Methodological advances permit the stereocontrolled construction of diverse fully synthetic tetracyclines containing an all-carbon quaternary center at position C5a

Tetrahedron 67 (20 1 1 ) 9853e9869

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Tetrahedron

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Methodological advances permit the stereocontrolled construction of diverse fully

synthetic tetracyclines containing an all-carbon quaternary center at position C5a

*

Peter M. Wright, Andrew G. Myers

Department of Chemistry & Chemical Biology, Harvard University, Cambridge, MA 02138, United States

a r t i c l e i n f o

a b s t r a c t

Article history:

Received 9 August 2011

Received in revised form 28 September 2011

Accepted 29 September 2011

Available online 6 October 2011

Here we describe chemical innovations that enable the preparation of fully synthetic tetracyclines

containing an all-carbon quaternary, stereogenic center at position C5a, a structurally novel class of

compounds in this important family of therapeutic agents. In the key transformation and an important

extension of the powerful MichaeleClaisen cyclization (AB plus D) approach to the construction of fully

synthetic tetracyclines, we show that the six-membered C ring comprising a C5a quaternary carbon

center can be assembled by highly stereocontrolled coupling reactions of

toluate ester anion D-ring precursors. Novel and versatile -functionalization reaction sequences em-

ploying tris(methylthio)methyllithium and 2-lithio-1,3-dithiane have been developed to transform the

AB enone 1 (the key precursor to fully synthetic tetracyclines) into a diverse range of -substituted AB

enone products, including a highly efﬁcient, single-operation method for the synthesis of a -methyl

ester-substituted AB enone. A C5aeC11a-bridged cyclopropane tetracycline precursor was found to

undergo efﬁcient and regioselective ring-opening reactions with a range of nucleophiles in the presence

of magnesium bromide, thus providing another avenue for the preparation of fully synthetic tetracyclines

containing an all-carbon quaternary center at position C5a. Two compounds prepared from the bridged

cyclopropane intermediate served as (further) diversiﬁable branch-points, allowing maximally expedient

synthesis of C5a-substituted tetracyclines by ﬁnal-step diversiﬁcation.

b-substituted AB enones and o-

Keywords:

Tetracycline

Enone synthesis

MichaeleClaisen cyclization

Quaternary center

Cyclopropane ring-opening

b

1. Introduction

Previous work has demonstrated that our fully synthetic ap-

proach to tetracyclines allows modiﬁcations at positions C6eC10

To date more than 3000 fully synthetic molecules of the tetra-

cycline class, broadly deﬁned, have been prepared by a general and

convergent process that involves a MichaeleClaisen coupling of the

AB enone 1 with structurally diverse D-ring precursors followed by

deprotection, a route of typically 3e4 steps (Fig. 1).^1,2Most of the

candidate antibiotics prepared in this way would have been difﬁ-

cult if not impossible to obtain by chemical transformations of

natural tetracyclines (‘semisynthetic’ processes). A key enablement

that permitted the development of this streamlined route was the

introduction by Stork and Hagedorn of the 3-benzyloxyisoxazole

function as a masked form of the vinylogous carbamic acid of the

A ring of tetracyclines, a protective group that is readily cleaved by

hydrogenolysis.³It is therefore appropriate that the present report,

in which we build upon our earlier work through methodological

advances that permit for the ﬁrst time modiﬁcation of position C5a

of the tetracycline scaffold, appear in this special publication ded-

icated to Professor Gilbert Stork, a pioneering investigator in syn-

thetic organic chemistry of extraordinary accomplishment.

that are not feasible by semisynthesis.^1,2One area of focus in our

current research is the development of chemical pathways that

enable modiﬁcations at other positions, such as C5a, that have not

previously been viable. Position C5a is one of two points of fusion of

the B and C rings of tetracyclines and, as such, substitution of this

position gives rise to a quaternary carbon center. Inspection of

X-ray crystallographic data of tetracycline bound to the 30S subunit

of the ribosome of Thermus Thermophilus suggests that substitution

of position C5a would not obviously impede ribosome binding and

thus could present an interesting and unexplored avenue for the

discovery of potential new antibiotics to address problems such as

bacterial resistance.^4,5To apply our general route for tetracycline

synthesis to C5a-substituted analogs it was ﬁrst necessary to de-

velop methodology to prepare AB enones containing different

b-substituents, and then to determine if these modiﬁed AB enones

would successfully undergo MichaeleClaisen cyclization reactions

with D-ring precursors, transformations that would give rise to

a quaternary, stereogenic center at position C5a. The most rapid and

straightforward approach to the synthesis of

enones appeared to be the direct functionalization of the AB enone

1. While introduction of simple alkyl groups such as -methyl

b-substituted AB

* Corresponding author. E-mail addresses: pwright@fas.harvard.edu (P.M. Wright),

myers@chemistry.harvard.edu (A.G. Myers).

b

doi:10.1016/j.tet.2011.09.143

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P.M. Wright, A.G. Myers / Tetrahedron 67 (2011) 9853e9869

Fig. 1. Structurally diverse, fully synthetic tetracyclines, now incorporating angular substitution of position C5a.

proved to be relatively straightforward (though low-yielding), in-

troduction of more highly oxidized -substituents was less so, and

2. Results and discussion

2.1. New methods for -functionalization of enones

b

provided us with the opportunity to pursue a number of chemical

innovations, which we detail herein. The subsequent stereo-

controlled construction of the C ring, comprising an all-carbon

quaternary center at position C5a, was viewed to be a challenging

transformation, and its successful implementation we view to be

a signiﬁcant advance. During the course of our investigations we

also serendipitously discovered a C5aeC11a bridged cyclopropane-

containing tetracycline intermediate that has proven to be an

extraordinarily versatile precursor to a diverse array of C5a-

substituted tetracyclines, providing another avenue for the syn-

thesis of this novel class of substituted tetracycline antibiotics.

b

As a ﬁrst step toward the stereocontrolled construction of all-

carbon quaternary, C5a-substituted tetracyclines we ﬁrst sought

to develop methods to transform the AB enone 1 into b-substituted

AB enones as novel cyclization substrates (Schemes 1e3 below).

A conventional reaction sequence served for the synthesis of the

simple b-methyl-substituted AB enone 3 (Scheme 1). Speciﬁcally,

conjugate addition of lithium dimethylcuprate to the AB enone 1 in

the presence of trimethylsilylchloride⁶afforded the corresponding

b-methyl-substituted trimethylsilyl enol ether 2 in 85% yield (1D-

Scheme 1. Two-step syntheses of modiﬁed AB enones with methyl, methyl ester, triﬂuoroethyl ester, and thioester groups at the

enone 1.

b-position, starting from the b-unsubstituted AB

P.M. Wright, A.G. Myers / Tetrahedron 67 (2011) 9853e9869

9855

Scheme 2. Synthesis of the b-methyl ester-substituted AB enone 5 from the b-unsubstituted AB enone 1 in a single operation.

Scheme 3. Two protocols for the synthesis of the

enone 9.

b-methoxymethoxymethyl AB enone 10 from the AB enone 1; the ﬁrst, and more efﬁcient, proceeds via the

b-carbaldehyde AB

NOESY experiments support the 5a-S-stereochemistry depicted, in

accord with all precedent in this system);¹oxidation of this in-

termediate with palladium acetate in dimethyl sulfoxide (DMSO) at

the AB enone containing a

yield. The detailed mechanism of the transformation of the in-

termediate 4 into the -substituted AB enone 5 is not known, but

presumably involves some variation of a sequence involving

b-methyl ester substituent (5) in 85%

b

80 ^ꢀC then afforded the

b

-methyl-substituted AB enone 3 in modest

a-

yield (44% yield on 160-mg scale, and 34% yield on 2.8-g scale).^7,8

Attempted oxidation of the intermediate trimethylsilyl enol ether

2 with the alternative oxidant o-iodoxybenzoic acid (IBX) was not

successful.⁹

bromination of the trimethylsilyl enol ether, bromonium-induced

conversion of the tris(methylthio)methyl substituent into the cor-

responding methyl ester (with incorporation of one molar equiva-

lent each of methanol and water), and elimination of hydrogen

bromide. By modiﬁcation of the reaction solvent we found that

different esters could be synthesized, including active esters. For

example, addition of NBS (5 equiv) to a solution of the trimethylsilyl

enol ether 4 in 2,2,2-triﬂuoroethanol and water (500:1 mixture) at

To transform the AB enone 1 into

b-substituted AB enones with

more highly oxidized -substituents we were led to explore novel

b

chemistry, as precedented methods were deemed to be too indirect

or were impracticable in the present application.^10e12First, we

developed a versatile sequence for

b

-functionalization of the AB

23 ^ꢀC afforded the corresponding

b-triﬂuoroethyl ester-substituted

enone 1 initiated by conjugate addition of the Seebach reagent

tris(methylthio)methyllithium¹³(THF, ꢁ78/ꢁ45 ^ꢀC) followed by

trapping of the resulting enolate at ꢁ45 ^ꢀC with chloro-

AB enone 6 in 87% yield. Alternatively, treatment of a solution of

substrate 4 in tert-butanol with NBS (4 equiv) at 23 ^ꢀC afforded the

AB enone 7 bearing an S-methyl thioester at the

yield.¹⁵The transformations of Schemes 1e3 represent novel, di-

rect, and highly efﬁcient -functionalization reactions of an enone

substrate. Important foundational precedents include the conver-

sion of a -cyano-substituted trimethylsilyl enol ether to the cor-

responding

b-position in 82%

trimethylsilane.¹⁴The corresponding

b-tris(methylthio)methyl tri-

methylsilyl enol ether (4) was isolated as a single stereoisomer

(stereochemistry not determined) in 89% yield after puriﬁcation by

ﬂash-column chromatography. We found that oxidation of the tri-

methylsilyl enol ether function and transformation of the tris(me-

thylthio)methyl group occurred simultaneously upon treatment of

a solution of 4 in the solvent mixture 500:1 methanol/water with

an excess of N-bromosuccinimide (NBS, 5 equiv) at 23 ^ꢀC, affording

b

-cyano enone upon sequential treatment with

NBS and triethylamine^10aas well as the original discovery that

dithianes undergo oxidative hydrolysis in the presence of

N-halosuccinimides.¹⁶

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P.M. Wright, A.G. Myers / Tetrahedron 67 (2011) 9853e9869

In a further optimization, we found that transformation of the

b

-

methyl]stannane¹⁹and n-butyllithium) in the presence of HMPA

at ꢁ78 ^ꢀC, trapping of the resulting enolate with chloro-

unsubstituted AB enone 1 to the -methyl ester-substituted AB

b

enone 5 could be achieved directly, and most efﬁciently (90% yield),

in a single operation (Scheme 2).

trimethylsilane (affording the b-methoxymethoxymethyl trime-

thylsilyl enol ether 11 in 40e55% yield), and then oxidation of the

intermediate 11 with palladium acetate in DMSO at 50 ^ꢀC (pro-

viding AB enone 10 in 25e52% yield).

A related strategy was effective for the synthesis of the AB enone

9 bearing a

expedient route to AB enones with

b

-carbaldehyde substituent, which in turn provided an

-alkoxymethyl substituents

b

(Scheme 3). Thus, conjugate addition of the CoreyeSeebach reagent

2-lithio-1,3-dithiane¹⁷to the AB enone 1 in the presence of hex-

amethylphosphoramide (HMPA)¹⁸at ꢁ78 ^ꢀC followed by quench-

ing of the resulting enolate intermediate with chlorotrime-

2.2. Stereocontrolled construction of all-carbon quaternary

centers by MichaeleClaisen cyclization reactions of b-

substituted AB enones

thylsilane provided the

b-(1,3-dithian-2-yl) trimethylsilyl enol

Having established versatile methodology for the synthesis of

-substituted AB enone substrates, we next investigated the fea-

ether 8 as a single stereoisomer (90% yield; stereochemistry not

determined). Treatment of the latter product with NBS (6 equiv) in

the solvent mixture 100:1 tert-butanol/water at 23 ^ꢀC afforded the

b

sibility of constructing the C ring of tetracyclines with an all-

carbon quaternary C5a stereocenter by a MichaeleClaisen cycli-

zation reaction (Scheme 4). The D-ring precursors 12 (with OBoc

protection at ‘C10’) and 13 (with OBn protection at ‘C10’) were

chosen for initial cyclization experiments. These precursors com-

prise the D-ring functionality of minocycline (Scheme 4) and are

known from prior research to be highly effective substrates in

b-carbaldehyde AB enone 9 in 90% yield. Selective reduction of the

aldehyde group occurred upon warming a solution of 9 and sodium

triacetoxyborohydride in benzene at 40 ^ꢀC. The resulting primary

alcohol was then protected as a methoxymethyl ether in the

presence of chloromethyl methyl ether and N,N-diisopropylethyl-

amine in benzene at 50 ^ꢀC to afford the

b-methoxymethoxymethyl

MichaeleClaisen cyclization reactions.^1bAddition of the

b-methyl-

AB enone 10 (85% yield over two steps). AB enone 10 could also be

prepared in fewer steps but much lower (and highly variable) yield

by the reaction of the AB enone 1 with (methoxymethoxy)meth-

yllithium (prepared in situ from tri-n-butyl[(methoxymethoxy)

substituted AB enone 3 (1 equiv) to a bright red solution of the

o-toluate ester anion formed by deprotonation of the minocycline

D-ring precursor 12 (3 equiv) with lithium diisopropylamide (LDA,

3 equiv) in the presence of N,N,N⁰,N⁰-tetramethylethylenediamine

Scheme 4. Stereocontrolled formation of an all-carbon quaternary center by MichaeleClaisen cyclization reactions of o-toluate ester anions with b-substituted AB enones.

P.M. Wright, A.G. Myers / Tetrahedron 67 (2011) 9853e9869

9857

(TMEDA, 6 equiv) at ꢁ78 ^ꢀC, followed by warming to ꢁ10 ^ꢀC,

provided the MichaeleClaisen cyclization product 14 in 80% yield

as a single stereoisomer after puriﬁcation by ﬂash-column chro-

matography. A minor by-product (<5%), thought to be the product

of 1,2-additionecyclization (by lactonization), was isolated sepa-

rately. The stereochemical assignment of the MichaeleClaisen cy-

clization product (14), with C5a-R conﬁguration, is supported by

NOE studies; this stereochemistry is homologous with that of

MichaeleClaisen cyclization products derived from the non-

substituted AB enone 1.^1,2In both cases, addition appears to oc-

cur from a single diastereoface of the enone, that opposite the

C12a tert-butyldimethylsilyloxy substituent.^1bThere are two ex-

amples in the literature of MichaeleClaisen cyclization reactions of

Stork and Hagedorn,³reveals the vinylogous carbamic acid func-

tion of the A ring of tetracyclines in the ﬁnal step of the synthetic

sequence.

2.3. Discovery and diversiﬁcation of a C5aeC11a bridged

cyclopropane-containing tetracycline intermediate

In a search for a versatile branch point for the synthesis of

various C5a-substituted tetracyclines we were led to a serendipi-

tous but highly effective solution (Scheme 6). Removal of the

methoxymethyl ether protective group within the Michaele-

Claisen cyclization product 15 was achieved by treatment with

perchloric acid (CAUTION!),²¹providing the substituted neopentyl

alcohol 19 (73% yield). Addition of phosgene to a solution of 19 in

dichloromethane/pyridine (10:1) at 0 ^ꢀC unexpectedly afforded

the C5aeC11a-bridged cyclopropane tetracycline precursor 20 in

81% yield. After the fact, the formation of 20 is easily rationalized.

In this context it is interesting to note that Barton et al. had pre-

viously reported that the (C11,C12) 1,3-diketone can participate in

an internal nucleophilic addition, albeit in that case with addition

to an electrophilic carbonyl group that had been introduced at

position C4.²²

achiral b

-methyl cyclohexenones with o-toluate ester anions,²⁰but

we are unaware of any examples beyond those described here of

the stereocontrolled construction of a six-membered ring con-

taining a quaternary center by a MichaeleClaisen cyclization

reaction.

