. Computed (SMD(MeCN)-M06-2X/6-31+G(d,p)) pathway for oxidopyrylium generation from the syn reactant. Relative free energies are shown in kcal/mol and are based on complexes with NMP. Note that, in the TSS for acetate loss, the “ammonium proton” is actually much closer to the oxygen of the substrate.

[5 + 2] Cycloadditions of several differently substituted oxidopyrylium ions were examined with SMD(MeCN)-M06-2X/6-31+G(d,p) and these were consistently predicted to occur in a concerted manner with relatively synchronous formation of the two new C–C σ-bonds. A representative TSS is shown in Figure 4. Barriers for cycloaddition were predicted to be 19:1) with 4-methoxybenzyl alcohol provided acetal 9d as a single diastereomer (dr >19:1); crude 1H NMR analysis revealed a mixture of diastereomerically pure acetals 9b:9d (4.4:1.0). Treatment of acetal 9d (dr >19:1) with 5-hexen-1-ol also delivered acetal 9b as a single diastereomer (dr >19:1); crude 1H NMR analysis revealed a mixture of diastereomerically pure acetals 9d:9b (3.2:1.0). Four carbonyl-based examples of stepwise conjugate additions were also investigated (Scheme 7).14 First, ketones 6a and 6h were treated with aq. LiOH in THF to afford


23


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acetals 8a and 8h with excellent diastereoselectivity (eq. 1-2). Although microwave irradiation23 (120 °C) of carboxylic acid 10 in acetonitrile gave the desired ester 12 in 53% yield (eq. 3), similar attempts of µW-assisted conversion of amide 11 were unsuccessful with no reaction observed even at 200 °C in trifluorotoluene (eq. 4).15

SCHEME 6. Reversibility Studies with Acetals 9b and 9d

SCHEME 7. Various Carbonyl Nucleophiles toward Stepwise Conjugate Addition

a

aq. LiOH, THF, 23 C. b 120 °C (µW), CH3CN, 20 min. c 200 °C (µW), PhCF3, 20 min.


24

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In an effort to better understand mechanistic aspects of the conjugate addition portion of the cascade, methyl-enone 4a and ethyl-enone 4h were subjected to standard cascade conditions (Scheme 8). As expected, the cascade conditions afforded very similar synthetic results as the stepwise process (cf. Scheme 7, eq. 1-2). Upon cycloaddition to deliver ketones 6a/6h (not shown), one possible mechanism could involve nucleophilic attack of water to provide hydrates 14a/14h. However, preliminary ground state energetic calculations of potential hydrate intermediates14 provided substantial insight in contrast to this proposed reaction pathway. Interestingly, the relative energies of the methyl- and ethyl-substituted hydrates corresponding to the required conformation leading to products 8a/8h reveal differing ground state energetics. Whereas the productive methyl-substituted conf-14a is lower in energy than conf-14a’, the productive ethyl-substituted conf-14h is higher in energy than conf-14h’. Although not decisive, these results suggest that a different stereochemical outcome for the ethyl-substituted enone 4h would be favored in contrast to the methyl-substituted enone 4a provided rotation of the transient hydrate intermediate was permitted. With initial hydrate formation unlikely, an alternative mechanism may involve the formation of an oxocarbenium such as intermediates 16/17 followed by a subsequent nucleophilic attack of water (Scheme 9). In this particular pairwise comparison, both enal anti-2a and enone anti-4a afford the corresponding lactols 7a/8a in good yield with high diastereoselectivity. Although the reaction conditions are similar, the reaction with enone 4a requires a significantly higher proportion of water and a significantly higher reaction temperature.14 If the carbonyl were to form a covalent C–O bond with the alkene (C-2), the more Lewis basic ketone24 should be more likely to achieve this and therefore proceed at lower temperature. Taken together, these results indicate that oxocarbenium-enolates 16/17 are also unlikely intermediates toward lactols 7a/8a.


25


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SCHEME 8. Methyl & Ethyl Ketones with Corresponding Hydrate Conformations H

O NMP, 60 °C AcO R(O)C

O

O CH3CN:H2O, 2h

anti-4a (R = Me) anti-4h (R = Et) via ketone 6a/6h

O O

HO R H H 8a (75%, dr >19:1) 8h (64%, dr >19:1)

conjugate add.

O HO R

O relative energy of hydrate conformers: methyl vs. ethyl

O

OH H

HO HO

O

R

H conf-14a' (R = Me): E = 0.67 kcal/mol

conf-14a (R = Me): E = 0.00 kcal/mol

conf-14h' (R = Et): E = 0.00 kcal/mol

conf-14h (R = Et): E = 0.83 kcal/mol

H

H

SCHEME 9. Comparison of Reaction Conditions for Enal 2a and Enone 4a O AcO R(O)C

H NMP, CH3CN:H2O

O

O

O

HO 23 °C; 5% H2O 60 °C; 50% H2O

anti-2a (R = H) anti-4a (R = Me)

O 1

1

H 2 3

O

2 R

5

R H H 7a (69%, dr >19:1) 8a (75%, dr >19:1)

nucleophilic attack from convex face H2 O

[5+2]

H

O

H oxocarbenium

O

H 15 (R = H) 6a (R = Me)

formation?


1

1

H 2 3

O

2 R

4

O

5

4

O

H 16 (R = H) 17 (R = Me)

26

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Based on the contradictory evidence reported, neither a hydrate Va nor oxocarbenium Vb intermediate-based mechanistic scenario seems plausible (Scheme 10). Another scenario in which neither hydrate Va nor oxocarbenium Vb are formed can be rationalized by simultaneous generation of both O−C bonds in a highly-ordered, asynchronous concerted pathway (i.e. V). Preliminary conformational analysis and energy minimization of ketone 6a revealed a structure 0.3 kcal/mol higher in energy than the lowest energy conformation.14 This conformation projects a lone pair of electrons toward the β-carbon of the α,β−unsaturated ketone suggesting n–π* stabilization.25 Thus, two O−C bond forming events can result from this n–π* interaction in an asynchronous concerted pathway. As discussed previously, the unified stereochemical outcome of all lactols 7-9 in general and, more specifically, analysis of methyl lactol 8a and ethyl lactol 8h (cf. Scheme 8) support the asynchronous concerted scenario. Although it is possible that unique mechanisms may be operative for each carbonyl moiety, a reversible, but highly selective, n–π*mediated asynchronous concerted nucleophilic attack-conjugate addition sequence represents the most straightforward interpretation of the data. SCHEME 10. Asynchronous Concerted Nucleophilic Attack-Conjugate Addition


27


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The hypothesis that the n–π* interaction preorganized the carbonyl for conjugate addition was also scrutinized using SMD(MeCN)-M06-2X/6-31+G(d,p) calculations. A scan around the Ccarbonyl–Cmethine bond was carried out for aldehyde 15 and the lowest energy structure is shown in Figure 5. The carbonyl oxygen of the aldehyde group in this structure is not near the enone C=C π-bond. Although the system is not preorganized for n–π* interaction, the n–π* interaction clearly manifests itself along the reaction coordinate for conjugate addition, as this interaction leads to C–O bond formation. In addition, we were able to find a conjugate addition TSS from the hydroxide adduct of the aldehyde shown in Figure 5 and this reaction is predicted to have a free energy barrier of only ~4 kcal/mol. It is also predicted to be readily reversible (reverse barrier of 19:1), anti-2/syn-2 mixture as a yellow oil (1.0 g, 4.5 mmol, 10%, dr 2.3:1.0), and syn-2a as a yellow oil (1.3 g, 5.8 mmol, 13%, dr >19:1); anti-2a: Rf = 0.28 (hexanes:Et2O 75:25); 1H NMR (500 MHz, CDCl3) δ 6.88 (dd, J = 10.3, 3.7 Hz, 1H), 6.49 (d, J


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= 3.7 Hz, 1H), 6.20 (d, J = 10.3 Hz, 1H), 5.83-5.75 (m, 1H), 5.03-4.98 (m, 1H), 4.97-4.94 (m, 1H), 4.47 (dd, J = 7.6, 3.9 Hz, 1H), 2.13 (s, 3H), 2.09-2.04 (m, 2H), 1.99-1.92 (m, 1H), 1.781.71 (m, 1H), 1.55-1.48 (m, 2H);

13

C NMR (125 MHz, CDCl3) δ 195.6, 169.7, 141.7, 138.4,

128.8, 115.0, 87.3, 75.9, 33.6, 29.3, 24.1, 21.1; syn-2a: Rf = 0.20 (hexanes:Et2O 75:25); 1H NMR (500 MHz, CDCl3) δ 6.84 (dd, J = 10.4, 2.7 Hz, 1H), 6.54 (dd, J = 2.7, 1.2 Hz, 1H), 6.21 (dd, J = 10.4, 1.2 Hz, 1H), 5.82-5.74 (m, 1H), 5.03-4.99 (m, 1H), 4.97-4.95 (m, 1H), 4.21 (dd, J = 7.6, 6.4 Hz, 1H), 2.13 (s, 3H), 2.12-2.04 (m, 2H), 1.88-1.83 (m, 2H), 1.65-1.48 (m, 2H);

13

C NMR

(125 MHz, CDCl3) δ 195.7, 169.5, 142.9, 138.2, 128.6, 115.2, 87.8, 79.7, 33.5, 32.4, 24.7, 21.2. All other spectral data was consistent with previously published data.13 Acetoxypyranone 2b: To a flame-dried, 2-neck, round bottom flask was added Mg turnings (650 mg, 27.8 mmol, 1.50 equiv.), a crystal of iodine, followed by anhydrous Et2O (11 mL) and a condenser. Next, ~10% of 5-bromo-1-pentene (2.3 mL, 19.7 mmol, 1.1 equiv.) was added. Upon initiation, the remaining 5-bromo-1-pentene was added dropwise over 10 min. The resulting solution was stirred for 30 minutes at ambient temperature, diluted with anhydrous Et2O (34 mL), and cooled to 0 °C. Aldehyde16 1b (4.29 g, 17.9 mmol, 1.0 equiv.) was added dropwise and the resulting solution was allowed to stir at 23 °C for 1 h at which point the reaction was quenched with sat. aq. NH4Cl (20 mL). The reaction was stirred for 10 min and was extracted with Et2O (50 mL). The combined organic solution was washed sequentially with sat. aq. NH4Cl (20 mL), H2O (20 mL), and sat. aq. NaCl (20 mL), dried with Na2SO4, filtered, and concentrated. Purification by flash column chromatography (hexanes:EtOAc 90:10) delivered the alcohol (not shown) as a yellow oil (3.41 g, 12.1 mmol, 61%). To a solution of alcohol (3.41 g, 12.1 mmol, 1.0 equiv.) in CH2Cl2 (60 mL) was added VO(acac)2 (320 mg, 1.22 mmol, 0.1 equiv.). The solution was cooled to 0 °C and 5.5 M tBuOOH in decane (3.3 mL, 18.2 mmol, 1.5 equiv.) was added slowly. The reaction was stirred at 0 °C for 1 h, quenched with sat. aq. Na2S2O3 (50 mL),


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and stirred for 30 min. The resulting aqueous solution was extracted with CH2Cl2 (2 × 50 mL), dried with Na2SO4, filtered, and concentrated. Purification by flash column chromatography (hexanes:EtOAc 90:10) delivered the hydroxypyranone (not shown) as a yellow oil (3.04 g, 9.3 mmol, 77%, dr 7.7:1.0). To a solution of hydroxypyranone (3.04 g, 9.3 mmol, 1.0 equiv.) in acetic anhydride (8.7 mL, 93 mmol, 10 equiv.) was added pyridine (2.0 mL, 23.3 mmol, 2.5 equiv.) followed by DMAP (569 mg, 4.7 mmol, 0.5 equiv.) at 0 °C. The resulting solution was allowed to warm to 23 °C and stirred for 17 h. The solution was diluted with CH2Cl2 (100 mL), washed with 0.5 M HCl (2 × 100mL), sat. aq. NaHCO3 (100 mL), sat. aq. NaCl (100 mL), dried with MgSO4, filtered, and concentrated. Purification by flash column chromatography (hexanes:EtOAc 90:10) delivered acetoxypyranone 2b as a colorless oil (2.59 g, 7.0 mmol, 76%, dr 7.7:1.0). Characterization data for acetoxypyranone anti-2b: Rf = 0.41 (hexanes:EtOAc 90:10); 1H NMR (500 MHz, CDCl3) δ 7.22 (d, J = 10.3 Hz, 1H), 6.14 (d, J = 10.3 Hz, 1H), 5.845.76 (m, 1H), 5.03-4.99 (m, 1H), 4.97-4.94 (m, 1H), 4.51 (dd, J = 7.6, 3.9 Hz, 1H), 4.12 (d, J = 10.6 Hz, 1H), 3.79 (d, J = 10.6 Hz, 1H), 2.10-2.04 (m, 2H), 2.05 (s, 3H), 2.00-1.92 (m, 1H), 1.78-1.70 (m, 1H), 1.57-1.50 (m, 2H), 0.88 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H);

13

C NMR (125

MHz, CDCl3) δ 196.2, 169.4, 144.4, 138.4, 127.3, 114.7, 99.3, 76.4, 66.2, 33.5, 29.6, 25.7, 24.0, 21.5, 18.3, -5.37, -5.40; IR (neat) νmax 1244, 1128, 835, 778 cm-1; ESI-HRMS calculated for C19H32O5SiNa [M+Na]+ 391.1917, found 391.1908. Acetoxypyranone 2c: To a stirred solution of furan (5.63 mL, 77.4 mmol, 3.0 equiv.) in anhydrous Et2O (129 mL) cooled at –78 °C was added 1.97 M n-BuLi in hexane (26.2 mL, 51.6 mmol, 2.0 equiv.). The solution was allowed to stir at –78 °C for 1.5 h and then at 0 °C for 30 min. The solution was then cooled back to –78 °C and aldehyde17 1c (2.58 g, 25.8 mmol, 1.0 equiv.) was added dropwise. The reaction was allowed to stir for 1 h at –78 °C and warmed to 23 °C for 30 min. The reaction mixture was quenched slowly with H2O (100 mL) and separated.


33


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The aqueous layer was extracted with Et2O (3 × 120 mL). The combined organic extracts were washed with H2O (3 × 120 mL), brine (260 mL), dried with MgSO4, filtered, and concentrated. Purification by flash column chromatography (hexanes:EtOAc 80:20) delivered alcohol (not shown) as a yellow oil (3.16 g, 18.8 mmol, 73%). Alcohol (288 mg, 1.71 mmol, 1.0 equiv.) was dissolved in 4:1 THF/H2O (4.3mL) and cooled to 0 °C. N-bromosuccinimide (304 mg, 1.71 mmol, 1.0 equiv.) was added portionwise over 30 min at which point the reaction mixture was quenched with sat. aq. NaHCO3 (4 mL) and extracted with Et2O (3 × 4 mL). The organic solution was washed with brine (2 mL), dried with Na2SO4, filtered, and concentrated to provide crude hydroxypyranone (not shown). To a solution of hydroxypyranone (~1.71 mmol, 1.0 equiv.) in CH2Cl2 (4.3 mL) was added pyridine (345 µL, 4.28 mmol, 2.5 equiv.) followed by acetyl chloride (158 µL, 2.22 mmol, 1.3 equiv.) at 0 °C. The resulting solution was allowed to stir at 0 °C for 15 min at which point the reaction mixture was diluted with CH2Cl2 (10 mL). The resulting solution was washed with ice cold sat. aq. NaCl (2 × 8 mL), dried with Na2SO4, filtered, and concentrated. Purification by flash column chromatography (hexanes:Et2O 50:50) delivered anti/syn-2c as a yellow oil (189 mg, 0.836 mmol, 49%, dr 1.8:1.0); anti-2c: Rf = 0.24 (hexanes:Et2O 50:50); 1H NMR (400 MHz, CDCl3) δ 6.93 (dd, J = 10.4, 3.6 Hz, 1H), 6.58 (d, J = 3.6 Hz, 1H), 6.25 (d, J = 10.4 Hz, 1H), 5.94-5.83 (m, 1H), 5.31-5.24 (m, 1H), 5.21-5.17 (m, 1H), 4.65 (dd, J = 3.8, 3.7 Hz, 1H), 4.06-4.02 (m, 2H), 3.90-3.85 (m, 2H), 2.12 (s, 3H);

13

C

NMR (100 MHz, CDCl3) δ 193.2, 169.5, 142.2, 134.4, 128.9, 117.7, 87.3, 76.6, 72.8, 68.6, 21.0; syn-2c: Rf = 0.17 (hexanes:Et2O 50:50); 1H NMR (400 MHz, CDCl3) δ 6.89 (dd, J = 10.4, 2.5 Hz, 1H), 6.57 (dd, J = 2.5, 1.3 Hz, 1H), 6.26 (dd, J = 10.4, 1.3 Hz, 1H), 5.94-5.83 (m, 1H), 5.315.24 (m, 1H), 5.21-5.17 (m, 1H), 4.48 (dd, J = 7.0, 3.6 Hz, 1H), 4.06-4.02 (m, 2H), 3.88 (dd, J = 10.8, 7.0 Hz, 1H), 3.78 (dd, J = 10.8, 3.6 Hz, 1H), 2.14 (s, 3H); 13C NMR (100 MHz, CDCl3) δ


