An Oxidative Mannich Cyclization Methodology for the Stereocontrolled Synthesis of Highly Functionalized Piperidines

J . Org. Chem. 1998, 63, 841-859

841

An Oxid a tive Ma n n ich Cycliza tion Meth od ology for th e

Ster eocon tr olled Syn th esis of High ly F u n ction a lized P ip er id in es

Xiao-Dong Wu, Seock-Kyu Khim, Xiaoming Zhang, Ericka M. Cederstrom, and

Patrick S. Mariano*^,1

Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland 20742

Received September 12, 1997

Studies focusing on the development and application of a new oxidative methodology for promoting

Mannich cyclizations have been conducted. The general features of these processes were explored

with selected R-silylamino and R-silylamido allyl- and vinylsilanes. Representative conditions for

affecting conversion of the R-silylamine and -amide functionalities into intermediate N-alkyl and

N-acyliminium cations involve either 9,10-dicyanoanthracene SET-sensitized photooxidation or ceric

ammonium or tetra-n-butylammonium nitrate oxidations. The applicability of these procedures

for promoting Mannich cyclizations was first demonstrated by the preparation of methylidenepi-

peridines and -hydroazepines. Further studies have led to observations which show that Mannich

cyclizations of stereochemically labeled R-silylamino vinylsilanes proceed to furnish tetrahydro-

pyridines. Also, unlike their amine analogues, R-silylamido (E)-vinylsilanes undergo cyclization

to produce tetrahydropyridines with retention of absolute and relative stereochemistry. The

differences are due to the fact that N-acyliminium cations serve as intermediates in reactions of

the R-silylamide systems. Moreover, the oxidation procedure is ideally suited for intermediate

N-acyliminium cation generation in stereocontrolled reactions of R-silylamido allylsilanes. Finally,

the preparative utility of the new cyclization method, when used in conjunction with an R-amino

acid based strategy for substrate generation, was demonstrated by applications in concise routes

for the synthesis of the aza-sugars, (-)-1-deoxymannojirimycin and (+)-1-deoxyallonojirimycin.

Sch em e 1

In tr od u ction

Mannich and related cyclization reactions of alkene-

tethered iminium cations play important roles in the

methodologies for preparation of functionalized five- and

six-membered N-heterocyclic compounds.^2,3For the spe-

cific case of piperidine ring construction, Mannich cy-

clizations of iminium salts which contain N-linked 1-(tri-

methylsilyl)buten-4-yl and 2-[(trimethylsilyl)methyl]buten-

4-yl groups (1 and 3) are particularly attractive processes.

As shown in Scheme 1, reactions of these substrates lead

to regiocontrolled production of piperidines possessing

either endo- (2) or exocyclic (4) unsaturation. Overman,²

Grieco,⁴and Speckamp⁵have demonstrated that a num-

ber of classical methods can be used to generate the

requisite iminium cation intermediates and that the

cyclizations can be employed effectively in complex

molecule synthesis.

Sch em e 2

However, the vinyl- and allylsilane versions of Mannich

cyclizations have several potentially limiting features.

For example, stereoelectronic requirements can reduce

the versatility of the vinylsilane reactions. Overman⁶has

shown that in certain cases, only N-[1-(trimethylsillyl)-

buten-4-yl] substituted iminium salts with Z- and not

E-double bond stereochemistry successfully undergo cy-

clization. This phenomenon has been attributed to

stabilization of the transient piperidyl cation intermedi-

ates or transition states 5 by pseudoaxially rather than

pseudoequatorially disposed â-TMS groups (Scheme 2).

The negative impact that this has on synthetic applica-

tions stems from the fact that (E)-vinylsilanes generally

are more easily accessed as compared to their Z-stereoi-

somers (see below).

(1) Current address: Department of Chemistry, University of New

Mexico, Albuquerque, NM 87131-1096.

(2) Overman, L. E.; Ricca, D. J . In Comprehensive Organic Synthesis;

Heathcock, C. H., Trost, B. M., Fleming, I., Eds., Pergamon: Oxford,

1991; Vol. 2, pp 1007-1046.

(3) Overman, L. E. Acc. Chem. Res. 1992, 25, 352-359.

(4) (a) Grieco, P. A.; Fobare, W. F. Tetrahedron Lett. 1986, 27, 5067.

(b) Grieco, P. A.; Fobare, W. F. J . Chem. Soc., Chem. Commun. 1987,

185.

(5) Speckamp, W. N.; Hiemstra, H. Tetrahedron 1985, 41, 4367.

(6) Flann, C.; Malone, T. C.; Overman, L. E. J . Am. Chem. Soc. 1987,

109, 6097. Overman, L. E.; Burk, R. M. Tetrahedron Lett. 1984, 25,

5739.

Another potential limitation is the intervention of

competitive aza-Cope rearrangements of N-butenylimin-

ium cations. Extensive studies by Overman³indicate

that N-(3-hydroxybuten-4-yl)-substituted systems un-

Published on Web 01/22/1998

842 J . Org. Chem., Vol. 63, No. 3, 1998

Wu et al.

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dergo this [3.3]-rearrangement process followed internal-

enol Mannich addition to yield 3-acylpyrrolidines. While

the two-step sequence in its own right is quite useful in

the context of natural product syntheses, its operation

(Scheme 3) would confound an approach to piperidine

ring formation using hydroxy substituted vinyl- or allyl-

silanes. Moreover, rapid reversible aza-Cope rearrange-

ment in stereochemically defined allyl and vinylsilane-

tethered iminium cations could compromise absolute and/

or relative stereochemical control in the Mannich cycliza-

tion process (Scheme 4).

aldehyde condensation, imine protonation, or silver-

promoted R-cyanoamine elimination. This could be a

particularly attractive procedure for N-acyliminium cat-

ion generation, where a more limited repertoire of

preparative methodologies exist¹²and with which some

of the potential limitations of the Mannich cyclization

process might be overcome (see below).

Our interest in this area of chemistry arose out of

earlier investigations of R-silylamine SET-photochemis-

try⁷in which we uncovered a novel methodology for

iminium cation generation. The results of both explor-

atory⁷and mechanistic⁸efforts showed that photoinduced

SET-oxidation of R-silylamines is rapidly followed by

solvent-promoted desilylation to generate R-amino radi-

cals in a highly regiocontrolled manner. In addition, we

observed that R-amino radicals are efficiently trans-

formed into iminium cations in the presence of mild

oxidizing agents owing to their exceptionally low oxida-

tion potentials (ca. -1 V).⁹An example of this is found

in the 9,10-dicyanoanthracene (DCA)- or 3-methyllumi-

flavin-sensitized photoreactions of the silylamino enone

6 in which the product of R-amino radical cyclization

(piperidine 7) predominates at low sensitizer (i.e., oxi-

dant) concentration and the product arising by iminium

cation formation and hydrolysis (pyrrolidine 8) becomes

competitive at high oxidant concentration (Scheme 5).^7c,10

These observations led to the proposal that R-sily-

lamines would serve as useful precursors of iminium

cations under mild oxidative conditions. The suggestion

was initially tested by using the enone 6. Metal cation

(e.g., Hg(II), Pb(IV), and Mn(III)) as well as electrochemi-

cal oxidations of 6 were shown to lead to selective

formation of the iminium cation derived pyrrolidine 8.¹¹

In the context of Mannich cyclization chemistry, we

believed that an oxidative procedure for initiating imi-

nium cation formation might serve as a useful alternative

to the classical methods involving acid-catalyzed amine-

Guided by these thoughts, we designed a broad study

to (1) explore the scope and limitations of the oxidative

method to promote Mannich cyclizations of vinyl- and

allylsilane systems, (2) investigate and contrast stereo-

chemical features of the oxidative N-acyl- and N-alkyl-

iminium ion cyclizations, and (3) develop a new R-amino

acid based strategy for polyhydroxylated piperidine

synthesis. The results of this effort are reported below

along with applications of the oxidative Mannich meth-

odology to the preparation of selected aza-sugars.