MichaeleClaisen reaction of the b-methoxymethoxymethyl AB

enone 10 and the minocycline D-ring precursor 13 (chosen so as to

allow later deprotection of the methoxymethyl ether at C5a

without concomitant cleavage of the C10 phenoxy protective

group) was also efﬁcient, affording the cyclization product 15, with

a protected C5a-hydroxymethyl-substituted quaternary center, in

Cyclopropanes with geminal electron-withdrawing substituents

are known to undergo nucleophilic ring-opening,²³

a trans-

formation often enhanced in the presence of Lewis acids.²⁴We

were led to explore the use of magnesium salts as Lewis acid ac-

tivators in this system in view of the well documented afﬁnity of

Mg^2þfor binding to the (C11,C12) 1,3-diketone function of tetra-

cyclines, complexation which is critical for inhibition of the ribo-

some.⁴We observed that the bridged cyclopropane intermediate

20 underwent regioselective ring-opening at the bridging carbon

atom in the presence of various nucleophiles and magnesium

bromide as Lewis acid. The ring-opened products were readily

deprotected in the typical two-step sequence to furnish the cor-

responding C5a-substituted tetracyclines (Table 1). For example,

reaction of the C5aeC11a-bridged cyclopropane tetracycline

72% yield (Scheme 4). Reaction of the b-methyl ester AB enone 5

with the anion formed from the minocycline D-ring precursor 12

afforded a complex mixture of products containing the desired

MichaeleClaisen cyclization product 16 as one component.

Cycloadduct 16 was isolated in 23% yield after puriﬁcation by se-

quential ﬂash-column chromatography and reverse-phase high-

performance liquid chromatography (rp-HPLC). Two-step depro-

tection of cyclization products 14 and 16 under typical condi-

tions^1,3provided C5a-methylminocycline (17, 100% yield,

Scheme 5) and C5a-carbomethoxyminocycline (18, 89% yield),

respectively, after puriﬁcation by rp-HPLC. Thus, hydrogenolytic

deprotection of the 3-benzyloxyisoxazole function, as reported by

Scheme 5. Synthesis of C5a-methylminocycline (17) and C5a-carbomethoxyminocycline (18) by two-step deprotection of cyclization products 14 and 16, respectively.

Scheme 6. Discovery of a C5aeC11a-bridged cyclopropane tetracycline precursor (20).

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P.M. Wright, A.G. Myers / Tetrahedron 67 (2011) 9853e9869

Table 1

Fully synthetic tetracyclines prepared from the C5aeC11a bridged cyclopropane intermediate 20 by magnesium bromide-promoted ring-opening followed by two-step

deprotection

precursor 20 with pyrrolidine (10 equiv) in the presence of a stoi-

chiometric amount of anhydrous magnesium bromide in THF at

23 ^ꢀC, followed by direct deprotection of the crude ring-opened

product (21), provided C5a-pyrrolidinomethylminocycline (22) in

74% yield over the three steps after puriﬁcation by rp-HPLC. A

number of different amines and alcohols were found to function

effectively as nucleophiles in the magnesium bromide-promoted

cyclopropane ring-opening reaction (Table 1). Ring-opening re-

actions were typically performed with a large excess of nucleophile

(ꢂ7 equiv) and stoichiometric or superstoichiometric quantities of

anhydrous magnesium bromide in THF (in the cases of low mo-

lecular weight alcohols as nucleophiles, the alcohol was used as

solvent) at a range of temperatures (23e75 ^ꢀC, see Experimental

section for details). Partial (and inconsequential) loss of the ben-

zyl ether phenolic protective group was observed to occur in the

cyclopropane ring-opening reaction in some instances.

The C5aeC11a-bridged cyclopropane intermediate 20 also

served as a precursor to tetracyclines with aminomethyl (32) and

piperazinylmethyl (34) substituents at position C5a (Scheme 7),

highly versatile compounds which functioned as further branch-

points for the synthesis of C5a-substituted tetracyclines (Figs. 2

and 3). Thus, treatment of cyclopropane 20 with sodium azide in

dimethylformamide at 23 ^ꢀC afforded the azido-substituted ring-

opened product 31 in 78% yield after puriﬁcation by ﬂash-column

chromatography.²⁵Addition of trimethylphosphine (2 equiv) to

a solution of the azide 31 and 2-(tert-butoxycarbonyloxyimino)-2-

phenylacetonitrile (BoceON, 2 equiv) in THF at ꢁ10 ^ꢀC followed by

warming to 23 ^ꢀC afforded the corresponding tert-butyl carbamate

(51% yield).²⁶Two-step deprotection of the tert-butyl carbamate

intermediate was best achieved by an inverted deprotection se-

quence (hydrogenolysis followed by treatment with hydroﬂuoric

acid),²⁷providing C5a-aminomethylminocycline 32 after puriﬁca-

tion by rp-HPLC (69% yield over two steps). In addition, magnesium

bromide-promoted ring-opening of cyclopropane 20 with N-tert-

butoxycarbamyl-piperazine followed by deprotection of the ring-

opened product 33 provided C5a-piperazinylmethylminocycline

(34, 58% yield over three steps). Final-step diversiﬁcation of 32

and 34 was readily achieved, affording a range of novel tetracy-

clines with C5a substituents incorporating amides, sulfonamides,

and amines (Figs. 2 and 3). In this manner the C5aeC11a-bridged

cyclopropane 20 served as a common precursor for the synthesis of

more than 25 structural variants of minocycline with a diverse

range of substituents at C5a.

3. Conclusion

Synthetic methodological advances have permitted efﬁcient and

stereocontrolled construction of diverse fully synthetic tetracy-

clines containing an all-carbon quaternary center at position C5a.

These examples serve to further demonstrate the broad applica-

bility of the MichaeleClaisen cyclization reaction as a powerful

method for the assembly of stereochemically complex six-

membered rings.²⁸New strategies presented herein for the in-

troduction of ester, thioester, and aldehyde substituents at the

b-position of cyclohexenones are anticipated to be of value in many

contexts. The discovery of highly diversiﬁable bridged

a

cyclopropane-containing tetracycline intermediate enabled efﬁ-

cient synthesis of numerous C5a-substituted tetracyclines, a struc-

turally novel class of compounds in this important family of

therapeutic agents. Although it is conceivable that many of these

structures could also have been accessed by MichaeleClaisen cy-

clization reactions of individually prepared

b-substituted AB

enones, the discovery of a diversiﬁable late-stage intermediate

greatly expedited the process of synthesis, in that a single

MichaeleClaisen cycloadduct served as a precursor to large num-

bers of C5a-substituted tetracyclines. The success of the C-ring-

P.M. Wright, A.G. Myers / Tetrahedron 67 (2011) 9853e9869

9859

Scheme 7. Synthesis of substrates for ﬁnal-step diversiﬁcation from cyclopropane 20.

Fig. 2. Fully synthetic tetracyclines prepared by ﬁnal-step diversiﬁcation of C5a-aminomethylminocycline (32).

forming cyclization reactions of

b

-substituted AB enones described

pool of fully synthetic tetracyclines is achievable, in the sense that

each modiﬁed AB enone could in theory be coupled with the

hundreds of different D-ring precursors that have been found to be

effective coupling partners with the AB enone 1.

herein, combined with the extraordinary number and diversity of

D-ring precursors known to be effective nucleophiles in this key

coupling reaction, implies that a multiplicative expansion of the

Fig. 3. Fully synthetic tetracyclines prepared by ﬁnal-step diversiﬁcation of C5a-piperazinylmethylminocycline (34).

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P.M. Wright, A.G. Myers / Tetrahedron 67 (2011) 9853e9869

4. Experimental

saturated aqueous sodium chloride solution (2ꢃ100 mL). The or-

ganic phase was dried over anhydrous sodium sulfate. The dried

solution was ﬁltered and the ﬁltrate was concentrated. The product

was puriﬁed by ﬂash-column chromatography (7% ethyl acetate/

4.1. General experimental procedures

All reactions were performed in round-bottom ﬂasks ﬁtted with

rubber septa under a positive pressure of argon, unless otherwise

noted. Air- and moisture-sensitive liquids were transferred via sy-

ringe or stainless steel cannula. Organic solutions were concen-

trated by rotary evaporation (house vacuum, ca. 25e40 Torr) at

ambient temperature, unless otherwise noted. Analytical thin-layer

chromatography (TLC) was performed using glass plates pre-coated

hexanes), providing

2 as a white solid (3.01 g, 85%). R_f¼0.57 (15% ethyl acetate/hexanes);

¹H NMR (500 MHz, CDCl₃)

b-methyl-substituted trimethylsilyl enol ether

d

7.48 (dd, 2H, J¼8.0, 1.5 Hz), 7.36e7.31

(m, 3H), 5.36 (AB quartet, 2H), 4.69 (d, 1H, J¼3.0 Hz), 3.76 (d, 1H,

J¼10.0 Hz), 2.55e2.52 (m, 1H), 2.44 (s, 6H), 2.32e2.25 (m, 2H), 1.84

(d, 1H, J¼13.5 Hz), 1.18 (d, 3H, J¼7.5 Hz), 0.87 (s, 9H), 0.22 (s, 3H),

0.11 (s, 3H), ꢁ0.04 (s, 9H); ¹³C NMR (125 MHz, CDCl₃)

d 189.7, 181.5,

ꢀ

with silica gel (0.25 mm, 60 A pore-size, 230e400 mesh, Merck

167.4, 147.2, 135.2, 128.6, 128.5, 128.4, 110.7, 108.3, 80.7, 72.2, 61.1,

46.3, 41.9, 26.2, 26.0, 25.1, 24.0, 18.8, ꢁ0.5, ꢁ2.8, ꢁ3.6; FTIR (neat

ﬁlm), 2955 (w), 1721 (m), 1653 (w), 1614 (w), 1510 (m), 1471 (w),

1250 (m), 1198 (m), 1148 (m), 936 (m), 833 (s) cm^ꢁ1; HRMSeESI (m/

z): [MþH]^þcalcd for C₃₀H₄₇N₂O₅Si₂, 571.3018; found, 571.3041.

KGA) impregnated with a ﬂuorescent indicator (254 nm). TLC plates

were visualized by exposure to ultraviolet light, then were stained

with aqueous potassium permanganate solution. Flash-column

chromatography was performed as described by Still et al.,²⁹

ꢀ

employing silica gel (60 A, 32e63

mm, standard grade, Dynamic

Adsorbents, Inc.).

4.2.2.

(75 mg, 0.329 mmol, 1.15 equiv) was added to a solution of

-methyl-substituted trimethylsilyl enol ether (163 mg,

b

-Methyl-substituted AB enone 3⁸. Palladium (II) acetate

Materials. Commercial solvents and reagents were used as re-

ceived with the following exceptions. Diisopropylamine, TMEDA,

chlorotrimethylsilane, and hexamethylphosphoramide were dis-

tilled from calcium hydride under an atmosphere of argon or

dinitrogen. Tetrahydrofuran was puriﬁed by the method of Pang-

born et al.³⁰The molarity of n-butyllithium solutions was de-

termined by titration against a standard solution of diphenylacetic

acid in tetrahydrofuran (average of three determinations).³¹

Instrumentation. Proton magnetic resonance (¹H NMR) spectra

were recorded on Varian INOVA 400 (400 MHz), 500 (500 MHz) or

600 (600 MHz) NMR spectrometers at 23 ^ꢀC. Proton chemical shifts

b

2

0.286 mmol, 1 equiv) in anhydrous dimethyl sulfoxide (3.0 mL) at

23 ^ꢀC. The resulting mixture was heated to 80 ^ꢀC. After stirring at

this temperature for 16 h, the reaction mixture was allowed to cool

to 23 ^ꢀC. The cooled suspension was diluted with ethyl acetate

(20 mL) and the whole was ﬁltered through a pad of Celite. Hexanes

(20 mL) were added to the ﬁltrate and the resulting solution was

washed sequentially with saturated aqueous sodium bicarbonate

solution (20 mL) and saturated aqueous sodium chloride solution

(2ꢃ20 mL). The organic phase was dried over anhydrous sodium

sulfate. The dried solution was ﬁltered and the ﬁltrate was con-

centrated. The product was puriﬁed by ﬂash-column chromatog-

are expressed in parts per million (ppm,

to residual protium in the NMR solvent (CHCl₃,

d

scale) and are referenced

7.26). Data are

d

represented as follows: chemical shift, multiplicity (s¼singlet,

d¼doublet, t¼triplet, q¼quartet, m¼multiplet and/or multiple

resonances, br¼broad), integration, and coupling constant (J) in

hertz. Carbon nuclear magnetic resonance spectra (¹³C NMR) were

recorded on Varian INOVA 500 (125 MHz) NMR spectrometers at

23 ^ꢀC. Carbon chemical shifts are expressed in parts per million

raphy (10% ethyl acetate/hexanes), affording the

substituted AB enone 3 as a pale yellow solid (63 mg, 44%). R_f¼0.26

(15% ethyl acetate/hexanes); ¹H NMR (500 MHz, CDCl₃)

7.50 (d,

2H, J¼7.0 Hz), 7.40e7.32 (m, 3H), 5.93 (s, 1H), 5.35 (AB quartet, 2H),

3.74 (d, 1H, J¼11.0 Hz), 2.81e2.70 (m, 3H), 2.46 (s, 6H), 2.01 (s, 3H),

0.82 (s, 9H), 0.26 (s, 3H), 0.05 (s, 3H); ¹³C NMR (125 MHz, CDCl₃)

b-methyl-

d

(ppm,

NMR solvent (CDCl₃,

d

scale) and are referenced to the carbon resonance of the

77.0). Infrared (IR) spectra were obtained

d 193.1, 188.1, 181.2, 167.5, 161.2, 135.0, 128.5, 128.5, 124.7, 108.4,

d

82.5, 72.5, 59.8, 47.5, 42.0, 30.4, 25.9, 24.4, 19.0, ꢁ2.5, ꢁ4.2; FTIR

(neat ﬁlm), 2930 (w), 1719 (s), 1672 (m), 1510 (m), 1472 (w), 1175

(m), 1045 (m), 936 (s), 829 (m) cm^ꢁ1; HRMSeESI (m/z): [MþH]^þ

calcd for C₂₇H₃₇N₂O₅Si, 497.2466; found, 497.2494.

using a Shimadzu 8400S FT-IR spectrometer and were referenced to

a polystyrene standard. Data are represented as follows: frequency

of absorption (cm^ꢁ1), intensity of absorption (s¼strong,

m¼medium, w¼weak, br¼broad). High-resolution mass spectra

were obtained at the Harvard University Mass Spectrometry Facility.