34

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193.2, 169.4, 143.6, 134.4, 129.1, 117.6, 87.7, 79.1, 72.5, 70.1, 21.1; anti/syn-2c: IR (neat) νmax 1751, 1684, 1105; ESI-HRMS calculated for C11H15O5 [M+H]+ 227.0919, found 227.0888. Acetoxypyranone 2d: To a solution of bromohydrin 1d (5.38 g, 28.2 mmol, 1.0 equiv.) in CH2Cl2 (140 mL) was added imidazole (3.07 g, 45.1 mmol, 1.6 equiv.) and TBSCl (6.37 g, 42.3 mmol, 1.5 equiv.) at 0 °C and warmed to 23 °C over 3 h. The solution was diluted with water (100 mL) and CH2Cl2 (140 mL) and separated. The combined organic solution was washed with sat. aq. NH4Cl (100 mL) and sat. aq. NaCl (100 mL), separated, dried over MgSO4, filtered, and concentrated to deliver the crude protected alcohol (not shown) as a yellow oil (8.60 g, 28.2 mmol, quantitative). To a solution of bromide (8.60 g, 28.2 mmol, 1.0 equiv) and toluene (10 mL) in a pressure flask was added K2CO3 (7.79 g, 56 mmol, 2.0 equiv) and allylamine (21 mL, 282 mmol, 10.0 equiv). The reaction was heated to 75 °C for 24 h. The reaction was cooled to ambient temperature, diluted with CH2Cl2 (120 mL), then washed with H2O (80 mL) and sat. aq. Na2CO3 (80 mL). The combined aqueous layer was extracted with CH2Cl2 (80 mL) and the combined organic layers were combined and washed with brine (2 × 80 mL), dried over MgSO4, and concentrated. Purification by flash column chromatography (hexanes:EtOAc 70:30) afforded the allyl amine (not shown) as a yellow oil (6.28 g, 22.3 mmol, 79%): Rf = 0.55 (hexanes:EtOAc 70:30); 1H NMR (500 MHz, CDCl3) δ 7.35 (dd, J = 1.8, 0.8 Hz, 1H), 6.31 (dd, J = 3.2, 1.8 Hz, 1H), 6.23-6.21 (m, 1H), 5.89 (app. ddt, J = 17.2, 10.3, 5.9 Hz, 1H), 5.17 (app. dq, J = 17.2, 1.7 Hz, 1H), 5.08 (app. dq, J = 10.3, 1.4 Hz, 1H), 4.85 (dd, J = 8.1, 4.6 Hz, 1H), 3.32-3.27 (m, 1H), 3.27-3.22 (m, 1H), 2.99 (dd, J = 12.0, 8.1 Hz, 1H), 2.85 (dd, J = 12.0, 4.6, 1H), 0.87 (s, 9H), 0.07 (s, 3H), -0.08 (s, 3H);

13

C NMR (125 MHz, CDCl3) δ 155.8, 141.6, 136.9, 115.7, 110.1,

106.5, 67.9, 54.4, 52.0, 25.8, 18.2, -4.9, -5.1; IR (neat) νmax 831, 776, 733 cm-1; ESI-HRMS calculated for C15H28NO2Si [M+H]+ 282.1889, found 282.1876. To a solution of allyl amine (1.65 g, 5.9 mmol, 1.0 equiv.) in CH2Cl2 (30 mL) was added Et3N (980 µL, 7.0 mmol, 1.2


35


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equiv.) and methyl chloroformate (540 µL, 7.0 mmol, 1.2 equiv.) at 0 °C. The reaction was warmed to 23 °C, stirred 1.5 h, diluted with CH2Cl2 (40 mL), and quenched with sat. aq. NH4Cl (60 mL). The separated organic solution was washed with sat. aq. NaCl (2 × 20 mL), dried with MgSO4,

filtered,

and

concentrated.

Purification

by

flash

column

chromatography

(hexanes:EtOAc 90:10) afforded carbamate (not shown) as a yellow oil (1.86 g, 5.5 mmol, 93%). To a solution of carbamate (1.86 g, 5.5 mmol, 1.0 equiv.) in THF (20 mL) was added a 1.0 M solution of TBAF (9.6 mL, 9.6 mmol, 1.75 equiv.) at 0 °C. The reaction was warmed to 23 °C, stirred 45 min, diluted with EtOAc (80 mL), and quenched with sat. aq. NH4Cl (80 mL). The aqueous layer was extracted with EtOAc (50 mL) and the combined organic extracts were washed with sat. aq. NaCl (2 × 60 mL), dried with MgSO4, filtered, and concentrated. Purification by flash column chromatography (hexanes:EtOAc 70:30) afforded alcohol (not shown) as a yellow oil (1.12 g, 4.98 mmol, 89%). To a solution of alcohol (1.12 g, 4.98 mmol, 1.0 equiv.) in CH2Cl2 (25 mL) was added VO(acac)2 (132 mg, 0.50 mmol, 0.1 equiv.). The solution was cooled to 0 °C and 5.5 M tBuOOH in decane (1.8 mL, 9.6 mmol, 1.8 equiv.) was added slowly. The reaction was stirred at 0 °C for 30 min, warmed to 23 °C, and stirred 4 h. Upon concentration via rotary evaporation, purification by flash column chromatography (hexanes:EtOAc 60:40 to 50:50) delivered the hydroxypyranone (not shown) as a yellow oil (904 mg, 3.75 mmol, 77%, dr 2.5:1.0). To a solution of hydroxypyranone (904 mg, 3.75 mmol, 1.0 equiv) in dry CH2Cl2 (50 mL) at 0 °C was added pyridine (670 µL, 8.3 mmol, 2.2 equiv) and acetyl chloride (345 µL, 4.88 mmol, 1.3 equiv) dropwise. The reaction was allowed to stir for 30 minutes, quenched with sat. aq. NaCl (25 mL), and separated. The aqueous layer was extracted with CH2Cl2 (2 × 20 mL) and the combined organics were dried with Na2SO4 and concentrated. Purification by flash column chromatography (hexanes:EtOAc 60:40) delivered anti-2d/syn-2d as a yellow oil (839 mg, 2.96 mmol, 79%, dr 2.5:1); anti-2d: Rf = 0.34 (hexanes:Et2O 60:40); 1H


36

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NMR (500 MHz, DMSO-d6) δ 7.12 (dd, J = 10.3, 3.7 Hz, 1H), 6.48 (dd, J = 3.7, 0.7 Hz, 1H), 6.27 (dd, J = 10.3, 0.7 Hz, 1H), 5.80-5.70 (m, 1H), 5.14-5.06 (m, 2H), 4.72-4.62 (m, 1H), 3.963.89 (m, 1H), 3.81-3.74 (m, 1H), 3.59 (s, 3H), 3.58-3.54 (m, 1H), 3.46-3.38 (m, 1H), 2.09 (s, 3H);

13

C NMR (125 MHz, DMSO-d6) δ 193.8, 169.0, 155.9, 143.3, 133.9, 127.8, 116.1, 86.0,

73.7, 52.41, 52.39, 49.6, 20.6; syn-2c: Rf = 0.34 (hexanes:Et2O 60:40); 1H NMR (500 MHz, DMSO-d6) δ 7.09 (dd, J = 10.3, 2.6 Hz, 1H), 6.54 (dd, J = 2.6, 1.4 Hz, 1H), 6.28 (dd, J = 10.3, 1.4 Hz, 1H), 5.80-5.70 (m, 1H), 5.14-5.06 (m, 2H), 4.57-4.51 (m, 1H), 3.96-3.89 (m, 1H), 3.853.80 (m, 1H), 3.59 (s, 3H), 3.58-3.54 (m, 1H), 3.46-3.38 (m, 1H), 2.11 (s, 3H);

13

C NMR (125

MHz, DMSO-d6) δ 193.7, 168.8, 155.9, 144.6, 133.9, 127.9, 116.1, 86.0, 76.4, 52.41, 52.39, 49.6, 20.6; anti/syn-2d: IR (neat) νmax 1754, 1693; ESI-HRMS calculated for C13H17NO6Na [M+Na]+ 306.0954, found 306.0939. Acetoxypyranone 2e: To a flame-dried, 2-neck, round bottom flask was added Mg turnings (299 mg, 12.3 mmol, 1.5 equiv.), backfilled with argon, and allowed to stir vigorously overnight. To the flask was then added anhydrous Et2O (8 mL) and a condenser. Next, ~10% of 5-bromo-1hexene (1.23 mL, 9.2 mmol, 1.5 equiv.) was added through a pressure equalizing addition funnel followed by I2. Upon initiation, remaining 5-bromo-1-hexene was added dropwise over 10 min. The resulting solution was refluxed for 1 h, diluted with anhydrous Et2O (23 mL), and cooled to 0 °C. Furfural 1e (510 µL, 6.1 mmol, 1.0 equiv.) was added and the resulting solution was allowed to stir at 23 °C for 1 h at which point the reaction was quenched with sat. aq. NH4Cl (60 mL). The reaction was stirred for 10 min and extracted with Et2O (2 × 60 mL). The combined organic solution was washed sequentially with sat. aq. NH4Cl (2 × 60 mL), H2O (2 × 60 mL), and sat. aq. NaCl (2 × 60 mL), dried with Na2SO4, filtered, and concentrated. Purification by column chromatography (hexanes:EtOAc 90:10) delivered alcohol (not shown) as a colorless oil (660 mg, 3.7 mmol, 60% yield). To a solution of alcohol (660 mg, 3.7 mmol, 1.0 equiv.) in


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CH2Cl2 (37 mL) was added VO(acac)2 (98 mg, 0.37 mmol, 0.1 equiv.). The solution was cooled to 0 °C and 5.5 M tBuOOH in decane (1.0 mL, 5.5 mmol, 1.5 equiv.) was added slowly. The reaction was allowed to warm to 23 °C and stirred for 3 h, quenched with sat. aq. Na2S2O3 (30 mL), and stirred for 1 h. The resulting emulsion was diluted with CH2Cl2 (30 mL), filtered through Celite to remove suspended solids, and separated. The aqueous solution was extracted with CH2Cl2 (3 × 30 mL). The combined organic solution was washed with sat. aq. Na2S2O3 (2 × 30 mL), dried with Na2SO4, filtered, and concentrated to provide crude hydroxypyranone (not shown). To a solution of hydroxypyranone (~3.12 mmol, 1.0 equiv.) in CH2Cl2 (8 mL) was added pyridine (628 µL, 7.8 mmol, 2.5 equiv.) followed by acetyl chloride (333 µL, 4.7 mmol, 1.5 equiv) at 0 °C. The resulting solution was allowed to stir at 0 °C for 15 min. The solution was washed with ice cold sat. aq. NaCl (2 × 10 mL), dried with Na2SO4, filtered, and concentrated to provide acetoxypyranone 2e as a mixture of diastereomers (dr 2.3:1.0 anti/syn). Purification by flash column chromatography (hexanes:Et2O 75:25) delivered anti-2e as a yellow oil (224 mg, 0.94 mmol, 30%, dr >19:1), anti-2e/syn-2e mixture as a yellow oil (41 mg, 0.17 mmol, 6%, dr 1.4:1.0), and syn-53 as a yellow oil (113 mg, 0.47 mmol, 15%, dr >19:1); anti-2e: Rf = 0.58 (hexanes:Et2O 50:50); 1H NMR (400 MHz, CDCl3) δ 6.88 (dd, J = 10.2, 3.6 Hz, 1H), 6.50 (d, J = 3.6 Hz, 1H), 6.20 (d, J = 10.2 Hz, 1H), 5.79 (app. ddt, J = 17.1, 10.3, 6.6 Hz, 1H), 5.10-4.96 (m, 1H), 4.96-4.90 (m, 1H), 4.46 (dd, 7.6, 4.0 Hz, 1H) 2.13 (s, 3H), 2.08-2.02 (m, 2H), 1.99-1.90 (m, 2H), 1.79-1.69 (m, 2H), 1.43-1.40 (m, 2H); syn-2e: Rf = 0.47 (hexanes:Et2O 50:50); 1H NMR (400 MHz, CDCl3) δ 6.84 (dd, J = 10.4, 2.7 Hz, 1H), 6.54 (dd, J = 2.7, 1.2 Hz, 1H), 6.21 (dd, J = 10.4, 1.2 Hz, 1H), 5.79 (app. ddt, J = 17.0, 10.3, 6.7 Hz, 1H), 5.00 (app. ddt, J = 17.0, 2.0, 1.7 Hz, 1H), 4.94 (app. ddt, J = 10.2, 2.0, 1.2 Hz, 1H), 4.21 (dd, J = 7.3, 6.2 Hz, 1H), 2.14 (s, 3H), 2.09-2.03 (m, 2H), 1.89-1.82 (m, 2H), 1.58-1.34 (m, 4H); 13C NMR was not obtained for


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this compound, but full characterization was obtained for the anti-acetoxypyranone-enal 3e (vide infra). Acetoxypyranone 2f: To a stirred solution of furan (355 µL, 4.84 mmol, 1.0 equiv.) in anhydrous Et2O (16 mL) cooled at –78 °C was added 2.5 M n-BuLi in hexane (2.1 mL, 5.3 mmol, 1.1 equiv.). The solution was allowed to stir at –78 °C for 1.5 h, warmed to 0 °C, and stirred for 30 min. The solution was cooled back to –78 °C and aryl aldehyde19 1f (1.55 g, 9.7 mmol, 2.0 equiv.) was added dropwise. Upon stirring for 1 h, the reaction was warmed to 23 °C, and stirred for an additional 30 min. The reaction mixture was quenched with H2O (12 mL) and the aqueous layer was extracted with Et2O (3 × 12 mL). The combined organic solution was washed with H2O (3 × 12 mL), sat. aq. NaCl (20 mL), dried with MgSO4, filtered, and concentrated. Purification by flash column chromatography (hexanes:Et2O 80:20 to 60:40) delivered benzylic alcohol (not shown) as a yellow oil (684 mg, 2.99 mmol, 62%): Rf = 0.28 (hexanes:Et2O 75:25); 1H NMR (400 MHz, CDCl3) δ 7.59-7.55 (m, 1H), 7.39 (dd, J = 1.8, 0.8 Hz, 1H), 7.29-7.25 (m, 2H), 7.22-7.18 (m, 1H), 6.30 (dd, J = 3.2, 1.8 Hz, 1H), 6.08 (d, J = 4.1 Hz, 1H), 6.05 (app. dt, J = 3.2, 0.8 Hz, 1H), 5.83 (app. ddt, J = 17.0, 10.3, 6.6 Hz, 1H), 5.034.95 (m, 2H), 2.72 (m, 2H), 2.31-2.23 (m, 2H), 2.27 (d, J = 4.1 Hz, 1H);

13

C NMR (100 MHz,

CDCl3) δ 156.1, 142.6, 139.2, 138.6, 138.0, 129.6, 128.2, 126.9, 126.6, 115.2, 110.4, 107.8, 66.8, 35.3, 32.0; IR (neat) νmax 3353, 1640, 732; ESI-HRMS calculated for C15H16O2Na [M+Na]+ 251.1048, found 251.1039. To a solution of benzylic alcohol (250 mg, 1.10 mmol, 1.0 equiv.) in CH2Cl2 (6 mL) was added VO(acac)2 (43 mg, 0.16 mmol, 0.15 equiv.). The solution was cooled to 0 °C and 5.5 M tBuOOH in decane (319 µL, 1.75 mmol, 1.6 equiv.) was added. The reaction mixture was warmed to 23 °C, stirred for 4 h, quenched with sat. aq. Na2S2O3 (6 mL), and allowed to stir for 30 min. The aqueous layer was extracted with CH2Cl2 (3 × 10 mL) and the combined organic extracts were dried with Na2SO4, filtered through silica, and concentrated.


