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Supporting Online Material for

Total Synthesis of (+)-11,11'-Dideoxyverticillin A Justin Kim, James A. Ashenhurst, Mohammad Movassaghi*

*To whom correspondence should be addressed. E-mail: [email protected]

Published 10 April 2009, Science 324, 238 (2009)

DOI: 10.1126/science.1170777

This PDF file includes:

Materials and Methods SOM Text Figs. S1 to S5 Tables S1 to S14 References

Total Synthesis of (+)-11,11'-Dideoxyverticillin A Page S1 / S54 Justin Kim, James A. Ashenhurst, and Mohammad Movassaghi*

Total Synthesis of (+)-11,11'-Dideoxyverticillin A

Justin Kim, James A. Ashenhurst, and Mohammad Movassaghi*

Massachusetts Institute of Technology, Department of Chemistry Cambridge, Massachusetts 02139

Supporting Material

General Procedures S1 Materials S1 Instrumentation S2 Additional Notes and Fig. S1-S5 S3-5 (–)-(S)-Methyl 2-((S)-2-(tert-butoxycarbonylamino)-3-(1-(phenylsulfonyl)-1H-indol-3-yl)- propan-amido)propanoate (9) S6 (–)-(3S,6S)-3-Methyl-6-((1-(phenylsulfonyl)-1H-indol-3-yl)methyl)piperazine-2,5-dione (10) S7 Monomeric Tetracyclic Diketopiperazine Bromide (+)-11 S8 Monomeric Tetracyclic N-Methyl Diketopiperazine Bromide (+)-12 S9 Dimeric Octacyclic Diketopiperazine (+)-13 S10 Dimeric Octacyclic Tetraol (+)-14 S11 Dimeric Octacyclic Diol (+)-15 S12 Dimeric Octacyclic Diaminodiol (+)-16 S13 Dimeric Decacyclic Bisdithiepanethione (+)-18 S14 (+)-11,11'-Dideoxyverticillin A (1) S15-17 X-ray Diffraction Data for Dimeric Octacyclic Tetraol (+)-14 S18 X-ray Diffraction Data for (+)-11,11'-Dideoxyverticillin A (1) S27 References S34 Copy of 1H and 13C NMR Spectra S35 General Procedures. All reactions were performed in oven-dried or flame-dried round-bottomed flasks. The flasks were fitted with rubber septa and reactions were conducted under a positive pressure of argon. Stainless steel syringes or cannulae were used to transfer air- and moisture-sensitive liquids. Where necessary (so noted), solutions were deoxygenated by dinitrogen purging for a minimum of 10 min. Flash column chromatography was performed as described by Still et al. using granular silica gel (60-Å pore size, 40–63 µm, 4-6% H2O content, Zeochem) (S1). Analytical thin–layer chromatography was performed using glass plates pre-coated with 0.25 mm 230–400 mesh silica gel impregnated with a fluorescent indicator (254 nm). Thin layer chromatography plates were visualized by exposure to ultraviolet light and an aqueous solution of ceric ammonium molybdate (CAM) followed by heating (>1 min) on a hot plate (~250 ºC). Organic solutions were concentrated on Büchi R-200 rotary evaporators at ~20 torr (house vacuum) at 25–35 °C. Materials. Commercial reagents and solvents were used as received with the following exceptions: dichloromethane, acetonitrile, tetrahydrofuran, methanol, pyridine, and triethylamine were purchased from J.T. Baker (CycletainerTM) and were purified by the method of Grubbs et al. under positive argon pressure (S2).


Instrumentation. Proton nuclear magnetic resonance (1H NMR) spectra were recorded with Varian inverse probe 500 INOVA and Varian 500 INOVA spectrometers, are reported in parts per million on the δ scale, and are referenced from the residual protium in the NMR solvent (CDCl3: δ 7.24 (CHCl3), DMSO-d6: δ 2.50 (DMSO-d5)). Data is reported as follows: chemical shift [multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constant(s) in Hertz, integration, assignment]. Carbon-13 nuclear magnetic resonance (13C NMR) spectra were recorded with a Varian 500 INOVA spectrometer, are reported in parts per million on the δ scale, and are referenced from the carbon resonances of the solvent (CDCl3: δ 77.23, DMSO-d6: δ 39.51). Data is reported as follows: chemical shift (assignment). Infrared data (IR) were obtained with a Perkin-Elmer 2000 FTIR, and are reported as follows: frequency of absorption (cm–1), intensity of absorption (s = strong, m = medium, w = weak, br = broad). Optical rotations were measured on a Jasco-1010 polarimeter. We are grateful to Dr. Li Li for obtaining the mass spectrometric data at the Department of Chemistry’s Instrumentation Facility, Massachusetts Institute of Technology. The structure of dimeric octacyclic tetraol (+)-14 and (+)-11,11'-dideoxyverticillin A (1) were obtained with the assistance of Dr. Peter Müller at the X-ray diffraction facility of the Department of Chemistry, Massachusetts Institute of Technology. Positional Numbering System. At least three numbering schemes for dimeric diketopiperazine alkaloids exist in the literature (S3-S5). In assigning the 1H and 13C NMR data of all intermediates en route to our total synthesis of (+)-1 we wished to employ a uniform numbering scheme. For ease of direct comparison, particularly between early intermediates, non-thiolated diketopiperazines, and advanced compounds, the numbering scheme used by Barrow for (+)-WIN-64821 (using positional numbers 1-18) was optimal and is used in this supporting document. In key instances the products are accompanied by the numbering system as shown below for this document. For consistency with Fenical’s report, when referring to (+)-1 by name we use the original numbering system found in the isolation report. The alternate name (not used) for (+)-1 would be “(+)-12,12'-dideoxyverticillin A”.

NH

N

H

HN

N

H

NN

O

O

O

O

Me

Me

S

S

S

S

12

17

11a

10b

7

6

9

5

11

1

3

(+)-11,11'-Dideoxyverticillin A (1)

NH

N

H

HN

N

H

NN

O

O

O

O

Me

Me

S

S

S

S18

17

11

3

8

1

6

10

12

13

1510a

6a

5a

NH

N

H

HN

N

H

NHHN

O

O

O

O17

11

3

8

1

6

10

12

13

15Ph

Fenical's isolation report This document

MeMe

Ph

MeMe

(+)-WIN-64821 (+)-1

Barrow's numbering for the simpler diketopiperazine

framework


Additional Notes. A) The halocyclization of the diketopiperazine (–)-10.

NSO2Ph

N

H

NH

O

O

Br

(+)-11, 76%

PhO2SNHN

NH

O

O

Me

Br2

MeCN, 0 °C

(–)-10

H

Me

H2

3

NSO2Ph

N

H

NH

O

O

BrH

Me

H+2

3

(–)-S1, 19%

Fig. S1. Diastereoselective synthesis of tetracyclic diketopiperazine bromide (+)-11. • Under the optimal reaction conditions, the tetracyclic diketopiperazine bromide (+)-11 was

the major product of the halocyclization (76%), and the corresponding (2R,3R)-diastereomer (–)-S1 was isolated in 19% yield.

• Use of excess bromine was necessary for complete conversion of (–)-10 to tetracyclic bromide (+)-11. The amount of bromine used did not affect the level of diastereoselection.

• Lower reaction temperatures (–40 °C) resulted in a slightly higher level of diastereoselection (5:1) albeit with less efficient conversion.

• The use of several other less electrophilic halogenating agents was less effective. B) Sensitivity and epimerization of tetracyclic and dimeric octacyclic diketopiperazines.

N

O

N

Me

ONSO2Ph

H

BrH

H

KOEt

EtOH, 23 °C61%

N

O

N

Me

ONSO2Ph

H

Br

S2

H

H

(+)-12

Me Me

Fig. S2. Epimerization of tetracyclic diketopiperazine (+)-12.

11

152

• Treatment of the base sensitive tetracyclic bromide (+)-12 with potassium ethoxide resulted in

epimerization to the (11R)-diastereomer S2 in 61% yield. The trans-diketopiperazine substructure of S2 is directly assigned by exclusion of known cis-diastereomers (both endo- and exo-diketopiperazines). The C11 stereochemistry is consistent with the chemical shift of the D-tryptophan derivatives in this series.

Cs2CO3, CD3OD

orNaOEt, EtOH

NSO2Ph

N

H

SO2PhN

N

H

NN

O

O

O

OR

R

Me

R

R

Me

11

R = H, S3R = D, S3-d4

15

11'

(+)-13

15'

Me Me

NSO2Ph

N

H

SO2PhN

N

H

NN

O

O

O

OH

H

Me

H

H

Me

11

15

11'

15'

Me Me

Fig. S3. Deuterium incorporation and epimerization studies of dimeric octacyclic diketopiperazine (+)-13.

H H

3%

% nOe

3%

• No immediate deuterium incorporation into (+)-13 was observed upon its dissolution in

methanol-d4 in the absence of a base additive. • However, dissolution of dimeric octacyclic diketopiperazine (+)-13 in methanol-d4 with

cesium carbonate (10 equiv) at 23 °C lead to complete deuterium incorporation at all four Cα-methines, rapidly giving a complex mixture of diastereomers. Within 6 h, the major product was the corresponding (11R,11'R)-diastereomer S3-d4 as a single symmetrical diastereomer. The stereochemistry of S3-d4 was assigned by analogy to the non-deuterated sample prepared below.

• Treatment of dimeric diketopiperazine (+)-13 with sodium ethoxide (20 equiv) in ethanol at 23 °C resulted in the (11R,11'R)-S3 in 75% yield. The stereochemistry of C11 was assigned based on observed key nOe data (Fig. S3).


• Octacyclic dimer S3 is less prone to enolization at C11 as compared to (+)-13. While treatment of S3 with cesium carbonate in methanol-d4 at 23 °C did not result in deuterium incorporation at C11 of S3, after reflux for 12 h full deuterium incorporation was observed giving S3-d4.

• Taken together these observations highlight the preference for conversion of the L-tryptophan derived (11S)-stereochemistry of (+)-13 to the corresponding (11R)-stereochemistry, an observation that played a key role in our ultimate strategy for securing the carbon-sulfur C11- and C11'-stereochemistry (and by relay the C15- and C15'-stereochemistry).

C) Comparison of the base stability of octacyclic tetraol (+)-14 with octacyclic diol (+)-15. • Treatment of a solution of octacyclic tetraol (+)-14 in chloroform-d1 with 1,8-

diazabicyclo[5.4.0]undec-7-ene (10 equiv) at 23 °C led to immediate signal broadening (in situ 1H NMR monitoring) and decomposition. In contrast, treatment of the octacyclic diol (+)-15 under identical conditions led to no observable change or decomposition over 24 h and resulted in full recovery of (+)-15.

• The low mass balance in the conversion of octacyclic tetraol (+)-14 to alkaloid (+)-1 (Fig. 4C) may be due in part to competing reduction of the tautomeric α-ketoamide 27 (Fig. 4B) or the corresponding derivative from the highly sensitive diaminotetraol 28 (Fig. 4C).  

D) Oxidation of the (11R,11'R)-octacyclic diketopiperazine S3 using the optimal reaction conditions.

NSO2Ph

N

H

SO2PhN

N

H

NN

O

O

O

OH

H

11

15

11'

15'

Me Me

S3

Py2AgMnO4

CH2Cl2, 23 °C2 h

68% NSO2Ph

N

H

SO2PhN

N

H

NN

O

O

O

OH

H

Me

OH

HO

Me

11

15

11'

15'

Me Me

S4

Fig. S4. Oxidation of the dimeric octacyclic diketopiperazine S3.

Me

Me

• Treatment of (11R,11'R)-octacyclic diketopiperazine S3 with Py2AgMnO4 under the optimal

conditions developed for octacyclic dimer (+)-13 led to isolation of diol S4 as a single diastereomer in 68% yield. The C11 and C11' methines were not hydroxylated, whereas C15 and C15' methines were both hydroxylated.

E) Notes on the optimal conditions used for tetrahydroxylation of octacyclic dimer (+)-13. • The Cα-methine of amino acids has an approximate bond dissociation (BDE) energy of 82–96

kcal/mol that varies as a function of the φ,ψ angles (S6-S7). • While several representative amino acid derived cyclic-substrates, including 13, 21, 24, and

S3, were successfully oxidized under these conditions at the desired Cα-methines, the unsuccessful oxidation of simple N-acetyl-L-proline methyl ester and N-acetyl-L-alanine methyl ester highlight the sensitivity of this chemistry to subtle variations in BDE’s of the Cα-methines of interest. Geometrical constraints in the successful substrates may in part be responsible for lower BDE’s.