4.2.3.

tion of n-butyllithium in hexanes (2.5 M, 518

1.25 equiv) was added dropwise via syringe to a solution of tris(-

b

-Tris(methylthio)methyl trimethylsilyl enol ether 4. A solu-

mL, 1.30 mmol,

4.2. Experimental procedures

methylthio)methane (176 mL, 1.30 mmol, 1.25 equiv) in tetrahy-

4.2.1.

b

-Methyl-substituted trimethylsilyl enol ether 2. A round-

drofuran (11 mL) at ꢁ78 ^ꢀC. The resulting colorless solution was

bottomed ﬂask charged with copper (I) iodide (1.89 g, 9.95 mmol,

1.6 equiv) was ﬂame-dried under high vacuum. After cooling to

room temperature, the ﬂask was blanketed with dry argon. Tetra-

hydrofuran (50 mL) was added and the resulting suspension was

cooled to 0 ^ꢀC. A solution of methyllithium in ethyl ether (1.6 M,

12.2 mL, 19.6 mmol, 3.15 equiv) was added dropwise via syringe

over 5 min. The resulting solution was stirred at 0 ^ꢀC for 20 min,

then was cooled to ꢁ78 ^ꢀC. A solution of the AB enone 1 (3.0 g,

stirred at this temperature for 20 min, whereupon a solution of the

AB enone

1 (500 mg, 1.04 equiv, 1 equiv) in tetrahydrofuran

(3.0 mL) was added dropwise via syringe, forming a bright orange-

yellow solution. The reaction solution was allowed to warm slowly

to ꢁ45 ^ꢀC over 60 min, then chlorotrimethylsilane (199

mL,

1.55 mmol, 1.5 equiv) was added. The (yellow) reaction mixture

was stirred at ꢁ45 ^ꢀC for 30 min, then was partitioned between

aqueous potassium phosphate buffer solution (pH 7.0, 0.2 M,

20 mL) and dichloromethane (30 mL). The phases were separated

and the aqueous phase was extracted with dichloromethane

(20 mL). The organic extracts were combined and the combined

solution was dried over anhydrous sodium sulfate. The dried so-

lution was ﬁltered and the ﬁltrate was concentrated, affording an

orange-yellow oil. The crude product was puriﬁed by ﬂash-column

6.22 mmol, 1 equiv) and

chlorotrimethylsilane

(1.25 mL,

9.95 mmol, 1.6 equiv) in tetrahydrofuran (10 mL) was added to the

cuprate solution dropwise via syringe at ꢁ78 ^ꢀC. After stirring

at ꢁ78 ^ꢀC for 90 min, the cooling bath was removed and the

product solution was diluted with ethyl acetate (100 mL) and

hexanes (100 mL). A mixture of saturated aqueous ammonium

chloride solution and saturated aqueous ammonium hydroxide

solution (19:1, 100 mL) was then added carefully. The phases were

separated and the organic phase was washed sequentially with

saturated aqueous ammonium chloride solution (100 mL) and

chromatography (6% ethyl acetate/hexanes), providing b-tris(me-

thylthio)methyl trimethylsilyl enol ether 4 as a pale yellow foam

(654 mg, 89%). R_f¼0.69 (20% ethyl acetate/hexanes); ¹H NMR

(500 MHz, CDCl₃)

d 7.49e7.47 (m, 2H), 7.37e7.32 (m, 3H), 5.37 (AB

P.M. Wright, A.G. Myers / Tetrahedron 67 (2011) 9853e9869

9861

quartet, 2H), 5.36 (d, 1H, J¼2.0 Hz), 4.00 (d, 1H, J¼9.3 Hz), 3.15e3.12

a stirring solution of

ether

(3.0 mL) and water (6.0

b

-tris(methylthio)methyl trimethylsilyl enol

(m, 1H), 2.52 (dd, 1H, J¼14.4, 4.2 Hz), 2.45 (s, 6H), 2.42e2.39 (m,

1H), 2.18 (s, 9H), 2.14e2.06 (m, 1H), 0.86 (s, 9H), 0.22 (s, 3H), 0.12 (s,

4

(80 mg, 0.113 mmol, 1 equiv) in 2,2,2-triﬂuoroethanol

L, 500:1 mixture of 2,2,2-triﬂuoroethanol

m

3H), ꢁ0.01 (s, 9H); ¹³C NMR (125 MHz, CDCl₃)

d

189.6, 181.6, 167.2,

and water) at 23 ^ꢀC. The bright orange reaction solution was

allowed to stir at 23 ^ꢀC for 45 min, then was concentrated. The

resulting yellow oil was dissolved in dichloromethane (20 mL) and

the resulting solution was washed with saturated aqueous sodium

bicarbonate solution (20 mL). The phases were separated and the

aqueous phase was extracted with dichloromethane (20 mL). The

organic extracts were combined and the combined solution was

dried over anhydrous sodium sulfate. The dried solution was ﬁltered

and the ﬁltrate was concentrated. The crude product was puriﬁed by

ﬂash-column chromatography (10% ethyl acetate/hexanes), pro-

150.5, 135.2, 128.6, 128.5, 128.4, 108.7, 103.8, 81.6, 75.1, 72.2, 61.7,

46.6, 42.1, 41.7, 26.1, 21.2, 19.0, 14.1, ꢁ0.3, ꢁ2.6, ꢁ3.3; FTIR (neat

ﬁlm), 1722 (m), 1651 (w), 1614 (w), 1510 (m), 1472 (w), 1254 (m),

1206 (w), 903 (m), 839 (s) cm^ꢁ1; HRMSeESI (m/z): [MþH]^þcalcd

for C₃₃H₅₃N₂O₅S₃Si₂, 709.2650; found, 709.2617.

4.2.4.

(151 mg, 0.846 mmol, 5.0 equiv) was added in one portion to

a stirring solution of -tris(methylthio)methyl trimethylsilyl enol

ether 4 (120 mg, 0.169 mmol, 1 equiv) in methanol (4.5 mL) and

water (9.0 L, 3.0 equiv, 500:1 mixture of methanol and water) at

b-Methyl ester-substituted AB enone 5. N-Bromosuccinimide

b

viding the b-triﬂuoroethyl ester-substituted AB enone 6 as a yellow

m

solid (60 mg, 87%). R_f¼0.33 (15% ethyl acetate/hexanes); ¹H NMR

23 ^ꢀC. The pale yellow reaction solution was allowed to stir at 23 ^ꢀC

for 30 min, then was concentrated. The resulting yellow oil was

dissolved in dichloromethane (20 mL) and the resulting solution

was washed with saturated aqueous sodium bicarbonate solution

(20 mL). The phases were separated and the aqueous phase was

extracted with dichloromethane (20 mL). The organic extracts were

combined and the combined solution was dried over anhydrous

sodium sulfate. The dried solution was ﬁltered and the ﬁltrate was

concentrated. The crude product was puriﬁed by ﬂash-column

chromatography (11% ethyl acetate/hexanes, grading to 15%), pro-

(500 MHz, CDCl₃)

d

7.50 (d, 2H, J¼6.9 Hz), 7.41e7.35 (m, 3H), 6.90 (d,

1H, J¼2.3 Hz), 5.36 (AB quartet, 2H), 4.68e4.62 (m, 2H), 3.65 (d, 1H,

J¼11.0 Hz), 3.22 (d, 1H, J¼18.8 Hz), 2.95e2.87 (m, 2H), 2.47 (s, 6H),

0.80 (s, 9H), 0.27 (s, 3H), 0.04 (s, 3H); ¹³C NMR (125 MHz, CDCl₃)

d

194.0,186.7,181.0,167.4,164.1,145.2,134.9,132.7,128.6,128.5,128.5,

122.5 (q, J¼276.5 Hz), 108.3, 82.4, 72.7, 61.3 (q, J¼37.5 Hz), 59.3, 47.0,

41.9, 25.9, 24.5, 18.9, ꢁ2.5, ꢁ4.1; FTIR (neat ﬁlm), 1742 (m), 1721 (s),

1688 (m),1607 (w),1510 (m),1167 (s), 936 (s) cm^ꢁ1; HRMSeESI (m/z):

[MþH]^þcalcd for C₂₉H₃₆F₃N₂O₇Si, 609.2238; found, 609.2299.

viding the

b

-methyl ester-substituted AB enone 5 as a yellow solid

4.2.7.

nimide (48 mg, 0.271 mmol, 4.0 equiv) was added in one portion to

a stirring solution of -tris(methylthio)methyl trimethylsilyl enol

b-S-Methyl thioester-substituted AB enone 7. N-Bromosucci-

(78 mg, 85%). R_f¼0.26 (15% ethyl acetate/hexanes); ¹H NMR

(500 MHz, CDCl₃)

d

7.50 (d, 2H, J¼6.9 Hz), 7.40e7.33 (m, 3H), 6.82

b

(d, 1H, J¼1.8 Hz), 5.36 (AB quartet, 2H), 3.87 (s, 3H), 3.65 (d, 1H,

J¼10.5 Hz), 3.21 (d, 1H, J¼18.8 Hz), 2.91e2.84 (m, 2H), 2.46 (s, 6H),

0.80 (s, 9H), 0.26 (s, 3H), 0.03 (s, 3H); ¹³C NMR (125 MHz, CDCl₃)

ether 4 (48 mg, 0.068 mmol, 1 equiv) in tert-butanol (3.0 mL) at

23 ^ꢀC. The resulting bright yellow suspension was allowed to stir at

23 ^ꢀC for 45 min (slowly clearing to give a yellow solution). The

reaction mixture was diluted with dichloromethane (20 mL) and the

resulting solution was washed with saturated aqueous sodium bi-

carbonate solution (20 mL). The phases were separated and the

aqueous phase was extracted with dichloromethane (20 mL). The

organic extracts were combined and the combined solution was

dried over anhydrous sodium sulfate. The dried solution was ﬁltered

and the ﬁltrate was concentrated. The crude product was puriﬁed by

ﬂash-column chromatography (8% ethyl acetate/hexanes), providing

d

194.2, 187.0, 181.1, 167.4, 166.1, 147.1, 134.9, 131.4, 128.6, 128.5,

128.5, 108.3, 82.5, 72.6, 59.3, 52.9, 47.2, 41.9, 25.9, 24.6, 19.0, ꢁ2.5,

ꢁ4.1; FTIR (neat ﬁlm), 1721 (s), 1684 (m), 1609 (w), 1510 (m), 1252

(m), 1173 (m), 1030 (m), 831 (m), 737 (m) cm^ꢁ1; HRMSeESI (m/z):

[MþH]^þcalcd for C₂₈H₃₇N₂O₇Si, 541.2365; found, 541.2368.

4.2.5.

method). A solution of n-butyllithium in hexanes (2.5 M, 104

0.259 mmol, 1.25 equiv) was added dropwise via syringe to a solu-

tion of tris(methylthio)methane (35.2 L, 0.259 mmol, 1.25 equiv)

b-Methyl ester-substituted AB enone

5

(single-operation

mL,

the b-S-methyl thioester-substituted AB enone 7 as a pale yellow

m

solid (31 mg, 82%). R_f¼0.51 (20% ethyl acetate/hexanes); ¹H NMR

in tetrahydrofuran (2.0 mL) at ꢁ78 ^ꢀC. The resulting colorless so-

lution was stirred at this temperature for 20 min, whereupon a so-

lution of the AB enone 1 (100 mg, 0.207 mmol, 1 equiv) in

tetrahydrofuran (0.4 mL) was added dropwise via syringe, forming

a bright orange-yellow solution. The reaction solution was allowed

to warm slowly to ꢁ45 ^ꢀC over 30 min, then chlorotrimethylsilane

(500 MHz, CDCl₃) d 7.51e7.50 (m, 2H), 7.41e7.35 (m, 3H), 6.72 (d, 1H,

J¼2.4 Hz), 5.36 (AB quartet, 2H), 3.70 (d, 1H, J¼10.7 Hz), 3.30 (d, 1H,

J¼19.5 Hz), 2.98e2.93 (m, 1H), 2.89 (dd, 1H, J¼10.5, 3.7 Hz), 2.49 (s,

6H), 2.45 (s, 3H), 0.82 (s, 9H), 0.26 (s, 3H), 0.05 (s, 3H); ¹³C NMR

(125 MHz, CDCl₃)

d 194.2, 192.9, 186.8, 181.0, 167.4, 153.2, 134.9,

128.6, 128.5, 128.5, 127.8, 108.3, 82.6, 72.6, 59.3, 47.3, 41.9, 25.9, 25.9,

24.4, 19.0, 11.9, ꢁ2.5, ꢁ4.0; FTIR (neat ﬁlm), 1721 (m), 1684 (w), 1661

(w), 1510 (m), 1136 (w), 1040 (m), 937 (s), 735 (s) cm^ꢁ1; HRMSeESI

(m/z): [MþH]^þcalcd for C₂₈H₃₇N₂O₆SSi, 557.2136; found, 557.2109.

(39.7

mixture was allowed to warm to 23 ^ꢀC over 30 min, whereupon

methanol (4.0 mL), water (8.0 L, 2.1 equiv, 500:1 mixture of

mL, 0.311 mmol, 1.5 equiv) was added. The resulting (yellow)

m

methanol and water) and N-bromosuccinimide (221 mg,

1.24 mmol, 6.0 equiv) were added in sequence. The reaction mix-

ture was allowed to stir at 23 ^ꢀC for 30 min, then was concentrated.

The resulting oily (yellow) suspension was dissolved in dichloro-

methane (15 mL) and the resulting solution was washed with sat-

urated aqueous sodium bicarbonate solution (15 mL). The phases

were separated and the aqueous phase was extracted with

dichloromethane (15 mL). The organic extracts were combined and

the combined solution was dried over anhydrous sodium sulfate.

The dried solution was ﬁltered and the ﬁltrate was concentrated.

The crude product was puriﬁed by ﬂash-column chromatography

4.2.8.

b-(1,3-Dithian-2-yl) trimethylsilyl enol ether 8. A solution of

n-butyllithium in hexanes (2.5 M, 2.91 mL, 7.27 mmol, 1.15 equiv)

was added to a solution of 1,3-dithiane (862 mg, 6.95 mmol,

1.1 equiv) in tetrahydrofuran (60 mL) at ꢁ78 ^ꢀC. The resulting so-

lution was stirred at this temperature for 30 min, at which point

hexamethylphosphoramide (2.44 mL, 13.9 mmol, 2.2 equiv) was

added dropwise. After stirring at ꢁ78 ^ꢀC for a further 2 min, a so-

lution of the AB enone 1 (3.05 g, 6.32 mmol, 1 equiv) in tetrahy-

drofuran (15 mL) was added to the reaction solution dropwise via

syringe. The brownish-yellow reaction mixture was stirred at

ꢁ78 ^ꢀC for 40 min whereupon chlorotrimethylsilane (1.20 mL,

9.48 mmol, 1.5 equiv) was added. After stirring at ꢁ78 ^ꢀC for

40 min, aqueous potassium phosphate buffer solution (pH 7.0,

0.2 M, 100 mL) was added to the reaction solution. The resulting

mixture was allowed to warm to 23 ^ꢀC, then was extracted with

(7% acetone/hexanes), providing the

b-methyl ester-substituted AB

enone 5 as a yellow solid (101 mg, 90%).

4.2.6.

b-Triﬂuoroethyl ester-substituted AB enone 6. N-Bromosucci-

nimide (100 mg, 0.564 mmol, 5.0 equiv) was added in one portion to

9862

P.M. Wright, A.G. Myers / Tetrahedron 67 (2011) 9853e9869

dichloromethane (3ꢃ100 mL). The organic extracts were combined

and the combined solution was dried over anhydrous sodium sul-

fate. The dried solution was ﬁltered and the ﬁltrate was concen-

trated. The product was puriﬁed by ﬂash-column chromatography

organic extracts were combined and the combined solution was

dried over anhydrous sodium sulfate. The dried solution was ﬁl-

tered and the ﬁltrate was concentrated, affording an orange oil. The

product was puriﬁed by ﬂash-column chromatography (15% ethyl

acetate/hexanes, grading to 17% ethyl acetate/hexanes), providing

(8% ethyl acetate/hexanes), affording

thylsilyl enol ether 8 as a white foam (3.85 g, 90%). R_f¼0.53 (30%

ethyl acetate/hexanes); ¹H NMR (500 MHz, CDCl₃)

7.48 (d, 2H,

b-(1,3-dithian-2-yl) trime-

the

(124 mg, 85% yield, two steps). R_f¼0.40 (30% ethyl acetate/hex-

anes); ¹H NMR (500 MHz, CDCl₃)

b-methoxymethoxymethyl AB enone 10 as a pale yellow solid

d

J¼7.0 Hz), 7.38e7.31 (m, 3H), 5.36 (AB quartet, 2H), 4.98 (d, 1H,

J¼3.0 Hz), 4.12 (d, 1H, J¼5.0 Hz), 3.89 (d, 1H, J¼9.5 Hz), 2.96e2.82

(m, 5H), 2.46 (s, 6H), 2.34e2.29 (m, 1H), 2.28e2.23 (m, 2H),

2.15e2.09 (m, 1H), 1.90e1.80 (m, 1H), 0.86 (s, 9H), 0.21 (s, 3H), 0.10

d

7.50 (d, 2H, J¼7.0 Hz), 7.40e7.32

(m, 3H), 6.21 (s, 1H), 5.35 (AB quartet, 2H), 4.67 (AB quartet, 2H),

4.16 (m, 2H), 3.74 (d, 1H, J¼10.0 Hz), 3.38 (s, 3H), 2.80e2.74 (m, 3H),

2.45 (s, 6H), 0.82 (s, 9H), 0.26 (s, 3H), 0.05 (s, 3H); ¹³C NMR

(s, 3H), ꢁ0.01 (s, 9H); ¹³C NMR (125 MHz, CDCl₃)

d

189.4, 181.5,

(125 MHz, CDCl₃) d 193.1, 187.7, 181.1, 167.5, 159.7, 135.0, 128.5,

167.3, 149.5, 135.1, 128.7, 128.5, 128.4, 108.5, 104.8, 81.0, 72.3, 61.3,

54.9, 46.1, 41.9, 37.1, 31.1, 30.8, 26.1, 25.7, 21.8, 18.9, ꢁ0.4, ꢁ2.7, ꢁ3.6;

FTIR (neat ﬁlm), cm^ꢁ12953 (w), 1721 (s), 1653 (w), 1614 (w), 1510

(s), 1472 (w), 1454 (w), 1254 (s), 1204 (w), 1150 (w), 1024 (w), 934

(s), 901 (s), 835 (s); HRMSeESI (m/z): [MþH]^þcalcd for

C₃₃H₅₁N₂O₅S₂Si₂, 675.2772; found, 675.2783.