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Purification by flash column chromatography (hexanes:Et2O 80:20 to 60:40) delivered hydroxypyranone (not shown) as a dark oil (149 mg, 0.61 mmol, 56%). To a solution of hydroxypyranone (329 mg, 1.35 mmol, 1.0 equiv.) in CH2Cl2 (3.4 mL) was added pyridine (215 µL, 2.69 mmol, 2.0 equiv.) and acetyl chloride (115 µL, 1.61 mmol, 1.2 equiv.) at 0 °C. The solution was stirred for 20 min at which point the reaction mixture was diluted with CH2Cl2 (10 mL) and separated. The resulting organic solution was washed with ice cold sat. aq. NaCl (2 × 8 mL), dried with Na2SO4, filtered, and concentrated. Purification by flash column chromatography (hexanes:EtOAc 80:20) delivered anti-2f/syn-2f as a yellow oil (320 mg, 1.12 mmol, 83%, dr 3.5:1.0); anti-2f: 1H NMR (500 MHz, CDCl3) δ 7.32-7.17 (m, 4H), 7.00 (dd, J = 10.3, 3.8 Hz, 1H), 6.64 (d, J = 3.8 Hz, 1H), 6.35 (d, J = 10.3 Hz, 1H), 5.86 (app. ddt, J = 17.1, 10.3, 6.7 Hz, 1H), 5.71 (s, 1H), 5.08-5.03 (m, 1H), 5.01-4.97 (m, 1H), 2.74-2.64 (m, 2H), 2.40-2.30 (m, 2H), 2.16 (s, 3H);

13

C NMR (125 MHz, CDCl3) δ 194.7, 169.4, 141.7, 141.1, 138.1, 133.4, 129.8,

129.3, 129.2, 129.1, 126.5, 115.1, 87.4, 76.5, 35.3, 32.6, 21.1; syn-2f: 1H NMR (500 MHz, CDCl3) δ 7.32-7.17 (m, 4H), 6.97 (dd, J = 10.4, 2.4 Hz, 1H), 6.63 (dd, J = 2.4, 1.4 Hz, 1H), 6.44 (dd, J = 10.4, 1.4 Hz, 1H), 5.92-5.82 (m, 1H), 5.48 (s, 1H), 5.10-5.05 (m, 1H), 5.02-4.98 (m, 1H), 2.85-2.72 (m, 2H), 2.40-2.30 (m, 2H), 1.83 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 194.3, 169.2, 144.6, 141.5, 138.0, 135.0, 130.3, 129.3, 129.0, 128.8, 126.2, 115.2, 88.1, 78.7, 35.2, 32.2, 20.7; anti/syn-2f: Rf = 0.65 (hexanes:EtOAc 60:40); IR (neat) νmax 1753, 1696, 1208, 1002, 756; ESI-HRMS calculated for C17H19O4 [M+H]+ 287.1283, found 287.1248. Acetoxypyranone 2g: To a solution of furan (1.0 mL, 13.8 mmol, 1.0 equiv) in THF (5 mL) was added n-BuLi (6.6 mL, 16.6 mmol, 1.2 equiv.) dropwise at –78 °C and stirred 1.5 hours. Upon warming to 0 °C, the reaction was stirred for 30 min and re-cooled to –78 °C. A solution of aldehyde 1g (4.46 g, 27.5 mmol, 2.0 equiv.) in THF (20 mL) was added dropwise, stirred for 1 h, warmed to 23 °C, and stirred an additional 30 min. The reaction was quenched slowly with H2O


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(25 mL) and then extracted with Et2O (3 × 50 mL). The organic extracts were combined, washed with sat. aq. NaCl (2 × 25 mL), dried with MgSO4, filtered, and concentrated. Purification by flash column chromatography (hexanes:EtOAc 90:10) delivered the benzylic allyl ether (not shown) as a yellow oil (3.18 g, 13.8 mmol, quantitative): Rf = 0.38 (hexanes:EtOAc 80:20); 1H NMR (500 MHz, CDCl3) δ 7.38 (dd, J = 1.9, 0.9 Hz, 1H), 7.36 (dd, J = 8.5, 1.8 Hz, 1H), 7.28 (ddd, J = 8.9, 7.5, 1.8 Hz, 1H), 6.99 (ddd, J = 8.5, 7.5, 1.0 Hz, 1H), 6.90 (dd, J = 8.9, 1.0 Hz, 1H), 6.31 (dd, J = 3.3, 1.9 Hz, 1H), 6.12 (app. dt, J = 3.3, 0.9 Hz, 1H), 6.07 (d, J = 6.5 Hz, 1H), 5.98 (app. ddt, J = 17.3, 10.6, 5.2 Hz, 1H), 5.33 (app. dq, J = 17.3, 1.6 Hz, 1H), 5.26 (app. dq, J = 10.6, 1.6 Hz, 1H), 4.56 (app. dt, J = 5.2, 1.6 Hz, 2H), 3.08 (d, J = 6.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 155.8, 142.1, 132.9, 129.5, 129.1, 128.0, 121.1, 117.6, 112.2, 110.2, 106.8, 69.0, 66.9; IR (neat) νmax 1601, 751 cm-1; ESI-HRMS calculated for C14H14O3Na [M+Na]+ 253.0841, found 253.0834. To a solution of allyl ether (3.18 g, 27.5 mmol, 1.0 equiv.) in CH2Cl2 (40 mL) was added VO(acac)2 (308 mg, 1.39 mmol, 0.10 equiv.). The solution was cooled to 0 °C and 5.5 M tBuOOH in decane (4.4 mL, 24.3 mmol, 1.75 equiv.) was added. The reaction mixture was warmed to 23 °C, stirred for 2 h, and concentrated. Purification by flash column chromatography (hexanes:EtOAc 70:30) delivered hydroxypyranone (not shown) as a yellow oil (1.70 g, 6.9 mmol, 51%). To a solution of hydroxypyranone (1.70 g, 6.9 mmol, 1.0 equiv) in CH2Cl2 (75 mL) at 0 °C was added pyridine (1.2 mL, 15.2 mmol, 2.2 equiv.) and AcCl (640 µL, 9.0 mmol, 1.3 equiv.). The reaction was stirred 30 min, quenched with sat. aq. NaCl (50 mL), and separated. The aqueous layer was extracted with CH2Cl2 (2 × 30 mL) and the combined organics were concentrated. Purification by flash column chromatography (hexanes:EtOAc 80:20) delivered anti-2g as a yellow oil (797 mg, 2.76 mmol, 40%, dr >19:1), anti-2g/syn-2g mixture as a yellow oil (818 mg, 2.83 mmol, 41%, dr 1.0:1.2); characterization was obtained for anti-2g: Rf = 0.25 (hexanes:EtOAc 80:20); 1H NMR (500 MHz, CDCl3) δ 7.32 (ddd, J = 8.3, 7.5, 1.8 Hz, 1H), 7.29


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(dd, J = 8.5, 1.8 Hz, 1H), 6.97 (ddd, J = 8.5, 7.5, 1.0 Hz, 1H), 6.94 (dd, J = 10.3, 3.7 Hz, 1H), 6.91 (dd, J = 8.3, 1.0 Hz, 1H), 6.62 (dd, J = 3.7, 0.4 Hz, 1H), 6.33 (dd, J = 10.3, 0.4 Hz, 1H), 5.97 (dddd, J = 17.3, 10.5, 5.3, 5.1 Hz, 1H), 5.74 (s, 1H), 5.36 (app. dq, J = 17.3, 1.6 Hz, 1H), 5.23 (app. dq, J = 10.5, 1.6 Hz, 1H), 4.57 (app. ddt, J = 12.8, 5.1, 1.6 Hz, 1H), 4.49 (app. ddt, J = 12.8, 5.3, 1.6 Hz, 1H), 2.16 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 193.4, 169.2, 156.4, 140.8, 132.9, 130.2, 130.1, 128.7, 124.5, 120.8, 117.1, 112.5, 87.2, 74.8, 69.1, 20.7; IR (neat) νmax 1748, 1700, 1209, 752 cm-1; ESI-HRMS calculated for C16H16O5Na [M+Na]+ 311.0895, found 311.0880. General Procedure A (cross-metathesis with crotonaldehyde or methyl vinyl ketone): A solution of acetoxypyranone 2 in anhydrous CH2Cl2 was degassed for 10 min by bubbling Ar via balloon. Crotonaldehyde or methyl vinyl ketone and Grubbs–Hoveyda 2nd generation catalyst were added sequentially and the reaction degassed with Ar for an additional 10 min. Upon stirring at 23 °C for 24 h, the reaction was concentrated and purified via flash column chromatography (FCC) to afford unsaturated aldehyde 3 or ketone 4. anti-Acetoxypyranone-enal 3a: The general procedure A was followed with anti-2a (1.70 g, 7.58 mmol, 1.0 equiv., dr >19:1), CH2Cl2 (39 mL), crotonaldehyde (3.1 mL, 37.9 mmol, 5.0 equiv.), Grubbs–Hoveyda 2nd generation catalyst (357 mg, 0.57 mmol, 0.075 equiv.) for 24 h. Purification by FCC (hexanes:EtOAc 80:20 to 70:30) delivered anti-3a as a brown oil (1.55 g, 6.14 mmol, 81%, dr >19:1): Rf = 0.23 (hexanes:EtOAc 70:30); 1H NMR (500 MHz, CDCl3) δ 9.50 (d, J = 7.8 Hz, 1H), 6.90 (dd, J = 10.2, 3.9 Hz, 1H), 6.83 (dt, J = 15.7, 6.7 Hz, 1H), 6.50 (d, J = 3.9 Hz, 1H), 6.22 (d, J = 10.2 Hz, 1H), 6.12 (ddt, J = 15.7, 7.8, 1.5 Hz, 1H), 4.49 (dd, J = 7.3, 3.9 Hz, 1H), 2.38-2.34 (m, 2H), 2.13 (s, 3H), 2.02-1.95 (m, 1H), 1.85-1.77 (m, 1H), 1.671.61 (m, 2H);

13

C NMR (125 MHz, CDCl3) δ 195.2, 194.0, 169.6, 157.9, 141.8, 133.3, 128.6,


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87.0, 75.5, 32.4, 29.1, 23.0, 21.0; IR (neat) νmax 1750, 1683, 1636, 1275 cm-1; ESI-HRMS calculated for C13H16O5Na [M+Na]+ 275.0895, found 275.0885.13 Experimental details for anti-Acetoxypyranone-enone 4a: The general procedure A was followed with anti-2a (1.0 g, 4.46 mmol, 1.0 equiv., dr >19:1), CH2Cl2 (10.0 mL), methyl vinyl ketone (2.2 mL, 26.8 mmol, 6.0 equiv.), and Grubbs–Hoveyda 2nd generation catalyst (210 mg, 0.33 mmol, 0.075 equiv) for 24 h. Purification by FCC (hexanes:EtOAc 80:20 to 70:30) delivered anti-4a as an olive green oil (983 mg, 4.34 mmol, 83%, dr >19:1): Rf = 0.23 (hexanes:EtOAc 70:30); 1H NMR (500 MHz, CDCl3) δ 6.88 (dd, J = 10.2, 3.8 Hz, 1H), 6.77 (dt, J = 15.9, 6.8 Hz, 1H), 6.49 (d, J = 3.8 Hz, 1H), 6.21 (d, J = 10.2 Hz, 1H), 6.07 (dt, J = 15.9, 1.5 Hz, 1H), 4.47 (dd, J = 7.4, 3.7 Hz, 1H), 2.27-2.22 (m, 2H), 2.23 (s, 3H), 2.13 (s, 3H), 2.00-1.93 (m, 1H), 1.82-1.74 (m, 1H), 1.63-1.57 (m, 2H);

13

C NMR (125 MHz,CDCl3) δ 198.7, 195.3,

169.7, 147.6, 141.8, 131.8, 128.8, 87.2, 75.7, 32.3, 29.3, 27.0, 23.4, 21.1; IR (neat) νmax 1751, 1695, 1672, 1626, 1215 cm-1; ESI-HRMS calculated for C14H18O5Na [M+Na]+ 289.1052, found 289.1048.14 anti-Acetoxypyranone-enal 3b: The general procedure A was followed with acetoxypyranone 2b (414 mg, 1.02 mmol, dr 7.7:1.0, 1.0 equiv), CH2Cl2 (5.0 mL), crotonaldehyde (410 µL, 5.1 mmol, 5.0 equiv.), and Grubbs–Hoveyda 2nd generation catalyst (48 mg, 0.08 mmol, 0.075 equiv.) for 16 h. Purification by FCC (hexanes:EtOAc 85:15) delivered anti-3b as a colorless oil (256 mg, 0.65 mmol, 65%, dr >19:1): Rf = 0.18 (hexanes:EtOAc 85:15); 1H NMR (500 MHz, CDCl3) δ 9.51 (d, J = 7.9 Hz, 1H), 7.22 (d, J = 10.3 Hz, 1H), 6.83 (app. dt, J = 15.7, 6.8 Hz, 1H), 6.16 (d, J = 10.3 Hz, 1H), 6.13 (app. ddt, J = 15.7, 7.9, 1.5 Hz, 1H), 4.54 (dd, J = 7.3, 3.9 Hz, 1H), 4.12 (d, J = 10.6 Hz, 1H), 3.78 (d, J = 10.6 Hz, 1H), 2.39-2.34 (m, 2H), 2.06 (s, 3H), 2.031.96 (m, 1H), 1.84-1.76 (m, 1H), 1.69-1.63 (m, 2H), 0.88 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 195.5, 193.9, 169.4, 158.0, 144.5, 133.2, 127.2, 99.2, 76.1, 66.1,


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32.2, 29.5, 25.7(3), 23.1, 21.4, 18.2, -5.40, -5.42; IR (neat) νmax 1694, 1109, 1050, 836, 777 cm-1; ESI-HRMS calculated for C20H32O6SiNa [M+Na]+ 419.1866, found 419.1856. anti-Acetoxypyranone-enone 4b: The general procedure A was followed with acetoxypyranone 2b (202 mg, 0.55 mmol, dr 7.7:1.0, 1.0 equiv), CH2Cl2 (1.5 mL), methyl vinyl ketone (274 µL, 3.29 mmol, 6 equiv.), Grubbs–Hoveyda 2nd generation catalyst (26 mg, 0.04 mmol, 0.075 equiv.) for 24 h. Purification by FCC (hexanes:EtOAc 85:15) delivered anti-4b as a pale yellow oil (110 mg, 0.27 mmol, 49%, dr >19:1): Rf = 0.26 (hexanes:EtOAc 85:15); 1H NMR (500 MHz, CDCl3) δ 7.21 (d, J = 10.3, 1H), 6.77 (app. dt, J = 16.0, 6.9 Hz, 1H), 6.14 (d, J = 10.3 Hz, 1H), 6.07 (app. dt, J = 16.0, 1.5 Hz, 1H), 4.52 (dd, J = 7.4, 3.9 Hz, 1H), 4.11 (d, J = 10.5 Hz, 1H), 3.78 (d, J = 10.5 Hz, 1H), 2.23 (s, 3H), 2.27-2.23 (m, 2H), 2.05 (s, 3H), 2.01-1.95 (m, 1H), 1.82-1.73 (m, 1H), 1.64-1.58 (m, 2H), 0.87 (s, 9H), 0.07 (s, 3H), 0.05 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 198.5, 195.8, 169.4, 147.6, 144.5, 131.6, 127.2, 99.2, 76.1, 66.2, 32.1, 30.9, 29.5, 26.8, 25.7(3), 23.3, 21.4, 18.2, -5.40, -5.42; IR (neat) νmax 1743, 1698, 1676, 1117, 836, 777 cm-1; ESI-HRMS calculated for C21H34O6SiNa [M+Na]+ 433.2002, found 433.2014. Acetoxypyranone-enal 3c: The general procedure A was followed with acetoxypyranone 2c (180 mg, 0.80 mmol, dr 1.8:1.0, 1.0 equiv.), CH2Cl2 (4 mL), crotonaldehyde (330 µL, 4.00 mmol, 5.0 equiv.), and Grubbs–Hoveyda 2nd generation catalyst (37 mg, 0.06 mmol, 0.075 equiv.) for 24 h. Purification by FCC (hexanes:EtOAc 70:30 to 50:50) delivered anti-3c/syn-3c as a dark green oil (94 mg, 0.37 mmol, 47%, dr 1.4:1.0); anti-3c: 1H NMR (400 MHz, CDCl3) δ 9.57 (d, J = 7.8 Hz, 1H), 6.94 (dd, J = 10.3, 3.7 Hz, 1H), 6.79 (app. dt, J = 15.8, 4.2 Hz, 1H), 6.57 (d, J = 3.7 Hz, 1H), 6.38-6.28 (m, 1H), 6.26 (d, J = 10.3 Hz, 1H), 4.65 (dd, J = 4.3, 2.8 Hz, 1H), 4.33-4.30 (m, 2H), 4.01-3.93 (m, 2H), 2.13 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 193.3, 192.9, 169.5, 152.4, 142.3, 132.1, 128.9, 87.1, 76.4, 70.5, 69.7, 21.0; syn-3c: 1H NMR (400 MHz, CDCl3) δ 9.56 (d, J = 7.9 Hz, 1H), 6.91 (dd, J = 10.4, 2.4 Hz, 1H), 6.78 (app. dt, J = 15.8,


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4.1 Hz, 1H), 6.58 (d, J = 2.4 Hz, 1H), 6.38-6.28 (m, 1H), 6.28 (d, J = 10.4 Hz, 1H), 4.47 (dd, J = 6.1, 3.2 Hz, 1H), 4.33-4.30 (m, 2H), 3.93-3.84 (m, 2H), 2.14 (s, 3H);