Resu lts a n d Discu ssion

Gen er a l F ea tu r es of th e Oxid a tive Ma n n ich Cy-

cliza tion P r ocess. Initial studies were conducted in

order to determine the feasibility of the oxidative Man-

nich cyclization reaction and to probe several of its

general features. The initial goal was to evaluate dif-

ferent oxidative conditions for iminium cation generation

from R-silylamine precursors and the compatibility of

these conditions with the presence of vinyl- and allylsi-

lane functionality in potential Mannich cyclization sub-

strates. For this purpose, three allylsilane derivatives,

13-15, were prepared by the sequences shown in Scheme

6 which start with the known¹³silyl alcohols 9 and 10.

Photooxidation of 14 was investigated first. Accord-

ingly, irradiation (λ > 320 nm) of an MeCN solution

containing saturated (excess) DCA and 14 leads to

production of the methylidenepiperidine 16 in a 53%

isolated yield (Scheme 7). Cyclization of 14 is also

promoted by (ⁿBu₄N)₂Ce(NO₃)₆(CTAN),¹⁴Pb(OAc)₄, and

Mn(OAc)₃. For example, treatment of 14 with 2 equiv of

CTAN in MeCN at 25 °C, followed by alumina chroma-

tography, gives piperidine 16 in a 45% yield. A more

quantitative evaluation of the efficiencies of these pro-

cesses was obtained by comparing the GLC yields of 16

for the various reactions of 14 (see Table 1).

(7) (a) Yoon, U. C.; Mariano, P. S. Acc. Chem. Res. 1992, 25, 233.

(b) Xu, W.; Zhang, X. M.; Mariano, P. S. J . Am. Chem. Soc. 1991, 113,

8863. (c) J eon, Y. T.; Lee, C. P.; Mariano, P. S. J . Am. Chem. Soc. 1991,

113, 8847.

(8) (a) Zhang, X. M.; Yeh, S. R.; Hong, S.; Freccero, M.; Albini, A.;

Falvey, D. E.; Mariano, P. S. J . Am. Chem. Soc. 1994, 116, 4211. (b)

Su, Z.; Falvey, D. E.; Yoon, U. C.; Mariano, P. S. J . Am. Chem. Soc.

1997, 119, 5261.

(9) Wayner, D. D. M.; McPhee, D. J .; Griller, D. J . J . Am. Chem.

Soc. 1988, 110, 132.

(10) Unpublished results taken from the Ph.D. dissertation of Dino

Ferri at the University of Maryland, 1996.

(11) Zhang, X. M.; J ung, Y. S.; Mariano, P. S.; Fox, M. A.; Martin,

P. S.; Merkert, J . Tetrahedron Lett. 1993, 34, 5239.

(12) Speckamp, W. N. Recl. Trav. Chem. Pays-Bas 1981, 100, 345.

(13) Ahmed-Schoffield, R.; Mariano, P. S. J . Org. Chem. 1985, 50,

5667.

(14) Dehmlow, E. V.; Makrand, I. K. J . Chem. Res. 1986, 32.

Oxidative Mannich Cyclizations

J . Org. Chem., Vol. 63, No. 3, 1998 843

Sch em e 6

Sch em e 8

16 and 18 in a combined 46% yield. Also, 16 and 18 are

produced as a 1:1 mixture in a 32% yield when 13 is

oxidized with CTAN.¹⁵Regiocontrol is lacking in these

reactions and efficiencies are lower when compared to

similar cyclizations starting with the silicon substituted

substrate 14.

St er eoch em ica lly Mor e Com p lex r-Silyla m in o

Allylsila n es. The results of the brief exploratory study

gave impetus to our continuing work on this process. Our

attention next turned to stereochemically and function-

ally more complex substrates. The subgoal of this work

was to probe a general strategy for stereocontrolled,

functionalized piperidine ring construction based on

Mannich cyclizations of R-amino acid derived substrates.

Accordingly, ^L-alanine was converted to the R-amino

aldehyde 19 (>90% ee) by a procedure previously devel-

oped in our laboratory (Scheme 9).¹⁶Addition of 1-[(tri-

methylsilyl)methyl]-1-vinyllithium to 19 in THF at -78

°C gave the silylamino alcohol 20 as a single anti-

diastereomer¹⁷with no loss of enantiomeric purity and

in a 65% yield. To block potential intervention of either

iminium cation capture by the pendent alcohol or se-

quential aza-Cope/Mannich cyclization,³20 was first

transformed to the acetate derivative 21.

Oxidative cyclization of 21 promoted by reaction with

CTAN in MeCN at 25 °C, occurred efficiently (75%) to

produce a mixture of separable stereoisomeric piperidines

22 and 25 in a 1:1.2 ratio. To gain information about

the origin of the stereorandomization accompanying this

reaction, the enantiomeric purities of 22 and 25 were

determined by conversion to the respective alcohol de-

rivatives 23 and 26 (KCN, MeOH) and then to the

Mosher esters 24 and 27 ((R)- and (S)-methoxy(trifluo-

romethyl)phenylacetic acid (MTPAcOH), DCC). ¹H NMR

analysis of the esters shows that the cis-piperidine 22 is

produced in only a 4% ee while the trans-isomer 25 has

a 24% ee.

Sch em e 7

Ta ble 1. Th e Efficien cies of Oxid a tive Ma n n ich

Cycliza tion s of Silyla m in o-Allylsila n e 14

conditions^a

time (h) Glc yield (%) isolated yield (%)

hν, saturated DCA

2 equiv CTAN

1 equiv Pb(OAc)₄

1 equiv Mn(OAc)₃

1 equiv Hg(OAc)₂

2

1

3

100

62

60

55

0

53

45

b

0.1

a

All reactions were conducted in anhydrous MeCN at 25 °C.

Not determined.

b

The homologous silylamino-allylsilane 15 also partici-

pates in this cyclization reaction. Treatment of 15 in

MeCN under the CTAN or DCA-photooxidation condi-

tions results in its conversion to the hydroazepine deriva-

tive 17 in 62% and 60% yields, respectively.

The extensive loss of both absolute and relative ster-

eochemistry in the oxidation reaction of 21 suggests the

possible operation of a competitive aza-Cope/CdN ste-

reomutation process. A mechanism for this is outlined

in Scheme 10. Cyclization of the initially formed iminium

cation 28 should yield trans-piperidine 25 in an enantio-

and diastereoselective manner. However, reversible

[3.3]-rearrangement of 28 via the iminium cation 29

competes with this process and leads to complete ran-

domization of stereochemistry and, as a result, produc-

tion of both 22 and 25 in racemic forms.

Two features of these processes deserve brief comment.

First, the reactions display high regioselectivities associ-

ated with iminium cation formation. Thus, oxidation

occurs exclusively at the R-TMS center even when the

relatively easily oxidized benzylic site is available. This

selectivity is a result of the larger rates of tertiary

aminium radical R-desilylation vs R-deprotonation.⁸Sec-

ond, the yields of the oxidation reactions are modestly

high despite the fact that the products are also tertiary

amines. Clearly, the rates of oxidation of R-silylamines

must exceed those of their non-silicon analogues, a point

which has been discussed earlier in the context of our

SET-photochemical studies.⁷

(15) The different ratios of 16 and 18 arising from oxidation

reactions under the photochemical and CTAN conditions is likely a

result of the different relative rates of aminium radical deprotonation

at the NCH₃vs NCH₂Ph centers and the fact that the active base in

each process is most likely different.

(16) Khim, S. K.; Cederstrom, E.; Ferri, D. C.; Mariano, P. S.

Tetrahedron 1996, 52, 3195. Kim, S. K.; Wu, X.; Mariano, P. S.

Tetrahedron Lett. 1996, 37, 571.