128.5, 128.5, 122.4, 108.4, 96.0, 83.0, 72.6, 68.4, 59.6, 55.5, 47.5, 41.9,

25.9, 25.8, 19.0, ꢁ2.5, ꢁ4.1; FTIR (neat ﬁlm), cm^ꢁ12951 (w), 2930

(w), 1719 (s), 1674 (m), 1510 (s), 1175 (m), 1152 (m), 1038 (s), 934 (s),

829 (s), 735 (s); HRMSeESI (m/z): [MþH]^þcalcd for C₂₉H₄₁N₂O₇Si,

557.2678; found, 557.2690.

4.2.11.

b

-Methoxymethoxymethyl trimethylsilyl enol ether 11. A so-

L, 0.936 mmol,

solution of tri-n-butyl[(methox-

4.2.9.

0.889 mmol, 6.0 equiv) was added in one portion to a stirring so-

lution of -(1,3-dithian-2-yl) trimethylsilyl enol ether 8 (100 mg,

0.148 mmol, 1 equiv) in tert-butanol (4.0 mL) and water (40 L) at

b

-Carbaldehyde AB enone 9. N-Bromosuccinimide (158 mg,

lution of n-butyllithium in hexanes (2.5 M, 374 m

2.1 equiv) was added to

a

b

ymethoxy)methyl]stannane¹⁹(326 mg, 0.893 mmol, 2.0 equiv) in

tetrahydrofuran (4.0 mL) at ꢁ78 ^ꢀC. The resulting solution was

stirred at this temperature for 15 min, at which point hexame-

m

23 ^ꢀC. The reaction mixture was stirred at this temperature for 1 h,

then was partitioned between dichloromethane (20 mL) and sat-

urated aqueous sodium bicarbonate solution (20 mL). The phases

were separated and the aqueous phase was extracted with

dichloromethane (20 mL). The organic extracts were combined and

the combined solution was dried over anhydrous sodium sulfate.

The dried solution was ﬁltered and the ﬁltrate was concentrated.

The crude product was puriﬁed by ﬂash-column chromatography

thylphosphoramide (313 mL, 1.78 mmol, 4.0 equiv) was added

dropwise. After stirring at ꢁ78 ^ꢀC for a further 1 min, a solution of

the AB enone 1 (215 mg, 0.446 mmol, 1 equiv) in tetrahydrofuran

(1.0 mL) was added to the reaction solution dropwise via syringe.

The reaction mixture was stirred at ꢁ78 ^ꢀC for 30 min whereupon

chlorotrimethylsilane (170 mL, 1.34 mmol, 3.0 equiv) was added.

After stirring at ꢁ78 ^ꢀC for 30 min, aqueous potassium phosphate

buffer solution (pH 7.0, 0.2 M, 10 mL) was added to the reaction

solution. The resulting mixture was allowed to warm to 23 ^ꢀC, then

was extracted with ethyl acetate (3ꢃ20 mL). The organic extracts

were combined and the combined solution was dried over anhy-

drous sodium sulfate. The dried solution was ﬁltered and the ﬁltrate

was concentrated. The product was puriﬁed by ﬂash-column

(12% ethyl acetate/hexanes), affording the

enone 9 as a yellow solid (68 mg, 90%). R_f¼0.18 (15% ethyl acetate/

hexanes); ¹H NMR (500 MHz, CDCl₃)

9.82, (s, 1H), 7.50 (d, 2H,

b-carbaldehyde AB

d

J¼6.9 Hz), 7.41e7.35 (m, 3H), 6.66 (d, 1H, J¼2.7 Hz), 5.36 (AB

quartet, 2H), 3.58 (d,1H, J¼11.0 Hz), 3.17 (d,1H, J¼19.7 Hz), 2.90 (dd,

1H, J¼10.8, 4.8 Hz), 2.77e2.71 (m, 1H), 2.44 (s, 6H), 0.78 (s, 9H), 0.27

(s, 3H), 0.05 (s, 3H); ¹³C NMR (125 MHz, CDCl₃)

d

194.6, 193.4, 186.5,

chromatography (10% ethyl acetate/hexanes), affording b-methox-

181.2, 167.4, 152.5, 137.2, 134.9, 128.6, 128.5, 128.5, 108.3, 83.2, 72.7,

59.4, 47.0, 41.8, 25.9, 21.5, 19.0, ꢁ2.5, ꢁ4.0; FTIR (neat ﬁlm), 1721

(m), 1694 (m), 1607 (w), 1510 (m), 1173 (w), 1036 (m), 937 (s), 737

(s) cm^ꢁ1; HRMSeESI (m/z): [MþH]^þcalcd for C₂₇H₃₅N₂O₆Si,

511.2259; found, 511.2286.

ymethoxymethyl trimethylsilyl enol ether 11 as a pale yellow solid

(156 mg, 55%). R_f¼0.43 (20% ethyl acetate/hexanes); ¹H NMR

(500 MHz, CDCl₃)

d 7.49e7.46 (m, 2H), 7.36e7.30 (m, 3H), 5.36 (AB

quartet, 2H), 4.78 (d, 1H, J¼2.4 Hz), 4.67 (s, 2H), 3.82 (d, 1H,

J¼9.8 Hz), 3.54e3.45 (m, 2H), 3.38 (s, 3H), 2.71e2.66 (m, 1H), 2.42

(s, 6H), 2.30e2.22 (m, 2H), 2.01 (d, 1H, J¼13.7 Hz), 0.86 (s, 9H), 0.23

(s, 3H), 0.12 (s, 3H), ꢁ0.05 (s, 9H); ¹³C NMR (125 MHz, CDCl₃)

4.2.10.

yborohydride (205 mg, 0.918 mmol, 3.5 equiv) was added in one

portion to a solution of the -carbaldehyde AB enone 9 (134 mg,

b-Methoxymethoxymethyl AB enone 10. Sodium triacetox-

d

189.6, 181.6, 167.4, 148.9, 135.1, 128.7, 128.5, 128.4, 108.3, 105.8,

b

96.5, 81.1, 73.0, 72.2, 61.0, 55.2, 46.1, 41.9, 32.4, 26.0, 20.1, 18.9, ꢁ0.5,

ꢁ2.8, ꢁ3.6; HRMSeESI (m/z): [MþNa]^þcalcd for C₃₂H₅₀N₂O₇Si₂Na,

653.3049; found, 653.3056.

0.262 mmol, 1 equiv) in benzene (2.0 mL) at 23 ^ꢀC. The resulting

solution was heated to 40 ^ꢀC. After stirring at 40 ^ꢀC for 5 ½ h, the

reaction mixture was allowed to cool to 23 ^ꢀC. The cooled solution

was diluted with dichloromethane (30 mL), and the resulting so-

lution was added slowly and carefully to saturated aqueous sodium

bicarbonate solution (30 mL). The phases were separated and the

aqueous phase was extracted with dichloromethane (30 mL). The

organic extracts were combined and the combined solution was

dried over anhydrous sodium sulfate. The dried solution was ﬁl-

tered and the ﬁltrate was concentrated. N,N-Diisopropylethylamine

4.2.12.

ration). Palladium (II) acetate (242 mg, 1.06 mmol, 1.05 equiv) was

added to a solution of -methoxymethoxymethyl trimethylsilyl

b-Methoxymethoxymethyl AB enone 10 (alternative prepa-

b

enol ether 11 (635 mg, 1.01 mmol, 1 equiv) in anhydrous dimethyl

sulfoxide (8.0 mL) at 23 ^ꢀC. The resulting mixture was heated to

50 ^ꢀC. After stirring at this temperature for 14 ½ h, the reaction

mixture was allowed to cool to 23 ^ꢀC. The cooled suspension was

diluted with ethyl acetate (50 mL) and the whole was ﬁltered

through a pad of Celite. Hexanes (50 mL) were added to the ﬁltrate

and the resulting solution was washed sequentially with saturated

aqueous sodium bicarbonate solution (50 mL) and saturated

aqueous sodium chloride solution (50 mL). The aqueous phases

were combined and the combined solution was extracted with

ethyl acetate/hexanes (1:1, 100 mL). The organic extracts were

combined and the combined solution was dried over anhydrous

sodium sulfate. The dried solution was ﬁltered and the ﬁltrate was

(229

mL, 1.31 mmol, 5.0 equiv) and chloromethyl methyl ether

(59.8

mL, 0.787 mmol, 3.0 equiv) were added sequentially to a so-

lution of the crude reduction product in benzene (1.5 mL) at 23 ^ꢀC.

The reaction ﬂask was sealed and the solution was heated to 50 ^ꢀC.

After stirring at 50 ^ꢀC for 24 h, the reaction mixture was allowed to

cool to 23 ^ꢀC. The cooled solution was partitioned between

dichloromethane (30 mL) and saturated aqueous sodium bi-

carbonate solution (30 mL). The layers were separated and the

aqueous phase was extracted with dichloromethane (30 mL). The

P.M. Wright, A.G. Myers / Tetrahedron 67 (2011) 9853e9869

9863

concentrated. The product was puriﬁed by ﬂash-column chroma-

tography (17% ethyl acetate/hexanes), affording the -methox-

3H); HRMSeESI (m/z): [MþH]^þcalcd for C₂₄H₂₉N₃O₇, 472.2078;

b

found, 472.2087.

ymethoxymethyl AB enone 10 as a pale yellow solid (290 mg, 52%).

4.2.14. MichaeleClaisen cyclization product 15. A freshly prepared

solution of lithium diisopropylamide (1.0 M, 7.86 mL, 7.86 mmol,

3.6 equiv) was added dropwise via syringe to a solution of phenyl

ester 13 (2.84 g, 7.86 mmol, 3.6 equiv) and TMEDA (2.27 mL,

15.1 mmol, 7.0 equiv) in tetrahydrofuran (60 mL) at ꢁ78 ^ꢀC, form-

ing a bright red solution. After stirring at ꢁ78 ^ꢀC for 40 min, a so-

4.2.13. C5a-Methylminocycline (17). A freshly prepared solution of

lithium diisopropylamide in tetrahydrofuran (1.0 M, 1.21 mL,

1.21 mmol, 3.0 equiv) was added dropwise via syringe to a solution

of phenyl ester 12 (449 mg, 1.21 mmol, 3.0 equiv) and TMEDA

(365 mL, 2.42 mmol, 6.0 equiv) in tetrahydrofuran (15 mL) at

ꢁ78 ^ꢀC, forming a bright red solution. After stirring at ꢁ78 ^ꢀC for

lution of the b-methoxymethoxymethyl AB enone 10 (1.20 g,

40 min, a solution of the

b-methyl-substituted AB enone 3 (200 mg,

2.16 mmol, 1 equiv) in tetrahydrofuran (15 mL) was added to the

reaction solution dropwise via syringe. The resulting mixture was

allowed to warm slowly to ꢁ10 ^ꢀC over 80 min, then was parti-

tioned between aqueous potassium phosphate buffer solution (pH

7.0, 0.2 M, 100 mL) and dichloromethane (100 mL). The phases

were separated and the aqueous phase was further extracted with

dichloromethane (2ꢃ75 mL). The organic extracts were combined

and the combined solution was dried over anhydrous sodium sul-

fate. The dried solution was ﬁltered and the ﬁltrate was concen-

trated, affording an orange-yellow oil. The product was puriﬁed by

ﬂash-column chromatography (3.5% ethyl acetate/dichloro-

methane), providing the MichaeleClaisen cyclization product 15 as

a yellow solid (1.29 g, 72%). R_f¼0.31 (30% ethyl acetate/hexanes); ¹H

0.403 mmol, 1 equiv) in tetrahydrofuran (3.0 mL) was added to the

reaction solution dropwise via syringe. The resulting mixture was

allowed to warm slowly to ꢁ10 ^ꢀC over 80 min, then was parti-

tioned between aqueous potassium phosphate buffer solution (pH

7.0, 0.2 M, 60 mL) and dichloromethane (60 mL). The phases were

separated and the aqueous phase was extracted with dichloro-

methane (2ꢃ40 mL). The organic extracts were combined and the

combined solution was dried over anhydrous sodium sulfate. The

dried solution was ﬁltered and the ﬁltrate was concentrated,

affording an orange-yellow oil. The product was puriﬁed by ﬂash-

column chromatography (15% ethyl acetate/hexanes, grading to

20%), providing the MichaeleClaisen cyclization product 14 as

a yellow solid (249 mg, 80%). R_f¼0.28 (20% ethyl acetate/hexanes);

NMR (500 MHz, CDCl₃)

d

16.77 (s, 1H), 7.51 (d, 4H, J¼8.0 Hz),

¹H NMR (600 MHz, CDCl₃)

d

15.96 (s, 1H), 7.49 (d, 2H, J¼7.8 Hz),

7.41e7.28 (m, 6H), 7.21 (d, 1H, J¼9.0 Hz), 6.90 (d, 1H, J¼9.0 Hz), 5.38

(s, 2H), 5.17 (AB quartet, 2H), 4.47 (d, 1H, J¼6.5 Hz), 4.34 (d, 1H,

J¼6.5 Hz), 4.15 (d, 1H, J¼9.5 Hz), 3.78 (d, 1H, J¼16.5 Hz), 3.38 (d, 1H,

J¼9.0 Hz), 3.27 (d, 1H, J¼9.5 Hz), 3.12 (s, 3H), 2.63 (s, 6H), 2.65e2.58

(m,1H), 2.51 (s, 6H), 2.51e2.41 (m, 2H), 2.32 (dd,1H, J¼14.5, 2.0 Hz),

0.93 (s, 9H), 0.29 (s, 3H), 0.20 (s, 3H); ¹³C NMR (125 MHz, CDCl₃)

7.39e7.33 (m, 3H), 7.26e7.24 (m, 1H), 7.04 (d, 1H, J¼8.5 Hz), 5.36 (s,

2H), 4.16 (d, 1H, J¼10.0 Hz), 3.20 (d, 1H, J¼16.1 Hz), 2.75 (d, 1H,

J¼16.1 Hz), 2.66 (s, 6H), 2.54e2.50 (m, 7H), 2.37 (d, 1H, J¼14.4 Hz),

2.16 (dd, 1H, J¼14.8, 4.5 Hz), 1.56 (s, 9H), 1.12 (s, 3H), 0.90 (s, 9H),

0.25 (s, 3H), 0.21 (s, 3H); ¹³C NMR (125 MHz, CDCl₃)

d 186.8, 185.6,

181.7, 178.3, 167.6, 152.3, 150.4, 145.4, 136.4, 135.1, 128.5, 128.4,

128.3, 124.2, 123.9, 122.3, 112.0, 108.1, 83.8, 81.7, 72.4, 60.7, 47.0,

44.2, 41.9, 40.6, 32.4, 32.1, 29.8, 27.7, 26.4, 19.2, ꢁ1.9, ꢁ2.3; FTIR

(neat ﬁlm), 1759 (w), 1721 (m), 1613 (w), 1510 (m), 1456 (w), 1265

(m), 1152 (m), 737 (s) cm^ꢁ1; HRMSeESI (m/z): [MþH]^þcalcd for

C₄₂H₅₅N₃O₉Si, 774.3780; found, 774.3796.

d 186.9, 184.6, 183.0, 181.6, 167.7, 154.7, 145.7, 136.8, 136.1, 135.1,

128.5, 128.4, 128.4, 128.3, 127.7, 127.0, 125.0, 120.7, 113.7, 108.1, 107.2,

96.1, 82.3, 72.9, 72.4, 71.4, 61.1, 54.6, 46.4, 44.4, 41.9, 35.8, 34.7, 28.4,

26.5, 19.3, ꢁ2.0, ꢁ2.1; FTIR (neat ﬁlm), 2932 (w), 1721 (s), 1611 (w),

1510 (m), 1472 (m), 1452 (m), 1269 (w), 1148 (w), 1107 (w), 1040 (s),

1020 (s), 922 (w), 831 (s), 733 (s) cm^ꢁ1; HRMSeESI (m/z): [MþH]^þ

calcd for C₄₆H₅₈N₃O₉Si, 824.3937; found, 824.3885.