F) Synthesis of epidithiodiketopiperazines.

11

15

NSO2Ph

N

H

N

O

O

H

Me

H

Me

21

1. NBS, AIBN, 80 °C2. NaI, 2-Me-2-butene 88% (2-steps)

NSO2Ph

N

H

N

O

O

Me

S5

NSO2Ph

N

H

N

O

O

Me

S

S

BF3•OEt2, H2S PhSSPh

23 °C, 28 h53%

MeMe Me Me

3

1. Py2AgMnO42. TFA, CH2Cl2 59% (2-steps)

23, >2:1 dr

or

Fig. S5. Synthesis of the pentacyclic epidithiodiketopiperazine 23. • We initially prepared diene S5 via a sequence involving free-radical bromination to a

tetrabromide intermediate that was converted to the diene of interest in 88% yield (2-steps). • While these bromination conditions did not translate to the necessary conversion of dimeric

octacyclic diketopiperazine (+)-13 to the corresponding tetraene 26 (Fig. 4B), they did provide us with insight that led to the development of the optimal conditions.

• Diene S5 was later accessed by permanganate oxidation of tetracyclic diketopiperazine 21 to the corresponding diol 22 (Fig. 4) followed by acid promoted dehydration, a reaction pathway later observed in rapid dehydration of tetraol (+)-14 to tetraene 26 (Fig. 4B). In tetracyclic model systems, oxidation of the diketopiperazine was also possible by sequential treatment with potassium hexamethyldisilazide and Davis oxaziridine to give the corresponding diols. However, these conditions were highly ineffective in the more challenging dimeric diketopiperazine series, requiring the development of the stereoselective tetrahydroxylation strategy described in the text.

• Treatment of diene S5 with hydrogen sulfide in the presence of a Lewis acid and diphenyl disulfide (an internal oxidant we included for efficient disulfide formation), gave the desired pentacyclic epidithiodiketopiperazine 23.

• In this model system and the closely related C3-allyl series, the epidithiodiketopiperazines are formed with at least 2:1 diastereomeric ratio favoring the diastereomer with the desired C11 and C15 stereochemistry–(11S,15S)–as supported by circular dichroism (CD) studies. Even higher levels of C11-stereochemical control were observed with other alkyl thiols nucleophiles.

• Importantly, the level of diastereoselection favoring the desired and natural stereochemistry is greatly enhanced in the dimeric system with a larger C3 (and C3') substituent.

• It is important to note that simple exposure of the penultimate intermediate 5 to air leads to direct and rapid formation of (+)-1, suggesting the cis-dithiodiketopiperazine stereochemistry of 5 as illustrated (Fig. 3). A series of studies for the nucleophilic introduction of the carbon–sulfur bonds at C11 and C15, including those described above for synthesis of 23, all point to a high preference for nucleophilic thiol addition at C11 favoring the (11S)-stereochemistry. While the proposed C11 and C15 stereochemistry of (+)-18 could not be confirmed by nOe studies, the proposed intermolecular nucleophilic addition at C11 of 17 are consistent with the inferred stereochemistry for (+)-18 based on the above observations, rapid air oxidation of 5, and the X-ray structure of (+)-1.

G) Use of PPY in silylation of octacyclic tetraol (+)-14. • Fu’s (R)-(+)-4-pyrrolidinopyrindinyl(pentamethylcyclopentadienyl)iron catalyst (PPY) was

the most effective additive for the silylation of (+)-14. The use of 4-dimethylaminopyridine (DMAP), or 4-pyrrolidinopyridine provided the desired diol (+)-15 in 46% and 52% yield, respectively.

• Interestingly, the use of (S)-PPY in this transformation provided the desired product in only 36% yield.

• Based on analysis of the crude reaction mixture, the greater efficiency of PPY over DMAP (55% vs. 46%) in this transformation is thought to be the enhanced selectivity for silylation of the C15 alcohol over the C11 alcohol. Only one t-butyldimethylsilyl group per diketopiperazine substructure is allowed, and the attenuation of the C15 alcohol reactivity is critical.


NHBoc

CO2H

PhO2SN

(–)-S6

MeO2C

HCl•H2N

Me

(–)-S7

EDC•HCl, HOBt

Et3N, CH2Cl223 ºC, 14 h

95 %

102

5

8

1213 16

17

(–)-9

PhO2SN

O

NHBoc

HN

Me

CO2Me

(–)-(S)-Methyl 2-((S)-2-(tert-butoxycarbonylamino)-3-(1-(phenylsulfonyl)-1H-indol-3-yl)propan-amido)propanoate (9): A round-bottomed flask was charged sequentially with N-sulfonylated tryptophan (–)-S6 (S8) (8.16 g, 18.4 mmol, 1 equiv, >99% ee, prepared from commercially available N-Boc tryptophan in one step), N-hydroxybenzotriazole, (3.74 g, 27.6 mmol, 1.50 equiv), L-alanine methyl ester hydrochloride (S7, 3.81 g, 27.3 mmol, 1.48 equiv), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (5.60 g, 34.2 mmol, 1.85 equiv), and powdered 4Å molecular sieves (4.0 g), and the contents were placed under an atmosphere of argon. Anhydrous dichloromethane (180 mL) was introduced via cannula and the resulting mixture was placed in an ice-water bath. After 30 min, triethylamine (11.5 mL, 82.5 mmol, 4.48 equiv) was added via syringe and the mixture was allowed to warm slowly to room temperature. After 14 h, aqueous potassium hydrogen sulfate solution (1M, 150 mL) was added, and the mixture was extracted. The organic layer was washed with saturated aqueous sodium bicarbonate solution (150 mL), was washed with deionized water (150 mL), was dried over anhydrous sodium sulfate, was filtered, and was concentrated under reduced pressure. The resulting colorless foam was purified by flash column chromatography on silica gel (eluent: 40% ethyl acetate in hexanes) to provide dipeptide (–)-9 (9.30 g, 95%) as a colorless foam. 1H NMR (500 MHz, CDCl3, 20 ºC): δ 7.95 (d, J = 8.3, 1H, C8H), 7.84 (d, J = 8.2, 2H,

SO2Ph-o-H ), 7.54 (d, J = 7.8, 1H, C5H), 7.51 (t, J = 7.4, 1H, SO2Ph-p-H), 7.43 (s, 1H, C2H), 7.41 (app-t, J = 7.7, 2H, SO2Ph-m-H), 7.30 (app-t, J = 7.6, 1H, C7H), 7.22 (app-t, J = 7.5, 1H, C6H), 6.39 (d, J = 7.0, 1H, NamideH), 5.06 (s, 1H, NBocH), 4.50-4.43 (m, 1H, C11H), 4.43-4.37 (q, J = 7.1, 1H, C15H), 3.68 (s, 3H, OCH3), 3.22-3.07 (br-d, J = 6.3, 2H, C12H), 1.41 (s, 9H, C(CH3)3, 1.27 (d, J = 7.1, 3H, CCH3).

13C NMR (125.8 MHz, CDCl3, 20 ºC): δ 173.0 (C16), 170.7 (C13), 155.5 (Ccarbamate), 138.4 (SO2Ph-ipso-C), 135.4 (C9), 134.1 (SO2Ph-p-C), 130.9 (C4), 129.5 (SO2Ph-m-C), 127.0 (SO2Ph-o-C), 125.3 (C2), 124.8 (C7), 123.6 (C6), 119.9 (C5), 117.9 (C3), 113.9 (C8), 80.7 (OC(CH3)3), 54.5 (C11), 52.8 (OCH3), 48.4 (C15), 28.5 (OC(CH3)3), 28.1 (C12), 18.6 (C17).

FTIR (thin film) cm–1: 3387 (br-s), 2980 (w), 1658 (s), 1366 (m), 1175 (m).

HRMS (ESI) (m/z): calc’d for C26H32N3O7S [M+H]+: 530.1955, found: 530.1977. [α]D22: –6.4 (c = 1.0, DMF).

TLC (50% ethyl acetate in hexanes), Rf: 0.24 (UV, CAM).


(–)-9

1. TFA, CH2Cl2, 0 °C

2. t-BuOH, morpholine 48 h, 23 °C

84%

PhO2SNHN

NH

O

O

Me

(–)-10

12

5

1716

13

8

PhO2SN

O

NHBoc

HN

Me

CO2Me

(–)-(3S,6S)-3-Methyl-6-((1-(phenylsulfonyl)-1H-indol-3-yl)methyl)piperazine-2,5-dione (10): Trifluoroacetic acid (20 mL) was added to a solution of the dipeptide (–)-9 (3.81 g, 7.18 mmol, 1 equiv) in anhydrous dichloromethane (50 mL) at 0 °C. After 4 h, the resulting orange solution was concentrated, and the resulting orange–brown residue was dissolved in t-butanol (150 mL) and morpholine (30 mL) at 23 °C. After 4 h, a white precipitate was observed in the clear yellow reaction solution. After 44 h, the resulting thick white suspension was concentrated under reduced pressure. The resulting paste was dissolved in N,N–dimethylformamide (120 mL) at 65 °C and slowly poured into deionized water (120 mL) at 23 °C. After 12 h, the resulting suspension was filtered and was dried for 12 h at 50 °C under reduced pressure to afford the diketopiperazine (–)-10 (2.4 g, 84%) as a flocculent white solid. (The simple trituration of the product readily provides access to large quantities of the desired product (>20g) by allowing all prior steps to be carried out on multi-gram scale without chromatographic purification.) 1H NMR (500 MHz, DMSO-d6, 20 ºC): δ 8.18 (s, 1H, N10H), 8.06 (s, 1H, N14H), 7.90 (d, J

= 7.4, 2H, SO2Ph-o-H), 7.85 (d, J = 8.2, 1H, C8H), 7.67 (app-t, J = 6.8, 1H, SO2Ph-p-H), 7.63 (d, J = 7.9, 1H, C5H), 7.57 (app-t, J = 8.0, 2H, SO2Ph-m-H), 7.54 (s, 1H, C2H), 7.30 (app-t, J = 7.7, 1H, C7H), 7.22 (app-t, J = 7.8, 1H, C6H), 4.23 (app-t, J = 4.3, 1H, C11H), 3.66 (q, J = 7.0, 1H, C15H), 3.20 (dd, J = 14.5, 4.1, 1H, C12H), 3.00 (dd, J = 14.5, 4.7, 1H, C12H), 0.44 (d, J = 7.0, 3H, CCH3).

13C NMR (125.8 MHz, DMSO-d6, 20 ºC): δ 167.8 (C13), 166.5 (C16), 137.0 (SO2Ph-ipso-C), 134.5 (SO2Ph-p-C), 133.9 (C9), 130.9 (C4), 129.9 (SO2Ph-m-C), 126.6 (SO2Ph-o-C), 125.4 (C2), 124.7 (C7), 123.2 (C6), 120.5 (C5), 117.3 (C3), 112.8 (C8), 54.3 (C11), 49.6 (C15), 27.8 (C12), 19.3 (C17).

FTIR (Nujol mull) cm–1: 3180 (br, m), 2830 (m), 1662 (s), 1442 (s), 1374 (m).

HRMS (ESI) (m/z): calc’d for C20H19N3NaO4S [M+Na]+ : 420.0994, found: 420.0988.

[α]D22: –40 (c = 1.0, DMF).

M.p.: 260°C (dec). TLC (10% methanol in dichloromethane), Rf: 0.44 (UV, CAM).