(17) (a) This stereochemical outcome is consistent with a simple

Felkin-Ahn prediction and similar to that observed in other addition

reactions of chiral R-amino carbonyl compounds (ref 17b). (b) Morrison,

J . D.; Mosher, H. S. Asymmetric Organic Reactions; Prentice Hall:

Englewood Cliffs, New J ersey, 1971; pp 103-107.

The unique function of the R-silylamine group in

governing both efficiency and regiochemistry is demon-

strated by the contrasting behavior of the amino-allyl-

silane 13 under the oxidative cyclization conditions

(Scheme 8). Upon DCA-promoted photooxidation, this

substance is converted to an ca. 1:3 mixture of piperidines

844 J . Org. Chem., Vol. 63, No. 3, 1998

Wu et al.

Sch em e 9

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Sch em e 11

Clearly, despite the high-yielding nature of the allyl-

silane-terminated Mannich cyclization reaction, its syn-

thetic utility is compromised by the significant loss of

absolute and relative stereochemistry. This pitfall should

not be unique for the oxidative protocol but, rather, more

generally associated with all allylsilane Mannich cycliza-

tions. A possible solution to this problem, and one that

emphasizes the specific advantages of the oxidative

method, involves the use of N-acyl- rather than N-

alkyliminium cation intermediates. We reasoned that

destabilization of an iminium cation related to 28 (Scheme

10) by replacement of the N-Bn by a N-Bz group would

enhance the rate of cyclization relative to aza-Cope

rearrangement. If so, this change would result in a

highly stereospecific process.

Sch em e 12

To evaluate this proposal, the diastereomeric R-silyl-

amido allylsilanes 34 and 37 were prepared starting from

the known,¹⁶L-alanine-derived amino alcohol 30 (Scheme

11). A distinguishing feature of this sequence is that the

vinyllithium addition to aldehyde 32 (>90% ee) leads to

both anti (52%) and syn (6%) amido alcohols 33 and 36

1

in only 50% ee (by H NMR analysis of the Mosher ester

single piperidine with complete retention of the original

diastereomeric and enantiomeric purity (Scheme 12).

Specifically, CAN-promoted reaction of 34 yields the

trans-piperidine 38 with an enantiomeric purity of 50%

35 obtained by reaction with (R)-methoxy(trifluorometh-

yl)phenylacetyl chloride ((R)-MTPAcCl). Acylation of 33

and 36 provides the respective acetates 34 and 37 which

were subjected to the oxidative cyclization protocol by

using in this case¹⁸(NH₄)₂Ce(NO₃)₆(CAN) as the oxidant.

Each reaction occurs to yield a

1

as determined by H NMR analysis of the Mosher ester

27 of alcohol 26 (derived by LiAlH₄reduction). Similarly,

cyclization of the syn-diastereomer 37 yields cis-piperi-

dine 39 exclusively with complete retention of enantio-

meric purity.

(18) We have found that CTAN and CAN are about as equally

effective in promoting these processes.

Oxidative Mannich Cyclizations

J . Org. Chem., Vol. 63, No. 3, 1998 845

Sch em e 13

In accord with the mechanistically based prediction,

cyclizations of allylsilane-terminated N-acyliminium cat-

ions proceed in a highly stereocontrolled fashion. Thus,

N-acyl substituents appear to play a critical role in

governing the relative rates of the aza-Cope and Mannich

cyclization processes.¹⁹Moreover, the oxidative method

appears to be ideally suited for generation of these types

of “activated” iminium cations starting with N-(R-silyl)-

amides or N-(R-silyl) carbamates.^20,21

Vin ylsila n e Oxid a tive Ma n n ich Cycliza tion s. An

extensive effort by Overman and co-workers has provided

a number of examples in which vinylsilanes serve as

terminating groups (vinyl anion equivalents) in Mannich

cyclization processes.^2,6,22Two important findings of

Overman’s efforts, related to cyclizations which produce

1,2,5,6-tetrahydropyridine products, are the enhanced

reactivity of (Z)- vs (E)-vinylsilanes and the loss of

stereochemical integrity in reaction of enantiomerically

pure substrates.^22cThe original aim of our investigations

in this area was to determine if implementation of the

oxidative methodology could lead to solutions of these two

potentially detrimental problems. In the interim period,

collaborative studies by Overman’s and our group²³led

to a correction of the original conclusions about the

stereochemical course of these processes. Our contribu-

tion to this study along with additional efforts which

demonstrate the synthetic advantages of the oxidative

protocol are presented below.

1

analyzed by H NMR. This procedure showed that 43

has a >90% ee and, thus, that the oxidative Mannich

cyclization is highly enantiospecific. Contrary to the

earlier report,^22cwe also found that 43, generated by use

of Grieco-Mannich cyclization conditions (aqueous form-

aldehyde, TFA, H₂O-THF, 25 °C), has a high enantio-

meric purity ([R]²⁵_D) +56°). These results in conjunction

with those coming from parallel studies by the Overman

group lead to a correction²³of the original stereochemical

conclusions about vinylsilane-terminated Mannich cycli-

zations. Specifically, these processes are highly enantio-

specific and, consequently, can be applied in the stereo-

controlled preparation of substituted tetrahydropyridines.

Information about the general synthetic potential of

these cyclization reactions as well as their limitations has

come from further studies with the functionally and

stereochemically more complex R-silylamino vinylsilanes

50 and 52 and their amide analogues 59 and 63.

Preparation of 50 is accomplished by a route beginning

with addition of lithium trimethylsilylacetylide to the

L-alanine-derived aldehyde 19. The process produces the

propargylic alcohol 46 as a single anti-diastereomer¹⁶

(Scheme 14). A number of reduction conditions were

attempted to affect stereoselective conversion of 46 to the

(Z)-vinylsilane 47. In our hands, the best, but yet still

not satisfactory, method employs controlled catalytic

hydrogenation with 5% Pd/C in EtOAc at -10 °C. This

reaction yields 47 (71%) along with its E-isomer 48 (28%)

and a trace quantity of the saturated analogue 49.

Acetylation of 47 gives 50, one of the substrates selected

to further probe the oxidative cyclization methodology.

A more direct route is used to prepare the (E)-

vinylsilane 48. Thus, (E)-[(trimethylsilyl)vinyl]lithium,

derived by tin-lithium exchange with the tin derivative

51,²⁴adds to aldehyde 19 to generate 48 (81%) which is

then acetylated to give the E-substrate 52 (Scheme 14).

Oxidation of the silylamino (E)-vinylsilane 52 with 2

equiv of CTAN in anhydrous MeCN leads to only low

yielding formation of the secondary amine 57 (Scheme

15). No trace of the piperidine 53 could be detected by

¹H NMR and TLC analysis of the crude product mixture.

In contrast, the (Z)-vinylsilane 50 reacts under identical

conditions (or with use of CAN as the oxidant) to yield

the piperidine 53 along with the product of desilylmethy-

lation, 54.

As pointed out above, one of the potentially useful

characteristics of the oxidative Mannich cyclization pro-

cess resides in the mild (25 °C, nonacidic) conditions

needed for N-alkyl and N-acyliminium cation generation.

As part of our preliminary thinking, we questioned

whether the mild conditions could alter the stereochem-

ical course of vinylsilane cyclizations. This is particularly

true in the case of the photooxidative process which, in

theory, could be conducted at low temperatures. To

address this issue, we designed experiments in which the

oxidative conditions are used to prepare the same types

of iminium cation intermediates in the cyclizations

originally studied by Overman and co-workers.^22cFor

this purpose, the R-silylamino (Z)-vinylsilane 42 was

synthesized by silylmethylation of the secondary amine

40 (Scheme 13), a substance prepared from ^L-alanine by

a minor modification of the sequence reported earlier by

Overman.^22cImportantly, 40 generated in this manner

1

has >95% ee as determined by both GLC and H NMR

analysis of its Mosher amide 41 (from reaction with (R)-

MTPAcCl).