13

C NMR (100 MHz,

CDCl3) δ 193.2, 192.7, 169.3, 152.3, 144.2, 132.1, 129.3, 87.8, 78.9, 71.0, 70.1, 21.1; anti/syn3c: Rf = 0.30 (hexanes:EtOAc 50:50); IR (neat) νmax 1750, 1683, 1105; ESI-HRMS calculated for C12H15O6 [M+H]+ 255.0869, found 255.0862. Acetoxypyranone-enone 4c: The general procedure A was followed with acetoxypyranone 2c (188 mg, 0.83 mmol, dr 1.8:1.0, 1.0 equiv.), CH2Cl2 (8.3 mL), methyl vinyl ketone (340 µL, 4.16 mmol, 5.0 equiv.), and Grubbs–Hoveyda 2nd generation catalyst (39 mg, 0.06 mmol, 0.075 equiv.) for 24 h. Purification by FCC (hexanes:EtOAc 50:50) delivered anti/syn-4c as a dark brown oil (172 mg, 0.53 mmol, 64%, dr 2.2:1.0); anti-4c: Rf = 0.37 (hexanes:EtOAc 50:50); 1H NMR (400 MHz, CDCl3) δ 6.94 (dd, J = 10.3, 3.7 Hz, 1H), 6.73 (app. dt, J = 16.1, 4.3 Hz, 1H), 6.57 (d, J = 3.7 Hz, 1H), 6.27 (app. dt, J = 16.1, 1.9 Hz, 1H), 6.26 (d, J = 10.3 Hz, 1H), 4.64 (dd, J = 4.4, 2.7 Hz, 1H), 4.24-4.21 (m, 2H), 3.96 (dd, J = 10.9, 4.4 Hz, 1H), 3.90 (dd, J = 10.9, 2.7 Hz, 1H), 2.26 (s, 3H), 2.13 (s, 3H);

13

C NMR (100 MHz, CDCl3) δ 198.2, 193.0, 169.5, 142.5,

142.3, 130.8, 128.9, 87.2, 76.4, 70.7, 69.5, 27.4, 21.0; syn-4c: Rf = 0.32 (hexanes:EtOAc 50:50); 1

H NMR (400 MHz, CDCl3) δ 6.90 (dd, J = 10.4, 2.5 Hz, 1H), 6.74 (app. dt, J = 16.1, 4.4 Hz,

1H), 6.58 (dd, J = 2.5, 1.3 Hz, 1H), 6.30 (app. dt, J = 16.1, 1.9 Hz, 1H), 6.28 (dd, J = 10.4, 1.3 Hz, 1H), 4.47 (dd, J = 6.4, 3.3 Hz, 1H), 4.23-4.20 (m, 2H), 3.94 (dd, J = 10.8, 6.4 Hz, 1H), 3.84 (dd, J = 10.8, 3.3 Hz, 1H), 2.26 (s, 3H), 2.14 (s, 3H);

13

C NMR (100 MHz, CDCl3) δ 198.1,

192.8, 169.3, 144.0, 142.4, 130.6, 129.3, 87.8, 79.0, 70.8, 70.3, 27.5, 21.1; anti/syn-4c: IR (neat) νmax 1750, 1695, 1675, 1634, 1214; ESI-HRMS calculated for C13H17O6 [M+H]+ 269.1025, found 269.1016. Acetoxypyranone-enal 3d: The general procedure A was followed with acetoxypyranone 2d (517 mg, 1.82 mmol, dr 2.5:1.0, 1.0 equiv), CH2Cl2 (10 mL), crotonaldehyde (740 µL, 9.1 mmol,


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5.0 equiv.), and Grubbs–Hoveyda 2nd generation catalyst (88 mg, 0.14 mmol, 0.075 equiv.) for 24 h. Purification by FCC (hexanes:EtOAc 60:40 to 50:50 to 40:60) delivered acetoxypyranoneenal 3d as a brown oil (~256 mg, ~0.82 mmol, ~45%): acetoxypyranone-enal 2d was not fully characterized due to the presence of impurities. Acetoxypyranone-enone 4d: The general procedure A was followed with acetoxypyranone 2d (513 mg, 1.81 mmol, dr 2.5:1.0, 1.0 equiv), CH2Cl2 (10 mL), methyl vinyl ketone (750 µL, 9.1 mmol, 5.0 equiv.), and Grubbs–Hoveyda 2nd generation catalyst (85 mg, 0.14 mmol, 0.075 equiv.) for 24 h. Purification by FCC (DCM:MeOH 98:2) delivered acetoxypyranone-enone 4d as a brown oil (~412 mg, ~1.27 mmol, ~70%): acetoxypyranone-enal 3d was not fully characterized due to the presence of impurities. Acetoxypyranone-enal 3e: The general procedure A was followed with anti-acetoxypyranone 2e (224 mg, 0.94 mmol, dr >19:1, 1.0 equiv.), CH2Cl2 (4.7 mL), crotonaldehyde (384 µL, 4.70 mmol, 5.0 equiv.), and Grubbs–Hoveyda 2nd generation catalyst (44 mg, 0.07 mmol, 0.075 equiv.) for 24 h. Purification by FCC (hexanes:EtOAc 80:20) delivered anti-3e as a dark brown oil (139 mg, 0.52 mmol, 56%, dr >19:1): Rf = 0.45 (hexanes:EtOAc 60:40); 1H NMR (500 MHz, CDCl3) δ 9.50 (d, J = 7.9 Hz, 1H), 6.88 (dd, J = 10.3, 3.6 Hz, 1H), 6.82 (app. dt, J = 15.6, 6.8 Hz, 1H), 6.49 (d, J = 3.6 Hz, 1H), 6.20 (d, J = 10.3 Hz, 1H), 6.10 (app. ddt, J = 15.6, 7.9, 1.5 Hz, 1H), 4.47 (dd, J = 7.4, 4.0 Hz, 1H), 2.38-2.30 (m, 2H), 2.13 (s, 3H), 2.00-1.90 (m, 1H), 1.83-1.73 (m, 1H), 1.57-1.50 (m, 2H), 1.50-1.41 (m, 2H);

13

C NMR (125 MHz, CDCl3) δ 195.5, 194.2,

169.6, 158.4, 141.7, 133.3, 128.7, 87.2, 75.8, 32.6, 29.5, 27.8, 24.3, 21.1; IR (neat) νmax 2740, 1751, 1684, 1635, 1216; ESI-HRMS calculated for C14H18O5Na [M+Na]+ 289.1052, found 289.1047. Acetoxypyranone-enal 3f: The general procedure A was followed with acetoxypyranone 2f (90 mg, 0.31 mmol, dr 3.5:1.0, 1.0 equiv.), CH2Cl2 (1.6 mL), crotonaldehyde (154 µL, 1.88 mmol,


46

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6.0 equiv.), and Grubbs–Hoveyda 2nd generation catalyst (15 mg, 0.02 mmol, 0.075 equiv.) for 24 h. Purification by FCC (hexanes:EtOAc 70:30) delivered anti/syn-3f as a dark brown oil (76 mg, 0.24 mmol, 77%, dr 3.8:1.0); anti-3f: 1H NMR (400 MHz, CDCl3) δ 9.51 (d, J = 7.8 Hz, 1H), 7.36-7.20 (m, 4H), 7.02 (dd, J = 10.3, 3.7 Hz, 1H), 6.87 (app. dt, J = 15.6, 6.5 Hz, 1H), 6.64 (dd, J = 3.7, 0.4 Hz, 1H), 6.36 (dd, J = 10.3, 0.4 Hz, 1H), 6.14 (app. ddt, J = 15.6, 7.8, 1.5 Hz, 1H), 5.65 (s, 1H), 2.91-2.59 (m, 4H), 2.16 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 194.1, 194.0, 169.4, 157.3, 142.0, 139.6, 133.5, 133.3, 129.7, 129.6, 129.5, 128.9, 126.9, 87.3, 76.9, 34.0, 31.3, 21.1; syn-3f: 1H NMR (400 MHz, CDCl3) δ 9.50 (d, J = 7.8 Hz, 1H), 7.36-7.20 (m, 4H), 7.00 (dd, J = 10.4, 2.3 Hz, 1H), 6.88 (app. dt, J = 15.6, 6.6 Hz, 1H), 6.63 (dd, J = 2.3, 1.3 Hz, 1H), 6.45 (dd, J = 10.4, 1.3 Hz, 1H), 6.17 (app. ddt, J = 15.6, 7.8, 1.5 Hz, 1H), 5.43 (s, 1H), 2.91-2.59 (m, 4H), 1.85 (s, 3H);

13

C NMR (100 MHz, CDCl3) δ 194.4, 194.1, 169.1, 157.3, 144.8, 140.0,

134.9, 133.3, 130.2, 129.7, 129.4, 129.3, 126.7, 88.1, 78.9, 34.0, 31.0, 20.6; anti/syn-3f: Rf = 0.18 (hexanes:EtOAc 70:30); IR (neat) νmax 1750, 1683, 1634, 1211, 754; satisfactory HRMS data were not obtained. Acetoxypyranone-enone 4f: The general procedure B was followed with acetoxypyranone 2f (66 mg, 0.23 mmol, dr 3.5:1.0, 1.0 equiv.), CH2Cl2 (1.2 mL), methyl vinyl ketone (110 µL, 1.37 mmol, 6.0 equiv.), and Grubbs–Hoveyda 2nd generation catalyst (11 mg, 0.02 mmol, 0.075 equiv.) for 24 h. Purification by FCC (hexanes:EtOAc 70:30 to 50:50) delivered anti/syn-4f as a dark brown oil (62 mg, 0.19 mmol, 82%, dr 3.7:1.0); anti-4f: 1H NMR (400 MHz, CDCl3) δ 7.34-7.18 (m, 4H), 7.01 (dd, J = 10.3, 3.7 Hz, 1H), 6.81 (app. dt, J = 16.0, 6.8 Hz, 1H), 6.63 (dd, J = 3.7, 0.4 Hz, 1H), 6.35 (dd, J = 10.3, 0.4 Hz, 1H), 6.10 (app. dt, J = 16.0, 1.5 Hz, 1H), 5.66 (s, 1H), 2.80-2.70 (m, 2H), 2.58-2.48 (m, 2H), 2.23 (s, 3H), 2.16 (s, 3H);

13

C NMR (100 MHz,

CDCl3) δ 198.7, 194.1, 169.4, 147.0, 141.9, 139.9, 133.5, 131.7, 129.64, 129.57, 129.4, 128.9, 126.8, 87.4, 77.2, 33.8, 31.6, 27.1, 21.1; syn-4f: 1H NMR (400 MHz, CDCl3) δ 7.34-7.18 (m,


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4H), 7.00 (dd, J = 10.4, 2.4 Hz, 1H), 6.83 (app. dt, J = 15.9, 7.2 Hz, 1H), 6.62 (dd, J = 2.4, 1.4 Hz, 1H), 6.44 (dd, J = 10.4, 1.4 Hz, 1H), 6.12 (app. dt, J = 15.9, 1.5 Hz, 1H), 5.43 (s, 1H), 2.902.80 (m, 2H), 2.62-2.50 (m, 2H), 2.24 (s, 3H), 1.83 (s, 3H);

13

C NMR (100 MHz, CDCl3) δ

198.7, 194.4, 169.2, 147.0, 144.7, 140.4, 135.0, 131.9, 130.2, 129.7, 129.3, 129.2, 126.6, 88.1, 78.8, 33.9, 31.4, 27.0, 20.6; anti/syn-4f: Rf = 0.17 (hexanes:EtOAc 70:30); IR (neat) νmax 1753, 1695, 1671, 1626, 1210, 729; satisfactory HRMS data were not obtained. Acetoxypyranone-enal 3g: The general procedure A was followed with anti-acetoxypyranone 2g (533 mg, 1.85 mmol, dr >19:1, 1.0 equiv), CH2Cl2 (8.0 mL), crotonaldehyde (760 µL, 9.3 mmol, 5.0 equiv.), Grubbs–Hoveyda 2nd generation catalyst (88 mg, 0.14 mmol, 0.075 equiv.) for 24 h. Purification by FCC (CH2Cl2:Et2O 95:5) delivered anti-3g as a white foam (172 mg, 0.54 mmol, 30%, dr >19:1): Rf = 0.40 (CH2Cl2:Et2O 95:5); 1H NMR (500 MHz, CDCl3) δ 9.61 (d, J = 7.8 Hz, 1H), 7.37-7.31 (m, 2H), 7.05-7.01 (m, 1H), 6.99 (dd, J = 10.3, 3.8 Hz, 1H), 6.91-6.88 (m, 1H), 6.89 (app. dt, J = 15.8, 3.9 Hz, 1H), 6.65 (d, J = 3.8 Hz, 1H), 6.41 (app. ddt, J = 15.8, 7.8, 2.0 Hz, 1H), 6.34 (d, J = 10.3 Hz, 1H), 5.77 (s, 1H), 4.86 (ddd, J = 16.7, 3.9, 2.0 Hz, 1H), 4.78 (ddd, J = 16.7, 3.9, 2.0 Hz, 1H), 2.17 (s, 1H);

13

C NMR (125 MHz, CDCl3) δ 193.5, 192.9,

169.6, 155.9, 150.5, 141.5, 132.3, 130.62, 130.61, 128.9, 124.7, 121.9, 112.6, 87.5, 75.1, 67.1, 21.1; IR (neat) νmax 1748, 1684, 1210, 753 cm-1; MP 55–57 °C; ESI-HRMS calculated for C17H16O6Na [M+Na]+ 339.0845, found 339.0830. Acetoxypyranone-enal 4g: The general procedure A was followed with anti-acetoxypyranone 2g (309 mg, 1.07 mmol, dr >19:1, 1.0 equiv), CH2Cl2 (8.0 mL), methyl vinyl ketone (440 µL, 5.4 mmol, 5 equiv.), and Grubbs–Hoveyda 2nd generation catalyst (50 mg, 0.08 mmol, 0.075 equiv.) for 24 h. Purification by FCC (CH2Cl2:Et2O 95:5) delivered anti-4g as a dark brown solid (181 mg, 0.55 mmol, 51%, dr >19:1): Rf = 0.36 (CH2Cl2:Et2O 95:5); 1H NMR (500 MHz, CDCl3) δ 7.38-7.33 (m, 2H), 7.06-7.02 (m, 1H), 7.00 (dd, J = 10.2, 3.7 Hz, 1H), 6.92-6.89 (m, 1H), 6.86


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(app. dt, J = 16.1, 4.2 Hz, 1H), 6.67 (d, J = 3.7 Hz, 1H), 6.39 (app. dt, J = 16.1, 1.9 Hz, 1H), 6.37 (d, J = 10.2 Hz, 1H), 5.77 (s, 1H), 4.79 (app. dq, J = 15.9, 4.2, 1.9 Hz, 1H), 4.72 (app. dq, J = 15.9, 4.2, 1.9 Hz, 1H), 2.30 (s, 3H), 2.20 (s, 3H);

13

C NMR (125 MHz, CDCl3) δ 197.8, 193.6,

169.6, 156.2, 141.4, 140.9, 130.9, 130.64, 130.63, 129.0, 124.8, 121.8, 112.7, 87.6, 75.2, 67.4, 27.6, 21.1; IR (neat) νmax 1744, 1696, 1670, 1213, 750 cm-1; MP 84–86 °C; ESI-HRMS calculated for C18H18O6Na [M+Na]+ 353.1001, found 353.0984. General Procedure B (cycloaddition of terminal olefins): To a solution of acetoxypyranone 2 in CH3CN (0.1 M) was added N-methylpyrrolidine (NMP, 4.0 equiv.) and heated to 60 °C for 3-6 h. The reaction was concentrated and purified via flash column chromatography (FCC) to afford cycloadduct 5. Cycloadduct 5a: General procedure B was not utilized for this reaction. To an oven-dried 1 dram vial was added anti-2a (0.1 mmol, 1.0 equiv.) as a stock solution in anhydrous CH3CN (0.1 M). N-methylpyrrolidine (cf. Table 2, entry 6) was added (0.4 mmol, 4.0 equiv.) and the vial was backfilled with Ar, capped, and stirred for 6 h. Acetic acid (0.44 mmol, 4.4 equiv.) was added to quench the reaction and the resulting solution was concentrated and the yield determined by NMR analysis with trimethoxybenzene as an internal standard and spectral data was consistent with previously published data: 1H NMR: (400 MHz, CDCl3) δ 7.13 (dd, J = 9.8, 4.4 Hz, 1H), 5.96 (d, J = 9.8, 1H), 4.88 (dd, J = 6.6, 4.4 Hz, 1H), 2.45-2.38 (m, 1H), 2.35-2.28 (m, 1H), 2.16 (dd, J = 12.0, 8.8 Hz, 1H), 1.98-1.76 (m, 4H), 1.73-1.68 (m, 1H), 1.63-1.57 (m, 1H).26 Cycloadduct 5b: The general procedure B was followed with anti-acetoxypyranone 2b (211 mg, 0.52 mmol, dr 7.7:1.0, 1.0 equiv), CH3CN (5.0 mL), and NMP (220 µL, 2.1 mmol, 4.0 equiv) for 3 h; FCC (hexanes:Et2O 90:10) afforded 5b as a white solid (115 mg, 0.37 mmol, 65%, dr >19:1): Rf = 0.24 (hexanes:Et2O 90:10); 1H NMR (500 MHz, CDCl3) δ 7.18 (d, J = 9.9 Hz, 1H), 6.01 (d, J = 9.9 Hz, 1H), 3.82 (d, J = 10.3 Hz, 1H), 3.78 (d, J = 10.3 Hz, 1H), 2.43-2.38 (m, 1H),