2%1%

% nOe

5

8

2

NSO2Ph

N

H

NH

O

O

Br

(+)-11

13

PhO2SNHN

NH

O

O

Me

Br2

MeCN, 0 °C

76%(–)-10

H

Me

H

17

1%

2%

Monomeric Tetracyclic Diketopiperazine Bromide (+)-11: A solution of bromine (2.07 M, 12.0 mL, 24.9 mmol, 4.12 equiv) in acetonitrile was added over 15 seconds via syringe to a suspension of diketopiperazine (–)-10 (2.40 g, 6.04 mmol, 1 equiv) in acetonitrile (60 mL) at 0 °C. After 5 min, a mixture of saturated aqueous sodium thiosulfate solution and saturated aqueous sodium bicarbonate solution (1:1, 100 mL) was added to the resulting orange reaction solution. The mixture was extracted with ethyl acetate (3 × 200 mL), and the combined organic layers were dried over anhydrous sodium sulfate, were filtered, and were concentrated under reduced pressure to yield a colorless foamy residue. The residue along with silica gel (10 g) was dissolved in acetone (100 mL), and after 5 min the volatiles were removed under reduced pressure. The sample of product adsorbed onto silica gel was purified by flash column chromatography on silica gel (eluent: 10% isopropanol, 40% hexanes, 50% dichloromethane) to provide the desired endo-(2S,3S)-monomeric tetracyclic diketopiperazine bromide (+)-11 (2.19 g, 76%) as the major product. (The minor exo-(2R,3R)-diastereomer S1 was also isolated from this reaction (540 mg, 19%)). 1H NMR (500 MHz, CDCl3, 20 ºC): δ 7.94 (d, J = 7.6, 2H, SO2Ph-o-H), 7.56 (d, J =

8.2, 1H, C8H), 7.50 (t, J = 7.5, 1H, SO2Ph-p-H), 7.40 (app-t, J = 7.8, 2H, SO2Ph-m-H), 7.34 (d, J = 7.7, 1H, C5H), 7.29 (t, J = 8.5, 1H, C7H), 7.11 (t, J = 7.5, 1H, C6H), 6.24 (s, 1H, C2H), 5.39 (s, 1H, N14H), 4.42 (dd, J = 8.9, 5.9, 1H, C11H), 4.08 (q, J = 6.9, 1H, C15H), 3.37 (dd, J = 14.3, 5.9, 1H, C12Ha), 2.98 (dd, J = 14.3, 9.1, 1H, C12Hb), 1.47 (d, J = 6.9, 3H, CCH3).

13C NMR (125.8 MHz, CDCl3, 20 ºC): δ 168.5 (C16), 168.1 (C13), 138.9 (C9), 138.0 (SO2Ph-ipso-C), 133.9 (SO2Ph-p-C), 133.5 (C4), 131.1 (C7), 129.1 (SO2Ph-m-C), 128.4 (SO2Ph-o-C), 125.9 (C6), 125.0 (C5), 117.0 (C8), 87.1 (C2), 61.3 (C3), 58.8 (C11), 52.3 (C15), 40.0 (C12), 15.6 (C17).

FTIR (thin film) cm–1: 3409 (br, s), 1694 (s), 1364 (m), 1170 (m), 1090 (w).

HRMS (ESI) (m/z): calc’d for C20H18BrN3NaO4S [M+Na]+ : 498.0094, found: 498.0074.

[α]D22: +120 (c = 1.1, CHCl3).

M.p. (CDCl3): 93 °C (dec). TLC (10% isopropanol, 40% hexanes, 50% dichloromethane), Rf: 0.43 (UV, CAM).


K2CO3, MeI

Acetone, 23 °C

77 %

5

8

12

17

2

18

NSO2Ph

N

H

N

O

O

Br

(+)-12

NSO2Ph

N

H

NH

O

O

Me

Br

(+)-11

13H

Me

H

3%

1%% nOe

Me

Monomeric Tetracyclic N-Methyl Diketopiperazine Bromide (+)-12: Potassium carbonate (13.8 g, 99.8 mmol, 25.1 equiv) and methyl iodide (32 mL) were sequentially added to a vigorously stirred solution of tetracyclic amide (+)-11 (1.90 g, 3.98 mmol, 1 equiv) in acetone (48 mL) at 23 °C. The reaction flask was covered in aluminum foil, and the suspension was stirred for 5 days at 23 °C. The volatiles were removed, and the resulting white residue was partitioned between ethyl acetate (200 mL) and deionized water (200 mL). The layers were separated, and the aqueous layer was further extracted with ethyl acetate (200 mL). The combined organic layers were dried over anhydrous sodium sulfate, were filtered, and were concentrated under reduced pressure to provide crude (+)-12 as a yellow foam. This residue was purified by flash column chromatography on silica gel (eluent: 5% isopropyl alcohol, 45% dichloromethane, 50% hexanes) to afford the (11S)-monomeric tetracyclic N-methyl diketopiperazine bromide (+)-12 (1.32 g, 77%) as a colorless foam. (In addition to (+)-12, a minor (11R)-diastereomer was also isolated (11%), highlighting the sensitivity of this system to epimerization.) 1H NMR (500 MHz, CDCl3, 20 ºC): δ 7.92 (d, J = 7.9, 2H, SO2Ph-o-H), 7.54 (d, J =

8.0, 1H, C8H), 7.50 (t, J = 7.5, 1H, SO2Ph-p-H), 7.39 (app-t, J = 7.7, 2H, SO2Ph-m-H), 7.33 (d, J = 8.1, 1H, C5H), 7.27 (t, J = 8.3, 1H, C7H), 7.11 (t, J = 7.5, 1H, C6H), 6.24 (s, 1H, C2H), 4.35 (app-dd, J = 8.9, 6.5, 1H, C11H), 4.04 (q, J = 7.0, 1H, C14H), 3.34 (dd, J = 14.4, 6.6, 1H, C12Ha), 3.04 (dd, J = 14.4, 8.9, 1H, C12Hb), 2.89 (s, 3H, NCH3), 1.58 (d, J = 7.0, 3H, CCH3).

13C NMR (125.8 MHz, CDCl3, 20 ºC): δ 167.7 (C16), 167.4 (C13), 138.9 (C9), 138.0 (SO2Ph-ipso-C), 133.9 (C4), 133.8 (SO2Ph-p-C), 130.9 (C7), 129.1 (SO2Ph-m-C), 128.4 (SO2Ph-o-C), 126.0 (C6), 125.0 (C5), 117.1 (C8), 87.3 (C2), 61.1 (C3), 58.2 (C11), 57.2 (C14), 41.4 (C12), 29.7 (C18), 14.6 (C17).

FTIR (thin film) cm–1: 3440 (s, br), 1675 (s), 1384 (m), 1170 (m), 1090 (m).

HRMS (ESI) (m/z): calc’d for C21H20BrN3NaO4S [M+Na]+ : 512.0250, found: 512.0267.

[α]D22: +84 (c = 1.0, CHCl3).

TLC (5% isopropanol, 45% hexanes, 50% dichloromethane), Rf: 0.34 (UV, CAM).


NSO2Ph

N

H

SO2PhN

N

H

N

MeNO

O

O

OH

H

Me

H

H

Me

(+)-13

12

8 17

2

1813

CoCl(PPh3)3

Me2CO, 0 °C, 10 min

46 %

N

N

H

N

O

O

Me

Br

SO2Ph

(+)-12

% nOe

2%

1%

2%Me

Me11

Dimeric Octacyclic Diketopiperazine (+)-13: Tris(triphenylphosphine)cobalt (I) chloride complex (S9-S10) (442 mg, 502 µmol, 1.50 equiv) was added as a solid to a solution of tetracyclic bromide (+)-12 (164.0 mg, 334.4 µmol, 1 equiv) in anhydrous, degassed (N2 stream, 10 min) acetone (3.3 mL) at 0 °C. The reaction mixture was allowed to warm to 23 °C. After 10 min, the resulting blue-green solution was diluted with dichloromethane (20 mL) and partitioned with saturated aqueous ammonium chloride (20 mL). The organic layer was collected, and the aqueous layer was further extracted with dichloromethane (2 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, were filtered, and were concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluent: 5% isopropyl alcohol, 45% hexane, 50% dichloromethane) to yield dimeric octacyclic diketopiperazine (+)-13 (63.0 mg, 46%) as a colorless solid. On a 1.91-g scale the above procedure provided the desired product (+)-13 in 44% yield (701 mg). Notably, on larger scales (e.g., 8.07-g scale, 12:(11R)-12=5:1) this dimerization can provide the desired product (+)-13 with similar efficiency (2.41 g, 43%) even without the challenging chromatographic separation of the minor diastereomer (11R)-12 whose byproducts are easily separated post-dimerization. 1H NMR (500 MHz, CDCl3, 20 ºC): δ 8.07 (d, J = 7.7, 4H, SO2Ph-o-H), 7.60 (t, J = 7.3,

2H, SO2Ph-p-H), 7.52 (app-t, J = 7.7, 4H, SO2Ph-m-H), 7.32 (d, J = 7.6, 2H, C5H), 7.28 (t, J = 7.6, 2H, C7H), 7.19 (t, J = 7.5, 2H, C6H), 7.03 (d, J = 8.0, 2H, C8H), 6.42 (s, 2H, C2H), 4.58 (app-t, J = 8.9, 2H, C11H), 3.97 (q, J = 7.0, 2H, C15H), 2.82 (s, 6H, NCH3), 2.75 (dd, J = 15.0, 9.5, 2H, C12Ha), 2.56 (dd, J = 15.0, 8.6, 2H, C12Hb), 1.35 (d, J = 7.0, 6H, CCH3).

13C NMR (125.8 MHz, CDCl3, 20 ºC): δ 169.3 (C16), 168.2 (C13), 142.2 (C9), 141.7 (SO2Ph-ipso-C), 135.5 (C4), 133.1 (SO2Ph-p-C), 129.6 (C6), 129.1 (SO2Ph-m-C), 127.5 (C5), 127.2 (SO2Ph-o-C), 125.2 (C7), 117.4 (C8), 81.9 (C2), 59.5 (C3), 57.4 (C11), 57.1 (C15), 34.1 (C18), 29.9 (C12), 15.1 (C17).

FTIR (thin film) cm–1: 3064 (br, m), 1681 (s), 1478 (m), 1343 (s), 1163 (s).

HRMS (ESI) (m/z): calc’d for C42H40N6NaO8S2 [M+Na]+: 843.2241, found: 843.2260.

[α]D21: +21 (c = 1.0, CHCl3).

M.p.: 193–195 °C (dec). TLC (10% isopropanol, 40% dichloromethane, 50% hexanes), Rf: 0.39 (UV, CAM).


NSO2Ph

N

H

SO2PhN

N

H

NMe

MeNO

O

O

OOH

HO

Me

OH

HO

Me

(+)-14

Py2AgMnO4

CH2Cl223 °C, 2 h

63%NSO2Ph

N

H

SO2PhN

N

H

NMeMeN

O

O

O

O

Me

Me

(+)-13

12

8 17

2

18

13

Dimeric Octacyclic Tetraol (+)-14: Bis(pyridine)silver(I) permanganate (S11) (4.43 g, 11.5 mmol, 4.80 equiv) was added as a solid to a solution of dimeric octacyclic diketopiperazine (+)-13 (1.97 g, 2.40 mmol, 1 equiv) in anhydrous dichloromethane (24 mL) at 23 °C. After 2 h, the resulting thick brown suspension was poured into an aqueous sodium bisulfite solution (1 M, 100 mL), and the resulting mixture was extracted with dichloromethane (3 × 100 mL). The combined organic layers were washed with aqueous copper sulfate solution (1M, 1 × 100 mL), were dried over anhydrous sodium sulfate, were filtered, and were concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluent: 30% acetone in dichloromethane) to afford dimeric octacyclic tetraol (+)-14 as a colorless solid (1.33 g, 63%). Crystals suitable for X-ray diffraction were obtained by vapor diffusion of pentane into a saturated solution of dimeric octacyclic tetraol (+)-14 in acetone at 23 °C. For a thermal ellipsoid representation of (+)-14 see page S18. (Signal broadening in the 1H NMR spectrum of (+)-14 is partly attributed to the influence of hydrogen bonding by the C15OH. Silylation of this hydroxyl group dramatically decreases signal broadening in addition to providing a less polar compound evident by its Rf on silica gel.)

1H NMR (500 MHz, CDCl3, 20 ºC): δ 7.95 (d, J = 7.3, 4H, SO2Ph-o-H), 7.59 (t, J = 7.2,

2H, SO2Ph-p-H), 7.51 (app-t, J = 7.6, 4H, SO2Ph-m-H), 7.31 (br-s, 2H, C6H), 7.23-7.15 (m, 6H, C5H, C7H, C8H), 6.85 (s, 2H, C2H), 5.54 (br-s, 2H, OH), 4.07 (br-s, 2H, OH), 3.06 (d, J = 13.3, 2H, C12Ha, 2.89 (s, 6H, NCH3), 2.90-2.83 (br-d, 2H, C12Hb), 1.32 (s, 6H, CCH3).