Treatment of 42 with 2 equiv of CTAN at 25 °C in

anhydrous MeCN leads to production of optically active

([R]²⁵) +56°) tetrahydropyridine 43 in 61% yield. To

D

determine the enantiomeric purity of 43, it is converted

to the piperidine 44 by catalytic hydrogenolysis-hydro-

genation. The Mosher amide 45 was then generated and

(19) Personal communication from Professor L. E. Overman.

(20) Kim, H. J .; Yoon, U. C.; J ung, Y. S.; Park, N. S.; Cederstrom,

E. M.; Mariano, P. S. (manuscript in preparation).

(21) (a) Narasaka (ref 21b) has also demonstrated that R-tin amides

undergo oxidation to produce N-acyliminium cations. (b) Narasaka,

K.; Kohno, Y.; Shimada, S. Chem. Lett. 1993, 125.

(22) (a) Overman, L. E.; Bell, K. L.; Ito, F. J . Am. Chem. Soc. 1984,

106, 4192. (b) Overman, L. E.; Lin, N. H. J . Org. Chem. 1985, 50, 3669.

(c) Daub, G. W.; Heerding, D. A.; Overman, L. E. Tetrahedron 1988,

44, 3919. (d) Overman, L. E.; Ricca, D. J . J . Compr. Org. Synth. 1991,

2, 1007.

(23) Castro, P.; Overman, L. E.; Zhang, X. M.; Mariano, P. S.

Tetrahedron Lett. 1993, 34, 5243.

(24) (a) Cunico, R. E.; Clayton, G. J . Org. Chem. 1976, 41, 1480. (b)

Pillot, F. J .; Dunogues, J . P.; Calas, J .; Lapouyade, R. Synth. Commun.

1979, 9, 395.

846 J . Org. Chem., Vol. 63, No. 3, 1998

Wu et al.

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Sch em e 16

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Sch em e 15

Sch em e 19

We have already demonstrated how a change in the

N-substituent from alkyl to acyl can markedly affect the

enantio- and diastereoselectivities of allylsilane-termi-

nated iminium cation cyclizations. The energetic origin

of this effect (i.e., reactant vs transition state destabiliza-

tion) suggests that it could also influence the reactivity

of vinylsilane systems and, perhaps, alter the Z-stereo-

chemical requirement. Support for this conjecture is

found in the results of studies with the R-silylamides 59

and 63. The benzamide derivative 59 is prepared by a

two-step sequence (Scheme 16) beginning with addition

of the (E)-vinyllithium reagent derived from 51 to alde-

hyde 32 followed by acetylation of the intermediate

alcohol 58. The enantiomeric purity of 59 was deter-

These results provide another example of the stereo-

chemical requirements for six-membered ring forming,

vinylsilane-terminated Mannich cyclizations (see above).

Furthermore, they show that cyclization of the Z-sub-

strate 50 occurs in an enantio- and diastereoselective

manner. The former conclusion comes from the observa-

tion that 53 has a >90% ee (conversion of 53 to alcohol

55 and Mosher ester 56) and the latter from the fact that

53 has trans C-5,C-6 stereochemistry.

1

mined to be >90% by H NMR analysis of the Mosher

ester 60.

Similarly, (E)-vinyllithium addition to the ^L-pyro-

glutamic acid derived aldehyde 61 (62% ee)¹⁶yields a

separable 3.3:1 mixture of the allylic alcohols 62 and 64

Oxidative Mannich Cyclizations

J . Org. Chem., Vol. 63, No. 3, 1998 847

Sch em e 20

(Scheme 17) which are then converted to the correspond-

ing acetates 63 and 65.

this process by using alternative bases, solvents, and

alkylating agents were unsuccessful. TBDMS protection

of the primary alcohol group in 70 is followed by N-

benzoylation and NaBH₄reduction to provide alcohol 73.

Swern oxidation then gives aldehyde 74. To assess if

racemization occurs in these steps, 74 was immediately

reduced with NaBH₄, and the resulting alcohol was

converted to its Mosher ester. Analysis of this substance

In contrast to the N-alkyl analogue, (E)-vinylsilane 59

is oxidized by CAN to produce the trans-tetrahydropyr-

idine 66 with a >90% ee (by LiAlH₄reduction to the

N-benzyl alcohol 55 and Mosher ester 56) (Scheme 18).

The lactam-containing substrate 63 also undergoes oxi-

dative Mannich cyclization forming the indolizidinone 67

(Scheme 19). The enantiomeric purity of 67 is deter-

mined by use of a sequence involving hydrolysis to form

1

by H NMR showed that 74 has a 70% ee.

Reaction of aldehyde 74 with E-[(trimethylsilyl)vinyl-

]lithium yields two separable diastereomeric alcohols, 75

and 79, in a 3.6:1 ratio. Initial assignment of syn-

1

alcohol 68, Mosher esterification giving 69, and H NMR

analysis. The observed 62% ee for 67 matches that of

the aldehyde precursor 61. These results show that (E)-

vinylsilanes serve as effective terminator groups in

stereocontrolled, tetrahydropyridine Mannich cyclization

processes of N-acyliminium cations.

(26) Curiously, epimer 65 does not cyclize when treated with CAN.

Instead, an MeCN (Ritter-type) trapping product is produced. Simi-

larly, the diacetate of 80 does not undergo oxidative Mannich cycliza-

tion. Thus, it appears that other factors can also influence the rates of

these processes.

Ap p lica tion to 1-Deoxy-Aza -Su ga r Syn th esis. The

results presented above show that the oxidative Mannich

cyclization process, when coupled with an R-amino acid

based protocol for substrate synthesis, serves as a

versatile method for the stereocontrolled preparation of

highly functionalized piperidines. To demonstrate the

synthetic potential of this chemistry, application to the

synthesis of (-)-1-deoxymannojirimycin (90) and (+)-1-

deoxyallonojirimycin (91), two biologically interesting

aza-sugars,^27a-pwere explored. The sequences commence

with the conversion of ^D-serine to the R-silylamido ester

70 (Scheme 20). Attempts to improve the 31% yield of

(27) (a) Hughes, A. B.; Rudge, A. J . Nat. Prod. Rep. 1994, 11, 135.

(b) Look, G. C.; Fotsch, C. H.; Wong, C. H. Acc. Chem. Res. 1993, 26,

182. (c) Vanden Borek, L. A.; Vremus, D. J .; Heskamp, B. M.; Van

Breckel, C. A.; Tan, M. C.; Bolscher, J . G.; Ploegh, H. L., Van

Kamenade, F. J .; de Goede, R. E.; Miedema, F. Recl. Trav. Chim. Pays-

Bas 1993, 112, 82. (d) Winchester, B.; Fleet, G. W. J . Glycobiology 1992,

2, 199. (e) Tyms, A. S.; Taylor, D. L.; Sunkara, P. S.; Kang, M. S.

Glycoprotein Synthesis and Human Immunodeficiency Viruses. In

Design of Anti-AIDS Drugs; Declerq, E., Ed.; Elsevier: New York, 1990;

pp 257-318. (f) Fleet, G. W. J .; Gough, M. J .; Shing, T. K. M.

Tetrahedron Lett. 1984, 25, 4029. (g) Legler, G.; J ulich, E. Carbohydr.

Res. 1994, 128, 61. (h) Bernotas, R. C.; Ganem, B. Tetrahedron Lett.

1985, 26, 1123. (i) Fleet, G. W. J .; Smith, P. W. Tetrahedron Lett. 1985,

26, 1469. (j) Fleet, G. W. J .; Fellows, L. E.; Smith, P. W. Tetrahedron

Lett. 1987, 28, 979. (k) Fleet, G. W. J .; Ramsden, N. G.; Witty, D. R.

Tetrahedron Lett. 1988, 29, 2871. (l) Ikota, N. Heterocycles 1989, 29,

1469. (m) Iida, H.; Yamazaki, N.; Kibayashi, C. J . Org. Chem. 1987,

52, 3337. (n) Altenbach, H.-J .; Himmedldirk, K. Tetrahedron 1995, 52,

1077. (o) Fellow, L. E.; Bell, E. A.; Lynnm, D. G.; Nakanishi, K. J .