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2.32-2.26 (m, 1H), 2.21 (dd, J = 12.0, 8.8 Hz, 1H), 1.95-1.85 (m, 2H), 1.81-1.68 (m, 2H), 1.61 (dd, J = 12.0, 6.0 Hz, 1H), 1.60-1.57 (m, 1H), 0.91 (s, 9H), 0.09 (s, 6H);

13

C NMR (125 MHz,

CDCl3) δ 195.8, 152.8, 126.5, 98.2, 85.4. 66.0, 45.6, 39.9, 32.6, 30.2, 26.1, 25.8(3), -5.4(2); IR (neat) νmax 1696, 1103 cm-1; MP 24–25 °C; ESI-HRMS calculated for C17H28O3SiNa [M+Na]+ 331.1705, found 331.1696. Cycloadduct 5c: The general procedure B was followed with acetoxypyranone 2c (51 mg, 0.23 mmol, dr 1.8:1.0, 1.0 equiv.), CH3CN (2.3 mL), and NMP (110 µL, 0.88 mmol, 4.0 equiv.) for 6 h; FCC (hexanes:EtOAc 50:50) afforded cycloadduct 5c as a yellow solid (32 mg, 0.19 mmol, 84%, dr >19:1): Rf = 0.30 (hexanes:EtOAc 50:50); 1H NMR (400 MHz, CDCl3) δ 7.21 (dd, J = 9.8, 4.4 Hz, 1H), 6.02 (d, J = 9.8 Hz, 1H), 5.05 (dd, J = 6.6, 4.3 Hz, 1H), 4.44 (d, J = 10.6 Hz, 1H), 4.13 (dd, J = 8.8, 8.6 Hz, 1H), 3.88 (d, J = 10.6 Hz, 1H), 3.73 (dd, J = 8.8, 6.0 Hz, 1H), 2.76-2.67 (m, 1H), 2.16 (dd, J = 12.1, 8.5 Hz, 1H), 2.04 (ddd, J = 12.1, 6.6, 5.7 Hz, 1H);

13

C

NMR (100 MHz, CDCl3) δ 194.5, 152.3, 126.5, 98.2, 77.8, 74.1, 70.4, 46.9, 34.6; IR (neat) vmax 1677, 1059, 1023; MP 70–72 °C; ESI-HRMS calculated for C9H11O3 [M+H]+ 167.0708, found 167.0702. Cycloadduct 5d: The general procedure B was followed with acetoxypyranone 2d (104 mg, 0.37 mmol, dr 2.5:1.0, 1.0 equiv.), CH3CN (4.0 mL), and NMP (150 µL, 1.48 mmol, 4.0 equiv.) for 2.5 h; FCC (hexanes:EtOAc 50:50) afforded cycloadduct 5d as a yellow solid (32 mg, 0.19 mmol, 87%, dr >19:1): Rf = 0.35 (hexanes:EtOAc 30:70); 1H NMR (400 MHz, DMSO-d6; VT = 70 °C) δ 7.48 (dd, J = 9.8, 4.5 Hz, 1H), 5.97 (d, J = 9.8 Hz, 1H), 5.05 (dd, J = 6.7, 4.5 Hz, 1H), 4.10 (d, J = 12.6 Hz, 1H), 3.90 (dd, J = 11.0, 9.3 Hz, 1H), 3.61 (s, 3H), 3.42 (d, J = 12.6 Hz, 1H), 3.25 (dd, J = 11.0, 7.1 Hz, 1H), 2.75-2.65 (m, 1H), 2.14 (dd, J = 12.3, 8.5 Hz, 1H), 2.03 (ddd, J = 12.3, 6.7, 4.6 Hz, 1H);

13

C NMR (100 MHz, DMSO-d6; VT = 70 °C) δ 193.3, 154.8, 154.0,


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124.1, 95.4, 76.0, 52.3, 51.8, 48.3, 42.6, 35.3; IR (neat) vmax 1686, 1116; MP 92–93 °C; ESIHRMS calculated for C11H13NO4Na [M+Na]+ 246.0742, found 246.0735. Cycloadduct 5f: The general procedure B was followed with acetoxypyranone 2f (80 mg, 0.28 mmol, dr 3.5:1.0, 1.0 equiv.), CH3CN (2.8 mL), and NMP (110 µL, 1.12 mmol, 4.0 equiv.) for 5 h; FCC (hexanes:EtOAc 70:30) afforded cycloadduct 5f as a white solid (63 mg, 0.28 mmol, 99%, dr >19:1): Rf = 0.56 (hexanes:EtOAc 60:40); 1H NMR (500 MHz, CDCl3) δ 7.35 (dd, J = 9.8, 4.6 Hz, 1H), 7.31-7.28 (m, 1H), 7.27-7.23 (m, 2H), 7.21-7.17 (m, 1H), 6.13 (d, J = 9.8 Hz, 1H), 4.90 (dd, J = 7.1, 4.6 Hz, 1H), 2.80-2.67 (m, 2H), 2.41-2.29 (m, 2H), 2.22-2.16 (m, 1H), 2.00-1.95 (m, 1H), 1.45-1.41 (m, 1H);

13

C NMR (125 MHz, CDCl3) δ 198.6, 153.1, 139.3,

133.2, 129.3, 128.3, 128.2, 126.9, 126.8, 88.5, 73.5, 38.8, 37.7, 30.0, 28.6; IR (neat) vmax 1683, 1220, 752; MP 85–87 °C; ESI-HRMS calculated for C15H15O2 [M+H]+ 227.1072, found 227.1062. Cycloadduct 5g: The general procedure B was followed with anti-acetoxypyranone 2g (172 mg, 0.60 mmol, dr >19:1, 1.0 equiv), CH3CN (5.0 mL), and NMP (240 µL, 2.29 mmol, 4.0 equiv) for 3 h; FCC (hexanes:EtAcO 70:30) afforded cycloadduct 5g as a white solid (113 mg, 0.50 mmol, 83%, dr >19:1): Rf = 0.21 (hexanes:EtAcO 70:30); 1H NMR (400 MHz, CDCl3) δ 7.41 (dd, J = 9.8, 4.7 Hz, 1H), 7.29 (ddd, J = 8.3, 7.3, 1.7 Hz, 1H), 7.24 (dd, J = 7.8, 1.7 Hz, 1H), 7.03 (ddd, J = 7.8, 7.3, 1.2 Hz, 1H), 6.99 (dd, J = 8.3, 1.2 Hz, 1H), 6.17 (d, J = 9.8 Hz, 1H), 4.87 (ddd, J = 7.1, 4.7, 0.6 Hz, 1H), 4.41 (dd, J = 10.8, 5.8, 1H), 3.48 (dd, J = 12.1, 10.8 Hz, 1H), 2.60-2.52 (m, 1H), 2.22 (ddd, J = 12.2, 8.4, 0.6 Hz, 1H), 1.83 (ddd, J = 12.2, 7.2, 4.7 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 196.6, 156.3, 153.5, 130.6, 130.1, 127.3, 121.8, 120.1, 117.4, 85.5, 72.3, 67.9, 36.5, 33.6; IR (neat) νmax 1680, 1606, 1221, 1046, 762 cm-1; MP 154–155 °C; ESI-HRMS calculated for C14H12O3Na [M+Na]+ 251.0684, found 251.0675.


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General Procedure C (cycloaddition of enones): To a solution of acetoxypyranone 4 in CH3CN (0.1 M) was added N-methylpyrrolidine (NMP, 4.0 equiv.) and heated to 60 °C for 1-12 h. The reaction was concentrated and the diastereomeric ratio determined by 1H NMR analysis of the crude sample, which was subsequently purified via flash column chromatography (FCC) to afford ketone 6. Ketone 6a: General procedure C was followed with anti-4b (792 mg, 2.97 mmol, dr >19:1, 1.0 equiv), CH3CN (15 mL), NMP (1.24 mL, 11.9 mmol, 4.0 equiv) for 2.5 h; FCC (hexanes:EtOAc 70:30) afforded 6a as a white solid (535 mg, 2.59 mmol, 87%, dr >19:1). Characterization data for the major adduct (presumed endo): Rf = 0.32 (hexanes:EtOAc 70:30); 1H NMR (500 MHz, CDCl3) δ 7.25 (dd, J = 9.8, 4.4 Hz, 1H), 6.02 (d, J = 9.8 Hz, 1H), 4.96 (dd, J = 6.0, 4.4 Hz, 1H), 3.22 (dd, J = 7.2, 6.0 Hz, 1H), 2.62-2.58 (m, 1H), 2.31-2.25 (m, 1H), 2.21 (s, 3H), 2.10-1.98 (m, 1H), 1.96-1.84 (m, 2H), 1.80-1.71 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 205.3, 196.6, 150.0, 127.0, 98.4, 76.5, 65.3, 47.7, 31.9, 30.2, 29.9, 25.8; IR (neat) νmax 1700, 1687, 1053 cm-1; MP 70–72 °C; ESI-HRMS calculated for C12H15O3 [M+H]+ 207.1021, found 207.1028.14 Ketone 6b: General procedure C was followed with anti-4b (89 mg, 0.22 mmol, dr >19:1, 1.0 equiv,), CH3CN (2.1 mL), and NMP (90 µL, 0.87 mmol, 4.0 equiv) for 24 h; FCC (hexanes:EtOAc 90:10) afforded 6b as a colorless oil (51 mg, 0.15 mmol, 63%, dr >19:1). Characterization data for the major adduct (presumed endo): Rf = 0.19 (hexanes:EtOAc 90:10); 1

H NMR (500 MHz, CDCl3) δ 7.11 (d, J = 9.8 Hz, 1H), 6.06 (d, J = 9.8 Hz, 1H), 3.87 (d, J =

11.0 Hz, 1H), 3.84 (d, J = 11.1 Hz, 1H), 3.19 (d, J = 7.5 Hz, 1H), 2.54-2.50 (m, 1H), 2.26-2.19 (m, 1H), 2.20 (s, 3H), 2.01-1.82 (m, 3H), 1.82-1.69 (m, 2H), 0.90 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 206.3, 196.8, 151.0, 127.0, 96.6, 86.04, 64.59, 64.55, 50.4, 31.9, 30.5, 30.0, 25.8(3), 25.5, 18.3, -5.3, -5.5; IR (neat) νmax 1696, 1100 cm-1; ESI-HRMS calculated for C19H31O4Si [M+H]+ 351.1991, found 351.1978.


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Ketone 6c: General procedure C was followed with 4c (134 mg, 0.50 mmol, dr 2.2:1.0, 1.0 equiv.), CH3CN (5 mL), and NMP (240 µL, 2.00 mmol, 4.0 equiv.) for 1 h; FCC (hexanes:EtOAc 60:40) afforded cycloadduct 6c as a white solid (87 mg, 0.42 mmol, 83%, dr >19:1) Characterization data for the major adduct (presumed endo): Rf = 0.26 (hexanes:EtOAc 50:50); 1H NMR (500 MHz, CDCl3) δ 7.20 (dd, J = 9.8, 4.3 Hz, 1H), 6.07 (d, J = 9.8 Hz, 1H), 5.16 (dd, J = 6.1, 4.3 Hz, 1H), 4.29 (d, J = 10.8 Hz, 1H), 4.10 (dd, J = 9.2, 8.2 Hz, 1H), 3.91 (d, J = 10.8 Hz, 1H), 3.90 (dd, J = 9.2, 4.5 Hz, 1H), 3.47 (dd, J = 6.3, 6.1 Hz, 1H), 3.02-2.96 (m, 1H), 2.23 (s, 3H);

13

C NMR (100 MHz, CDCl3) δ 203.6, 193.7, 149.4, 127.8, 98.0, 78.0, 72.9, 70.2,

63.8, 49.2, 30.2; IR (neat) vmax 1694, 1059; MP 89–91 °C; ESI-HRMS calculated for C11H13O4 [M+H]+ 209.0814, found 209.0795. Ketone 6d: General procedure C was followed with 4d (412 mg, 1.27 mmol, dr 2.5:1.0, 1.0 equiv), CH3CN (10 mL), and NMP (530 µL, 5.1 mmol, 4.0 equiv) for 2 h; FCC (CH2Cl2:MeOH 95:5) afforded 6d as a light brown solid (271 mg, 1.02 mmol, 80%, dr 8.7:1.0). Characterization data for the major adduct (presumed endo): Rf = 0.44 (CH2Cl2:MeOH 95:5); 1H NMR (500 MHz, DMSO-d6) δ 7.39 (dd, J = 9.8, 4.4 Hz, 1H), 6.03 (d, J = 9.8 Hz, 1H), 5.33 (dd, J = 6.7, 4.4 Hz, 1H), 4.01 (d, J = 12.9 Hz, 1H), 3.85 (dd, J = 11.1, 9.6 Hz, 1H), 3.75 (dd, J = 6.7, 5.9 Hz, 1H), 3.61 (s, 3H), 3.47 (dd, J = 11.1, 6.0 Hz, 1H), 3.46 (d, J = 12.9 Hz, 3H), 3.02-2.95 (m, 1H), 2.20 (s, 3H);

13

C NMR (125 MHz, DMSO-d6) δ 203.6, 192.9, 154.2, 151.5, 125.8, 95.8, 76.4, 75.5,

63.5, 56.8, 52.0, 48.5, 29.6; IR (neat) νmax 1712, 1688 cm-1; MP 110–113 °C; ESI-HRMS calculated for C13H15NO5Na [M+Na]+ 288.0848, found 288.0835. Ketone 6f: General procedure C was followed with 4f (62 mg, 0.19 mmol, dr 3.7:1.0, 1.0 equiv.), CH3CN (5 mL), and NMP (80 µL, 0.76 mmol, 4.0 equiv.) for 1 h; FCC (hexanes:EtOAc 70:30) afforded 6f as a white solid (46 mg, 0.17 mmol, 90%, dr >19:1). Characterization data for the major adduct (presumed endo): Rf = 0.33 (hexanes:EtOAc 60:40); 1H NMR (500 MHz,


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CDCl3) δ 7.33 (dd, J = 9.9, 4.6 Hz, 1H), 7.30-7.26 (m, 3H), 7.22-7.19 (m, 1H), 6.17 (d, J = 9.9 Hz, 1H), 5.08 (dd, J = 6.6, 4.6 Hz, 1H), 3.38 (app. t, J = 6.6 Hz, 1H), 2.83-2.65 (m, 3H), 2.372.31 (m, 1H), 2.28 (s, 3H), 1.57-1.48 (m, 1H) ;

13

C NMR (125 MHz, CDCl3) δ 204.2, 197.5,

150.0, 138.9, 133.0, 128.7, 128.5, 128.2, 127.9, 127.0, 88.6, 74.1, 65.8, 41.5, 30.2, 29.8, 28.3; IR (neat) vmax 1685, 1025, 751; MP 175–177 °C; ESI-HRMS calculated for C17H17O3 [M+H]+ 269.1178, found 269.1154. Ketone 6g: General procedure C was followed with 4f (123 mg, 0.37 mmol, dr >19:1, 1.0 equiv.), CH3CN (4.0 mL), and NMP (150 µL, 1.48 mmol, 4.0 equiv) for 2 h; FCC (CH2Cl2:Et2O 95:5) afforded 6g as a white solid (76 mg, 0.28 mmol, 76%, dr 5.0:1.0). Characterization data for the major adduct (presumed endo): Rf = 0.45 (CH2Cl2:Et2O 95:5); 1H NMR (400 MHz, CDCl3) δ 7.40 (dd, J = 9.8, 4.6 Hz, 1H), 7.31 (ddd, J = 8.3, 7.3, 1.7 Hz, 1H), 7.22 (dd, J = 7.8, 1.7 Hz, 1H), 7.04 (ddd, J = 7.8, 7.3, 1.2 Hz, 1H), 7.02 (dd, J = 8.3, 1.2 Hz, 1H), 6.21 (d, J = 9.8 Hz, 1H), 5.11 (dd, J = 6.8, 4.6 Hz, 1H), 4.53 (dd, J = 10.8, 5.9 Hz, 1H), 3.58 (dd, J = 11.4, 10.8 Hz, 1H), 3.29 (dd, J = 6.8, 6.0 Hz, 1H), 2.95 (ddd, J = 11.4, 6.0, 5.9 Hz, 1H), 2.27 (s, 3H);