13C NMR (125.8 MHz, CDCl3, 20 ºC): δ 169.3 (C16), 167.1 (C13), 142.1 (SO2Ph-ipso-C), 141.4 (C9), 134.0 (C4), 132.9 (SO2Ph-p-C), 129.9 (C6), 129.0 (SO2Ph-m-C), 126.8 (C5), 126.2 (SO2Ph-o-C), 125.0 (C7), 116.2 (C8), 86.6 (C11), 85.4 (C15), 82.6 (C2), 58.9 (C3), 43.8 (C12), 27.7 (C18), 23.1 (C17).

FTIR (thin film) cm–1: 3420 (br, m), 1684.3 (s), 1352 (s), 1168 (s), 1096 (m).

HRMS (ESI) (m/z): calc’d for C42H40N6NaO12S2 [M + Na]+: 907.2038, found: 907.2029.

[α]D21: +5.0 (c = 1.0, CHCl3).

M.p.: 181–185 °C (dec). TLC (50% acetone in dichloromethane), Rf: 0.22 (UV, CAM).


1%

N

H

SO2PhN

N

H

N

NO

O

O

OOH

HO

Me

OH

HO

Me

NSO2Ph

N

H

SO2PhN

N

H

N

NO

O

O

OOH

HO

Me

OSitBuMe2

Me2tBuSiO

Me

TBSCl, PPY

DMF, Et3N

23 °C, 30 min55%

N

Me

Me

Me

MeMeFe

N

PPY =

(+)-14 (+)-15

18

16

11

3

8 17

% nOe

1%MeMeMe Me

Dimeric Octacyclic Diol (+)-15: To a solution of dimeric octacyclic tetraol (+)-14 (11.8 mg, 13.3 µmol, 1 equiv) and (R)-(+)-4-pyrrolidinopyrindinyl(pentamethylcyclopentadienyl)iron (PPY, 0.3 mg, 0.7 µmol, 0.05 equiv) in anhydrous N,N-dimethylformamide (250 µL) at 23 °C was added triethylamine (11.1 µL, 79.8 µmol, 6.00 equiv) followed by tert-butyldimethylsilyl chloride (10.0 mg, 66.5 µmol, 5.00 equiv) in one portion. After 30 min, the reaction mixture was diluted with ethyl acetate (20 mL) and partitioned with saturated aqueous ammonium chloride solution (10 mL). The aqueous layer was further extracted with ethyl acetate (2 × 10 mL) and the combined organic layers were dried over anhydrous sodium sulfate, were filtered, and were concentrated under reduced pressure to provide a colorless solid. This solid was purified by flash column chromatography on silica gel (eluent: gradient, 10% ethyl acetate in hexanes to 30% ethyl acetate in hexanes) to afford the dimeric octacyclic diol (+)-15 (8.2 mg, 55%) as a white solid. 1H NMR (500 MHz, CDCl3, 20 ºC): δ 7.87 (d, J = 7.9, 4H, SO2Ph-o-H), 7.62 (br s, 2H,

C5H), 7.50 (t, J = 7.2, 2H, SO2Ph-p-H), 7.42 (t, J = 7.9, 4H, SO2Ph-m-H), 7.12 (m, 4H, C6H, C7H), 7.07-7.04 (m, 2H, C8H), 6.84 (s, 2H, C2H), 4.66 (s, 2H, OH), 3.26 (d, J = 15.1, 2H, C12Ha), 3.14 (d, J = 15.1, 2H, C12Hb), 2.87 (s, 6H, NCH3), 1.20 (s, 6H, CCH3), 0.80 (s, 18H, SiC(CH3)3), 0.11 (s, 6H, SiCH3), 0.10 (s, 6H, SiCH3).

13C NMR (125.8 MHz, CDCl3, 20 ºC): δ 168.1 (C16), 166.7 (C13), 143.0 (SO2Ph-ipso-C), 141.4 (C9), 134.1 (C4), 132.4 (SO2Ph-p-C), 129.5 (C7), 128.7 (SO2Ph-m-C), 126.3 (C5), 126.1 (SO2Ph-o-C), 124.9 (C6), 115.8 (C8), 87.0 (C15), 86.2 (C11), 82.5 (C2), 59.3 (C3), 44.7 (C12), 27.6 (C18), 25.8 (SiC(CH3)3), 25.5 (C17), 18.4 (SiC(CH3)3), –2.8 (SiCH3), –3.4 (SiCH3).

FTIR (thin film) cm–1: 3451 (br), 1722 (s), 1682 (s), 1358 (s), 1169 (s). HRMS (ESI) (m/z): calc’d for C54H68N6NaO12S2Si2 [M+Na]+:

1135.3767, found 1135.3733. [α]D22: +22 (c = 1.0, CHCl3).

M.p.: 138–141 °C (dec). TLC (30% ethyl acetate in hexanes), Rf: 0.26 (UV, CAM).


NH

N

H

HN

N

H

NMe

MeNO

O

O

OOH

HO

Me

OSitBuMe2

Me2tBuSiO

Me

(+)-16

5% Na(Hg), NaH2PO4

MeOH, 23 °C, 1 h

87%NSO2Ph

N

H

SO2PhN

N

H

NMe

MeNO

O

O

OOH

HO

Me

OSitBuMe2

Me2tBuSiO

Me

(+)-15

18

17

11

3

8 Dimeric Octacyclic Diaminodiol (+)-16: To a vigorously stirred white suspension of dimeric octacyclic diol (+)-15 (48.8 mg, 43.8 µmol, 1 equiv) and monobasic sodium phosphate (210 mg, 1.75 mmol, 40.0 equiv) in anhydrous methanol (1.7 mL) at 23 °C was added freshly prepared sodium amalgam (5%-Na, 370 mg, 803 µmol, 18.3 equiv Na) in one portion. After 51 min, a second portion of sodium amalgam (5%-Na, 370 mg, 803 µmol, 18.3 equiv Na) was added. After 15 min, the reaction mixture was diluted with ethyl acetate (20 mL) and partitioned with saturated aqueous sodium bicarbonate solution (20 mL). The aqueous layer was extracted with ethyl acetate (2 × 20 mL) and the combined organic layers were dried over anhydrous sodium sulfate, were filtered, and were concentrated under reduced pressure to afford a colorless solid. The solid was purified by flash column chromatography on silica gel (eluent: 30% ethyl acetate, 70% hexanes) to afford the dimeric octacyclic diaminodiol (+)-16 (31.8 mg, 87%) as a colorless solid. 1H NMR (500 MHz, CDCl3, 20 ºC): δ 7.14 (d, J = 7.6, 2H, C5H), 7.08 (app-t, J = 7.5

Hz, 2H, C7H), 6.75 (app-t, J = 7.4, 2H, C6H), 6.58 (d, J = 7.7, 2H, C8H), 5.86 (s, 2H, C2H), 5.53 (s, 2H, N1H), 4.24 (s, 2H, C11OH), 2.90 (s, 6H, NCH3), 2.85 (s, 4H, C12H), 1.68 (s, 6H, CCH3) , 0.85 (s, 18H, SiC(CH3)3), 0.23 (s, 6H, SiCH3), 0.14 (s, 6H, SiCH3).

13C NMR (125.8 MHz, CDCl3, 20 ºC): 167.7 (C13), 166.7 (C16), 148.6 (C9), 130.9 (C4), 129.3 (C7), 127.1 (C5), 119.2 (C6), 109.9 (C8), 87.1 (C15), 86.2 (C11), 82.0 (C2), 59.0 (C3), 44.4 (C12), 28.0 (C18), 25.7 (C(CH3)3), 23.8 (C17), 18.3 (C(CH3)3), –2.5 (SiCH3), –3.4 (SiCH3)

FTIR (thin film) cm–1: 3367 (br), 2929 (m), 1683 (s), 1387 (m), 1147 (m) HRMS (ESI) (m/z): calc’d for C42H60N6NaO8Si2 [M+Na]+: 855.3903

found: 855.3955 [α]D22: +98 (c = 0.77, CHCl3)

TLC (30% ethyl acetate in hexanes), Rf: 0.40 (UV, CAM).


TFA, CH2Cl2

K2CS3, 23 °C, 28 min

56%

8

3 11

17

18

NH

HN

N

S S

OO

Me

Me

S

HN

HN

N

SS

O O

Me

Me

S

(+)-18NH

N

H

HN

N

H

NMe

MeNO

O

O

OOH

HO

Me

OSitBuMe2

Me2tBuSiO

Me

(+)-16 Dimeric Decacyclic Bisdithiepanethione (+)-18: To a yellow solution of potassium trithiocarbonate (S12) (80.5 mg, 432 µmol, 10.0 equiv) in anhydrous dichloromethane (2.6 mL) and trifluoroacetic acid (1.1 mL) at 23 °C was added a solution of the dimeric diol (+)-16 (36.0 mg, 43.2 µmol, 1.00 equiv) in dichloromethane (700 µL). The transfer was completed with an additional portion of dichloromethane (300 µL). An additional portion of trifluoroacetic acid (100 µL) was added to the reaction mixture via syringe. After 28 min, the reaction mixture was diluted with dichloromethane (20 mL) and washed with saturated aqueous sodium bicarbonate (20 mL). The aqueous layer was extracted with dichloromethane (2 × 20 mL) and the combined organic layers were dried over anhydrous sodium sulfate, were filtered, and were concentrated under reduced pressure to yield a yellow powder. This powder was purified by flash column chromatography on silica gel (eluent: 3% acetone, 97% dichloromethane) to afford dimeric decacyclic bisdithiepanethione (+)-18 (18.3 mg, 56%) as a yellow powder. 1H NMR (500 MHz, CDCl3, 20 ºC): δ 7.33 (d, J = 7.6, 2H, C5H), 7.19 (app-t, J = 7.7

Hz, 2H, C7H), 6.90 (app-t, J = 7.4, 2H, C6H), 6.63 (d, J = 7.9, 2H, C8H), 5.48 (s, 2H, C2H), 5.13 (s, 2H, N1H), 3.50 (d, J = 15.2, 2H, C12Ha), 3.02 (s, 6H, NCH3), 2.75 (d, J = 15.2, 2H, C12Hb), 1.91 (s, 6H, CCH3).

13C NMR (125.8 MHz, CDCl3, 20 ºC): δ 215.4 (C19), 164.7 (C13), 161.8 (C16), 149.3 (C9), 131.0 (C7), 126.3 (C4), 126.0 (C5), 120.6 (C6), 111.0 (C8), 81.5 (C2), 74.9 (C11), 73.0 (C15), 59.0 (C3), 42.6 (C12), 28.5 (C18), 19.9 (C17).

FTIR (thin film) cm–1: 3364 (m, br), 1683 (s), 1608 (m), 1376 (m), 1003 (m).

HRMS (ESI) (m/z): calc’d for C32H29N6O4S6 [M+H]+: 753.0569 found: 753.0557

[α]D22: +280 (c = 1.0, CHCl3).

TLC (5% acetone in dichloromethane), Rf: 0.37 (UV, CAM).