Chem. Soc., Chem. Commun. 1979, 977. (p) Myers, A. I.; Price, D. A.;

Andres, C. J . Synlett. 1997, 5, 533.

(25) The ¹H NMR spectrum of 53 contains a small 2.0 Hz H-5,H-6

coupling and a modestly large 5.0 Hz H-4,H-5 coupling both of which

are consistent with its existence in a Macromodel-calculated (ca. 2 kcal/

mol) psuedo-diaxial conformation.

848 J . Org. Chem., Vol. 63, No. 3, 1998

Wu et al.

F igu r e 2. Chem-3D plot of the X-ray crystallographically

determined structure of diol 82.

81 (Scheme 21). The C-5,C-6 stereochemistry in 81

cannot be ascertained convincingly by using ¹H NMR

spectroscopy owing to line broadening associated with

slow amide rotation. Thus, 81 is converted to the

N-benzyl diol 83 by LiAlH₄reduction. ¹H NMR analysis

of 83 reveals an H-5,H-6 coupling of 3.5 Hz consistent

with the diequatorial disposition of these protons (see

above).²⁵X-ray crystallographic analysis of the related

diol 82 (Figure 2), arising by methanolysis of 81, con-

firmed the structure and stereochemistry of 81.

F igu r e 1. Chem-3D plot of the X-ray crystallographically

determined structure of diol 80.

Sch em e 21

The ∆^2,3-unsaturation in tetrahydropyridines 81 and

82, as planned, is useful for the stereocontrolled intro-

duction of properly positioned hydroxyl functionality in

the aza-sugar targets. Catalytic dihydroxylation²⁹is

ideal for approaches to aza-sugar targets with cis-2,3-

diol stereochemistry. As outlined in Scheme 21, reaction

of diacetate 81 with OsO₄/NMO in aqueous acetone yields

a mixture of the diols 84 and 86 in a 3:2 ratio which are

converted directly to the respective tetraacetates 85 and

87. The degree of stereoselectivity in this process is un-

expectedly low.³⁰To evaluate whether a free hydroxyl

at C-5 is a better stereochemical control element, diol 82

was subjected to dihydroxylation in the presence of the

chiral ligand, hydroquinidine 1,4-phthalazinediyl diether,

described by Sharpless.³¹Acetylation of the crude prod-

uct mixture followed by separation yields the tetraac-

etates 85 and 87, again in a 3:2 ratio. The diastereofacial

selectivity of this dihydroxylation process could not be

improved even when several other chiral ligands^31,32are

used.³³

The tetraacetates 85 and 87 serve as direct precursors

of the respective aza-sugars, (-)-1-deoxymannojirimycin

and (+)-1-deoxyallonojirimycin (Scheme 22). Each trans-

stereochemistry to 75, the major isomer, is made by

application of the Felkin-Ahn model.¹⁷X-ray crystal-

lographic analysis (see Figure 1) of the diol 80, derived

by treatment⁶of the minor-isomer 79 with aqueous HF,

provides unambiguous proof for this assignment. Also,

Mosher ester (78) analysis of 75 shows that it retains a

70% ee, identical with that of the aldehyde 74.

The R-silylamido vinylsilane 75 has the needed relative

and absolute stereochemistry for use as an intermediate

in the synthesis of the targeted aza-sugars. To prevent

competitive reactions involving the free hydroxyl or

desilylation to generate a free hydroxyl,²⁸75 is first

transformed into the diacetate 77. Oxidation of 77 with

CAN leads to formation of the desired tetrahydropyridine

(29) (a) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett.

1976, 23, 1973. (b) Aube, J .; Ghosh, S.; Tanol, M. J . Am. Chem. Soc.

1994, 116, 9009.

(30) (a) Cha, J . K.; Christ, W. J .; Kishi, Y. Tetrahedron Lett. 1983,

24, 3943. (b) Cha, J . K.; Christ, W. J .; Kishi, Y. Tetrahedron 1984, 42,

2247.

(31) (a) Sharpless, K. B.; Amberg, W.; Beller, M.; Chen, H.; Hartung,

J .; Kawanami, Y.; Lubben, D.; Manoury, E.; Ogino, Y.; Shibata, T.;

Ukita, T. J . Org. Chem. 1991, 56, 4585. (b) Cha, J . K.; Kim, N. O.

Chem. Rev. (Washington, D.C.) 1995, 95, 1. (c) Oishi, T.; Iwakuma, T.;

Hirama, M.; Ito, S. Synlett 1995, 404. (d) Oishi, T.; Iida, K.-I.; Hirama,

M. Tetrahedron Lett. 1993, 34, 3573. (e) Oishi, T.; Hirama, M. J . Org.

Chem. 1989, 54, 5834. (f) Annunziata, R.; Cinquini, M.; Cozzi, F.;

Raimondi, L. Tetrahedron 1987, 44, 6897. (g) Masamune, S.; Choy,

W.; Petersen, J . S.; Sita, L. R. Angew. Chem., Int. Ed. Engl. 1985, 24,

1.

(32) For example, hydroquinine 4-chlorobenzoate, hydroquinidine

4-chlorobenzoate, and hydroquinine 1,4-phthalazinediyl diether.

(33) When hydroquinine 1,4-phthalazinediyl diether is used in the

catalytic hydroxylation reaction of 82, the tetraacetates 85 and 87 are

formed in a 2:3 ratio.

(28) Treatment of the monoacetate of 75 with CAN results in

instantaneous O-desilylation.

Oxidative Mannich Cyclizations

J . Org. Chem., Vol. 63, No. 3, 1998 849

N-Ben zyl-N-[2-[(t r im et h ylsilyl)m et h yl]b u t -1-en -4-yl]-

a m in e (11). A solution of BuLi (2.1 mmol) in hexane was

added to a solution of 3-[(trimethylsilyl)methyl]-3-buten-1-ol

(9)¹³(250 mg, 1.71 mmol) in THF (3 mL) at -78 °C. After

stirring at -78 °C for 0.5 h, benzenesulfonyl chloride (300 mg,

1.71 mmol) was added and the resulting mixture was warmed

to 25 °C and stirred for 2.5 h. After concentration in vacuo,

excess benzylamine in MeCN (5 mL) was added to the residue

which was then stirred at reflux for 4 h, diluted with satd

NaHCO₃, and extracted with ether. The extracts were dried

and concentrated in vacuo to give a residue which was

subjected to column chromatography (Florisil, 10% ether-

hexanes) to afford 160 mg (40%) of the desired silylamine 11:

¹H NMR 0.02 (s, 9 H, SiMe₃), 1.51 (s, 2 H, CH₂Si), 2.18 (t,

J ) 7.0, 2 H, CH₂Cd), 2.73 (t, J ) 7.0, 2 H, CH₂NH), 3.78 (s,

2 H, NCH₂Ph), 4.56, 4.61 (s, 2 H, vinyl), 7.30 (m, 5 H, ArH);

¹³C NMR -1.4 (SiMe₃), 26.5 (CH₂Si), 38.4 (CH₂), 47.1 (CH₂N),

49.2 (CH₂Ph), 108.5 (CH₂dC), 126.8, 128.1, 128.3 (Ar), 140.4

(Ar C-ipso), 145.3 (CH₂dC); IR 1631, 1494, 1452, 1374, 1247,

1154; EIMS 247 (0.3), 196 (7), 188 (5), 186 (5), 172 (6), 150

(6), 120 (36), 91 (69); HRMS 247.1457, C₁₅H₂₅NSi requires

247.1456.