13

C NMR (100

MHz, CDCl3) δ 202.6, 195.8, 156.3, 150.1, 130.4, 130.2, 128.5, 122.3, 120.3, 117.5, 85.8, 73.1, 67.9, 62.4, 39.6, 30.1; IR (neat) νmax 1700, 1650, 760 cm-1; MP 155–157 °C; ESI-HRMS calculated for C16H14O4Na [M+Na]+ 293.0790, found 293.0782. General Procedure D (cascade with enals): To a solution of acetoxypyranone 3 in CH3CN:H2O (95:5, 0.1 M) was added N-methylpyrrolidine (NMP, 4.0 equiv.) and heated to 60 °C for 2-12 h. The reaction was concentrated and purified via flash column chromatography (FCC) to afford lactol 7. Lactol 7a: General procedure D was followed with 3a (100 mg, 0.40 mmol, dr 3.5:1.0, 1.0 equiv.), CH3CN(3.8 mL):H2O (200 µL H2O), and NMP (170 µL, 1.60 mmol, 4.0 equiv) for 12 h; FCC (hexanes:EtOAc 70:30) afforded lactol 7a as a pale orange oil (53 mg, 0.25 mmol, 63%, dr


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>19:1): Rf = 0.18 (hexanes:EtOAc 70:30); 1H NMR (500 MHz, CDCl3) δ 5.31 (dd, J = 6.7, 6.0 Hz, 1H), 5.27 (d, J = 2.8 Hz, 1H), 4.68 (ddd, J = 6.7, 4.2, 1.9 Hz, 1H), 3.38 (br. s, 1H), 2.70 (dd, J = 16.1, 4.2 Hz, 1H), 2.54 (dd, J = 6.0, 2.8 Hz, 1H), 2.48 (dd, J = 16.1, 1.9 Hz, 1H), 2.24-2.18 (m, 1H), 2.12 (ddd, J = 9.3, 6.7, 2.8 Hz, 1H), 2.06-1.99 (m, 1H), 1.93-1.85 (m, 1H), 1.80-1.72 (m, 2H), 1.59-1.53 (m, 1H);

13

C NMR (125 MHz, CDCl3) δ 211.1, 99.7, 99.6, 82.7, 72.9, 55.8,

53.0, 41.2, 33.4, 32.3, 27.0; IR (neat) νmax 3419, 1724, 1010 cm-1; ESI-HRMS calculated for C11H14O4Na [M+Na]+ 233.0790, found 233.0785. Lactol 7b: General procedure D was followed with anti-3b (100 mg, 0.25 mmol, dr >19:1, 1.0 equiv.), CH3CN (2.8 mL):H2O (150 µL H2O), and NMP (100 µL, 1.01 mmol, 4.0 equiv) for 2 h; FCC (hexanes:EtOAc 85:15) afforded lactol 7b as a white solid (28 mg, 0.08 mmol, 32%, dr >19:1): Rf = 0.20 (hexanes:EtOAc 85:15); 1H NMR (500 MHz, CDCl3) δ 5.10 (d, J = 10.9 Hz, 1H), 4.77 (d, J = 10.9 Hz, 1H), 4.49 (dd, J = 4.2, 2.0 Hz, 1H), 4.01 (d, J = 10.0 Hz, 1H), 3.99 (d, J = 10.0 Hz, 1H), 2.70 (dd, J = 16.0, 4.2 Hz, 1H), 2.57 (dd, J = 16.0, 2.0 Hz, 1H), 2.32-2.20 (m, 3H), 2.13-2.05 (m, 1H), 1.96-1.88 (m, 1H), 1.82-1.74 (m, 2H), 1.62-1.56 (m, 1H), 0.95 (s, 9H), 0.18 (s, 6H);

13

C NMR (125 MHz, CDCl3) δ 210.7, 100.0, 98.9, 92.9, 74.2, 65.3, 60.0, 54.9,

41.6, 33.6, 32.3, 26.7, 25.3(3), 18.4, -5.5, -5.6; IR (neat) νmax 3400, 1725, 1105 cm-1; MP 119– 120 °C; ESI-HRMS calculated for C18H30O5SiNa [M+Na]+ 377.1760, found 377.1751. Lactol 7c: General procedure D was followed with 3c (127 mg, 0.50 mmol, dr 1.4:1.0, 1.0 equiv.), CH3CN (4.8 mL):H2O (250 µL H2O), and NMP (240 µL, 2.00 mmol, 4.0 equiv) for 2 h; FCC (hexanes:EtOAc 40:60) afforded lactol 7c as a white solid (75 mg, 0.35 mmol, 70%, dr >19:1): Rf = 0.19 (hexanes:EtOAc 50:50); 1H NMR (400 MHz, CDCl3) δ 5.47 (dd, J = 6.1, 5.8 Hz, 1H), 5.33 (d, J = 2.1 Hz, 1H), 4.76 (ddd, J = 6.1, 4.1, 2.0 Hz, 1H), 4.29 (d, J = 10.4 Hz, 1H), 4.21 (dd, J = 8.5, 8.2 Hz, 1H), 3.93 (d, J = 10.4 Hz, 1H), 3.65 (dd, J = 8.4, 8.4 Hz, 1H), 2.79 (br. s, 1H), 2.77 (dd, J = 16.2, 4.1 Hz, 1H), 2.65 (dd, J = 5.8, 2.4 Hz, 1H), 2.59 (dd, J = 16.2, 2.0 Hz,


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1H), 2.51 (ddd, J = 8.4, 8.2, 2.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 207.1, 99.1, 98.9, 83.9, 73.4, 72.5, 72.0, 54.1, 52.0, 41.1; IR (neat) vmax 3388, 1726, 1008; MP 145–147 °C; ESI-HRMS calculated for C10H13O5 [M+H]+ 213.0763, found 213.0753. Lactol 7d: General procedure D was followed with 3d (256 mg, 0.82 mmol, dr 2.5:1.0, 1.0 equiv), CH3CN (14 mL):H2O (740 µL), NMP (340 µL, 3.28 mmol, 4.0 equiv) for 2 h; FCC (hexanes:EtOAc 40:60) afforded an inseparable mixture of lactol 7d (dr >19:1) and corresponding aldehyde (not shown, dr >19:1) as a pale oil (106 mg, 0.39 mmol, ~48%); characterization data for lactol 7d: Rf = 0.19 (hexanes:EtOAc 50:50); 1H NMR (500 MHz, DMSO-d6) δ 6.39-6.37 (m, 1H), 5.37-5.33 (m, 1H), 5.17-5.15 (m, 1H), 4.65-4.60 (m, 1H), 3.943.87 (m, 1H), 3.81-3.77 (m, 1H), 3.59-3.55 (m, 1H), 3.58 (s, 3H), 3.51-3.45 (m, 1H), 3.18-3.10 (m, 1H), 2.84-2.76 (m, 1H), 2.57-2.53 (m, 1H), 2.35-2.29 (m, 1H); 13C NMR (125 MHz, DMSOd6) line listings are not reported due to the complex scenario of inseparable lactol, aldehyde, corresponding rotamers, and instability to variable temperature experiments – the 13C spectrum is included in the supporting information; IR (neat) νmax 1733, 1676 cm-1; ESI-HRMS calculated for lactol: C12H15NO6Na [M+Na]+ 292.0797, found 292.0785. Lactol 7f: General procedure D was followed with 3f (100 mg, 0.32 mmol, dr 3.8:1.0, 1.0 equiv.), CH3CN (3.0 mL):H2O (125 µL), and NMP (450 µL, 1.27 mmol, 4.0 equiv.) for 2 h; FCC (hexanes:EtOAc 50:50) afforded lactol 7f as a yellow solid (21 mg, 0.08 mmol, 25%, dr >19:1): Rf = 0.28 (hexanes:EtOAc 50:50); 1H NMR (400 MHz, CDCl3) δ 7.26-7.12 (m, 4H), 5.41 (s, 1H), 5.37 (dd, J = 7.1, 6.8 Hz, 1H), 4.91 (ddd, J = 7.1, 4.0, 2.1 Hz, 1H), 3.02 (dd, J = 15.1, 4.0 Hz, 1H), 2.78-2.75 (m, 2H), 2.62 (dd, J = 15.1, 2.1 Hz, 1H), 2.60 (dd, J = 6.8, 2.8 Hz, 1H), 2.152.05 (m, 2H), 1.57-1.47 (m, 1H), 1.26 (br. s, 1H); 13C NMR (100 MHz, CDCl3) δ 213.6, 138.6, 133.3, 128.64(2), 128.62, 126.9, 99.8, 89.9, 80.0, 74.2, 56.3, 45.9, 42.4, 29.9, 27.9; IR (neat) vmax


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3374, 1728, 1020, 763; MP 213–215 °C; ESI-HRMS calculated for C16H17O4 [M+H]+ 273.1127, found 273.1127. General Procedure E (cascade with enones): To a solution of acetoxypyranone 4 in CH3CN:H2O (50:50, 0.1 M) was added N-methylpyrrolidine (NMP, 4.0 equiv.) and heated to 60 °C for 1-6 h. The reaction was concentrated and purified via flash column chromatography (FCC) to afford lactol 8. Lactol 8a: General procedure E was followed with anti-4a (100 mg, 0.37 mmol, dr >19:1, 1.0 equiv.), CH3CN (1.0 mL):H2O (1.0 mL), and NMP (160 µL, 1.50 mmol, 4.0 equiv.) for 2 h; FCC (hexanes:EtOAc 60:40) afforded lactol 8a as a white solid (63 mg, 0.28 mmol, 75%, dr >19:1) and ketone 6a (6 mg, 0.02 mmol, 6%, dr >19:1); characterization data for lactol 8a: Rf = 0.32 (hexanes:EtOAc 60:40); 1H NMR (500 MHz, CDCl3) δ 5.35 (dd, J = 6.9, 6.1 Hz, 1H), 4.63 (ddd, J = 6.9, 4.3, 1.8 Hz, 1H), 2.70 (br. s, 1H), 2.69 (dd, J = 16.2, 4.3 Hz, 1H), 2.47 (dd, J = 16.2, 1.8 Hz, 1H), 2.44 (dd, J = 6.1, 2.8 Hz, 1H), 2.25-2.22 (m, 1H), 2.15 (ddd, J = 9.5, 7.3, 2.8 Hz, 1H), 2.05-1.98 (m, 1H), 1.95-1.87 (m, 1H), 1.79-1.74 (m, 2H), 1.57-1.50 (m, 1H), 1.47 (s, 3H);

13

C

NMR (125 MHz, CDCl3) δ 211.2, 104.2, 99.9, 84.2, 73.1, 58.0, 52.1, 41.0, 33.5, 32.3, 27.2, 24.2; IR (neat) νmax 3442, 1713, 1151 cm-1; ESI-HRMS calculated for C12H16O4Na [M+Na]+ 247.0946, found 247.0948. Lactol 8c: General procedure E was followed with 4c (134 mg, 0.50 mmol, dr 2.2:1.0, 1.0 equiv.), CH3CN (2.5 mL):H2O (2.5 mL), and NMP (240 µL, 2.00 mmol, 4.0 equiv.) for 1 h; FCC (CH2Cl2) afforded lactol 8c as a white solid (68 mg, 0.30 mmol, 60%, dr >19:1): Rf = 0.19 (hexanes:EtOAc 50:50); 1H NMR (400 MHz, CDCl3) δ 5.50 (dd, J = 6.9, 5.5 Hz, 1H), 4.71 (ddd, J = 6.9, 4.1, 1.8 Hz, 1H), 4.32 (d, J = 10.4 Hz, 1H), 4.20 (dd, J = 8.5, 8.3 Hz, 1H), 3.92 (d, J = 10.4 Hz, 1H), 3.62 (dd, J = 8.5, 8.4 Hz, 1H), 2.76 (dd, J = 16.2, 4.1 Hz, 1H), 2.57 (dd, J = 16.2, 1.8 Hz, 1H), 2.55 (dd, J = 5.5, 2.4 Hz, 1H), 2.52 (dd, J = 8.4, 8.3, 2.4 Hz, 1H), 2.21 (br. s, 1H),


57


1.52 (s, 3H);

13

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C NMR (100 MHz, CDCl3) δ 207.5, 103.9, 99.3, 85.5, 73.6, 72.9, 72.2, 54.2,

53.4, 41.0, 24.2; IR (neat) vmax 3443, 1716, 1049, 1024; MP 176–178 °C; ESI-HRMS calculated for C11H15O5 [M+H]+ 227.0919, found 227.0908. Lactol 8f: General procedure E was followed with 4f (120 mg, 0.36 mmol, dr 3.7:1.0, 1.0 equiv.), CH3CN (1.8 mL):H2O (1.8 mL), and NMP (150 µL, 1.46 mmol, 4.0 equiv.) for 6 h; FCC (hexanes:EtOAc 70:30 to 50:50) afforded lactol 8f as a white solid (36 mg, 0.136 mmol, 35%, dr >19:1): Rf = 0.10 (hexanes:EtOAc 60:40); 1H NMR (500 MHz, CDCl3) δ 7.26-7.13 (m, 4H), 5.40 (dd, J = 7.2, 6.3 Hz, 1H), 4.84 (ddd, J = 7.2, 4.1, 2.1 Hz, 1H), 3.00 (dd, J = 15.2, 4.1 Hz, 1H), 2.80-2.76 (m, 2H), 2.60 (dd, J = 15.2, 2.1 Hz, 1H), 2.50 (dd, J = 6.3, 2.9 Hz, 1H), 2.29 (br. s, 1H), 2.12-2.03 (m, 2H), 1.57 (s, 3H), 1.54-1.49 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 213.8, 138.5, 133.4, 128.61, 128.59, 128.58, 126.9, 104.4, 90.1, 81.4, 74.2, 58.5, 45.0, 42.1, 30.0, 28.2, 24.3; IR (neat) vmax 3422, 1736, 764; MP 180–183 °C; ESI-HRMS calculated for C17H19O4 [M+H]+ 287.1283, found 287.1259. Lactol 8g: General procedure E was followed with anti-4g (202 mg, 0.61 mmol, dr >19:1, 1.0 equiv.), CH3CN (3.1 mL):H2O (3.1 mL), and NMP (260 µL, 2.45 mmol, 4.0 equiv.) for 1 h; FCC (CH2Cl2:EtOAc 85:15) afforded lactol 8g as a white solid (13 mg, 0.04 mmol, 7%, dr >19:1): Rf = 0.26 (CH2Cl2:EtOAc 85:15); 1H NMR (400 MHz, CDCl3) δ 7.29-7.24 (m, 1H), 7.10-7.06 (m, 1H), 6.99-6.94 (m, 2H), 5.37 (dd, J = 7.2, 5.9 Hz, 1H), 4.87 (ddd, J = 7.2, 3.9, 2.2 Hz, 1H), 4.30 (dd, J = 11.0, 5.7 Hz, 1H), 3.48 (dd, J = 12.3, 11.0 Hz, 1H), 3.01 (dd, J = 15.1, 3.9 Hz, 1H), 2.63 (dd, J = 15.1, 2.2 Hz, 1H), 2.35-2.29 (m, 2H), 2.27 (br. s, 1H), 1.57 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 211.8, 155.8, 130.3, 129.5, 121.9, 120.1, 117.4, 103.8, 86.6, 80.7, 73.9, 66.2, 54.0, 42.3, 41.9, 24.3; IR (neat) vmax 3396, 1732, 752; ESI-HRMS calculated for C17H19O4 [M+H]+ 287.1283, found 287.1259.