NH

N

H

HN

N

H

NN

O

O

O

O

Me

Me

S

S

S

S

(+)-11,11'-Dideoxyverticillin A (1)

ethanolamine

acetone, 23 °C, 15 min;KI3, pyridine

62%

NH

HN

N

S S

OO

Me

Me

S

HN

HN

N

SS

O O

Me

Me

S

(+)-18

18

17

11

3

8

MeMe

(+)-11,11'-Dideoxyverticillin A (1): To a solution of the dimeric decacyclic bisdithiepanethione (+)-18 (11.8 mg, 15.7 µmol, 1.00 equiv) in acetone (500 µL) at 23 °C was added ethanolamine (500 µL) via syringe. After 15 min, the reaction mixture was diluted with dichloromethane (15 mL) and aqueous hydrochloric acid solution (1 N, 10 mL). The organic layer was collected, and the aqueous layer was extracted with dichloromethane (2 × 5 mL). A solution of potassium tri-iodide in pyridine (2.5% w/v) was added drop wise to the combined organic layers until a persistent yellow color was observed. The resulting mixture was washed with aqueous hydrochloric acid (1 N, 20 mL) and the layers were separated. The aqueous layer was extracted with dichloromethane (2 × 10 mL), and the combined organic layers were dried over anhydrous sodium sulfate, were filtered, and were concentrated under reduced pressure to provide a brown residue. The residue was purified by flash column chromatography on silica gel (eluent: gradient, 100% dichloromethane to 10% acetone in dichloromethane) to afford 11,11'-dideoxyverticillin A (+)-1 (6.5 mg, 62%) as a colorless solid. Crystals suitable for X-ray diffraction were obtained by vapor diffusion of pentane into a saturated solution of 11,11’-dideoxyverticillin A (+)-1 in dichloromethane at 4 °C. For a thermal ellipsoid representation of (+)-1 see page S27. 1H NMR (500 MHz, CDCl3, 20 ºC): δ 7.38 (d, J = 7.5 Hz, 2H, C5H), 7.20 (dt, J = 7.5,

1.0 Hz, 2H, C7H), 6.86 (dt, J = 7.5, 1.0 Hz, 2H, C6H), 6.70 (d, J = 8.0 Hz, 2H, C8H), 5.28 (s, 2H, N1H), 5.24 (s, 2H, C2H), 3.82 (d, J = 15.0 Hz, 2H, C12H), 2.95 (s, 6H, C18H), 2.72 (d, J = 15.0 Hz, 2H, C12H), 1.86 (s, 6H, C17H).

13C NMR (125.8 MHz, CDCl3, 20 ºC): δ 165.8 (C13), 162.7 (C16), 149.5 (C9), 130.5 (C7), 127.9 (C4), 125.3 (C5), 120.3 (C6), 110.8 (C8), 80.8 (C2), 73.8 (C11), 73.4 (C15), 60.0 (C3), 39.9 (C12), 27.7 (C18), 18.0 (C17).

FTIR (thin film) cm–1: 3367 (m), 1683 (s), 1608 (m), 1468 (m), 1349 (m), 1319 (m), 1254 (m), 1213 (m), 1066 (m), 753 (m).

HRMS (ESI) (m/z): calc’d for C30H29N6O4S4 [M+H]+: 665.1133, found: 665.1128.

[α]D21: +590 (c = 1.0, CHCl3).

TLC (10% acetone in dichloromethane), Rf: 0.52 (UV, CAM).


Table S1. Comparison of our data for (+)-11,11'-Dideoxyverticillin A (1) with literature:

Assignment* Fenical’s Report† (+)-11,11'-Dideoxyverticillin A (1)

1H NMR, 300 MHz, CDCl3

This Work (+)-11,11'-Dideoxyverticillin A (1) 1H NMR, 500 MHz, CDCl3, 20 ºC

N1 5.30 (s) 5.28 (s)

C2 5.26 (s) 5.24 (s)

C3 - -

C4 - -

C5 7.41 (d, J = 8.0 Hz) 7.38 (d, J = 7.5 Hz)

C6 6.88 (ddd, J = 8.0, 7.0, 1.0 Hz) 6.86 (app-dt, J = 7.5, 1.0 Hz)

C7 7.21 (ddd, J = 8.0, 7.0, 1.0 Hz) 7.20 (app-dt, J = 7.5, 1.0 Hz)

C8 6.72 (d, J = 8.0 Hz) 6.70 (d, J = 8.0 Hz)

C9 - -

N10 - -

C11 - -

C12 3.84 (dd, J = 15.3 Hz) 2.74 (dd, J = 15.3 Hz) 3.82 (d, J = 15.0 Hz) 2.72 (d, J = 15.0 Hz)

C13 - -

N14 - -

C15 - -

C16 - -

C17 1.88 (s) 1.86 (s)

C18 2.97 (s) 2.95 (s)

* Please see page S2 for the positional numbering system used here. † (S13)


Table S2. Comparison of our data for (+)-11,11'-dideoxyverticillin A (1) with literature continued:

Assignment* Fenical’s Report† (+)-11,11'-Dideoxyverticillin A (1)

13C NMR, 100 MHz, CDCl3

This Work (+)-11,11'-Dideoxyverticillin A (1)

13C NMR, 125.8 MHz, CDCl3, 20 ºC C2 80.6 80.8

C3 59.8 60.0

C4 127.8 127.9

C5 125.1 125.3

C6 120.1 120.3

C7 130.3 130.5

C8 110.6 110.8

C9 149.3 149.5

C11 73.7 73.8

C12 39.8 39.9

C13 165.6 165.8

C15 73.2 73.4

C16 162.5 162.7

C17 17.8 18.0

C18 27.5 27.7

* Please see page S2 for the positional numbering system used here. † (S13)


Crystal Structure of Dimeric Octacyclic Tetraol (+)-14.

View 1:

View 2:


Table S3. Crystal data and structure refinement for dimeric octacyclic tetraol (+)-14. Identification code d08036 Empirical formula C51 H58 N6 O15 S2* Formula weight 1059.15 Temperature 100(2) K Wavelength 1.54178 Å Crystal system Orthorhombic Space group P2(1)2(1)2(1) Unit cell dimensions a = 11.7728(2) Å a= 90°. b = 12.0547(2) Å b= 90°. c = 35.2767(6) Å g = 90°. Volume 5006.38(15) Å3 Z 4 Density (calculated) 1.405 Mg/m3 Absorption coefficient 1.611 mm-1 F(000) 2232 Crystal size 0.44 x 0.15 x 0.07 mm3 Theta range for data collection 2.50 to 67.57°. Index ranges -14


Table S4. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103) for dimeric octacyclic tetraol (+)-14. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. _________________________________________________________________ x y z U(eq) _________________________________________________________________ S(1) 4606(1) -163(1) 1713(1) 21(1) S(1') 10431(1) 1919(1) 1810(1) 22(1) O(1) 4052(1) -335(2) 787(1) 25(1) O(1') 10578(2) 3927(2) 1180(1) 30(1) O(2) 4409(2) -759(2) -5(1) 40(1) O(2') 10132(2) 5879(2) 763(1) 35(1) O(3') 6354(2) 5186(2) 853(1) 34(1) O(3) 8083(2) -863(2) 147(1) 29(1) O(4) 6251(2) 1082(2) 307(1) 26(1) O(4') 8149(2) 3453(2) 544(1) 26(1) O(5') 10287(2) 1278(2) 2146(1) 30(1) O(5) 4879(2) -413(2) 2098(1) 30(1) O(6) 4007(2) 833(2) 1622(1) 27(1) O(6') 10940(2) 1417(2) 1485(1) 29(1) N(1') 8684(2) 3592(2) 1168(1) 21(1) N(1) 5981(2) -148(2) 795(1) 20(1) N(2) 6227(2) -1370(2) 148(1) 24(1) N(2') 8190(2) 5722(2) 935(1) 28(1) N(3') 9159(2) 2371(2) 1688(1) 21(1) N(3) 5821(2) -152(2) 1481(1) 20(1) C(1) 7307(2) 852(2) 1162(1) 19(1) C(1') 7486(2) 2073(2) 1303(1) 19(1) C(2') 7215(2) 2224(2) 1724(1) 20(1) C(2) 7756(2) -15(2) 1437(1) 19(1) C(3') 6163(2) 2303(2) 1899(1) 23(1) C(3) 8872(2) -321(2) 1508(1) 23(1) C(4') 6122(2) 2479(2) 2288(1) 27(1) C(4) 9093(2) -1122(2) 1782(1) 27(1) C(5) 8202(2) -1639(2) 1972(1) 27(1) C(5') 7114(2) 2601(2) 2496(1) 27(1) C(6') 8170(2) 2553(2) 2321(1) 25(1) C(6) 7078(2) -1375(2) 1891(1) 25(1) C(7') 8200(2) 2371(2) 1934(1) 21(1) C(7) 6880(2) -553(2) 1623(1) 20(1) C(8') 8763(2) 2441(2) 1293(1) 19(1) C(8) 6025(2) 523(2) 1141(1) 19(1) C(9') 9623(2) 4247(2) 1121(1) 25(1) C(9) 4978(2) -507(2) 646(1) 22(1) C(10) 5062(2) -1251(2) 289(1) 26(1) C(10') 9384(2) 5478(2) 1042(1) 29(1) C(11') 7357(2) 4952(2) 905(1) 27(1) C(11) 7108(2) -727(2) 254(1) 23(1) C(12) 6796(2) 234(2) 517(1) 21(1) C(12') 7741(2) 3745(2) 911(1) 22(1) C(13') 6844(2) 2928(2) 1052(1) 21(1) C(13) 7787(2) 682(2) 753(1) 21(1) C(14') 9673(3) 6079(2) 1411(1) 33(1) C(14) 4582(3) -2383(2) 401(1) 36(1) C(15') 7874(3) 6893(2) 896(1) 38(1) C(15) 6450(2) -2256(2) -126(1) 31(1)


C(16) 3813(2) -1292(2) 1532(1) 24(1) C(16') 11238(2) 3106(2) 1935(1) 22(1) C(17') 10736(2) 4045(2) 2083(1) 26(1) C(17) 4350(2) -2296(2) 1462(1) 29(1) C(18') 11423(2) 4897(2) 2210(1) 29(1) C(18) 3717(3) -3172(2) 1326(1) 37(1) C(19) 2568(3) -3041(3) 1257(1) 39(1) C(19') 12596(2) 4810(2) 2187(1) 34(1) C(20') 13081(2) 3854(2) 2034(1) 35(1) C(20) 2045(2) -2035(3) 1329(1) 36(1) C(21') 12406(2) 2992(2) 1907(1) 28(1) C(21) 2669(2) -1138(2) 1465(1) 30(1) O(1S) 7446(2) 2014(2) -275(1) 42(1) C(1S) 7864(2) 1767(2) -577(1) 30(1) C(2S) 8236(4) 2625(3) -850(1) 56(1) C(3S) 7995(3) 594(3) -703(1) 45(1) O(1T) 7238(2) 4705(2) -36(1) 32(1) C(1T) 6352(2) 4527(2) -207(1) 28(1) C(2T) 6152(3) 4999(3) -591(1) 38(1) C(3T) 5421(3) 3844(3) -36(1) 43(1) O(1U) 7474(2) 4907(2) 1783(1) 56(1) C(1U) 6921(3) 5293(2) 2040(1) 36(1) C(2U) 5672(3) 5455(3) 2004(1) 48(1) C(3U) 7469(2) 5592(2) 2411(1) 26(1) __________________________________________________________________ Table S5. Bond lengths [Å] and angles [°] for dimeric octacyclic tetraol (+)-14. _____________________________________ S(1)-O(5) 1.4277(19) S(1)-O(6) 1.4285(19) S(1)-N(3) 1.6484(19) S(1)-C(16) 1.769(2) S(1')-O(5') 1.4271(19) S(1')-O(6') 1.4289(19) S(1')-N(3') 1.650(2) S(1')-C(16') 1.773(2) O(1)-C(9) 1.216(3) O(1')-C(9') 1.206(3) O(2)-C(10) 1.423(3) O(2')-C(10') 1.405(3) O(3')-C(11') 1.227(3) O(3)-C(11) 1.221(3) O(4)-C(12) 1.416(3) O(4')-C(12') 1.424(3) N(1')-C(9') 1.369(3) N(1')-C(12') 1.444(3) N(1')-C(8') 1.460(3) N(1)-C(9) 1.365(3) N(1)-C(12) 1.447(3) N(1)-C(8) 1.463(3) N(2)-C(11) 1.348(3) N(2)-C(15) 1.465(3) N(2)-C(10) 1.466(3) N(2')-C(11') 1.354(3)

N(2')-C(15') 1.466(4) N(2')-C(10') 1.485(3) N(3')-C(7') 1.423(3) N(3')-C(8') 1.473(3) N(3)-C(7) 1.428(3) N(3)-C(8) 1.469(3) C(1)-C(2) 1.520(3) C(1)-C(8) 1.562(3) C(1)-C(13) 1.564(3) C(1)-C(1') 1.568(3) C(1')-C(2') 1.527(3) C(1')-C(13') 1.556(3) C(1')-C(8') 1.568(3) C(2')-C(3') 1.388(3) C(2')-C(7') 1.388(3) C(2)-C(7) 1.384(3) C(2)-C(3) 1.388(3) C(3')-C(4') 1.389(4) C(3)-C(4) 1.391(4) C(4')-C(5') 1.387(4) C(4)-C(5) 1.393(4) C(5)-C(6) 1.391(4) C(5')-C(6') 1.390(4) C(6')-C(7') 1.384(3) C(6)-C(7) 1.389(4) C(9')-C(10') 1.537(4) C(9)-C(10) 1.548(3) C(10)-C(14) 1.528(4) C(10')-C(14') 1.529(4)