Concentrated aqueous hydroﬂuoric acid solution (48 wt %,

2.0 mL) was added to a solution of the MichaeleClaisen cyclization

product 14 (249 mg, 0.322 mmol,1 equiv) in acetonitrile (3.0 mL) in

a polypropylene reaction vessel at 23 ^ꢀC. The reaction solution was

stirred vigorously at 23 ^ꢀC for 17 h, then was poured into water

(100 mL) containing dipotassium hydrogenphosphate trihydrate

(20.0 g). The resulting mixture was extracted with ethyl acetate

(100 mL, then 2ꢃ50 mL). The organic extracts were combined and

the combined solution was dried over anhydrous sodium sulfate.

The dried solution was ﬁltered and the ﬁltrate was concentrated,

affording an orange-brown solid. Methanol (3.0 mL) and dioxane

(3.0 mL) were added to the crude product, forming an orange-

brown solution. Palladium black (13.7 mg, 0.129 mmol, 0.4 equiv)

was added in one portion at 23 ^ꢀC. An atmosphere of hydrogen was

introduced by brieﬂy evacuating the ﬂask, then ﬂushing with pure

hydrogen (1 atm). The reaction mixture was stirred at 23 ^ꢀC for 1 h,

then was ﬁltered through a plug of Celite. The ﬁltrate was con-

centrated, affording a brownish yellow solid. The product was pu-

4.2.15. C5a-Carbomethoxyminocycline (18). A freshly prepared so-

lution of lithium diisopropylamide in tetrahydrofuran (1.0 M,

0.416 mL, 0.416 mmol, 3.0 equiv) was added dropwise via syringe

to a solution of phenyl ester 12 (155 mg, 0.416 mmol, 3.0 equiv) and

TMEDA (126 mL, 0.832 mmol, 6.0 equiv) in tetrahydrofuran (6 mL)

at ꢁ78 ^ꢀC, forming a bright red solution. After stirring at ꢁ78 ^ꢀC for

40 min, a solution of the b-methyl ester-substituted AB enone 5

(75 mg, 0.139 mmol, 1 equiv) in tetrahydrofuran (1.5 mL) was

added to the reaction solution dropwise via syringe. The resulting

mixture was allowed to warm slowly to ꢁ10 ^ꢀC over 75 min, then

was partitioned between aqueous potassium phosphate buffer

solution (pH 7.0, 0.2 M, 25 mL) and dichloromethane (25 mL). The

phases were separated and the aqueous phase was further

extracted with dichloromethane (2ꢃ20 mL). The organic extracts

were combined and the combined solution was dried over anhy-

drous sodium sulfate. The dried solution was ﬁltered and the ﬁltrate

was concentrated, affording a yellow solid. The crude product was

puriﬁed ﬁrst by ﬂash-column chromatography (15% acetone/hex-

anes), then by preparative HPLC on an Agilent Prep C18 column

riﬁed by preparative HPLC on an Agilent Prep C18 column [10 mm,

250ꢃ21.2 mm, UV detection at 350 nm, solvent A: 0.1% triﬂuoro-

acetic acid in water, solvent B: acetonitrile, 2 batches, injection

volume: 5.0 mL (4.0 mL 0.1% triﬂuoroacetic acid in water, 1.0 mL

acetonitrile), gradient elution with 5/40% B over 50 min, ﬂow

rate: 7.5 mL/min]. Fractions eluting at 24e31 min were collected

and concentrated, affording C5a-methylminocycline tri-

ﬂuoroacetate 17 as a yellow solid (188 mg, 100%, two steps). ¹H

[10

m

m, 250ꢃ21.2 mm, UV detection at 350 nm, solvent A: water,

solvent B: methanol, injection volume: 6.0 mL (5.0 mL methanol,

1.0 mL water), gradient elution with 85/100% B over 40 min, ﬂow

rate: 15 mL/min]. Fractions eluting at 25e28 min were collected

and concentrated, providing the MichaeleClaisen cyclization

product 16 as a yellow solid (26 mg, 23%). R_f¼0.34 (25% ethyl ace-

NMR (600 MHz, CD₃OD, triﬂuoroacetate)

d

7.90 (d, 1H, J¼9.4 Hz),

7.07 (d, 1H, J¼9.4 Hz), 4.13 (d, 1H, J¼1.0 Hz), 3.25 (s, 6H), 3.17 (d, 1H,

J¼15.8 Hz), 3.07e3.02 (m, 1H), 3.04 (s, 6H), 2.80 (d, 1H, J¼15.7 Hz),

2.05 (dd, 1H, J¼13.8, 2.9 Hz), 1.93 (dd, 1H, J¼14.1, 13.9 Hz), 1.26 (s,

tate/hexanes); ¹H NMR (500 MHz, CDCl₃)

d 15.97 (s,1H), 7.49 (d, 2H,

J¼7.3 Hz), 7.39e7.33 (m, 3H), 7.24 (d, 1H, J¼8.3 Hz), 7.03 (d, 1H,

J¼8.3 Hz), 5.37 (s, 2H), 4.11 (d, 1H, J¼9.3 Hz), 3.84 (d, 1H, J¼16.1 Hz),

9864

P.M. Wright, A.G. Myers / Tetrahedron 67 (2011) 9853e9869

3.36 (s, 3H), 2.80 (d, 1H, J¼16.1 Hz), 2.67e2.64 (m, 1H), 2.64 (s, 6H),

2.57e2.53 (m, 2H), 2.51 (s, 6H), 1.57 (s, 9H), 0.82 (s, 9H), 0.23 (s, 3H),

733 (s) cm^ꢁ1; HRMSeESI (m/z): [MþH]^þcalcd for C₄₄H₅₄N₃O₈Si,

780.3675; found,780.3654.

0.17 (s, 3H); ¹³C NMR (125 MHz, CDCl₃)

d 187.6, 186.2, 181.5, 176.3,

175.2, 167.6, 152.4, 150.0, 145.4, 135.0, 134.2, 128.5, 128.5, 128.3,

124.6, 124.4, 123.1, 108.0, 106.8, 83.8, 80.9, 72.5, 60.6, 52.4, 46.6,

44.2, 44.1, 41.9, 38.2, 27.7, 26.2, 19.1, ꢁ2.1, ꢁ2.9; FTIR (neat ﬁlm),

1761 (w), 1722 (m), 1512 (m), 1234 (s), 1150 (s), 833 (m), 733 (s)

4.2.17. C5aeC11a-Bridged cyclopropane tetracycline precursor

20. 4 A molecular sieves (2.4 g, small chunks) were added to a so-

lution of the substituted neopentyl alcohol 19 (720 mg,

0.923 mmol, 1 equiv) in dichloromethane (72 mL) and pyridine

(7.2 mL) at 23 ^ꢀC. The resulting mixture was stirred at 23 ^ꢀC for 1 h,

then was cooled to 0 ^ꢀC. A solution of phosgene in toluene (20 wt %,

ꢀ

cm^ꢁ1

;

HRMSeESI (m/z): [MþH]^þcalcd for C₄₃H₅₆N₃O₁₁Si,

818.3679; found, 818.3760.

Concentrated aqueous hydroﬂuoric acid solution (48 wt %,

0.8 mL) was added to a solution of the HPLC-puriﬁed product 16

from the cyclization step above (25.0 mg, 0.031 mmol, 1 equiv) in

acetonitrile (1.2 mL) in a polypropylene reaction vessel at 23 ^ꢀC. The

reaction solution was stirred vigorously at 23 ^ꢀC for 17 h, then was

poured into water (30 mL) containing dipotassium hydro-

genphosphate trihydrate (10.0 g). The resulting mixture was

extracted with ethyl acetate (30 mL, then 2ꢃ20 mL). The organic

extracts were combined and the combined solution was dried over

anhydrous sodium sulfate. The dried solution was ﬁltered and the

ﬁltrate was concentrated, affording an orange solid. Palladium

black (4.9 mg, 0.046 mmol, 1.5 equiv) was added in one portion to

a solution of the crude product in methanol (1.5 mL) and dioxane

(1.5 mL) at 23 ^ꢀC. An atmosphere of hydrogen was introduced by

brieﬂy evacuating the ﬂask, then ﬂushing with pure hydrogen

(1 atm). The reaction mixture was stirred at 23 ^ꢀC for 30 min, then

was ﬁltered through a plug of Celite. The ﬁltrate was concentrated,

affording a yellow solid. The product was puriﬁed by preparative

537 mL, 1.02 mmol, 1.1 equiv) was added dropwise to the cooled

mixture. The resulting solution was stirred at 0 ^ꢀC for 1 h, where-

upon aqueous potassium phosphate buffer solution (pH 7.0, 0.2 M,

20 mL) was added. The resulting mixture was allowed to warm to

23 ^ꢀC, then was ﬁltered to remove the molecular sieves. Dichloro-

methane (60 mL) and aqueous potassium phosphate buffer solu-

tion (pH 7.0, 0.2 M, 60 mL) were added and the phases were

separated. The aqueous phase was further extracted with

dichloromethane (2ꢃ60 mL). The organic extracts were combined

and the combined solution was dried over anhydrous sodium sul-

fate. The dried solution was ﬁltered and the ﬁltrate was concen-

trated, providing an orange-yellow oil. The product was puriﬁed by

ﬂash-column chromatography (20% ethyl acetate/hexanes, grading

to 30% ethyl acetate/hexanes), affording the C5aeC11a-bridged

cyclopropane tetracycline precursor 20 as a white solid (572 mg,

81%). R_f¼0.25 (30% ethyl acetate/hexanes); ¹H NMR (500 MHz,

CDCl₃)

d

7.52 (d, 2H, J¼7.3 Hz), 7.44e7.24 (m, 8H), 7.13 (d, 1H,

J¼9.0 Hz), 6.86 (d, 1H, J¼9.0 Hz), 5.35 (s, 2H), 5.05 (AB quartet, 2H),

4.01 (d, 1H, J¼10.5 Hz), 3.85 (d, 1H, J¼17.4 Hz), 2.77 (d, 1H,

J¼17.4 Hz), 2.68e2.57 (m, 3H), 2.62 (s, 6H), 2.49 (s, 6H), 2.25 (d, 1H,

J¼5.0 Hz), 1.71 (d, 1H, J¼5.0 Hz), 0.89 (s. 9H), 0.28, (s, 3H), 0.12 (s,

HPLC on an Agilent Prep C18 column [10

m

m, 250ꢃ21.2 mm, UV

detection at 350 nm, solvent A: 0.1% triﬂuoroacetic acid in water,

solvent B: acetonitrile, injection volume: 5.0 mL (4.0 mL 0.1% tri-

ﬂuoroacetic acid in water, 1.0 mL acetonitrile), gradient elution with

5/40% B over 50 min, ﬂow rate: 7.5 mL/min]. Fractions eluting at

27e32 min were collected and concentrated, affording C5a-

carbomethoxyminocycline triﬂuoroacetate 18 as a yellow solid

3H); ¹³C NMR (125 MHz, CDCl₃)

d 194.4, 191.8, 185.3, 180.9, 167.6,

152.6, 144.8, 136.7, 135.0, 132.2, 128.6, 128.5, 128.5, 128.4, 127.6,

127.1, 123.3, 123.2, 113.5, 107.9, 84.0, 72.6, 71.2, 58.8, 49.0, 44.8, 43.1,

41.8, 32.1, 31.1, 30.9, 26.6, 26.3, 19.5, ꢁ2.0, ꢁ2.6; FTIR (neat ﬁlm),

2938 (w), 1728 (s), 1711 (m), 1670 (w), 1510 (m), 1474 (m), 1452 (m),

1362 (w), 1258 (m), 916 (m), 827 (s), 733 (s) cm^ꢁ1; HRMSeESI (m/

z): [MþH]^þcalcd for C₄₄H₅₂N₃O₇Si, 762.3569; found,762.3569.

(17.1 mg, 89%). ¹H NMR (600 MHz, CD₃OD)

d

7.81 (d, 1H, J¼9.2 Hz),

7.03 (d, 1H, J¼9.2 Hz), 4.14 (s, 1H), 3.66 (d, 1H, J¼15.7 Hz), 3.61 (s,

3H), 3.14 (s, 6H), 2.97 (s, 6H), 2.87e2.83 (m, 2H), 2.53 (dd, 1H,

J¼14.3, 2.6 Hz), 2.04 (dd, 1H, J¼14.2, 14.1 Hz); HRMSeESI (m/z):

[MþH]^þcalcd for C₂₆H₃₀N₃O₉, 516.1977; found, 516.2011.

4.2.18. C5a-Pyrrolidinomethylminocycline (22). Anhydrous magne-

sium bromide (8.2 mg, 0.045 mmol, 2.0 equiv) was added to a so-

lution of the C5aeC11a-bridged cyclopropane 20 (17.0 mg,

4.2.16. Substituted neopentyl alcohol 19. Perchloric acid (CAU-

TION!)²¹(13.0 mL, 70% solution) was added dropwise over 5 min to

a solution of the MichaeleClaisen cyclization product 15 (1.04 g,

1.26 mmol, 1 equiv) in tetrahydrofuran (130 mL) at 23 ^ꢀC. After

stirring at this temperature for 10 min, the reaction solution was

slowly and carefully poured into ice-cold saturated aqueous sodium

bicarbonate solution (300 mL). The resulting mixture was extracted

with dichloromethane (2ꢃ250 mL, then 50 mL). The organic ex-

tracts were combined and the combined solution was dried over

anhydrous sodium sulfate. The dried solution was ﬁltered and the

ﬁltrate was concentrated, providing an orange-yellow oil. The

product was puriﬁed by ﬂash-column chromatography (55% ethyl

acetate/hexanes, grading to 75% ethyl acetate/hexanes), affording

the substituted neopentyl alcohol 19 as a yellow solid (720 mg,

73%). R_f¼0.26 (65% ethyl acetate/hexanes); ¹H NMR (500 MHz,

0.022 mmol, 1 equiv) and pyrrolidine (18 mL, 0.223 mmol, 10 equiv)

in tetrahydrofuran (0.5 mL) at 23 ^ꢀC. The reaction mixture was

stirred at 23 ^ꢀC for 16 h, then was partitioned between dichloro-

methane and saturated aqueous sodium bicarbonate solution

(10 mL each). The phases were separated and the aqueous phase

was extracted with dichloromethane (10 mL). The organic extracts

were combined and the combined solution was dried over anhy-

drous sodium sulfate. The dried solution was ﬁltered and the ﬁltrate

was concentrated. The crude ring-opened product (21) was dis-

solved in acetonitrile (1.2 mL). The resulting solution was trans-

ferred to a polypropylene reaction vessel and concentrated aqueous

hydroﬂuoric acid solution (48 wt %, 0.8 mL) was added. The re-

action mixture was stirred vigorously at 23 ^ꢀC for 20 h, then was

poured into water (30 mL) containing dipotassium hydro-

genphosphate (8.0 g). The resulting mixture was extracted with

ethyl acetate (3ꢃ40 mL). The organic extracts were combined and

the combined solution was dried over anhydrous sodium sulfate.

The dried solution was ﬁltered and the ﬁltrate was concentrated.