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General Procedure F (cascade with alcohols): To a solution of 3a (125 mg, 0.50 mmol, 1.0 equiv, dr 2.4:1) in CH3CN (0.1 M) was added activated 4Å MS (3Å MS for MeOH). Next, the appropriate alcohol (2 equiv.; 5% for MeOH) was added, followed by DABCO (4.0 equiv) and the reaction was heated to 60 °C for 1-6 h. The reaction was concentrated and purified via flash column chromatography (FCC) to afford lactol 9. Lactol 9a: General procedure F was followed with 3a (125 mg, 0.50 mmol, 1.0 equiv, dr 2.4:1), DABCO (222 mg, 1.98 mmol, 4.0 equiv), MeOH (250 µL, 5%), and 3Å molecular sieves in CH3CN (4.75 mL) for 6 hr; FCC (hexanes:EtOAc 95:5) afforded 9a as a pale yellow oil (70 mg, 0.31 mmol, 63%, dr >19:1): Rf = 0.56 (hexanes:EtOAc 70:30); 1H NMR (500 MHz, CDCl3) δ 5.24 (dd, J = 6.8, 6.0 Hz, 1H), 4.76 (s, 1H), 4.56 (ddd, J = 6.8, 4.4, 1.9 Hz, 1H), 3.29 (s, 3H), 2.71 (dd, J = 16.1, 4.4 Hz, 1H), 2.54-2.50 (m, 2H), 2.26-2.20 (m, 1H), 2.17-2.13 (m, 1H), 2.072.00 (m, 1H), 1.93-1.87 (m, 1H), 1.81-1.74 (m, 2H), 1.59-1.54 (m, 1H);

13

C NMR (125 MHZ,

CDCl3) δ 210.8, 105.8, 99.5, 82.7, 72.5, 55.1, 54.5, 53.0, 41.2, 33.4, 32.3, 26.9; IR (neat) νmax 2934, 1728, 1094, 1027 cm-1; ESI-HRMS calculated for C12H16O4Na [M+Na]+ 247.0946, found 247.0945. Lactol 9b: General procedure F was followed with 3a (125 mg, 0.50 mmol, 1.0 equiv, dr 2.4:1), DABCO (222 mg, 1.98 mmol, 4.0 equiv), and 5-hexen-1-ol (120 µL, 0.99 mmol, 2 equiv.) for 6 hr; FCC (hexanes:EtOAc 90:10) afforded 9b as a colorless oil (77 mg, 0.26 mmol, 53%, dr >19:1): Rf = 0.83 (hexanes:EtOAc 70:30); 1H NMR (500 MHz, CDCl3) δ 5.79 (ddt, J = 17.0, 10.2, 6.7, 1H), 5.25 (dd, J = 6.6, 6.0 Hz, 1H), 5.02-4.93 (m, 2H), 4.86 (s, 1H), 4.55 (ddd, J = 6.6, 4.4, 2.0 Hz, 1H), 3.61 (dt, J = 9.7, 6.7 Hz, 1H), 3.34 (dt, J = 9.7, 6.7 Hz, 1H), 2.71 (dd, J = 16.1, 4.4 Hz, 1H), 2.51 (dd, J = 16.1, 2.0 Hz, 1H), 2.51 (dd, J = 6.0, 2.8 Hz, 1H), 2.26-2.20 (m, 1H), 2.15 (ddd, J = 9.3, 6.8, 2.8 Hz, 1H), 2.08-2.00 (m, 3H), 1.94-1.87 (m, 1H), 1.81-1.73 (m, 2H), 1.60-1.52 (m, 3H), 1.44-1.38 (m, 2H);

13

C NMR (125 MHZ, CDCl3) δ 211.0, 138.8, 114.7,


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104.7, 99.6, 83.0, 72.5, 67.2, 55.3, 53.0, 41.3, 33.56, 33.45, 32.3, 29.1, 27.0, 25.6; IR (neat) νmax 2936, 1729, 1640, 1100, 1065 cm-1; ESI-HRMS calculated for C17H24O4Na [M+Na]+ 315.1572, found 315.1568. Lactol 9c: General procedure F was followed with 3a (125 mg, 0.50 mmol, 1.0 equiv, dr 2.0:1), DABCO (222 mg, 1.98 mmol, 4.0 equiv), and propargyl alcohol (59 µL, 1.0 mmol, 2.0 equiv) for 2.5 hr; FCC (hexane:EtOAc 90:10) afforded 9c as colorless oil (69.6 mg, 0.280 mmol, 57%, dr >19:1): Rf = 0.65 (hexane:EtOAc 60:40); 1H NMR (400 MHz, CDCl3) δ 5.27 (dd, J = 7.0, 6.0 Hz, 1H), 5.08 (s, 1H), 4.59 (ddd, J = 7.0, 4.2, 2.0 Hz, 1H), 4.19 (dd, J = 15.8, 2.4 Hz, 1H), 4.15 (dd, J = 15.8, 2.4 Hz, 1H), 2.72 (dd, J = 16.1. 4.2 Hz, 1H), 2.57 (dd, J = 6.0, 2.8 Hz, 1H), 2.53 (dd, J = 16.1, 2.0 Hz, 1H), 2.42 (t, J = 2.3 Hz, 1H), 2.28-2.15 (m, 2H), 2.13-2.04 (m, 1H), 1.971.85 (m, 1H), 1.85-1.72 (m, 2H), 1.62-1.53 (m, 1H);

13

C NMR (100 MHz, CDCl3) δ 210.6,

103.0, 99.5, 82.5, 79.2, 74.6, 72.9, 55.0, 53.8, 52.8, 41.1, 33.4, 32.2, 26.9; IR (neat) vmax 1726, 1023 cm-1; ESI-HRMS calculated for C14H16O4Na [M+Na]+ 271.0946, found 271.0945. Lactol 9d: General procedure F was followed with 3a (125 mg, 0.50 mmol, 1.0 equiv, dr 3.3:1), DABCO (222 mg, 1.98 mmol, 4.0 equiv), and 4-methoxy benzyl alcohol (124 µL, 1.00 mmol, 2.0 equiv.) for 1 hr; FCC (hexane:EtOAc 80:20) afforded 9d as a white solid (101 mg, 0.306 mmol, 62%, dr >19:1): Rf = 0.65 (hexane:EtOAc 70:30); 1H NMR (400 MHz, CDCl3) δ 7.26 (app. d, J = 8.6 Hz, 2H), 6.90 (app. d, J = 8.6 Hz, 2H), 5.31 (dd, J = 6.5, 6.3 Hz, 1H), 4.97 (s, 1H), 4.62 (ddd, J = 6.5, 4.1, 2.0 Hz, 1H), 4.60 (d, J = 11.5 Hz, 1H), 4.40 (d, J = 11.5 Hz, 1H), 3.83 (s, 3H), 2.75 (dd, J = 16.1, 4.1 Hz, 1H), 2.57 (dd, J = 6.3, 2.8 Hz, 1H), 2.56 (dd, J = 16.1, 2.0 Hz, 1H), 2.29-2.24 (m, 1H), 2.17 (ddd, J = 9.3, 6.8, 2.8 Hz, 1H), 2.09-2.00 (m, 1H), 1.961.88 (m, 1H), 1.83-1.75 (m, 2H), 1.62-1.53 (m, 1H);

13

C NMR (100 MHz, CDCl3) δ 211.0,

159.5, 129.8(2), 129.7, 114.0(2), 103.5, 99.6, 82.9, 72.6, 68.5, 55.4, 55.2, 53.0, 41.3, 33.5, 32.4,


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27.0; IR (neat) νmax 1721, 1612, 1246, 828 cm-1; ESI-HRMS calculated for C19H22O5Na [M+Na]+ 353.1365, found 353.1351. Lactol 9e: General procedure F was followed with 3a (125 mg, 0.50 mmol, 1.0 equiv, dr 3.3:1), DABCO (222 mg, 1.98 mmol, 4.0 equiv), and isopropanol (77 µL, 1.00 mmol, 2.0 equiv) for 4 h; FCC (hexane:EtOAc 90:10) afforded 9e as a white solid (66.2 mg, 0.262 mmol, 53%, dr >19:1): Rf = 0.76 (hexane:EtOAc 70:30); 1H NMR (400 MHz, CDCl3) δ 5.27 (dd, J = 6.8, 6.2 Hz, 1H), 4.98 (s, 1H), 4.56 (ddd, J = 6.8, 4.1, 2.0 Hz, 1H), 3.84 (qq, J = 6.24, 6.16, 1H), 2.71 (dd, J = 16.0, 4.1 Hz, 1H), 2.50 (dd, J = 16.0, 2.0 Hz, 1H), 2.47 (dd, J = 6.2, 2.8 Hz, 1H), 2.28-2.20 (m, 1H), 2.15 (ddd, J = 9.2, 6.6, 2.8 Hz, 1H), 2.08-1.99 (m, 1H), 1.96-1.85 (m, 1H), 1.81-1.72 (m, 2H), 1.60-1.56 (m, 1H), 1.15 (d, J = 6.24, 3H), 1.11 (d, J = 6.16, 3H);

13

C NMR (100 MHz,

CDCl3) δ 211.2, 102.8, 99.5, 83.1, 72.2, 68.8, 55.6, 53.1, 41.3, 33.5, 32.4, 27.0, 23.7, 21.8; IR (neat) vmax 1720, 1013, 989 cm-1; ESI-HRMS calculated for C14H20O4Na [M+Na]+ 275.1259, found 275.1262. Lactol 9f: General procedure F was followed with 3a (125 mg, 0.50 mmol, 1.0 equiv, dr 2.0:1), DABCO (222 mg, 1.98 mmol, 4.0 equiv), and p-cresol (105 µL, 1.00 mmol, 2.0 equiv) for 1.5 h; FCC (hexane:EtOAc 90:10) afforded 9f as a white solid (30 mg, 0.100 mmol, 20%, dr >19:1): Rf =0.79 (hexane:EtOAc 70:30); 1H NMR (400 MHz, CDCl3) δ 7.06 (app. d, J = 8.4, 2H), 6.86 (app. d, J = 8.4, 2H), 5.54 (s, 1H), 5.43 (dd, J = 7.1, 6.0 Hz, 1H), 4.70 (ddd, J = 7.1, 4.3, 1.9 Hz, 1H), 2.77 (dd, J = 6.0, 2.8 Hz, 1H), 2.73 (dd, J = 16.1, 4.3 Hz, 1H), 2.55 (dd, J =16.1, 1.9 Hz, 1H), 2.31-2.23 (m, 5H), 2.14-2.05 (m, 1H), 2.00-1.90 (m, 1H), 1.86-1.76 (m, 2H), 1.68-1.59 (m, 1H);

13

C NMR (100 MHz, CDCl3) δ 210.7, 154.4, 131.7, 130.1(2), 116.6(2), 103.4, 99.7, 82.8,

73.4, 55.3, 53.1, 41.2, 33.5, 32.4, 27.0, 20.7; IR (neat) vmax 1722, 1508, 985, 814 cm-1; ESIHRMS calculated for C18H20O4Na [M+Na]+ 323.1259, found 323.1258.


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Acetoxypyranone 2h: To a flame-dried, 2-neck, round bottom flask was added Mg turnings (1.02 g, 42.0 mmol, 1.5 equiv.), backfilled with Ar, and allowed to stir vigorously overnight. To the flask was then added anhydrous Et2O (35 mL) and a condenser. Next, ~10% of 5-bromo-1pentene (4.0 ml, 33.8 mmol, 1.2 equiv.) was added through a pressure equalizing addition funnel followed by I2. Upon initiation, remaining 5-bromo-1-pentene was added dropwise over 10 min. The resulting solution was refluxed for 1 h, diluted with anhydrous Et2O (105 mL), and cooled to 0 °C. d-Furfural21 (2.74 g, 28.2 mmol, 1.0 equiv.) was added and the resulting solution was allowed to stir at 23 °C for 1 h at which point the reaction was quenched with sat. aq. NH4Cl (40 mL). The reaction was stirred for 10 min and was extracted with Et2O (100 mL). The combined organic solution was washed sequentially with sat. aq. NH4Cl (50 mL), H2O (50 mL), and brine (50 mL), dried with Na2SO4, filtered, and concentrated. Excess bromide was removed under high vacuum to provide the alcohol as a colorless oil (4.35 g, 26.0 mmol, 92%): Rf = 0.54 (hexanes:EtOAc 70:30); 1H NMR (400 MHz, CDCl3) δ 7.36 (dd, J = 1.8, 0.8 Hz, 1H), 6.32 (dd, J = 3.2, 1.8 Hz, 1H), 6.22 (dd, J = 3.2, 0.8 Hz, 1H), 5.79 (ddt, J = 17.1, 10.3, 6.7 Hz, 1H), 5.044.94 (m, 2H), 2.09 (app. q, J = 7.3 Hz, 2H), 2.03 (s, 1H), 1.93-1.78 (m, 2H), 1.61-1.47 (m, 1H), 1.47-1.34 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 156.9, 142.0, 138.6, 114.9, 110.2, 105.9, 67.4 (t), 35.0, 33.5, 24.9; IR (neat) νmax 3362, 1641, 1154; ESI-HRMS calculated for C10H12DO [MOH]+ 150.1029, found 150.1033. To a solution of alcohol (4.35 g, 26.0 mmol, 1.0 equiv.) in CH2Cl2 (260 mL) was added VO(acac)2 (690 mg, 2.60 mmol, 0.1 equiv.). The solution was cooled to 0 °C and 5.5 M tBuOOH in decane (7.1 mL, 39.1 mmol, 1.5 equiv.) was added slowly. The reaction was allowed to warm to 23 °C and stirred for 3 h, quenched with sat. aq. Na2S2O3 (200 mL), and stirred for 1 h. The resulting emulsion was diluted with CH2Cl2 (250 mL), filtered over Celite to remove suspended solids, and separated. The resulting aqueous solution was extracted with CH2Cl2 (3 × 150 mL). The combined organic solution was washed with sat. aq.


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Na2S2O3 (2 × 250 mL), dried with Na2SO4, filtered, and concentrated to provide crude hydroxypyranone. To a solution of hydroxypyranone (~26 mmol, 1.0 equiv.) in anhydrous CH2Cl2 (65 mL) was added pyridine (4.2 mL, 52.1 mmol, 2 equiv.) followed by acetyl chloride (2.7 mL, 31.2 mmol, 1.2 equiv.) at 0 °C. The resulting solution was allowed to warm to 23 °C and stirred for 2 h. The solution was washed with ice cold sat. aq. NaCl (2 × 50 mL), dried with Na2SO4, filtered, and concentrated. Purification by flash column chromatography (hexanes:Et2O 75:25) delivered anti-2h as a yellow oil (1.00 g, 4.44 mmol, 17%, dr >19:1), anti-2h/syn-2h as a yellow oil (670 mg, 2.98 mmol, 11%, dr 1.0:2.4), and syn-2h as a yellow oil (333 mg, 1.48 mmol, 6%, dr 18:1); anti-2h: Rf = 0.56 (hexanes:Et2O 50:50); 1H NMR (500 MHz, CDCl3) δ 6.88 (dd, J = 10.0, 3.7 Hz, 1H), 6.49 (d, J = 3.7 Hz, 1H), 6.20 (d, J = 10.0 Hz, 1H), 5.79 (ddt, J = 17.0, 10.2, 6.7 Hz, 1H), 5.02-4.98 (m, 1H), 4.96-4.92 (m, 1H), 2.13 (s, 3H), 2.10-2.03 (m, 2H), 2.00-1.91 (m, 1H), 1.77-1.71 (m, 1H), 1.55-1.47 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 195.7, 169.7, 141.7, 138.4, 128.8, 115.0, 87.2, 75.5 (t), 33.6, 29.1, 24.0, 21.0; IR (neat) νmax 1751, 1700, 1640, 1220; ESI-HRMS calculated for C12H15DO4Na [M+Na]+ 248.1009, found 248.1019; syn2h: Rf = 0.47 (hexanes:Et2O 50:50); 1H NMR (500 MHz, CDCl3) δ 6.84 (dd, J = 10.3, 2.8 Hz, 1H), 6.54 (dd, J = 2.8, 1.3 Hz, 1 H), 6.21 (dd, J = 10.3, 1.3 Hz, 1H), 5.78 (ddt, J = 17.1, 10.3, 6.7 Hz, 1H), 5.04-4.98 (m, 1H), 4.98-4.93 (m, 1H), 2.13 (s, 3H), 2.12-2.01 (m, 2H), 1.88-1.82 (m, 2H), 1.65-1.48 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 195.7, 169.4, 142.8, 138.2, 128.4, 115.1, 87.6, 79.2 (t), 33.4, 32.4, 24.6, 21.1; IR (neat) νmax 1751, 1700, 1640, 1369, 1219, 1177, 911; ESI-HRMS calculated for C12H15DO4Na [M+Na]+ 248.1009, found 248.1017. After determination of the initial ratio (R0) of a mixture of hydrogenated anti-2a (10 mg, 0.046 mmol, 1.0 equiv.) and deuterated anti-2h (10 mg, 0.046 mmol, 1.0 equiv.) in CD3CN by 1H NMR, N-methylpyrrolidine (40 µL, 0.38 mmol, 4.1 equiv) was added. The reaction was allowed to stir


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at 23 °C. Crude 1H NMR analysis was utilized at various times to determine the final ratio (R) and the fractional conversion (F) and primary kinetic isotope effects were calculated.13,27 KIE data and calculations for the syn-2a/2h were obtained in a similar manner.13 Acetoxypyranone 2i: To a flame-dried, 2-neck, round bottom flask was added Mg0 turnings (111 mg, 4.57 mmol, 1.5 equiv), backfilled with argon, and allowed to stir vigorously overnight. To the flask was then added anhydrous Et2O (4 mL) and a condenser. Next, ~10% of 5-bromo-1pentene (410 µL, 3.69 mmol, 1.2 equiv) was added followed by I2. Upon initiation, remaining 5bromo-1-pentene was added dropwise over 10 min. The resulting solution was refluxed for 1 h, diluted with anhydrous Et2O (12 mL) and cooled to 0 °C. 5-d-furfural (297 mg, 3.06 mmol, 1.0 equiv) was added and the resulting solution was allowed to stir at 23 °C for 1 h at which point the reaction was quenched with sat. aq. NH4Cl (10 mL). The reaction was stirred for 10 min and was extracted with Et2O (15 mL). The combined organic solution was washed sequentially with sat. aq. NH4Cl (10 mL), H2O (10 mL), and brine (10 mL), dried with Na2SO4, filtered, and concentrated. Purification by flash column chromatography (hexanes:EtOAc 80:20) provided the alcohol as a colorless oil (118 mg, 0.71 mmol, 23%). To a solution of alcohol (97 mg, 0.58 mmol, 1.0 equiv) in CH2Cl2 (5.8 mL) was added VO(acac)2 (15 mg, 0.06 mmol, 0.1 equiv). The solution was cooled to 0 °C and 5.5 M tBuOOH in decane (160 µL, 0.87 mmol, 1.5 equiv) was added slowly. The reaction was warmed to 23 °C and stirred for 3 h, quenched with sat. aq. Na2S2O3 (5 mL) and stirred for 1 h. The resulting emulsion was diluted with CH2Cl2 (5 mL) and separated. The resulting aqueous solution was extracted with CH2Cl2 (3 × 5 mL). The combined organic layers were washed with sat. aq. Na2S2O3 (2 × 5 mL), dried with Na2SO4, filtered, and concentrated to provide crude hydroxypyranone. To a solution of hydroxypyranone (~0.58 mmol, 1.0 equiv) in anhydrous CH2Cl2 (3 mL) was added pyridine (65 µL, 0.81 mmol, 1.4 equiv) followed by acetyl chloride (82 µL, 1.16 mmol, 2 equiv) at 0 °C. The resulting solution was