N-Ben zyl-N-[2-[(tr im eth ylsilyl)m eth yl]p en t-1-en -5-yl]-

a m in e (12). A solution of BuLi (0.52 mmol) was added to a

solution of silyl alcohol 10¹³(100 mg, 0.58 mmol) in THF (3

mL) at -78 °C. After stirring fo 30 min, benzenesulfonyl

chloride (112 mg, 0.64 mmol) was introduced, and the resulting

mixture was warmed to 25 °C and stirred for 3 h. To the

residue obtained by concentration in vacuo was added excess

benzylamine in MeCN (10 mL), and the resulting mixture was

stirred at reflux for 3 h, diluted with satd NaHCO₃, and

extracted with ether. The extracts were dried and concen-

trated in vacuo to afford a residue which was subjected to

column chromatography (Florisil, 60% ether-hexanes) to give

80 mg (53%) of 12. ¹H NMR 0.02 (s, 9 H, SiMe₃), 1.51 (s, 2 H,

CH₂Si), 1.65 (m, 2 H, (CH₂)₃, 1.97 (t, J ) 6.8, 2 H, dCCH₂-

CH₂), 2.63 (t, J ) 7.5, 2 H, CH₂N), 3.78 (s, 2 H, NCH₂Ph),

4.50, 4.57 (s, 2 H, vinylic), 7.30 (m, 5 H, Ar); ¹³C NMR -1.3

(SiMe₃), 26.7 (CH₂), 28.2 (CH₂Si), 35.9 (CH₂dC), 49.2 (CH₂N),

54.0 (NCH₂PH), 107.0 (CH₂dC), 126.8, 128.1, 128.3 (Ar), 132.7

(Ar, C-ipso), 147.3 (dC); IR 3066, 3028, 2952, 1630; EIMS 261

(1), 133 (58), 121 (52), 91 (100); HRMS 261.1931, C₁₆H₂₇NSi

requires 261.1931.

Sch em e 22

formation is achieved by treatment with 10% HCl.

1-Deoxymannojirimycin hydrochloride (90) prepared in

this manner is identical in all respects to the natural

material^27f,oexcept for its optical rotation ([R]²⁶_D) -7.7°

vs [R]²⁰) -10.9°) which reflects a 70% ee translated

D

directly from aldehyde 74. Likewise, synthetic (+)-1-

deoxyallonojirimycin (91) has spectroscopic properties

that match those reported for this substance,²⁷ⁿand its

optical rotation [R]²⁸) +21.2° (vs [R]²⁰) +35.2°)²⁷ⁿ

D

corresponds to a 70% ee.

Su m m a r y

The studies described above, related to the develop-

ment of a new oxidative Mannich process, have provided

an opportunity to probe several generally interesting

features of the allylsilane and vinylsilane cyclizations.

The results have led to the correction of an important

stereochemical issue and the discovery of a technique to

avoid stereochemical problems which have limited the

synthetic application of this reaction. Finally, although

the Mannich cyclization processes proceed with only

modest efficiencies independent of the methods used for

their initiation,²³their application in R-amino acid based

strategies for polyhydroxylated piperidine (and perhaps

indolizidine) syntheses comprise new and generally

concise approaches to these interesting substances.

N-Ben zyl-N-m eth yl-N-[2-[(tr im eth ylsilyl)m eth yl]bu ten -

4-yl]a m in e (13). Iodomethane (0.66 g, 4.6 mmol) in MeCN

(10 mL) was added dropwise to a solution of 11 (1.0 g, 4.3

mmol) in MeCN (20 mL) at 0 °C. The resulting mixture was

stirred at 25 °C for 12 h, diluted with water, and extracted

with ether. The extracts were dried and concentrated in vacuo

to give a residue which was subjected to column chromatog-

raphy (Florisil, 10% ether-hexanes) to yield 0.26 g (24%) of

13. ¹H NMR -0.05 (s, 9 H, TMS), 1.45 (s, 2 H, CH₂TMS), 2.15

(m, 5 H, NCH₃, CH₂), 2.45 (t, J ) 8.7, 2 H, CH₂N), 3.45 (s, 2

Exp er im en ta l Section

Gen er a l P r oced u r es. Unless otherwise noted, ¹H NMR

and ¹³C NMR spectra were recorded in CDCl₃solutions by

using 200.13, 400.13, or 500.14 MHz operational frequencies

for ¹H observations and 50.32 and 100.62 MHz for ¹³C

observations. Chemical shifts are reported in parts per million

H, NCH₂Ph), 4.48 and 4.52 (s, 2 H, CH₂, 7.20 (m, 5 H, Ar); ¹³

C

1

relative to CDCl₃(7.24 ppm for H NMR and 77.0 ppm for ¹³C

NMR -1.4 (TMS), 27.0 (CH₂TMS), 35.9 (CH₂), 42.2 (NCH3),

56.2 (CH₂), 62.3 (NCH₂Ph), 107.5 (dCH₂), 126.9, 128.1, 129.1,

139.1 (Ar), 145.9 (Cd); IR (neat) 3065, 2953, 2789, 1753, 1718,

1701, 1685, 1630; EIMS 261 (M, 3), 134 (54), 91 (50), 73 (13);

HRMS 261.1909, C₁₆H₂₇NSi requires 261.1912.

Ir r a d ia tion of N-Ben zyl-N-m eth yl-N-[2-[(tr im eth ylsi-

lyl)m eth yl]bu ten -4-yl]a m in e (13). A N₂-purged solution of

13 (30 mg, 0.12 mmol), saturated with 9,10-dicyanoanthracene

in MeCN (80 mL), was irradiated for 3.5 h (85% coversion of

13). Concentration of the photolyzate followed by preparative

TLC (50% ether-hexanes) separation afforded piperidenes 16

(3 mg, 14%) and 18 (7.3 mg, 34%).

NMR) as the internal standard. ¹H NMR coupling constant

determinations (J values reported in hertz) and nuclei assign-

ments were aided by the use of homonuclear decoupling

experiments. ¹³C NMR resonance assignments were aided by

use of the DEPT technique to determine numbers of attached

hydrogens. Infrared (IR) spectra were obtained on samples

which were prepared as neat oils (liquids) unless otherwise

noted, and band assignments are in units of cm^-1

. Mass

spectrometric data determined by use of either the electron

impact (EIMS), chemical ionization (CIMS), or fast atom

bombardment (FAB) method are reported as m/z (relative

intensity) and high-resolution mass spectral data (HRMS) are

recorded as m/z. Optical rotations [R] were measured at 589

nm (sodium D line). All new compounds were obtained as oils

18: ¹H NMR 1.99 (s, 3 H, NCH₃), 2.13 (ddd, J ) 3.0, 11.1,

and 12.8, 1 H, H-5), 2.28 (m, 3 H, H-4, H-3), 2.47 (m, 1 H,

H-4), 2.79 (dd, J ) 3.5, 10.9, 1 H, H-1), 3.09 (ddd, J ) 2.1, 4.9,

and 9.8, 1 H, H-5), 4.67 and 4.71 (s, 2 H, dCH₂7.21-7.28 (m,

5 H, Ar); ¹³C NMR 34.7 (C-4), 43.8 (NCH₃), 44.0 (C-2), 57.9

(C-5), 61.1 (C-1), 107.8 (dCH₂), 126.1, 126.9, 128.5 133.5 (Ar),

146.5 (C3); IR (neat) 2925, 2853, 1728, 1685, 1560; EIMS 187

(M, 3), 91 (100), 71 (17); HRMS 187.1368, C₁₃H₁₇N requires

187.1361.

in >90% purity (by H and ¹³C NMR) unless otherwise noted.

1

Column chromatographic separations were performed by using

EM Type 60 silica gel (230-400 mesh), Florisil (100-200

mesh), or Type F-20 Alumina (neutral, 80-120 mesh). Pre-

parative TLC was performed on 20 × 20 cm plates coated with

EM Type-60 GF-254 silica gel.

850 J . Org. Chem., Vol. 63, No. 3, 1998

Wu et al.