C(11')-C(12') 1.523(4) C(11)-C(12) 1.529(3) C(12)-C(13) 1.531(3) C(12')-C(13') 1.529(3) C(16)-C(21) 1.380(4) C(16)-C(17) 1.387(4) C(16')-C(17') 1.379(4) C(16')-C(21') 1.386(4) C(17')-C(18') 1.382(4) C(17)-C(18) 1.379(4) C(18')-C(19') 1.388(4) C(18)-C(19) 1.383(4) C(19)-C(20) 1.385(4) C(19')-C(20') 1.395(4) C(20')-C(21') 1.382(4) C(20)-C(21) 1.391(4) O(1S)-C(1S) 1.211(3) C(1S)-C(2S) 1.481(4) C(1S)-C(3S) 1.490(4) O(1T)-C(1T) 1.223(3) C(1T)-C(2T) 1.491(4) C(1T)-C(3T) 1.498(4) O(1U)-C(1U) 1.206(4) C(1U)-C(2U) 1.489(5) C(1U)-C(3U) 1.505(4) O(5)-S(1)-O(6) 120.03(11) O(5)-S(1)-N(3) 106.17(10) O(6)-S(1)-N(3) 108.06(10) O(5)-S(1)-C(16) 107.44(11) O(6)-S(1)-C(16) 107.86(11) N(3)-S(1)-C(16) 106.56(11) O(5')-S(1')-O(6') 119.21(11) O(5')-S(1')-N(3') 106.68(11) O(6')-S(1')-N(3') 108.18(10) O(5')-S(1')-C(16') 107.12(11) O(6')-S(1')-C(16') 108.46(11) N(3')-S(1')-C(16') 106.53(11) C(9')-N(1')-C(12') 118.1(2) C(9')-N(1')-C(8') 122.2(2) C(12')-N(1')-C(8') 111.15(18) C(9)-N(1)-C(12) 114.38(19) C(9)-N(1)-C(8) 121.84(19) C(12)-N(1)-C(8) 111.38(18) C(11)-N(2)-C(15) 117.8(2) C(11)-N(2)-C(10) 124.6(2) C(15)-N(2)-C(10) 117.6(2) C(11')-N(2')-C(15') 118.0(2) C(11')-N(2')-C(10') 124.7(2) C(15')-N(2')-C(10') 117.1(2) C(7')-N(3')-C(8') 108.98(18) C(7')-N(3')-S(1') 124.19(16) C(8')-N(3')-S(1') 123.51(16) C(7)-N(3)-C(8) 109.33(18) C(7)-N(3)-S(1) 125.52(16) C(8)-N(3)-S(1) 123.51(16)

C(2)-C(1)-C(8) 101.07(18) C(2)-C(1)-C(13) 111.86(19) C(8)-C(1)-C(13) 105.73(18) C(2)-C(1)-C(1') 113.34(19) C(8)-C(1)-C(1') 112.60(18) C(13)-C(1)-C(1') 111.55(19) C(2')-C(1')-C(13') 111.83(19) C(2')-C(1')-C(8') 100.91(18) C(13')-C(1')-C(8') 105.41(18) C(2')-C(1')-C(1) 113.10(18) C(13')-C(1')-C(1) 112.03(18) C(8')-C(1')-C(1) 112.80(18) C(3')-C(2')-C(7') 119.9(2) C(3')-C(2')-C(1') 128.8(2) C(7')-C(2')-C(1') 111.1(2) C(7)-C(2)-C(3) 119.7(2) C(7)-C(2)-C(1) 111.4(2) C(3)-C(2)-C(1) 128.8(2) C(2')-C(3')-C(4') 118.8(2) C(2)-C(3)-C(4) 119.1(2) C(5')-C(4')-C(3') 120.7(2) C(3)-C(4)-C(5) 120.4(2) C(6)-C(5)-C(4) 120.9(2) C(4')-C(5')-C(6') 120.9(2) C(7')-C(6')-C(5') 117.9(2) C(7)-C(6)-C(5) 117.6(2) C(6')-C(7')-C(2') 121.8(2) C(6')-C(7')-N(3') 128.4(2) C(2')-C(7')-N(3') 109.7(2) C(2)-C(7)-C(6) 122.2(2) C(2)-C(7)-N(3) 109.0(2) C(6)-C(7)-N(3) 128.8(2) N(1')-C(8')-N(3') 111.20(18) N(1')-C(8')-C(1') 102.39(18) N(3')-C(8')-C(1') 105.39(18) N(1)-C(8)-N(3) 111.61(19) N(1)-C(8)-C(1) 102.40(17) N(3)-C(8)-C(1) 105.02(18) O(1')-C(9')-N(1') 123.3(2) O(1')-C(9')-C(10') 120.7(2) N(1')-C(9')-C(10') 115.5(2) O(1)-C(9)-N(1) 124.3(2) O(1)-C(9)-C(10) 119.3(2) N(1)-C(9)-C(10) 116.2(2) O(2)-C(10)-N(2) 107.3(2) O(2)-C(10)-C(14) 111.1(2) N(2)-C(10)-C(14) 110.3(2) O(2)-C(10)-C(9) 108.5(2) N(2)-C(10)-C(9) 113.2(2) C(14)-C(10)-C(9) 106.5(2) O(2')-C(10')-N(2') 110.4(2) O(2')-C(10')-C(14') 107.0(2) N(2')-C(10')-C(14') 109.5(2) O(2')-C(10')-C(9') 110.1(2) N(2')-C(10')-C(9') 114.3(2) C(14')-C(10')-C(9') 105.2(2)


O(3')-C(11')-N(2') 123.4(2) O(3')-C(11')-C(12') 120.5(2) N(2')-C(11')-C(12') 116.0(2) O(3)-C(11)-N(2) 124.0(2) O(3)-C(11)-C(12) 121.1(2) N(2)-C(11)-C(12) 114.8(2) O(4)-C(12)-N(1) 106.54(18) O(4)-C(12)-C(11) 109.79(19) N(1)-C(12)-C(11) 109.2(2) O(4)-C(12)-C(13) 112.0(2) N(1)-C(12)-C(13) 104.47(18) C(11)-C(12)-C(13) 114.4(2) O(4')-C(12')-N(1') 106.22(19) O(4')-C(12')-C(11') 108.9(2) N(1')-C(12')-C(11') 111.0(2) O(4')-C(12')-C(13') 111.74(19) N(1')-C(12')-C(13') 104.12(19) C(11')-C(12')-C(13') 114.5(2) C(12')-C(13')-C(1') 106.06(19) C(12)-C(13)-C(1) 105.77(18) C(21)-C(16)-C(17) 122.1(2) C(21)-C(16)-S(1) 118.2(2) C(17)-C(16)-S(1) 119.68(19) C(17')-C(16')-C(21') 122.2(2) C(17')-C(16')-S(1') 121.78(19)

C(21')-C(16')-S(1') 115.74(19) C(16')-C(17')-C(18') 118.8(2) C(18)-C(17)-C(16) 118.9(2) C(17')-C(18')-C(19') 120.5(3) C(17)-C(18)-C(19) 120.2(3) C(18)-C(19)-C(20) 120.1(3) C(18')-C(19')-C(20') 119.5(3) C(21')-C(20')-C(19') 120.8(3) C(19)-C(20)-C(21) 120.6(3) C(20')-C(21')-C(16') 118.2(2) C(16)-C(21)-C(20) 118.0(3) O(1S)-C(1S)-C(2S) 121.4(3) O(1S)-C(1S)-C(3S) 122.6(3) C(2S)-C(1S)-C(3S) 116.0(3) O(1T)-C(1T)-C(2T) 121.1(3) O(1T)-C(1T)-C(3T) 121.5(2) C(2T)-C(1T)-C(3T) 117.4(2) O(1U)-C(1U)-C(2U) 121.3(3) O(1U)-C(1U)-C(3U) 120.9(3) C(2U)-C(1U)-C(3U) 117.7(3) _____________________________________ Symmetry transformations used to generate equivalent atoms:

Table S6. Anisotropic displacement parameters (Å2x 103) for dimeric octacyclic tetraol (+)-14. The anisotropic displacement factor exponent takes the form: -2p2[ h2 a*2U11 + ... + 2 h k a* b* U12 ] ______________________________________________________________________________ U11 U22 U33 U23 U13 U12 ______________________________________________________________________________ S(1) 20(1) 21(1) 23(1) -2(1) 5(1) -3(1) S(1') 18(1) 20(1) 28(1) -2(1) -4(1) 2(1) O(1) 20(1) 29(1) 27(1) -2(1) 1(1) -1(1) O(1') 21(1) 35(1) 33(1) 4(1) -1(1) -6(1) O(2) 33(1) 60(1) 26(1) -7(1) -7(1) 20(1) O(2') 34(1) 40(1) 30(1) 8(1) 0(1) -14(1) O(3') 28(1) 25(1) 49(1) 7(1) -6(1) 2(1) O(3) 23(1) 32(1) 32(1) -6(1) 7(1) 0(1) O(4) 27(1) 26(1) 24(1) 4(1) 3(1) 3(1) O(4') 30(1) 30(1) 20(1) 3(1) -1(1) -2(1) O(5') 24(1) 26(1) 40(1) 5(1) -9(1) 1(1) O(5) 28(1) 36(1) 25(1) -1(1) 6(1) -7(1) O(6) 21(1) 26(1) 33(1) -2(1) 8(1) -2(1) O(6') 20(1) 27(1) 39(1) -10(1) -4(1) 3(1) N(1') 20(1) 23(1) 21(1) 1(1) 0(1) -4(1) N(1) 17(1) 24(1) 20(1) -2(1) 1(1) 0(1) N(2) 22(1) 25(1) 24(1) -5(1) -2(1) 2(1) N(2') 32(1) 22(1) 32(1) 5(1) -2(1) -5(1) N(3') 18(1) 22(1) 22(1) 0(1) 0(1) 2(1) N(3) 18(1) 22(1) 21(1) -1(1) 0(1) -1(1) C(1) 17(1) 19(1) 21(1) 0(1) 3(1) 0(1) C(1') 17(1) 18(1) 22(1) -1(1) 2(1) -1(1) C(2') 23(1) 14(1) 24(1) 0(1) 2(1) 0(1) C(2) 24(1) 15(1) 20(1) -2(1) 0(1) 1(1)