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allowed to warm to 23 °C and stirred for 1 h. The solution was washed with ice cold sat. aq. NaCl (2 × 3 mL), dried with Na2SO4, filtered, and concentrated to afford crude 2i as a mixture of diastereomers (dr 2.7:1.0 anti/syn). Purification by flash column chromatography (hexanes:Et2O 75:25) delivered anti-2i as a yellow oil (27 mg, 0.12 mmol, 21%, dr >19:1) and anti-2i/syn-2i as a yellow oil (25 mg, 0.11 mmol, 19%, dr 1.0:1.0); anti-2i: Rf = 0.48 (hexanes:Et2O 50:50); 1H NMR (500 MHz, CDCl3) δ 6.87 (d, J = 10.2 Hz, 1H), 6.19 (d, J = 10.2 Hz, 1H), 5.82-5.74 (m, 1H), 5.02-4.98 (m, 1H), 4.96-4.93 (m, 1H), 4.46 (dd, J = 7.6, 4.0, 1H), 2.12 (s, 3H), 2.08-2.03 (m, 2H), 1.99-1.91 (m, 1H), 1.77-1.70 (m, 1H), 1.54-1.48 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 195.6, 169.7, 141.6, 138.4, 128.9, 115.0, 87.0 (t), 75.9, 33.5, 29.3, 24.1, 21.0; IR (neat) νmax 1753, 1697, 1640, 1227; ESI-HRMS calculated for C12H15DO4Na [M+Na]+ 248.1009, found 248.1015. After determination of the initial ratio (R0) of a mixture of hydrogenated anti-2a (10 mg, 0.046 mmol, 1.0 equiv.) and deuterated anti-2i (10 mg, 0.046 mmol, 1.0 equiv.) in CD3CN by 1H NMR, N-methylpyrrolidine (40 µL, 0.38 mmol, 4.1 equiv) was added. The reaction was allowed to stir at 23 °C. Crude 1H NMR analysis was utilized at various times to determine the final ratio (R) and the fractional conversion (F) and secondary kinetic isotope effects were calculated.27 Methyl-lactol 8a: To a vial was added methyl-ketone cycloadduct 6a (30 mg, 0.145 mmol, 1.0 equiv.) followed by THF (2 mL) and H2O (200 µL). To this solution was added LiOH (4.2 mg, 0.17 mmol, 1.2 equiv.). The reaction was capped and allowed to stir for 2 h at room temperature. The reaction was then acidified with addition of 1 N HCl, diluted with brine (2 mL), and extracted with EtOAc (2 × 3 mL). Organics were combined, and concentrated via rotary evaporation. Purification by flash chromatography (hexanes:EtOAc 70:30) afforded lactol 8a as a white solid (25.7 mg, 0.116 mmol, 80%, dr >19:1): Rf = 0.32 (hexanes:EtOAc 60:40); 1H NMR (500 MHz, CDCl3) δ 5.35 (dd, J = 6.9, 6.1 Hz, 1H), 4.63 (ddd, J = 6.9, 4.3, 1.8 Hz, 1H), 2.70 (br.


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s, 1H), 2.69 (dd, J = 16.1, 4.3 Hz, 1H), 2.47 (dd, J = 16.2, 1.8 Hz, 1H), 2.44 (dd, J = 6.1, 2.8 Hz, 1H), 2.25-2.22 (m, 1H), 2.15 (ddd, J = 9.5, 7.3, 2.8 Hz, 1H), 2.05-1.98 (m, 1H), 1.95-1.87 (m, 1H), 1.79-1.74 (m, 2H), 1.57-1.50 (m, 1H), 1.47 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 211.2, 104.2, 99.9, 84.2, 73.1, 58.0, 52.1, 41.0, 33.5, 32.3, 27.2, 24.2; IR (neat) νmax 3442, 1713, 1151 cm-1; ESI-HRMS calculated for C12H16O4Na [M+Na]+ 247.0946, found 247.0948.14 Ethyl-lactol 8h: To a vial was added methyl-ketone cycloadduct 6h (53 mg, 0.241 mmol, 1.0 equiv.) followed by THF (2.2 mL) and H2O (220 µL). To this solution was added LiOH (20 mg, 0.481 mmol, 2 equiv.). The reaction was capped and allowed to stir for 24 h at room temperature. The reaction was then acidified with addition of 1 N HCl, diluted with brine (5 mL), and extracted with EtOAc (2 × 5 mL). Organics were combined, dried over Na2SO4 and concentrated via rotary evaporation. Purification by flash chromatography (hexanes:EtOAc 80:20) afforded lactol 8h as a white solid (23.9 mg, 0.100 mmol, 41%, dr >19:1): Rf = 0.19 (hexanes:EtOAc 70:30); 1H NMR (400 MHz, CDCl3) δ 5.36 (dd, J = 7.1, 5.9 Hz, 1H), 4.67 (ddd, J = 7.1, 4.3, 1.8 Hz, 1H), 2.71 (dd, J = 16.1, 4.3 Hz, 1H), 2.49 (dd, J = 16.1, 1.8 Hz, 1H), 2.48 (dd, J = 5.9, 2.8 Hz, 1H), 2.30-2.21 (m, 1H), 2.15 (ddd, J = 9.4, 7.2, 2.8 Hz, 1H), 2.09-2.01 (m, 2H), 1.98-1.89 (m, 1H), 1.86-1.75 (m, 3H), 1.71-1.62 (m, 1H), 1.61-1.50 (m, 1H), 0.99 (t, 7.6 Hz, 3H);

13

C

NMR (100 MHz, CDCl3) δ 211.3, 106.9, 99.9, 83.8, 73.1, 56.1, 51.4, 41.2, 33.6, 32.4, 30.6, 27.2, 8.6; IR (neat) νmax 3368, 1728, 1147 cm-1; ESI-HRMS calculated for C13H18O4Na [M+Na]+ 261.1102, found 261.1102.14 Lactone 12: A solution of crude carboxylic acid 10 (100 mg, 0.48 mmol, 1.0 equiv) in CH3CN (1 mL) was heated at 120 °C in a microwave reactor for 20 min and then concentrated via rotary evaporation. Purification by flash column chromatography (CH2Cl2:acetone 95:5) afforded 12 as a pale yellow solid (36.3 mg, 0.174 mmol, 36%): Rf = 0.84 (CH2Cl2:acetone 90:10); 1H NMR (400 MHz, CDCl3) δ 5.39 (dd, J = 7.7, 7.0 Hz, 1H), 5.14 (ddd, J = 7.7, 5.9, 1.3 Hz, 1H), 2.93


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(dd, J = 7.0, 1.8 Hz, 1H), 2.91 (dd, J = 17.0, 5.9 Hz, 1H), 2.69 (dd, J = 17.0, 1.3 Hz, 1H), 2.53 (app. dt, J = 8.8, 1.8 Hz, 1H), 2.41-2.32 (m, 1H), 2.28-2.18 (m, 1H), 2.05-1.76 (m, 3H), 1.651.55 (m, 1H);

13

C NMR (100 MHZ, CDCl3) δ 207.7, 175.1, 100.2, 78.9, 75.8, 54.2, 47.8, 40.9,

33.8, 31.6, 26.7; IR (neat) νmax 1765, 1722, 1025 cm-1; ESI-HRMS calculated for C11H13O4 [M+H]+ 209.0814, found 209.0814.14 Amide 13 (not observed): To a solution of carboxylic acid 10 (50 mg, 0.24 mmol, 1.0 equiv) in DMF (1 mL) was added 4-methoxybenzylamine (40 µL, 0.29 mmol, 1.2 equiv), EDCI (55 mg, 0.29 mmol, 1.2 equiv), and DMAP (35 mg, 0.29 mmol, 1.2 equiv) sequentially at 0 °C. The reaction stirred for 30 min at 0 °C and then warmed to 23 °C for 30 min with continuous stirring. The reaction mixture was diluted with EtOAc (4 mL), quenched with 5% HCl (2 mL), and the layers were separated. The organic layer was washed sequentially with sat. aq. NaHCO3 (2 mL), water (2 mL), and brine (2 mL), dried with Na2SO4, filtered, and concentrated. Purification by flash column chromatography (CH2Cl2:acetone 80:20) afforded amide 11 as a white solid (21 mg, 0.06 mmol, 26%, dr >19:1): Rf = 0.70 (CH2Cl2:acetone 80:20); 1H NMR (500 MHz, CDCl3) δ 7.18-7.15 (m, 3H), 6.88-6.85 (m, 2H), 6.07 (d, J = 9.8 Hz, 1H), 5.92 (bs, 1H), 4.92 (dd, J = 6.1, 4.4 Hz, 1H), 4.38-4.30 (m, 2H), 3.79 (s, 3H), 2.92 (dd, J = 7.0, 6.1 Hz, 1H), 2.69 (ddd, J = 8.7, 7.0, 3.1 Hz, 1H), 2.24 (dt, J = 13.9, 8.7 Hz, 1H), 1.95-1.81 (m, 3H), 1.72-1.62 (m, 2H); 13C NMR (125 MHZ, CDCl3) δ 196.7, 169.5, 159.4, 150.0, 130.0, 129.3 (2), 127.2 (2), 114.4, 98.4, 77.1, 57.7, 55.5, 48.9, 43.5, 31.4, 30.0, 25.7; IR (neat) νmax 3297, 2960, 1692, 1646, 1512, 1239, 1034, 823 cm-1; ESI-HRMS calculated for C19H21NO4Na [M+Na]+ 350.1368, found 350.1358. A solution of amide 11 (20 mg, 0.06 mmol, 1.0 equiv) in PhCF3 (0.6 mL) was heated at 200 °C in a microwave reactor for 20 min and then concentrated via rotary evaporation. No reaction was observed.


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Computational Methods. Preliminary conformation searches of cycloadducts 6a, 6h, 15 and corresponding hydrates (cf. Scheme 10; Va) were performed previously.14 Initial structures were generated utilizing a systematic conformation searching approach, and minimized with the MMFF94 force field using the Spartan ‘02 software package (Wavefunction, Inc.). Multiple representative low energy conformers generated from the search were transferred to the Gaussian03 software package (Gaussian, Inc.), and geometries were optimized at the B3LYP level of theory, and a 6-31G** basis set with d(6) Cartesian diffuse functions. The conductor polarized continuum model (CPCM) was used to account for acetonitrile solvation effects on conformational energies. All relative energy values were reported in kcal/mol. All new quantum chemical calculations were performed using the Gaussian09 software suite.28 We employed the M06-2X29,30,31 model chemistry utilizing the int=ultrafine parameter and the 6-31+G(d,p) basis set for all quantum chemical calculations. For the kinetic isotope effect investigation, we utilized the B3LYP32,33,34,35,36 model chemistry, for which scaling factors for vibrational frequencies are readily available,37,38,39,40 and the 6-31+g(d,p) basis set. These methods and basis sets provide a reasonable compromise between chemical accuracy and computational affordability. Intrinsic reaction coordinate41,42,43 (IRC) calculations were performed on all putative transition state structures (TSSs) to verify the minima to which they are connected. Various orientations for substrate-NMP complexes were examined manually and the lowest energy structures are shown. Experimentally, the solvent system used consisted of 95% acetonitrile and 5% water. However, because our calculations rely on dielectric constants to calculate implicit solvent effects, it is difficult to predict the dielectric of the blended system. As such, we used 100% acetonitrile as an implicit solvent. The SMD44 polarizable continuum model was used for all solvent calculations. The calculations were run at the experimental temperatures used, which impacts the frequency calculation only and does not impact the geometries obtained


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as minima or TSSs. The temperature is taken into account in the thermochemistry analysis and thus impacts the final energies obtained but does not change the calculated frequencies. Ball-andstick structures presented above were created using the CylView45 software. During analysis, structures were visualized with GaussView versions 546 and 647. The Quiver48,49,50 software was employed to calculate theoretical kinetic isotope effect (KIE) values from computed frequency data (see Supporting Information for a description of the difficulties encountered in locating proton transfer TSSs). This software makes use of the following equation:

In this formula,

corresponds to the imaginary frequency for the 1H system,

imaginary frequency for the isotopomer of interest, and the

is the

values are the Bigeleisen-

Mayer function values for the starting material, SM, and the transition state structure, TS. SUPPORTING INFORMATION Spectra for all new compounds, x-ray parameters, and details on computations are available free of charge via the internet at http://pubs.acs.org ACKNOWLEDGMENTS Acknowledgment is made to the Donors of the American Chemical Society Petroleum Research Fund (PRF #52391-UNI1). Acknowledgment is made to the National Science Foundation: individual research award (T.A.M.) from the Research at Primarily Undergraduate Institution (RUI) program (CHE-1565644), NMR analysis (CHE-0722385) and mass spectrometry analysis


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(CHE-1337497) from departmental instrumentation obtained from the Major Research Instrumentation (MRI) program. Acknowledgment is made to the XSEDE program (CHE030089) for support of computational work (D.J.T.). Acknowledgment is made to the GAANN fellowship program from the U.S. Department of Education (H.B.W.). Acknowledgment is made to Prof. Eric Jacobsen and Dr. Michael Witten for helpful discussions (T.A.M.) regarding the synthesis of nitrogen substrates. REFERENCES (1) (a) N. Nishiwaki, Methods and Applications of Cycloaddition Reactions in Organic Synthesis, Wiley-VCH: Weinheim, 2014. (b) S. Kobayashi, K. A. Jørgensen, Cycloaddition Reactions in Organic Chemistry, Wiley-VCH: Weinheim, 2002. (c) W. Carruthers, Cycloaddition Reactions in Organic Chemistry, Volume 8 (Tetrahedron Organic Chemistry), Pergamon: Oxford, 1990. (2) (a) Diels, O.; Alder, K. Synthesen in der hydroaromatischen Reihe. Justus Liebigs Ann. Chem. 1928, 460, 98-122. (b) Nicolaou, K. C.; Snyder, S. A; Montagnon, T.; Vassilikogiannakis, G. The Diels-Alder Reaction in Total Synthesis. Angew. Chem. Int. Ed. 2002, 41, 1668-1698. (c) Corey, E. J. Catalytic Enantioselective Diels-Alder Reactions: Methods, Mechanistic Fundamentals, Pathways, and Applications. Angew. Chem. Int. Ed. 2002, 41, 1650-1667. (3) (a) Pellissier, H. Recent Developments in the [5 + 2] Cycloaddition. Adv. Synth. Catal. 2018, 360, 1551-1583. (b) Pellissier, H. Recent Developments in the [5 + 2] Cycloaddition. Adv. Synth. Catal. 2011, 353, 189-218. (4) (a) Ylijoki, K. E. O.; Stryker, J. M. [5 + 2] Cycloaddition Reactions in Organic and Natural Product Synthesis. Chem. Rev. 2013, 113, 2244-2266. (b) Nguyen, T. V.; Hartmann, J. M.; Enders, D. Recent Synthetic Strategies to Access Seven-Membered Carbocycles in Natural Product Synthesis. Synthesis 2013, 45, 845-873. (c) Battiste, M. A.; Pelphrey, P. M. Wright, D. L. The Cycloaddition Strategy for the Synthesis of Natural Products Containing Carbocyclic Seven-Membered Rings. Chem. Eur. J. 2006, 12, 3438-3447. (5) (a) Bejcek, L. P.; Murelli, R. P. Oxidopyrylium [5 + 2] cycloaddition chemistry: Historical Perspective and recent advances (2008-2018). Tetrahedron 2018, 74, 2501-2521. (b) Liu, X.; Hu, Y.-J.; Fan, J.-H.; Zhao, J.; Li, S.; Li, C.-C. Recent synthetic studies towards natural products via [5 + 2] cycloaddition reactions. Org. Chem. Front. 2018, 5, 1217-1228. (c) Singh, V.; Krishna, U. M.; Vikrant, Trivedi, G. K. Cycloaddition of oxidopyrylium species in organic synthesis. Tetrahedron, 2008, 64, 3405-3428. (d) Mascareñas, J. L. The [5 + 2] Cycloaddition Chemistry of β-Alkoxy-γ-pyrones. Advances in Cycloaddition, 1999, 6, 1-54.


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(50) A modified version of Quiver provided by Prof. Daniel Singleton (Texas A&M), from whom this software can be requested, was utilized.


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Oxidopyrylium-Alkene [5 + 2] Cycloaddition Conjugate Addition

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