N-Ben zyl-N-[(tr im eth ylsilyl)m eth yl]-N-[2-[(tr im eth yl-

silyl)m eth yl]bu t-1-en -4-yl]a m in e (14). A solution of 11 (2.0

g, 85 mmol), iodo(methyltrimethyl)silane (2.7 g, 127 mmol),

and K₂CO₃(4.6 g, 425 mmol) in MeCN (100 mL) was stirred

at reflux for 12 h, diluted with water, and extracted with ether.

The extracts were dried and concentrated in vacuo to give a

residue which was subjected to column chromatography (Flo-

risil, 10% ether-hexanes) to afford 1.30 g (46%) of the desired

aminoallylsilane 14: ¹H NMR 0.02, 0.08 (s, 18 H, SiMe₃), 1.49

(s, 2 H, CH₂Si), 2.51 (t, J ) 7.7, 2 H, CH₂N), 3.54 (s, 2 H, NCH₂-

Ph), 4.53 (d, J ) 8.7, 2 H, vinyl), 7.35 (m, 5 H, ArH); ¹³C NMR

-1.3 (SiMe₃), 27.1 (CH₂SiMe₃), 35.4 (CH₂CH₂N), 45.9 (NCH₂-

Si), 56.0 (CH₂N), 62.0 (NCH₂Ph), 107.7 (dCH₂), 126.6, 128.0,

128.7 (Ar), 140.4 (Ar, C-ipso), 146.1 (CdCH₂); IR 3064, 3026,

2953, 2786, 1631; CIMS 334 (M + 1, 0.4), 206 (100), 91 (70),

73 (31); HRMS 333.2305, C₁₈H₃₅NSi₂requires 333.2308.

CTAN Oxid a tion of Am in oa llylsila n e 14. P r ep a r a tion

of 4-Meth ylid en ep ip er id in e 16. A solution of aminoallyl-

silane 14 (20 mg, 0.006 mmol), and (ⁿBu₄N)₂Ce(NO₃)₆(108 mg,

0.12 mmol) in MeCN (5 mL) was stirred at 25 °C for 4 h,

diluted with water, and extracted with CHCl₃. The extracts

were dried and concentrated in vacuo giving a residue which

after preparative TLC (30% ether-hexanes) separation af-

forded 5 mg (45%) of 16. ¹H NMR 2.24 (t, J ) 5.5, 4 H, (CH₂-

CH₂)₂N), 2.44 (t, J ) 5.5 H, 4 H, (CH₂)₂N), 3.51 (s, 2 H,

NCH₂Ph), 7.30 (m, 5 H, Ar); ¹³C NMR 34.5 (CH₂Cd), 54.9 (CH₂-

CH₂N), 62.9 (NCH₂Ph), 107.5 (CdCH₂), 126.9, 128.1, 129.0

(Ar), 138.6 (Ar C-ipso), 146.7 (CdCH₂); IR 3066, 3027, 2939,

2902, 2792, 2755; EIMS 187 (62), 186 (40), 111 (32), 91 (100);

HRMS 187.1358, C₁₃H₁₇N requires 187.1361.

(3R,4S)-2-[(Tr im eth ylsilyl)m eth yl]-3-h ydr oxy-4-[N-[(tr i-

m eth ylsilyl)m eth yl]-N-ben zyla m in o]-1-p en ten e (20). To

a solution of 2-(bromoallyl)trimethylsilane (1.8 g, 9.3 mmol)

in THF (10 mL) at -78 °C was added n-BuLi (1.4 M in hexane,

6.5 mL, 9.1 mmol). The resulting mixture was stirred at -78

°C for 1 h. To this mixture was added a solution of 19 (1.2 g,

4.9 mmol) in THF (10 mL) at -78 °C. The reaction mixture

was warmed to 25 °C, stirred for 5 h, diluted with satd NH₄-

Cl, and extracted with CH₂Cl₂. The extracts were washed with

brine, dried, and concentrated in vacuo, giving a residue which

was subjected to column chromatography (silica gel, hexane:

EtOAc, 100:1) to give 1.1 g (65%) of 20: [R]²⁹+2.9° (c 0.41);

D

¹H NMR -0.03 (s, 9H, TMS), 0.04 (s, 9H, TMS), 0.93 (d, J )

6.8, 3H, CH₃), 1.10 and 1.39 (ABq, J ) 13.9, 2H, CH₂TMS),

2.04 and 2.22 (ABq, J ) 14.8, 2H, NCH₂), 2.78 (dq, J ) 3.2,

6.8, 1H, CHCH₃), 3.50 and 3.76 (ABq, J ) 14.2, 2H, CH₂Ph),

4.05 (d, J ) 3.2, 1H, CHOH), 4.62 (s, 1H, CdCH₂), 4.86 (s,

1H, CdCH₂), 7.27 (m, 5H, Ar); ¹³C NMR -1.4 (TMS), -1.3

(TMS), 7.2 (CHCH₃), 23.2 (CH₂TMS), 41.7 (NCH₂TMS), 57.8

(CHCH₃), 58.5 (NCH₂Ph), 76.5 (CHOH), 107.2 (CdCH₂), 126.8,

128.2, 128.6, and 140.5 (Ar), 148.8 (CdCH₂); IR 2951, 1241,

839; CIMS 364 (M + 1, 12), 348 (28), 288 (36), 220 (100), 91

(84); HRMS 364.2501, C₂₀H₃₈NOSi₂requires 364.2492.

(3R,4S)-2-[(Tr im eth ylsilyl)m eth yl]-3-a cetoxy-4-[N-[(tr i-

m eth ylsilyl)m eth yl]-N-ben zyla m in o]-1-p en ten e (21).

A

solution of 20 (287 mg, 0.79 mmol), Ac₂O (0.15 mL, 1.6 mmol),

and 4-DMAP (2 mg) in pyridine (5 mL) was stirred for 1 h at

25 °C, diluted with CHCl₃, washed with brine and water, dried,

and concentrated in vacuo, giving a residue which was

subjected to column chromatography (silica gel, hexane:ether,

1

P h otooxid a tion of 14. A N₂-purged solution of 14 (20 mg,

0.006 mmol) saturated with DCA in MeCN (80 mL) was

irradiated (Uranium glass filtered-light) for 2 h (90% conver-

sion of 14 by GLC). Workup followed by preparative TLC (30%

ether-hexanes) separation afforded the cyclized product 16

(6 mg, 53%).

100:1) to give 214 mg (67%) of 21: [R]²⁵+13.1° (c 0.36); H

D

NMR -0.06 (s, 9H, TMS), -0.02 (s, 9H, TMS), 0.93 (d, J )

6.8, 3H, CHCH₃), 1.03 and 1.23 (ABq, J ) 14.3, 2H, CH₂TMS),

1.96 (s, 2H, NCH₂), 1.99 (s, 3H, COCH₃), 2.79 (dq, J ) 3.5,

6.8, 1H, CHCH₃), 3.46 and 3.55 (ABq, J ) 13.9, 2H, CH₂Ph),

4.53 (s, 1H, CdCH₂), 4.66 (s, 1H, CdCH₂), 5.18 (d, J ) 3.5,

1H, CHOCH₃), 7.15-7.30 (m, 5H, Ar); ¹³C NMR -1.4 (2TMS),

7.7 (CHCH₃), 21.4 (COCH₃), 22.9 (CH₂TMS), 40.4 (NCH₂TMS),

55.0 (CHCH3), 58.0 (NCH₂Ph), 78.3 (CHOCOCH₃), 108.6

(CdCH₂), 126.8, 128.2, 128.8, and 140.4 (Ar), 144.7 (CdCH₂),

169.7 (COCH3); IR 2953, 1739, 1371, 1234, 843; EIMS 405

(1), 220 (100), 91 (86); HRMS 405.2500, C₂₂H₃₉NO₂Si₂requires

405.2519.