C(3') 24(1) 15(1) 30(1) -1(1) 2(1) 0(1) C(3) 20(1) 20(1) 29(1) -4(1) 1(1) 0(1) C(4') 28(1) 21(1) 31(1) -1(1) 10(1) 2(1) C(4) 24(1) 24(1) 33(1) -5(1) -5(1) 3(1) C(5) 36(1) 21(1) 26(1) 1(1) -7(1) 0(1) C(5') 39(2) 22(1) 20(1) 1(1) 4(1) 4(1) C(6') 31(1) 19(1) 24(1) 2(1) -4(1) 2(1) C(6) 29(1) 23(1) 24(1) -1(1) -1(1) -6(1) C(7') 21(1) 15(1) 26(1) 3(1) 1(1) 3(1) C(7) 22(1) 20(1) 18(1) -6(1) -1(1) 0(1) C(8') 17(1) 20(1) 19(1) -2(1) -1(1) 0(1) C(8) 18(1) 18(1) 21(1) 0(1) 2(1) 1(1) C(9') 24(1) 30(1) 20(1) 0(1) -1(1) -8(1) C(9) 21(1) 22(1) 22(1) 2(1) -1(1) 2(1) C(10) 20(1) 32(1) 26(1) -4(1) -4(1) 3(1) C(10') 27(1) 31(1) 29(1) 5(1) -1(1) -7(1) C(11') 30(1) 28(1) 24(1) 5(1) -2(1) -1(1) C(11) 25(1) 24(1) 20(1) 2(1) -1(1) 3(1) C(12) 20(1) 22(1) 21(1) 1(1) 2(1) -1(1) C(12') 21(1) 24(1) 22(1) 0(1) -1(1) -2(1) C(13') 18(1) 20(1) 25(1) -1(1) -2(1) 0(1) C(13) 19(1) 24(1) 21(1) -2(1) 3(1) -3(1) C(14') 36(1) 29(1) 33(1) 2(1) -5(1) -7(1) C(14) 29(1) 36(2) 43(2) -15(1) 0(1) -7(1) C(15') 42(2) 25(1) 47(2) 7(1) -5(1) -3(1) C(15) 30(1) 30(1) 33(1) -10(1) -2(1) 6(1) C(16) 24(1) 24(1) 23(1) 2(1) 2(1) -8(1) C(16') 22(1) 22(1) 22(1) 0(1) -4(1) -2(1) C(17') 22(1) 28(1) 28(1) -3(1) -2(1) 2(1) C(17) 25(1) 25(1) 38(1) -2(1) -5(1) -1(1) C(18') 32(1) 24(1) 31(1) -4(1) 0(1) 1(1) C(18) 35(2) 24(1) 51(2) -4(1) -6(1) 0(1) C(19) 33(2) 34(2) 52(2) -7(1) -2(1) -9(1) C(19') 31(1) 27(1) 43(2) -6(1) -5(1) -5(1) C(20') 24(1) 31(1) 50(2) -4(1) -3(1) 2(1) C(20) 22(1) 38(2) 48(2) 0(1) -2(1) -6(1) C(21') 24(1) 25(1) 34(1) -2(1) -2(1) 2(1) C(21) 24(1) 31(1) 35(1) 1(1) 4(1) -2(1) O(1S) 50(1) 39(1) 38(1) 4(1) 12(1) -2(1) C(1S) 25(1) 35(1) 31(1) 1(1) 2(1) -2(1) C(2S) 73(2) 41(2) 54(2) 3(2) 28(2) -5(2) C(3S) 59(2) 37(2) 39(2) -2(1) -4(2) -1(2) O(1T) 31(1) 37(1) 27(1) 2(1) -4(1) -3(1) C(1T) 26(1) 27(1) 30(1) -1(1) 0(1) 2(1) C(2T) 33(1) 51(2) 32(1) 2(1) -6(1) -4(1) C(3T) 28(1) 51(2) 51(2) 15(2) 0(1) -4(2) O(1U) 65(2) 56(1) 45(1) -6(1) 18(1) -5(1) C(1U) 45(2) 28(1) 34(1) 0(1) 7(1) -6(1) C(2U) 49(2) 43(2) 53(2) 6(2) -9(2) -5(2) C(3U) 27(1) 25(1) 26(1) -3(1) 0(1) -8(1) ______________________________________________________________________________


Table S7. Hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2x 10 3) for dimeric octacyclic tetraol (+)-14. ________________________________________________________________________________ x y z U(eq) ________________________________________________________________________________ H(2O) 3790(20) -530(30) 90(10) 47 H(2O') 9800(30) 5620(30) 558(7) 42 H(4O) 6680(20) 1290(30) 141(7) 31 H(4O') 7700(20) 3760(20) 386(8) 32 H(3') 5483 2238 1755 28 H(3) 9478 13 1371 27 H(4') 5408 2515 2412 32 H(4) 9855 -1317 1839 32 H(5) 8364 -2180 2161 33 H(5') 7070 2719 2762 32 H(6') 8850 2642 2463 30 H(6) 6467 -1744 2014 30 H(8') 9229 1975 1117 23 H(8) 5514 1184 1127 23 H(13A) 6471 2551 836 25 H(13B) 6256 3319 1202 25 H(13C) 8062 1394 647 25 H(13D) 8424 146 755 25 H(14A) 10458 5908 1483 49 H(14B) 9156 5832 1612 49 H(14C) 9592 6880 1374 49 H(14D) 3857 -2282 533 54 H(14E) 5119 -2762 569 54 H(14F) 4462 -2830 172 54 H(15A) 7245 6961 715 57 H(15B) 8528 7316 803 57 H(15C) 7636 7184 1143 57 H(15D) 7084 -2041 -291 46 H(15E) 5770 -2381 -281 46 H(15F) 6644 -2940 9 46 H(17') 9932 4105 2097 31 H(17) 5141 -2379 1508 35 H(18') 11089 5547 2314 35 H(18) 4071 -3867 1280 44 H(19) 2138 -3643 1159 47 H(19') 13066 5397 2275 40 H(20') 13884 3794 2016 42 H(21) 1253 -1955 1286 43 H(21') 12735 2339 1803 33 H(21) 2318 -441 1510 36 H(2S1) 7630 2760 -1035 84 H(2S2) 8919 2369 -983 84 H(2S3) 8406 3314 -714 84 H(3S1) 7604 102 -525 67 H(3S2) 8803 402 -712 67 H(3S3) 7663 506 -956 67 H(2T1) 6800 5461 -665 58 H(2T2) 5461 5453 -588 58 H(2T3) 6061 4394 -774 58 H(3T1) 5627 3640 224 65


H(3T2) 5311 3171 -187 65 H(3T3) 4715 4275 -33 65 H(2U1) 5429 5247 1748 72 H(2U2) 5486 6235 2050 72 H(2U3) 5280 4988 2190 72 H(3U1) 7284 5026 2601 39 H(3U2) 7184 6314 2496 39 H(3U3) 8294 5630 2379 39 ____________________________________________________________________________ Table S8. Hydrogen bonds for dimeric octacyclic tetraol (+)-14 [Å and °]. ____________________________________________________________________________ D-H...A d(D-H) d(H...A) d(D...A)


Crystal Structure of (+)-11,11'-Dideoxyverticillin A (1).

View 1:

View 2:


Table S9. Crystal data and structure refinement for (+)-11,11'-Dideoxyverticillin A (1). Identification code 08235 Empirical formula C31.92 H31.77 Cl3.92 N6 O4 S4* Formula weight 830.65 Temperature 100(2) K Wavelength 0.71073 Å Crystal system Monoclinic Space group P 21 Unit cell dimensions a = 7.7892(7) Å a= 90°. b = 20.8034(18) Å b= 100.540(2)°. c = 11.1807(10) Å g = 90°. Volume 1781.2(3) Å3 Z 2 Density (calculated) 1.549 Mg/m3 Absorption coefficient 0.609 mm-1 F(000) 856 Crystal size 0.35 x 0.25 x 0.13 mm3 Theta range for data collection 1.85 to 29.57°. Index ranges -10


Table S10. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103) for (+)-11,11'-Dideoxyverticillin A (1). U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. ___________________________________________________________________ x y z U(eq) ___________________________________________________________________ S(1) 594(1) 10013(1) -1162(1) 20(1) S(2) 2920(1) 10336(1) -1614(1) 26(1) S(3) -2429(1) 6934(1) 2571(1) 22(1) S(4) -1641(1) 6545(1) 4295(1) 27(1) O(1) -218(2) 8698(1) -3077(1) 27(1) O(2) 5745(2) 9088(1) -319(1) 27(1) O(3) -3962(2) 8416(1) 3432(1) 28(1) O(4) 2087(2) 7532(1) 5294(1) 23(1) N(1) 2457(2) 9192(1) -2893(1) 20(1) N(2) 2807(2) 8989(1) -428(1) 15(1) N(3) 3623(2) 9142(1) 1742(1) 20(1) N(4) -2426(2) 7775(1) 4909(1) 19(1) N(5) 182(2) 7781(1) 3556(1) 16(1) N(6) 2745(2) 7543(1) 2652(1) 18(1) C(1) 793(2) 8707(1) 850(2) 14(1) C(2) -156(2) 8756(1) -488(2) 16(1) C(3) 1113(2) 9128(1) -1121(2) 15(1) C(4) 1026(2) 8972(1) -2458(2) 19(1) C(5) 2336(3) 9257(1) -4217(2) 30(1) C(6) 3780(2) 9540(1) -2058(2) 20(1) C(7) 5419(3) 9695(1) -2562(2) 30(1) C(8) 4249(2) 9180(1) -844(2) 19(1) C(9) 2798(2) 8714(1) 799(2) 16(1) C(10) 2351(3) 9512(1) 2138(2) 19(1) C(11) 2601(3) 10033(1) 2937(2) 27(1) C(12) 1142(3) 10370(1) 3122(2) 32(1) C(13) -529(3) 10214(1) 2520(2) 29(1) Cl(1) -2530(7) 10605(3) 2623(5) 22(1) C(14) -784(3) 9682(1) 1740(2) 22(1) C(15) 667(2) 9324(1) 1581(2) 18(1) C(16) 268(2) 8098(1) 1522(2) 15(1) C(17) -1623(2) 8144(1) 1765(2) 16(1) C(18) -1605(2) 7768(1) 2938(2) 16(1) C(19) -2791(2) 8029(1) 3771(2) 18(1) C(20) -3647(3) 7879(1) 5750(2) 26(1) C(21) -1027(2) 7312(1) 5172(2) 19(1) C(22) -569(3) 7122(1) 6506(2) 24(1) C(23) 605(2) 7555(1) 4706(2) 18(1) C(24) 1453(2) 8014(1) 2808(2) 15(1) C(25) 2091(2) 7162(1) 1642(2) 17(1) C(26) 2703(2) 6571(1) 1321(2) 22(1) C(27) 1782(3) 6268(1) 287(2) 24(1)


C(28) 292(3) 6547(1) -399(2) 22(1) C(29) -284(2) 7146(1) -81(2) 20(1) C(30) 634(2) 7463(1) 932(2) 16(1) C(1S) 3971(3) 6978(1) 8036(2) 27(1) Cl(1S) 4943(1) 7699(1) 8678(1) 33(1) Cl(2S) 5492(1) 6343(1) 8182(1) 46(1) C(2S) 1957(7) 5320(3) 4521(6) 39(1) Cl(3S) 3440(2) 5968(1) 4772(1) 51(1) Cl(4S) 2818(1) 4624(1) 5266(1) 32(1) C(2T) 2350(15) 5875(7) 4210(14) 72(3) Cl(3T) 4485(5) 6094(1) 4497(3) 42(1) Cl(4T) 2027(10) 5099(4) 4698(8) 103(3) ____________________________________________________________________ Table S11. Bond lengths [Å] and angles [°] for (+)-11,11'-Dideoxyverticillin A (1). _____________________________________ S(1)-C(3) 1.8830(18) S(1)-S(2) 2.0796(7) S(2)-C(6) 1.886(2) S(3)-C(18) 1.8703(19) S(3)-S(4) 2.0775(7) S(4)-C(21) 1.887(2) O(1)-C(4) 1.223(2) O(2)-C(8) 1.220(2) O(3)-C(19) 1.224(2) O(4)-C(23) 1.221(2) N(1)-C(4) 1.374(2) N(1)-C(6) 1.451(3) N(1)-C(5) 1.472(2) N(2)-C(8) 1.351(2) N(2)-C(3) 1.432(2) N(2)-C(9) 1.487(2) N(3)-C(10) 1.390(3) N(3)-C(9) 1.438(2) N(4)-C(19) 1.359(2) N(4)-C(21) 1.444(2) N(4)-C(20) 1.470(2) N(5)-C(23) 1.352(2) N(5)-C(18) 1.436(2) N(5)-C(24) 1.489(2) N(6)-C(25) 1.398(2) N(6)-C(24) 1.439(2) C(1)-C(15) 1.534(2) C(1)-C(2) 1.546(2) C(1)-C(16) 1.565(2) C(1)-C(9) 1.573(2) C(2)-C(3) 1.527(2)

C(3)-C(4) 1.518(2) C(6)-C(7) 1.521(3) C(6)-C(8) 1.535(3) C(10)-C(11) 1.394(3) C(10)-C(15) 1.401(3) C(11)-C(12) 1.383(3) C(12)-C(13) 1.390(3) C(13)-C(14) 1.401(3) C(13)-Cl(1) 1.781(6) C(14)-C(15) 1.392(3) C(16)-C(30) 1.527(2) C(16)-C(17) 1.548(2) C(16)-C(24) 1.570(2) C(17)-C(18) 1.524(2) C(18)-C(19) 1.527(3) C(21)-C(22) 1.520(2) C(21)-C(23) 1.545(2) C(25)-C(26) 1.388(3) C(25)-C(30) 1.408(2) C(26)-C(27) 1.396(3) C(27)-C(28) 1.395(3) C(28)-C(29) 1.392(3) C(29)-C(30) 1.390(2) C(1S)-Cl(2S) 1.763(2) C(1S)-Cl(1S) 1.772(3) C(2S)-Cl(4S) 1.743(5) C(2S)-Cl(3S) 1.764(6) C(2T)-Cl(3T) 1.697(11) C(2T)-Cl(4T) 1.737(12) C(3)-S(1)-S(2) 97.43(6) C(6)-S(2)-S(1) 98.46(6) C(18)-S(3)-S(4) 97.29(6) C(21)-S(4)-S(3) 99.00(6)