Palladium black (5.0 mg, 0.047 mmol, 2.8 equiv) was added in one

portion to a solution of the crude product in methanol (1.0 mL) and

dioxane (1.0 mL) at 23 ^ꢀC. An atmosphere of hydrogen was in-

troduced by brieﬂy evacuating the ﬂask, then ﬂushing with pure

hydrogen (1 atm). The reaction mixture was stirred at 23 ^ꢀC for 1

¼ h, then was ﬁltered through a plug of Celite. The ﬁltrate was

concentrated. The product was puriﬁed by preparative HPLC on an

CDCl₃) d 16.76 (s, 1H), 7.53e7.49 (m, 4H), 7.41e7.28 (m, 6H), 7.22 (d,

1H, J¼9.0 Hz), 6.90 (d, 1H, J¼9.0 Hz), 5.38 (s, 2H), 5.17 (AB quartet,

2H), 4.11 (d, 1H, J¼9.5 Hz), 3.66 (d, 1H, J¼16.0 Hz), 3.48 (d, 1H,

J¼11.0 Hz), 3.32 (d, 1H, J¼11.0 Hz), 2.64 (s, 6H), 2.68e2.59 (m, 1H),

2.56e2.48 (m, 1H), 2.51 (s, 6H), 2.38 (dd, 1H, J¼14.5, 4.5 Hz), 2.23

(br d, 1H, J¼14.0 Hz), 0.92 (s, 9H), 0.25 (s, 3H), 0.18 (s, 3H); ¹³C NMR

(125 MHz, CDCl₃)

d 186.7, 184.7, 182.7, 181.4, 167.7, 154.9, 145.7,

136.8, 135.9, 135.1, 128.5, 128.5, 128.5, 128.3, 127.8, 126.9, 125.3,

120.7, 113.7, 108.2, 107.3, 82.3, 72.4, 71.4, 68.2, 61.3, 46.2, 44.7, 42.0,

36.8, 34.5, 28.2, 26.5, 19.3, ꢁ1.8, ꢁ2.0; FTIR (neat ﬁlm), 2938 (w),

1719 (m), 1609 (w), 1510 (s), 1452 (s), 1265 (m), 1020 (m), 829 (s),

P.M. Wright, A.G. Myers / Tetrahedron 67 (2011) 9853e9869

9865

Agilent Prep C18 column [10

m

m, 250ꢃ21.2 mm, UV detection at

and the reaction mixture was heated to 55 ^ꢀC. After stirring at 55 ^ꢀC

for 14 h, the reaction mixture was allowed to cool to 23 ^ꢀC. The

cooled mixture was partitioned between dichloromethane and

saturated aqueous sodium bicarbonate solution (10 mL each). The

phases were separated and the aqueous phase was further

extracted with dichloromethane (10 mL). The organic extracts were

combined and the combined solution was dried over anhydrous

sodium sulfate. The dried solution was ﬁltered and the ﬁltrate was

concentrated. The crude ring-opened product was dissolved in

acetonitrile (1.2 mL). The resulting solution was transferred to

a polypropylene reaction vessel and concentrated aqueous hydro-

ﬂuoric acid solution (48 wt %, 0.8 mL) was added. The reaction

mixture was stirred vigorously at 23 ^ꢀC for 16 ½ h, then was poured

into water (30 mL) containing dipotassium hydrogenphosphate

(8.0 g). The resulting mixture was extracted with ethyl acetate

(3ꢃ40 mL). The organic extracts were combined and the combined

solution was dried over anhydrous sodium sulfate. The dried so-

lution was ﬁltered and the ﬁltrate was concentrated. Palladium

black (5.0 mg, 0.047 mmol, 2.8 equiv) was added in one portion to

a solution of the crude product in methanol (1.0 mL) and dioxane

(1.0 mL) at 23 ^ꢀC. An atmosphere of hydrogen was introduced by

brieﬂy evacuating the ﬂask, then ﬂushing with pure hydrogen

(1 atm). The reaction mixture was stirred at 23 ^ꢀC for 1 ³/₄h, then

was ﬁltered through a plug of Celite. The ﬁltrate was concentrated.

The product was puriﬁed by preparative HPLC on an Agilent Prep

350 nm, solvent A: 0.1% triﬂuoroacetic acid in water, solvent B:

acetonitrile, injection volume: 5.0 mL (4.0 mL 0.1% triﬂuoroacetic

acid in water, 1.0 mL acetonitrile), gradient elution with 5/35% B

over 50 min, ﬂow rate: 7.5 mL/min]. Fractions eluting at 39e43 min

were collected and concentrated, affording C5a-pyrrolidinomethyl-

minocycline bistriﬂuoroacetate 22 as a yellow solid (12.5 mg, 74%,

three steps). ¹H NMR (600 MHz, CD₃OD, bistriﬂuoroacetate)

d 7.55

(d, 1H, J¼9.0 Hz), 6.95 (d, 1H, J¼9.0 Hz), 4.05 (s, 1H), 3.84 (br s, 1H),

3.75e3.71 (br s, 1H), 3.73 (d, 1H, J¼14.4 Hz), 3.62 (d, 1H, J¼16.8 Hz),

3.20 (d, 1H, J¼13.2 Hz), 3.14 (d, 1H, J¼15.0 Hz), 3.13e3.03 (br s, 1H),

3.10 (s, 6H), 2.70 (s, 6H), 2.67 (d, 1H, J¼16.8 Hz), 2.59 (dd,1H, J¼15.0,

3.0 Hz), 2.50 (br s, 1H), 2.02e1.90 (m, 5H); HRMSeESI (m/z):

[MþH]^þcalcd for C₂₈H₃₇N₄O₇, 541.2657; found, 541.2684.

4.2.19. C5a-Piperidinylmethylminocycline (23). Anhydrous magne-

sium bromide (8.2 mg, 0.045 mmol, 2.0 equiv) was added to a so-

lution of the C5aeC11a-bridged cyclopropane 20 (17.0 mg,

0.022 mmol, 1 equiv) and piperidine (22 mL, 0.223 mmol, 10 equiv)

in tetrahydrofuran (0.5 mL) at 23 ^ꢀC. The reaction mixture was

stirred at 23 ^ꢀC for 21 h, then was heated to 45 ^ꢀC. After stirring at

this temperature for 14 h, the reaction mixture was allowed to cool

to 23 ^ꢀC. The cooled mixture was partitioned between dichloro-

methane (15 mL) and saturated aqueous sodium bicarbonate so-

lution (10 mL). The phases were separated and the aqueous phase

was extracted with dichloromethane (10 mL). The organic extracts

were combined and the combined solution was dried over anhy-

drous sodium sulfate. The dried solution was ﬁltered and the ﬁltrate

was concentrated. The crude ring-opened product was dissolved in

acetonitrile (1.2 mL). The resulting solution was transferred to

a polypropylene reaction vessel and concentrated aqueous hydro-

ﬂuoric acid solution (48 wt %, 0.8 mL) was added. The reaction

mixture was stirred vigorously at 23 ^ꢀC for 13 h, then was poured

into water (30 mL) containing dipotassium hydrogenphosphate

(8.0 g). The resulting mixture was extracted with ethyl acetate

(3ꢃ40 mL). The organic extracts were combined and the combined

solution was dried over anhydrous sodium sulfate. The dried so-

lution was ﬁltered and the ﬁltrate was concentrated. Palladium

black (5.0 mg, 0.047 mmol, 2.8 equiv) was added in one portion to

a solution of the crude product in methanol (1.0 mL) and dioxane

(1.0 mL) at 23 ^ꢀC. An atmosphere of hydrogen was introduced by

brieﬂy evacuating the ﬂask, then ﬂushing with pure hydrogen

(1 atm). The reaction mixture was stirred at 23 ^ꢀC for 1 ½ h, then

was ﬁltered through a plug of Celite. The ﬁltrate was concentrated.

The product was puriﬁed by preparative HPLC on an Agilent Prep

C18 column [10

mm, 250ꢃ21.2 mm, UV detection at 350 nm, solvent

A: 0.1% triﬂuoroacetic acid in water, solvent B: acetonitrile, in-

jection volume: 5.0 mL (4.0 mL 0.1% triﬂuoroacetic acid in water,

1.0 mL acetonitrile), gradient elution with 5/25% B over 50 min,

then 25/100% B over 20 min, ﬂow rate: 7.5 mL/min]. Fractions

eluting at 49e52 min were collected and concentrated, affording

C5a-morpholinomethylminocycline bistriﬂuoroacetate 24 as an

orange-yellow solid (7.5 mg, 56%, three steps). ¹H NMR (600 MHz,

CD₃OD, bistriﬂuoroacetate)

d

7.56 (d, 1H, J¼9.0 Hz), 6.95 (d, 1H,

J¼9.0 Hz), 4.04 (s, 1H), 3.77e3.69 (m, 4H), 3.53 (d, 1H, J¼16.8 Hz),

3.24 (d, 1H, J¼13.2 Hz), 3.18e3.14 (m, 1H), 3.08 (s, 6H), 2.99e2.94

(m, 2H), 2.88 (d,1H, J¼15.0 Hz), 2.81e2.72 (m, 2H), 2.74 (s, 6H), 2.62

(d, 1H, J¼16.8 Hz), 2.53 (br d, 1H, J¼14.4 Hz), 1.92 (dd, 1H, J¼14.2,

14.0 Hz); HRMSeESI (m/z): [MþH]^þcalcd for C₂₈H₃₇N₄O₈,

557.2606; found, 557.2611.

4.2.21. C5a-Diethylaminomethylminocycline (25). Anhydrous mag-

nesium bromide (7.2 mg, 0.039 mmol, 2.0 equiv) was added to

a solution of the C5aeC11a-bridged cyclopropane 20 (15.0 mg,

0.020 mmol, 1 equiv) and diethylamine (102 mL, 0.987 mmol,

C18 column [10

m

m, 250ꢃ21.2 mm, UV detection at 350 nm, solvent

50 equiv) in tetrahydrofuran (0.5 mL) at 23 ^ꢀC. The reaction ﬂask

was sealed and the reaction mixture was heated to 45 ^ꢀC. After

stirring at this temperature for 20 h, the reaction mixture was

allowed to cool to room temperature. The reaction ﬂask was

A: 0.1% triﬂuoroacetic acid in water, solvent B: acetonitrile, in-

jection volume: 5.0 mL (4.0 mL 0.1% triﬂuoroacetic acid in water,

1.0 mL acetonitrile), gradient elution with 5/35% B over 50 min,

ﬂow rate: 7.5 mL/min]. Fractions eluting at 40e44 min were col-

lected and concentrated, affording C5a-piperidinylmethylmino-

cycline bistriﬂuoroacetate 23 as a yellow solid (12.0 mg, 70%,

opened brieﬂy and a second portion of diethylamine (204 mL,

1.97 mmol, 100 equiv) was added. The ﬂask was re-sealed and the

reaction mixture was heated to 45 ^ꢀC. After stirring at this tem-

perature for a further 55 h, the reaction mixture was allowed to

cool to 23 ^ꢀC. The cooled mixture was partitioned between

dichloromethane and saturated aqueous sodium bicarbonate so-

lution (10 mL each). The phases were separated and the aqueous

phase was extracted with dichloromethane (10 mL). The organic

extracts were combined and the combined solution was dried over

anhydrous sodium sulfate. The dried solution was ﬁltered and the

ﬁltrate was concentrated. The crude ring-opened product was

dissolved in acetonitrile (1.2 mL). The resulting solution was

transferred to a polypropylene reaction vessel and concentrated

aqueous hydroﬂuoric acid solution (48 wt %, 0.8 mL) was added.

The reaction mixture was stirred vigorously at 23 ^ꢀC for 10 ½ h,

then was poured into water (30 mL) containing dipotassium

hydrogenphosphate (8.0 g). The resulting mixture was extracted

three steps). ¹H NMR (600 MHz, CD₃OD, bistriﬂuoroacetate)

d 7.56

(d, 1H, J¼9.0 Hz), 6.96 (d, 1H, J¼9.0 Hz), 4.10 (d, 1H, J¼2.4 Hz), 3.66

(d, 1H, J¼16.8 Hz), 3.46 (d, 1H, J¼14.4 Hz), 3.40e3.35 (br m, 1H),

3.27e3.23 (m, 1H), 3.23e3.18 (m, 1H), 3.10 (s, 6H), 3.10e3.00 (m,

2H), 2.71 (s, 6H), 2.71e2.62 (m, 2H), 2.59 (dd, 1H, J¼15.0, 3.0 Hz),

2.02 (dd, 1H, J¼15.1, 12.7 Hz), 1.95e1.88 (br m, 1H), 1.85e1.78 (br m,

2H), 1.72e1.61 (br m, 2H), 1.43e1.36 (br m, 1H); HRMSeESI (m/z):

[MþH]^þcalcd for C₂₉H₃₉N₄O₇, 555.2813; found, 555.2788.

4.2.20. C5a-Morpholinomethylminocycline (24). Anhydrous mag-

nesium bromide (6.3 mg, 0.034 mmol, 2.0 equiv) was added to

a solution of the C5aeC11a-bridged cyclopropane 20 (13.0 mg,

0.017 mmol, 1 equiv) and morpholine (15

mL, 0.17 mmol, 10 equiv)

in tetrahydrofuran (0.5 mL) at 23 ^ꢀC. The reaction ﬂask was sealed

9866

P.M. Wright, A.G. Myers / Tetrahedron 67 (2011) 9853e9869

with ethyl acetate (3ꢃ40 mL). The organic extracts were combined

and the combined solution was dried over anhydrous sodium

sulfate. The dried solution was ﬁltered and the ﬁltrate was con-

centrated. Palladium black (5.0 mg, 0.047 mmol, 2.8 equiv) was

added in one portion to a solution of the crude product in

methanol (1.0 mL) and dioxane (1.0 mL) at 23 ^ꢀC. An atmosphere

of hydrogen was introduced by brieﬂy evacuating the ﬂask, then

(dd, 1H, J¼1.8, 1.6 Hz), 6.86 (d, 1H, J¼9.0 Hz), 4.48 (AB quartet, 2H),

4.13 (s, 1H), 3.42 (d, 1H, J¼16.8 Hz), 3.25 (dd, 1H, J¼13.8, 1.2 Hz),

3.11 (s, 6H), 2.73 (s, 6H), 2.69 (d, 1H, J¼16.2 Hz), 2.14 (dd, 1H,

J¼15.0, 3.0 Hz), 1.98 (dd, 1H, J¼14.5, 14.2 Hz); HRMSeESI (m/z):

[MþH]^þcalcd for C₂₇H₃₂N₅O₇, 538.2296; found, 538.2285.

4.2.23. C5a-Cyclopropylaminomethylminocycline (27). Anhydrous

magnesium bromide (8.2 mg, 0.045 mmol, 2.0 equiv) was added to

a solution of the C5aeC11a-bridged cyclopropane 20 (17.0 mg,

ﬂushing with pure hydrogen (1 atm). The reaction mixture was

3

stirred at 23 ^ꢀC for 1

/

h, then was ﬁltered through a plug of

4

Celite. The ﬁltrate was concentrated. The product was puriﬁed by

preparative HPLC on an Agilent Prep C18 column [10 m,

0.022 mmol, 1 equiv) and cyclopropylamine (15 mL, 0.223 mmol,

m

10 equiv) in tetrahydrofuran (0.5 mL) at 23 ^ꢀC. The reaction mix-

ture was stirred at 23 ^ꢀC for 16 h, then was heated to 40 ^ꢀC. After

stirring at this temperature for 22 h, the reaction mixture was

allowed to cool to room temperature. The reaction ﬂask was

250ꢃ21.2 mm, UV detection at 350 nm, solvent A: 0.1% triﬂuoro-

acetic acid in water, solvent B: acetonitrile, injection volume:

5.0 mL (4.0 mL 0.1% triﬂuoroacetic acid in water, 1.0 mL acetoni-

trile), gradient elution with 5/40% B over 50 min, ﬂow rate:

7.5 mL/min]. Fractions eluting at 36e39 min were collected and

concentrated, affording C5a-diethylaminomethylminocycline bis-

triﬂuoroacetate 25 as a yellow solid (12.0 mg, 79%, three steps). ¹H

opened brieﬂy and a second portion of cyclopropylamine (15 mL,

0.223 mmol, 10 equiv) was added. The ﬂask was sealed and the

reaction mixture was heated to 40 ^ꢀC. After stirring at this tem-

perature for a further 13 h, the reaction mixture was allowed to

cool to 23 ^ꢀC. The cooled mixture was partitioned between

dichloromethane (15 mL) and saturated aqueous sodium bi-

carbonate solution (10 mL). The phases were separated and the

aqueous phase was extracted with dichloromethane (10 mL). The

organic extracts were combined and the combined solution was

dried over anhydrous sodium sulfate. The dried solution was ﬁl-

tered and the ﬁltrate was concentrated. The crude ring-opened

product was dissolved in acetonitrile (1.2 mL). The resulting so-

lution was transferred to a polypropylene reaction vessel and

concentrated aqueous hydroﬂuoric acid solution (48 wt %, 0.8 mL)

was added. The reaction mixture was stirred vigorously at 23 ^ꢀC

for 12 h, then was poured into water (30 mL) containing dipotas-

sium hydrogenphosphate (8.0 g). The resulting mixture was

extracted with ethyl acetate (3ꢃ40 mL). The organic extracts were

combined and the combined solution was dried over anhydrous

sodium sulfate. The dried solution was ﬁltered and the ﬁltrate was

concentrated. Palladium black (5.0 mg, 0.047 mmol, 2.8 equiv) was

added in one portion to a solution of the crude product in

methanol (1.0 mL) and dioxane (1.0 mL) at 23 ^ꢀC. An atmosphere

of hydrogen was introduced by brieﬂy evacuating the ﬂask, then

ﬂushing with pure hydrogen (1 atm). The reaction mixture was

stirred at 23 ^ꢀC for 3 ½ h, then was ﬁltered through a plug of

Celite. The ﬁltrate was concentrated. The product was puriﬁed by

NMR (600 MHz, CD₃OD, bistriﬂuoroacetate)

d 7.54 (d, 1H,

J¼9.0 Hz), 6.95 (d, 1H, J¼9.0 Hz), 4.10 (d, 1H, J¼3.0 Hz), 3.61 (d, 1H,

J¼16.8 Hz), 3.42 (d, 1H, J¼15.0 Hz), 3.25e3.20 (m, 2H), 3.16e3.02

(br m, 3H), 3.10 (s, 6H), 2.93 (br s, 1H), 2.73e2.69 (m, 1H), 2.70 (s,

6H), 2.52 (dd, 1H, J¼15.0, 3.0 Hz), 2.07 (dd, 1H, J¼14.1, 13.3 Hz),

1.28 (br s, 3H), 1.04 (br s, 3H); HRMSeESI (m/z): [MþH]^þcalcd for

C₂₈H₃₉N₄O₇, 543.2813; found, 543.2821.

4.2.22. C5a-N-Imidazolylmethylminocycline (26). Anhydrous mag-

nesium bromide (7.2 mg, 0.039 mmol, 3.0 equiv) was added to

a solution of the C5aeC11a-bridged cyclopropane 20 (10.0 mg,

0.013 mmol, 1 equiv) and imidazole (6.2 mg, 0.091 mmol,

7.0 equiv) in tetrahydrofuran (0.5 mL) at 23 ^ꢀC. The reaction ﬂask

was sealed and the reaction mixture was heated to 60 ^ꢀC. After

stirring at this temperature for 60 h, the reaction mixture was

allowed to cool to 23 ^ꢀC. The cooled mixture was partitioned be-

tween dichloromethane and saturated aqueous sodium bi-

carbonate solution (15 mL each). The phases were separated and

the aqueous phase was extracted with dichloromethane (15 mL).

The organic extracts were combined and the combined solution

was dried over anhydrous sodium sulfate. The dried solution was

ﬁltered and the ﬁltrate was concentrated. The crude ring-opened

product was dissolved in acetonitrile (1.2 mL). The resulting so-

lution was transferred to a polypropylene reaction vessel and

concentrated aqueous hydroﬂuoric acid solution (48 wt %, 0.8 mL)

was added. The reaction mixture was stirred vigorously at 23 ^ꢀC

for 18 h, then was poured into water (30 mL) containing dipotas-

sium hydrogenphosphate (8.0 g). The resulting mixture was

extracted with ethyl acetate (3ꢃ40 mL). The organic extracts were

combined and the combined solution was dried over anhydrous

sodium sulfate. The dried solution was ﬁltered and the ﬁltrate was

concentrated. Palladium black (5.0 mg, 0.047 mmol, 3.6 equiv) was

added in one portion to a solution of the crude product in

methanol (1.0 mL) and dioxane (1.0 mL) at 23 ^ꢀC. An atmosphere

of hydrogen was introduced by brieﬂy evacuating the ﬂask, then

ﬂushing with pure hydrogen (1 atm). The reaction mixture was

stirred at 23 ^ꢀC for 1 ¼ h, then was ﬁltered through a plug of

Celite. The ﬁltrate was concentrated. The product was puriﬁed by

preparative HPLC on an Agilent Prep C18 column [10 mm,

250ꢃ21.2 mm, UV detection at 350 nm, solvent A: 0.1% triﬂuoro-

acetic acid in water, solvent B: acetonitrile, injection volume:

5.0 mL (4.0 mL 0.1% triﬂuoroacetic acid in water, 1.0 mL acetoni-

trile), gradient elution with 5/35% B over 50 min, ﬂow rate:

7.5 mL/min]. Fractions eluting at 35e36 min were collected and

concentrated, affording C5a-cyclopropylaminomethylminocycline

bistriﬂuoroacetate 27 as

a

yellow solid (3.0 mg, 18%, three

7.58 (d,

steps).^{27 1}H NMR (600 MHz, CD₃OD, bistriﬂuoroacetate)

d

1H, J¼9.0 Hz), 6.96 (d, 1H, J¼9.0 Hz), 4.00 (d, 1H, J¼2.4 Hz), 3.60 (d,

1H, J¼14.4 Hz), 3.55 (d, 1H, J¼16.8 Hz), 3.19e3.10 (m, 1H), 3.13 (s,

6H), 3.03 (d, 1H, J¼14.4 Hz), 2.76 (s, 6H), 2.76e2.70 (m, 1H),

2.62e2.58 (m, 1H), 2.25 (dd, 1H, J¼14.8, 2.8 Hz), 1.98 (dd, 1H,

J¼14.2, 13.8 Hz), 0.89e0.82 (m, 1H), 0.77e0.69 (m, 3H); HRMSeESI

(m/z): [MþH]^þcalcd for C₂₇H₃₅N₄O₇, 527.2500; found, 527.2502.

preparative HPLC on an Agilent Prep C18 column [10 mm,

250ꢃ21.2 mm, UV detection at 350 nm, solvent A: 0.1% triﬂuoro-

acetic acid in water, solvent B: acetonitrile, injection volume:

5.0 mL (4.0 mL 0.1% triﬂuoroacetic acid in water, 1.0 mL acetoni-

trile), gradient elution with 5/40% B over 50 min, ﬂow rate:

7.5 mL/min]. Fractions eluting at 25e27 min were collected and

concentrated, affording C5a-imidazolylmethylminocycline bistri-

ﬂuoroacetate 26 as a yellow solid (7.3 mg, 73%, three steps). ¹H

4.2.24. C5a-Methoxymethylminocycline (28). Anhydrous magne-

sium bromide (9.1 mg, 0.049 mmol, 2.5 equiv) was added to a so-

lution of the C5aeC11a-bridged cyclopropane 20 (15.0 mg,

0.020 mmol, 1 equiv) in methanol (1.5 mL) at 23 ^ꢀC. The reaction

ﬂask was sealed and the reaction mixture was heated to 65 ^ꢀC. After

stirring at 65 ^ꢀC for 24 h, the reaction mixture was allowed to cool

to 23 ^ꢀC. The cooled mixture was partitioned between aqueous

potassium phosphate buffer solution (pH 7.0, 0.2 M, 10 mL) and

dichloromethane (10 mL). The phases were separated and the

NMR (600 MHz, CD₃OD, bistriﬂuoroacetate)

d 8.42 (t, 1H,

J¼1.3 Hz), 7.51 (d, 1H, J¼9.0 Hz), 7.40 (dd, 1H, J¼1.8, 1.5 Hz), 7.23

P.M. Wright, A.G. Myers / Tetrahedron 67 (2011) 9853e9869

9867

aqueous phase was extracted with dichloromethane (10 mL). The

organic extracts were combined and the combined solution was

dried over anhydrous sodium sulfate. The dried solution was ﬁl-

tered and the ﬁltrate was concentrated. The crude ring-opened

product was dissolved in acetonitrile (1.2 mL). The resulting solu-

tion was transferred to a polypropylene reaction vessel and con-

centrated aqueous hydroﬂuoric acid solution (48 wt %, 0.8 mL) was

added. The reaction mixture was stirred vigorously at 23 ^ꢀC for 15 h,

then was poured into water (30 mL) containing dipotassium

hydrogenphosphate trihydrate (10.0 g). The resulting mixture was

extracted with ethyl acetate (3ꢃ30 mL). The organic extracts were

combined and the combined solution was dried over anhydrous

sodium sulfate. The dried solution was ﬁltered and the ﬁltrate was

concentrated. Palladium black (6.0 mg, 0.057 mmol, 2.8 equiv) was

added in one portion to a solution of the crude product in methanol

(1.0 mL) and dioxane (1.0 mL) at 23 ^ꢀC. An atmosphere of hydrogen

was introduced by brieﬂy evacuating the ﬂask, then ﬂushing with

pure hydrogen (1 atm). The reaction mixture was stirred at 23 ^ꢀC

for 2 ½ h, then was ﬁltered through a plug of Celite. The ﬁltrate was

concentrated. The product was puriﬁed by preparative HPLC on an

volume: 5.0 mL (4.0 mL 0.1% triﬂuoroacetic acid in water, 1.0 mL

acetonitrile), gradient elution with 5/40% B over 50 min, ﬂow

rate: 7.5 mL/min]. Fractions eluting at 41e44 min were collected

and concentrated, affording C5a-n-butoxymethylminocycline tri-

ﬂuoroacetate 29 as a yellow solid (7.3 mg, 56%, three steps). ¹H NMR

(600 MHz, CD₃OD, triﬂuoroacetate)

d

7.81 (d, 1H, J¼9.0 Hz), 7.04 (d,

1H, J¼9.6 Hz), 4.16 (s, 1H), 3.50 (d, 1H, J¼10.2 Hz), 3.38e3.30 (m,

3H), 3.21 (d, 1H, J¼9.6 Hz), 3.13 (s, 6H), 3.11e3.06 (m, 1H), 2.98 (s,

6H), 2.58 (d, 1H, J¼15.6 Hz), 2.42 (dd, 1H, J¼13.8, 3.0 Hz), 1.71 (dd,

1H, J¼13.9, 13.8 Hz), 1.50e1.39 (m, 2H), 1.34e1.24 (m, 2H), 0.87 (t,

3H, J¼7.2 Hz); HRMSeESI (m/z): [MþH]^þcalcd for C₂₈H₃₈N₃O₈,

544.2653; found, 544.2655.

4.2.26. C5a-Methoxyethoxymethylminocycline

(30). Anhydrous

magnesium bromide (6.2 mg, 0.034 mmol, 2.0 equiv) was added to

a solution of the C5aeC11a-bridged cyclopropane 20 (13.0 mg,

0.017 mmol, 1 equiv) in 2-methoxyethanol (0.5 mL) at 23 ^ꢀC. The

resulting mixture was heated to 60 ^ꢀC. After stirring at 60 ^ꢀC for

26 h, the reaction mixture was allowed to cool to 23 ^ꢀC. The cooled

mixture was partitioned between aqueous potassium phosphate

buffer solution (pH 7.0, 0.2 M, 10 mL) and dichloromethane

(10 mL). The phases were separated and the aqueous phase was

further extracted with dichloromethane (10 mL). The organic ex-

tracts were combined and the combined solution was dried over

anhydrous sodium sulfate. The dried solution was ﬁltered and the

ﬁltrate was concentrated. The crude ring-opened product was

dissolved in acetonitrile (1.2 mL). The resulting solution was

transferred to a polypropylene reaction vessel and concentrated

aqueous hydroﬂuoric acid solution (48 wt %, 0.8 mL) was added.

The reaction mixture was stirred vigorously at 23 ^ꢀC for 10 ½ h,

then was poured into water (30 mL) containing dipotassium

hydrogenphosphate (8.0 g). The resulting mixture was extracted

with ethyl acetate (3ꢃ40 mL). The organic extracts were combined

and the combined solution was dried over anhydrous sodium

sulfate. The dried solution was ﬁltered and the ﬁltrate was con-

centrated. Palladium black (5.0 mg, 0.047 mmol, 2.8 equiv) was

added in one portion to a solution of the crude product in

methanol (1.0 mL) and dioxane (1.0 mL) at 23 ^ꢀC. An atmosphere

of hydrogen was introduced by brieﬂy evacuating the ﬂask, then

Agilent Prep C18 column [10

m

m, 250ꢃ21.2 mm, UV detection at

350 nm, solvent A: 0.1% triﬂuoroacetic acid in water, solvent B:

acetonitrile, injection volume: 7.0 mL (6.0 mL 0.1% triﬂuoroacetic

acid in water, 1.0 mL acetonitrile), gradient elution with 5/40% B

over 50 min, ﬂow rate: 7.5 mL/min]. Fractions eluting at 29e33 min

were collected and concentrated, affording C5a-methoxymethy-

lminocycline triﬂuoroacetate 28 as a yellow solid (7.1 mg, 58%,

three steps). ¹H NMR (600 MHz, CD₃OD, hydrochloride)

d 7.82 (d,

1H, J¼9.4 Hz), 7.05 (d, 1H, J¼9.2 Hz), 4.15 (s, 1H), 3.49 (d, 1H,

J¼10.3 Hz), 3.36 (d, 1H, J¼15.6 Hz), 3.25 (s, 3H), 3.14 (s, 6H), 3.12 (d,

1H, J¼10.3 Hz), 3.08e3.04 (m, 1H), 2.99 (s, 6H), 2.56 (d, 1H,

J¼15.6 Hz), 2.41 (dd, 1H, J¼14.1, 2.9 Hz), 1.69 (dd, 1H, J¼14.1,

13.9 Hz); HRMSeESI (m/z): [MþH]^þcalcd for C₂₅H₃₂N₃O₈,

502.2184; found, 502.2186.

4.2.25. C5a-n-Butoxymethylminocycline (29). Anhydrous magne-

sium bromide (7.2 mg, 0.039 mmol, 2.0 equiv) was added to a so-

lution of the C5aeC11a-bridged cyclopropane 20 (15.0 mg,

0.020 mmol, 1 equiv) in n-butanol (1.0 mL) at 23 ^ꢀC. The resulting

mixture was heated to 75 ^ꢀC. After stirring at 75 ^ꢀC for 14 h, the

reaction mixture was allowed to cool to 23 ^ꢀC. The cooled mixture

was partitioned between aqueous potassium phosphate buffer

solution (pH 7.0, 0.2 M, 10 mL) and dichloromethane (10 mL). The

phases were separated and the aqueous phase was extracted with

dichloromethane (10 mL). The organic extracts were combined and

the combined solution was dried over anhydrous sodium sulfate.

The dried solution was ﬁltered and the ﬁltrate was concentrated.

The crude ring-opened product was dissolved in acetonitrile

(1.2 mL). The resulting solution was transferred to a polypropylene

reaction vessel and concentrated aqueous hydroﬂuoric acid solu-

tion (48 wt %, 0.8 mL) was added. The reaction mixture was stirred

vigorously at 23 ^ꢀC for 13 ½ h, then was poured into water (30 mL)

containing dipotassium hydrogenphosphate (8.0 g). The resulting

mixture was extracted with ethyl acetate (3ꢃ40 mL). The organic

extracts were combined and the combined solution was dried over

anhydrous sodium sulfate. The dried solution was ﬁltered and the

ﬁltrate was concentrated. Palladium black (5.0 mg, 0.047 mmol,

2.4 equiv) was added in one portion to a solution of the crude

product in methanol (1.0 mL) and dioxane (1.0 mL) at 23 ^ꢀC. An

atmosphere of hydrogen was introduced by brieﬂy evacuating the

ﬂask, then ﬂushing with pure hydrogen (1 atm). The reaction

ﬂushing with pure hydrogen (1 atm). The reaction mixture was

3

stirred at 23 ^ꢀC for 1

/

h, then was ﬁltered through a plug of

4

Celite. The ﬁltrate was concentrated. The product was puriﬁed by

preparative HPLC on an Agilent Prep C18 column [10 m,

m

250ꢃ21.2 mm, UV detection at 350 nm, solvent A: 0.1% triﬂuoro-

acetic acid in water, solvent B: acetonitrile, injection volume:

5.0 mL (4.0 mL 0.1% triﬂuoroacetic acid in water, 1.0 mL acetoni-

trile), gradient elution with 5/40% B over 50 min, ﬂow rate:

7.5 mL/min]. Fractions eluting at 32e34 min were collected and

concentrated, affording C5a-methoxyethoxymethylminocycline

triﬂuoroacetate 30 as a yellow solid (5.8 mg, 52%, three steps).