C(4)-N(1)-C(6) 117.75(15) C(4)-N(1)-C(5) 118.67(16) C(6)-N(1)-C(5) 120.57(16) C(8)-N(2)-C(3) 119.69(14) C(8)-N(2)-C(9) 125.09(15) C(3)-N(2)-C(9) 114.69(13) C(10)-N(3)-C(9) 109.13(14) C(19)-N(4)-C(21) 118.13(15) C(19)-N(4)-C(20) 119.50(16) C(21)-N(4)-C(20) 121.34(15) C(23)-N(5)-C(18) 119.84(15) C(23)-N(5)-C(24) 125.17(14) C(18)-N(5)-C(24) 114.87(13) C(25)-N(6)-C(24) 108.99(14) C(15)-C(1)-C(2) 113.23(14) C(15)-C(1)-C(16) 111.91(13) C(2)-C(1)-C(16) 113.41(14) C(15)-C(1)-C(9) 99.95(14) C(2)-C(1)-C(9) 105.49(13) C(16)-C(1)-C(9) 111.87(13) C(3)-C(2)-C(1) 104.26(13) N(2)-C(3)-C(4) 111.10(14) N(2)-C(3)-C(2) 104.89(13) C(4)-C(3)-C(2) 115.56(15) N(2)-C(3)-S(1) 112.55(12) C(4)-C(3)-S(1) 102.41(11) C(2)-C(3)-S(1) 110.58(12) O(1)-C(4)-N(1) 124.40(17) O(1)-C(4)-C(3) 123.00(17) N(1)-C(4)-C(3) 112.55(15) N(1)-C(6)-C(7) 114.36(16) N(1)-C(6)-C(8) 110.53(15) C(7)-C(6)-C(8) 110.53(16) N(1)-C(6)-S(2) 111.24(13) C(7)-C(6)-S(2) 105.94(15) C(8)-C(6)-S(2) 103.61(13) O(2)-C(8)-N(2) 124.74(17) O(2)-C(8)-C(6) 123.55(16) N(2)-C(8)-C(6) 111.70(15) N(3)-C(9)-N(2) 111.19(14) N(3)-C(9)-C(1) 106.99(14) N(2)-C(9)-C(1) 102.04(12) N(3)-C(10)-C(11) 127.61(18) N(3)-C(10)-C(15) 111.55(16) C(11)-C(10)-C(15) 120.77(19) C(12)-C(11)-C(10) 117.87(19) C(11)-C(12)-C(13) 122.12(19) C(12)-C(13)-C(14) 120.0(2) C(12)-C(13)-Cl(1) 128.0(2)

C(14)-C(13)-Cl(1) 112.0(3) C(15)-C(14)-C(13) 118.43(19) C(14)-C(15)-C(10) 120.64(17) C(14)-C(15)-C(1) 130.42(17) C(10)-C(15)-C(1) 108.94(15) C(30)-C(16)-C(17) 112.81(14) C(30)-C(16)-C(1) 114.01(13) C(17)-C(16)-C(1) 112.03(14) C(30)-C(16)-C(24) 100.06(13) C(17)-C(16)-C(24) 105.35(13) C(1)-C(16)-C(24) 111.62(14) C(18)-C(17)-C(16) 105.07(14) N(5)-C(18)-C(17) 105.09(14) N(5)-C(18)-C(19) 109.94(14) C(17)-C(18)-C(19) 115.55(15) N(5)-C(18)-S(3) 112.70(12) C(17)-C(18)-S(3) 109.79(12) C(19)-C(18)-S(3) 104.01(12) O(3)-C(19)-N(4) 124.24(17) O(3)-C(19)-C(18) 123.00(16) N(4)-C(19)-C(18) 112.74(16) N(4)-C(21)-C(22) 113.97(16) N(4)-C(21)-C(23) 110.48(14) C(22)-C(21)-C(23) 110.85(15) N(4)-C(21)-S(4) 110.36(12) C(22)-C(21)-S(4) 106.36(13) C(23)-C(21)-S(4) 104.29(12) O(4)-C(23)-N(5) 124.66(17) O(4)-C(23)-C(21) 124.08(16) N(5)-C(23)-C(21) 111.24(15) N(6)-C(24)-N(5) 113.45(14) N(6)-C(24)-C(16) 105.76(14) N(5)-C(24)-C(16) 102.17(13) C(26)-C(25)-N(6) 128.29(16) C(26)-C(25)-C(30) 121.86(17) N(6)-C(25)-C(30) 109.84(16) C(25)-C(26)-C(27) 117.76(18) C(28)-C(27)-C(26) 121.08(19) C(29)-C(28)-C(27) 120.49(18) C(30)-C(29)-C(28) 119.40(17) C(29)-C(30)-C(25) 119.30(17) C(29)-C(30)-C(16) 130.83(16) C(25)-C(30)-C(16) 109.68(15) Cl(2S)-C(1S)-Cl(1S) 111.56(12) Cl(4S)-C(2S)-Cl(3S) 112.1(3) Cl(3T)-C(2T)-Cl(4T) 112.5(8) _____________________________________ Symmetry transformations used to generate equivalent atoms:


Table S12. Anisotropic displacement parameters (Å2x 103) for (+)-11,11'-Dideoxyverticillin A (1). The anisotropic displacement factor exponent takes the form: -2p2[ h2 a*2U11 + ... + 2 h k a* b* U12 ] ______________________________________________________________________________ U11 U22 U33 U23 U13 U12 ______________________________________________________________________________ S(1) 23(1) 16(1) 23(1) 4(1) 8(1) 5(1) S(2) 29(1) 17(1) 33(1) 4(1) 10(1) -2(1) S(3) 27(1) 18(1) 18(1) 1(1) 0(1) -8(1) S(4) 41(1) 16(1) 21(1) 5(1) -1(1) -6(1) O(1) 29(1) 32(1) 20(1) -1(1) 1(1) -6(1) O(2) 15(1) 35(1) 30(1) 7(1) 4(1) 1(1) O(3) 22(1) 36(1) 28(1) 8(1) 4(1) 9(1) O(4) 20(1) 30(1) 19(1) 5(1) -1(1) 1(1) N(1) 22(1) 23(1) 17(1) 2(1) 6(1) 2(1) N(2) 14(1) 17(1) 14(1) 3(1) 3(1) 2(1) N(3) 18(1) 21(1) 18(1) 1(1) -2(1) -4(1) N(4) 18(1) 21(1) 17(1) 2(1) 4(1) -2(1) N(5) 14(1) 18(1) 16(1) 4(1) 0(1) -2(1) N(6) 18(1) 17(1) 18(1) 0(1) 1(1) 2(1) C(1) 14(1) 14(1) 14(1) 2(1) 2(1) 0(1) C(2) 14(1) 19(1) 14(1) 4(1) 2(1) 0(1) C(3) 14(1) 15(1) 15(1) 1(1) 3(1) 2(1) C(4) 23(1) 18(1) 16(1) 3(1) 4(1) 2(1) C(5) 35(1) 38(1) 18(1) 4(1) 11(1) 3(1) C(6) 19(1) 21(1) 23(1) 4(1) 8(1) 1(1) C(7) 22(1) 40(1) 31(1) 11(1) 12(1) -1(1) C(8) 18(1) 19(1) 22(1) 2(1) 7(1) 1(1) C(9) 14(1) 16(1) 15(1) 4(1) 0(1) 0(1) C(10) 28(1) 16(1) 13(1) 4(1) 2(1) -4(1) C(11) 42(1) 22(1) 15(1) 0(1) 0(1) -10(1) C(12) 61(2) 17(1) 19(1) -2(1) 13(1) -4(1) C(13) 47(1) 19(1) 24(1) 2(1) 17(1) 5(1) Cl(1) 21(2) 17(2) 28(3) 2(2) 10(2) 9(2) C(14) 30(1) 19(1) 20(1) 7(1) 10(1) 2(1) C(15) 23(1) 15(1) 15(1) 2(1) 4(1) 0(1) C(16) 16(1) 15(1) 13(1) 1(1) 1(1) -1(1) C(17) 15(1) 18(1) 16(1) 6(1) 1(1) -2(1) C(18) 16(1) 17(1) 16(1) 2(1) 1(1) -3(1) C(19) 16(1) 22(1) 17(1) 2(1) 3(1) -3(1) C(20) 20(1) 39(1) 22(1) 4(1) 8(1) -1(1) C(21) 21(1) 20(1) 15(1) 4(1) 2(1) -3(1) C(22) 28(1) 26(1) 17(1) 6(1) 2(1) -4(1) C(23) 19(1) 15(1) 18(1) 2(1) 2(1) -1(1) C(24) 14(1) 16(1) 14(1) 4(1) 1(1) 0(1) C(25) 17(1) 18(1) 18(1) 3(1) 4(1) -2(1) C(26) 22(1) 19(1) 25(1) 2(1) 6(1) 0(1) C(27) 30(1) 18(1) 25(1) -2(1) 9(1) -2(1)


C(28) 26(1) 22(1) 19(1) -2(1) 4(1) -5(1) C(29) 22(1) 20(1) 17(1) 2(1) 3(1) -4(1) C(30) 18(1) 13(1) 17(1) 1(1) 3(1) -3(1) C(1S) 20(1) 38(1) 24(1) 5(1) 4(1) 3(1) Cl(1S) 36(1) 32(1) 30(1) -3(1) 6(1) 12(1) Cl(2S) 40(1) 33(1) 61(1) -13(1) 2(1) 8(1) C(2S) 27(2) 58(3) 32(2) 6(2) 6(2) 20(2) Cl(3S) 71(1) 32(1) 44(1) -4(1) -5(1) 4(1) Cl(4S) 31(1) 39(1) 29(1) -5(1) 11(1) 0(1) C(2T) 45(5) 112(8) 59(8) -8(7) 8(6) 19(6) Cl(3T) 46(2) 30(1) 42(1) -6(1) -11(1) 9(1) Cl(4T) 95(5) 131(7) 103(5) -43(5) 74(4) -59(5) ______________________________________________________________________________ Table S13. Hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2x 10 3) for (+)-11,11'-Dideoxyverticillin A (1). ________________________________________________________________________________ x y z U(eq) ________________________________________________________________________________ H(3) 4530(30) 8977(11) 2250(20) 24 H(6) 3350(30) 7360(11) 3256(18) 21 H(2A) -392 8324 -851 19 H(2B) -1275 8990 -547 19 H(5A) 1324 9015 -4637 44 H(5B) 3402 9087 -4450 44 H(5C) 2202 9711 -4444 44 H(7A) 5956 9294 -2772 46 H(7B) 6247 9927 -1946 46 H(7C) 5110 9962 -3291 46 H(9) 3318 8273 889 19 H(11) 3737 10152 3340 32 H(12) 1287 10719 3680 38 H(13) -1497 10469 2637 34 H(14) -1921 9568 1329 27 H(17A) -1954 8598 1864 20 H(17B) -2459 7952 1086 20 H(20A) -4556 8183 5387 40 H(20B) -3011 8054 6518 40 H(20C) -4187 7469 5904 40 H(22A) -171 7502 6997 36 H(22B) 362 6799 6613 36 H(22C) -1604 6943 6767 36 H(24) 2001 8430 3124 18 H(26) 3716 6381 1789 26 H(27) 2174 5864 46 29 H(28) -332 6328 -1089 27


H(29) -1297 7336 -551 24 H(1S1) 2994 6860 8448 33 H(1S2) 3488 7049 7164 33 H(2S1) 873 5439 4812 47 H(2S2) 1649 5234 3637 47 H(2T1) 1901 5904 3324 87 H(2T2) 1673 6179 4623 87 ________________________________________________________________________________ Table S14. Hydrogen bonds for (+)-11,11'-Dideoxyverticillin A (1) [Å and °]. ____________________________________________________________________________ D-H...A d(D-H) d(H...A) d(D...A)

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