¹H NMR (600 MHz, CD₃OD, triﬂuoroacetate)

d 7.83 (d, 1 h,

J¼9.0 Hz), 7.05 (d, 1H, J¼9.0 Hz), 4.13 (s, 1H), 3.54e3.45 (m, 4H),

3.44e3.40 (m, 1H), 3.34 (d, 1H, J¼15.6 Hz), 3.27e3.25 (m, 1H), 3.26

(s, 3H), 3.18 (s, 6H), 3.11 (br d, 1H, J¼14.4 Hz), 2.99 (s, 6H), 2.61 (d,

1H, J¼16.2 Hz), 2.45 (dd, 1H, J¼14.4, 3.0 Hz), 1.71 (t, 1H, J¼14.4 Hz);

HRMSeESI (m/z): [MþH]^þcalcd for C₂₇H₃₆N₃O₉, 546.2446; found,

546.2459.

4.2.27. Azido-substituted ring-opened product (31). Sodium azide

(50.0 mg, 0.763 mmol, 3.0 equiv) was added to a solution of the

C5aeC11a-bridged cyclopropane 20 (194 mg, 0.255 mmol, 1 equiv)

in dimethylformamide (7.5 mL) at 23 ^ꢀC. The resulting solution was

stirred at this temperature for 14 h, then was partitioned between

saturated aqueous sodium chloride solution and diethyl ether

(60 mL each). The phases were separated and the aqueous phase

was further extracted with diethyl ether (60 mL). The organic

3

mixture was stirred at 23 ^ꢀC for 3 /₄h, then was ﬁltered through

a plug of Celite. The ﬁltrate was concentrated. The product was

puriﬁed by preparative HPLC on an Agilent Prep C18 column

[10

m

m, 250ꢃ21.2 mm, UV detection at 350 nm, solvent A: 0.1%

triﬂuoroacetic acid in water, solvent B: acetonitrile, injection

9868

P.M. Wright, A.G. Myers / Tetrahedron 67 (2011) 9853e9869

extracts were combined and the combined solution was dried over

anhydrous sodium sulfate. The dried solution was ﬁltered and the

ﬁltrate was concentrated. The product was puriﬁed by ﬂash-

column chromatography (12% ethyl acetate/hexanes), providing

the azido-substituted ring-opened product 31 as a yellow solid

(160 mg, 78%). R_f¼0.41 (30% ethyl acetate/hexanes); ¹H NMR

a solution of the C5aeC11a-bridged cyclopropane 20 (105 mg,

0.138 mmol, 1 equiv) and tert-butyl 1-piperazine carboxylate

(186 mg, 1.00 mmol, 7.2 equiv) in tetrahydrofuran (2.0 mL) at

23 ^ꢀC. The reaction ﬂask was sealed and the reaction mixture was

heated to 45 ^ꢀC. After stirring at 45 ^ꢀC for 36 h, the reaction

mixture was allowed to cool to 23 ^ꢀC. The cooled mixture was

partitioned between dichloromethane and saturated aqueous so-

dium bicarbonate solution (25 mL each). The phases were sepa-

rated and the aqueous phase was extracted with dichloromethane

(25 mL). The organic extracts were combined and the combined

solution was dried over anhydrous sodium sulfate. The dried so-

lution was ﬁltered and the ﬁltrate was concentrated. The product

mixture was ﬁltered through a short pad of silica gel (eluting with

40% ethyl acetate/hexanes) and the ﬁltrate was concentrated,

affording an orange-yellow oil. Methanol (2.5 mL) and dioxane

(2.5 mL) were added to the crude ring-opened product (33),

forming an orange-yellow solution. Palladium black (25 mg,

0.235 mmol, 1.7 equiv) was added in one portion at 23 ^ꢀC. An at-

mosphere of hydrogen was introduced by brieﬂy evacuating the

ﬂask, then ﬂushing with pure hydrogen (1 atm). The reaction

mixture was stirred at 23 ^ꢀC for 2 h, then was ﬁltered through

a plug of Celite. The ﬁltrate was concentrated, providing an orange

solid. Concentrated aqueous hydroﬂuoric acid (48 wt %, 1.5 mL)

was added to a solution of the crude product in acetonitrile

(2.0 mL) in a polypropylene reaction vessel at 23 ^ꢀC. The reaction

mixture was stirred vigorously at 23 ^ꢀC for 14 h. Excess hydro-

ﬂuoric acid was quenched by the careful addition of methoxy-

(500 MHz, CDCl₃)

d

16.72 (s, 1H), 7.51 (br d, 4H, J¼8.0 Hz), 7.41e7.26

(m, 7H), 6.95 (d, 1H, 8.5 Hz), 5.38 (s, 2H), 5.18 (AB quartet, 2H), 4.11

(d, 1H, J¼10.5 Hz), 3.72 (d, 1H, J¼16.5 Hz), 3.30 (d, 1H, J¼11.5 Hz),

3.13 (d, 1H, J¼11.5 Hz), 2.65 (s, 6H), 2.65e2.45 (m, 2H), 2.51 (s, 6H),

2.35e2.25 (m, 2H), 0.92 (s, 9H), 0.27 (s, 3H), 0.19 (s, 3H); ¹³C NMR

(125 MHz, CDCl₃)

d 186.5, 184.0, 183.6, 181.5, 167.7, 154.9, 145.9,

136.7, 135.3, 135.0, 128.5, 128.5, 128.5, 128.4, 127.9, 127.0, 125.8,

120.2, 114.0, 108.3, 107.3, 82.3, 72.5, 71.5, 61.1, 59.1, 46.6, 44.6, 41.9,

36.4, 35.2, 28.3, 26.5, 19.3, -1.9, -2.1; FTIR (neat ﬁlm), 2099 (s), 1721

(s), 1609 (m), 1510 (s), 1258 (m), 829 (s) cm^ꢁ1; HRMSeESI (m/z):

[MþH]^þcalcd for C₄₄H₅₃N₆O₇Si, 805.3740; found, 805.3722.

4.2.28. C5a-Aminomethylminocycline (32)^26,27. A solution of tri-

methylphospine in tetrahydrofuran (1.0 M, 398 mL, 0.398 mmol,

2.0 equiv) was added dropwise via syringe to a solution of the

azido-substituted ring-opened product 31 (160 mg, 0.199 mmol,

1 equiv) and 2-(tert-butoxycarbonyloxyimino)-2-phenylacetoni-

trile (98.0 mg, 0.398 mmol, 2.0 equiv) in tetrahydrofuran at

ꢁ10 ^ꢀC. The reaction mixture was allowed to warm to 23 ^ꢀC over

15 min. After stirring at this temperature for 15 h, the product so-

lution was partitioned between dichloromethane and water (60 mL

each). The phases were separated and the organic phase was

washed sequentially with water (60 mL) and saturated aqueous

sodium chloride solution (2ꢃ60 mL). The organic solution was then

dried over anhydrous sodium sulfate. The dried solution was ﬁl-

tered and the ﬁltrate was concentrated. The product was puriﬁed

by ﬂash-column chromatography (25% ethyl acetate/hexanes),

providing the desired tert-butyl carbamate as a yellow solid (90 mg,

51%). Methanol (2.5 mL) and dioxane (2.5 mL) were added to this

product, forming a yellow solution. Palladium black (25 mg,

0.235 mmol, 2.3 equiv) was added in one portion at 23 ^ꢀC. An at-

mosphere of hydrogen was introduced by brieﬂy evacuating the

ﬂask, then ﬂushing with pure hydrogen (1 atm). The reaction

mixture was stirred at 23 ^ꢀC for 1 h, whereupon more palladium

black (25 mg) was added. The resulting mixture was stirred at 23 ^ꢀC

for a further 2 h, then was ﬁltered through a plug of Celite. The

ﬁltrate was concentrated, providing an orange solid. Concentrated

aqueous hydroﬂuoric acid (48 wt %, 1.4 mL) was added to a solution

of the crude product in acetonitrile (2.0 mL) in a polypropylene

reaction vessel at 23 ^ꢀC. The reaction mixture was stirred vigorously

at 23 ^ꢀC for 15 h. Excess hydroﬂuoric acid was quenched by the

careful addition of methoxytrimethylsilane (9.0 mL). The resulting

mixture was concentrated. The product was puriﬁed by preparative

trimethylsilane

concentrated. The product was puriﬁed by preparative HPLC on an

Agilent Prep C18 column [10

m, 250ꢃ21.2 mm, UV detection at

(10.0 mL).

The

resulting

mixture

was

m

350 nm, solvent A: 0.1% triﬂuoroacetic acid in water, solvent B:

acetonitrile, 2 batches, injection volume (for each batch): 5.0 mL

(4.0 mL 0.1% triﬂuoroacetic acid in water, 1.0 mL acetonitrile),

gradient elution with 5/35% B over 50 min, ﬂow rate: 7.5 mL/

min]. Fractions eluting at 22e29 min were collected and concen-

trated, affording C5a-piperazinylmethylminocycline bistri-

ﬂuoroacetate 34 as a yellow solid (63 mg, 58%, three steps). ¹H

NMR (600 MHz, CD₃OD, bistriﬂuoroacetate)

d 7.58 (d, 1H,

J¼9.6 Hz), 6.93 (d, 1H, J¼9.0 Hz), 4.06 (s, 1H), 3.44 (d, 1H,

J¼16.2 Hz), 3.11 (br d, 1H, J¼12.6 Hz), 3.08e3.02 (m, 2H), 3.05 (s,

6H), 3.01e2.95 (m, 2H), 2.82 (s, 6H), 2.61e2.56 (m, 3H), 2.50 (d,

1H, J¼16.2 Hz), 2.48e2.42 (m, 3H), 2.20 (dd, 1H, J¼13.8, 3.0 Hz),

1.74 (dd, 1H, J¼14.1, 13.9 Hz); HRMSeESI (m/z): [MþH]^þcalcd for

C₂₈H₃₈N₅O₇, 556.2766; found, 556.2771.

4.2.30. General procedure for ﬁnal-step diversiﬁcation of C5a-

aminomethylminocycline (32) and C5a-piperazinylmethylminocycline

(34). 4.2.30.1. C5a-N-acetylaminomethylminocycline

chloride (0.9 L, 0.013 mmol, 2.3 equiv) was added to a solution of

C5a-aminomethylminocycline bistriﬂuoroacetate 32 (4.0 mg,

0.0056 mmol, 1 equiv) and N,N-diisopropylethylamine (4.6 L,

L) at 0 ^ꢀC. The resulting

(35). Acetyl

m

HPLC on an Agilent Prep C18 column [10

mm, 250ꢃ21.2 mm, UV

detection at 350 nm, solvent A: 0.1% triﬂuoroacetic acid in water,

solvent B: acetonitrile, injection volume: 5.0 mL (4.0 mL 0.1% tri-

ﬂuoroacetic acid in water, 1.0 mL acetonitrile), gradient elution with

5/40% B over 50 min, ﬂow rate: 7.5 mL/min]. Fractions eluting at

22e27 min were collected and concentrated, affording C5a-

aminomethylminocycline bistriﬂuoroacetate 32 as a yellow solid

(50 mg, 69%, two steps). ¹H NMR (500 MHz, CD₃OD, bistri-

m

0.027 mmol, 4.8 equiv) in methanol (200

m

solution was allowed to warm to 23 ^ꢀC over 5 min. The reaction

mixture was stirred at this temperature for 1 h, then was concen-

trated. The product was puriﬁed by preparative HPLC on an Agilent

Prep C18 column [10

m

m, 250ꢃ21.2 mm, UV detection at 350 nm,

solvent A: 0.1% triﬂuoroacetic acid in water, solvent B: acetonitrile,

injection volume: 5.0 mL (4.0 mL 0.1% triﬂuoroacetic acid in water,

1.0 mL acetonitrile), gradient elution with 5/40% B over 50 min,

ﬂow rate: 7.5 mL/min]. Fractions eluting at 25e28 min were col-

lected and concentrated, affording C5a-N-acetylaminomethylmino-

cycline triﬂuoroacetate 35 as a yellow solid (3.2 mg, 89%). ¹H NMR

ﬂuoroacetate)

d

7.88 (d, 1H, J¼9.0 Hz), 7.10 (d, 1H, J¼9.0 Hz), 4.09 (d,

1H, J¼2.5 Hz), 3.60 (d,1H, J¼17.0 Hz), 3.34 (d, 1H, J¼14.5 Hz), 3.18 (s,

6H), 3.16 (s, 6H), 3.20e3.14 (m, 1H), 3.02 (d, 1H, J¼14.5 Hz), 2.95 (d,

1H, J¼17.0 Hz), 2.33 (dd, 1H, J¼15.0, 3.0 Hz), 1.96 (dd, 1H, J¼14.6,

13.7 Hz); HRMSeESI (m/z): [MþH]^þcalcd for C₂₄H₃₁N₄O₇, 487.2187;

found 487.2181.

(600 MHz, CD₃OD, triﬂuoroacetate)

d

7.80 (d, 1H, J¼9.0 Hz), 7.03 (d,

1H, J¼9.0 Hz), 3.89 (s, 1H), 3.46 (d, 1H, J¼14.4 Hz), 3.27 (d, 1H,

J¼13.8 Hz), 3.23 (d, 1H, J¼16.8 Hz), 3.15e3.08 (m, 13H), 2.63 (d, 1H,

J¼16.2 Hz), 2.11 (dd, 1H, J¼14.4, 2.4 Hz), 1.91 (s, 3H), 1.69 (dd, 1H,

4.2.29. C5a-Piperazinylmethylminocycline (34)²⁷. Anhydrous mag-

nesium bromide (51.0 mg, 0.276 mmol, 2.0 equiv) was added to

P.M. Wright, A.G. Myers / Tetrahedron 67 (2011) 9853e9869

9869

J¼13.9, 13.8 Hz); HRMSeESI (m/z): [MþH]^þcalcd for C₂₆H₃₃N₄O₈,

alkoxycarbonyl substituents in enone substrates: (a) Kim, S.; Lee, P. H.; Kim, S. S.

Bull. Korean Chem. Soc. 1989, 10, 218e219; (b) Kim, J. H.; Jung, H. K. Bull. Korean

Chem. Soc. 2004, 25, 1729e1732.

529.2293; found 529.2299.

12. Alternative synthetic sequences for the preparation of enones with

b-alkox-

ymethyl and -aldehyde substituents from unsubstituted enone starting

b

Acknowledgements

materials: (a) Kienzle, F.; Minder, R. E. Helv. Chim. Acta 1976, 59, 439e452; (b)

Heguaburu, V.; Schapiro, V.; Pandolﬁ, E. Tetrahedron Lett. 2010, 51,

6921e6923.

This work was generously supported by the National Institutes

of Health (AI048825). We thank AstraZeneca for a Graduate Student

Fellowship (P.M.W.).

€

13. (a) Seebach, D. Angew. Chem., Int. Ed. Engl. 1967, 6, 442e443; (b) Burstinghaus,

€

R.; Seebach, D. Chem. Ber. 1977, 110, 841e851; (c) Grobel, B.-T.; Seebach, D.

Synthesis 1977, 357e402; (d) ‘Tris(methylthio)methane’ Electronic Encyclope-

dia of Reagents for Organic Synthesis 2007.

Supplementary data

14. Other examples of conjugate addition-enolate trapping reactions of tris(me-

thylthio)methyllithium with a,b-unsaturated carbonyl compounds: (a) Damon,

R. E.; Schlessinger, R. H. Tetrahedron Lett. 1976, 19, 1561e1564; (b) Mikolajczyk,

M.; Kielbasinski, P.; Wieczorek, M. W.; Blaszczyk, J.; Kolbe, A. J. Org. Chem. 1990,

55, 1198e1203.

¹H and ¹³C NMR spectroscopic data. Supplementary data asso-

ciated with this article can be found, in the online version, at

doi:10.1016/j.tet.2011.09.143.

ꢁ

15. Degani, I.; Dughera, S.; Fochi, R.; Gatti, A. Synthesis 1996, 4, 467e469.

16. Corey, E. J.; Erickson, B. W. J. Org. Chem. 1971, 36, 3553e3560.

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the amines 32 and 34 most efﬁciently the usual order of deprotection steps was

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b-position

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-

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substrate), phosphoniosilylation methodology has been used to introduce b-

Article Doi

Methodological advances permit the stereocontrolled construction of diverse fully synthetic tetracyclines containing an all-carbon quaternary center at position C5a

DOI: 10.1016/j.tet.2011.09.143

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Article abstract of DOI:10.1016/j.tet.2011.09.143

Full text of DOI:10.1016/j.tet.2011.09.143

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