N-Ben zyl-N-[(tr im eth ylsilyl)m eth yl]-N-[4-[(tr im eth yl-

silyl)m eth yl]-p en ten yl]a m in e (15). A solution of 12 (350

mg, 1.3 mmol), K₂CO₃(724 mg, 6.5 mmol), and iodomethane

(430 mg, 1.95 mmol) in MeCN (10 mL) was heated at reflux

for 12 h and then diluted with water. The resulting mixture

was extracted with ether, and the combined ethereal extracts

were dried and concentrated in vacuo to give a brown oil

which was subjected to column chromatography (florisil, 10%

ether-hexanes) to yield 331 mg (71%) of 15. ¹H NMR -0.08

(s, 9 H, SiMe₃), 0.03 (s, 9 H, SiMe₃), 1.49 (s, 2 H, CH₂dCCH₂-

SiMe₃), 1.58 (m, 2 H, NCH₂CH₂), 1.92 (m, 4 H, NCH₂SiMe₃,

CH₂CdCH₂), 2.31 (t, J ) 7.1 Hz, 2 H, CH₂CH₂N), 3.47 (s, 2 H,

NCH₂Ph), 4.47, 4.53 (s, 2 H, vinyl), 7.20-7.26 (m, 5 H, ArH );

¹³C NMR -1.3 (SiMe₃), 25.5 (CH₂CH₂N), 27.0 (CH₂dCCH₂-

SiMe₃), 36.0 (CH₂dCCH₂CH₂), 46.1 (NCH₂SiMe₃), 57.1

(CH₂CH₂N), 62.2 (NCH₂Ph), 106.6 (CH₂dC), 126.6, 128.0,

128.7 (aromatic), 140.6 (aromatic, C-ipso), 147.8 (CH₂dC); IR

(neat) 3066, 3028, 2953, 2788, 1420,1248, 855 cm^-1; EIMS 347

(6), 332 (15), 274 (86), 206 (39), 91 (85), 73 (100); HRMS

347.2484, C₂₀H₃₇NSi requires 347.2465.

CTAN Oxid a tion of Am in oa llylsila n e 15. P r ep a r a tion

of 4-Meth ylid en eh yd r oa zep in e 17. Application of the same

procedure was used for transformation of 14 to 16, starting

with the silylamine 15 (35 mg, 0.1 mmol), and resulted in the

formation of hydroazepine 17 (11 mg, 62%): ¹H NMR 1.68 (m,

2 H, H-5, H-5′), 2.35 (t, J ) 6.2, 2 H, H-4, H-4′), 2.39 (t, J )

5.5, 2 H, H-2, H-2′), 2.63 (qt, J ) 5.3, 4 H, H-6, H-6′, H-1, H-1′),

3.62 (s, 2 H, NCH₂Ph), 4.68 (s, 1 H, vinyl), 4.70 (d, J ) 0.9, 2

H, vinyl), 7.15-7.35 (m, 5 H, Ar); ¹³C NMR 27.4 (C-5), 35.2

(C-4), 36.5 (C-2), 55.1 (C-6), 56.9 (C-1), 62.1 (NCH₂Ph), 110.5

(CH₂dC), 126.8, 128.1, 128.8 (Ar), 139.5 (Ar-ipso), 150.5 (C-

3); IR 3065, 3026, 1933, 2807, 1685, 1638; EIMS 201 (13), 91

(100); HRMS 201.1514, C₁₄H₁₉N requires 201.1517.

CTAN Oxid a tion of Am in oa llylsila n e 21. P r ep a r a tion

of 4-Meth ylid en ep ip er id in yl Aceta tes 22 a n d 25.

A

solution of 21 (43.0 mg, 0.11 mmol) and CTAN (211 mg, 0.21

mmol) in dry MeCN (20 mL) was stirred for 5 h at 25 °C,

diluted with isopropyl alcohol and CHCl₃, washed with brine

and water, dried, and concentrated in vacuo, giving a residue

which was subjected to column chromatography (silica gel,

hexane:ether, 10:1) to give 21 mg (75%) of a mixture of 22 and

25 in a 1:1.2 ratio (¹H NMR). These substances were sepa-

rated by preparative TLC (silica gel, 5:1 hexanes-ether).

1

22: R_f0.20 (5:1 hexanes-EtOAc); [R]²⁵-0.11° (c 0.90); H

NMR 0.93 (d, J ) 6.5, 3H, CHCH₃), 2.09 (s, 3H, COCH₃), 2.23-

2.34 (m, 2H, CH₂CH₂N), 2.43 (ddd, J ) 11.4, 4.6, 4.6, 1H, Hb,

CH₂N), 2.56 (ddd, J ) 11.4, 9.7, 4.4, 1H, Ha, CH₂N), 3.12 (dq,

J ) 4.9, 6.5, 1H, CHCH₃), 3.62 and 3.66 (ABq, J ) 13.6, 2H,

CH₂Ph), 4.80 (d, J ) 1.1, 1H, CdCH₂), 4.85 (s, 1H, CdCH₂),

5.42 (d, J ) 4.9, 1H, CHOCOCH₃), 7.29 (m, 5H, Ar); ¹³C NMR

6.9 (CHCH₃), 21.1 (COCH₃), 32.9 (CH₂CH₂N), 46.9 (CH₂CH₂N),

56.6 (CHCH₃), 58.0 (NCH₂Ph), 74.9 (CHOCOCH₃), 108.1

(CdCH₂), 127.0, 128.3, 128.6, and 139.1 (Ar), 142.0 (CdCH₂),

170.0 (COCH₃); IR 2966, 2931, 2814, 1743, 1655; EIMS 259

(28), 244 (74), 216 (55), 199 (81), 91 (100), 83 (37); HRMS

259.1577, C₁₆H₂₁NO₂requires 259.1572.

25: R_f0.18 (5:1 hexanes-EtOAc); ¹H NMR 1.05 (d, J ) 6.5,

3H, CHCH₃), 2.12 (s, 3H, COCH₃), 2.15-2.20 (m, 1H, CH₂-

CH₂N), 2.34 (m, 1H, CH₂CH₂N), 2.43 (m, 1H, CH₂CH₂N), 2.70

(ddd, J ) 11.3, 7.3, 3.7, 1H, CH₂CH₂N), 2.79 (dq, J ) 5.7, 6.4,

1H, CHCH₃), 3.46 and 3.84 (ABq, J ) 13.7, 2H, CH₂Ph), 4.83

(s, 1H, CdCH₂), 4.87 (s, 1H, CdCH₂), 5.00 (d, J ) 5.7, 1H,

CHOCOCH₃), 7.20-7.34 (m, 5H, Ar); ¹³C NMR 12.2 (CHCH₃),

21.2 (COCH₃), 31.6 (CH₂CH₂N), 49.2 (CH₂CH₂N), 57.5 (CH₂-

Ph), 58.8 (CHCH₃), 77.0 (CHOCOCH₃), 110.4 (CdCH₂), 126.9,

P h otooxid a tion of 15. A N₂-purged solution of 15 (35 mg,

0.1 mmol) and excess DCA in MeCN (100 mL) was irradiated

(Uranium glass filtered-light) for 1.5 h (70% conversion of 15

by GLC). Concentration of the photolyzate followed by pre-

parative TLC (50% ether-hexanes) separation afforded 7 mg

of 17.

Oxidative Mannich Cyclizations

J . Org. Chem., Vol. 63, No. 3, 1998 851

128.2, 128.6, and 139.4 (Ar), 142.6 (CdCH₂), 170.3 (COCH₃);

EIMS 259 (5), 244 (28), 199 (32), 91 (100); HRMS 259.1568,

brine and concentrated in vacuo to give a residue which was

subjected to column chromatography (silica gel, 3:1 hexanes/

EtOAc) to give 5.94 g (76%) of 31. [R]²⁶+0.60° (c 7.54, CHCl₃);

¹H NMR 0.12 (s, 9H, TMS), 0.98 (d, J ) 5.0, 3H, CHCH₃), 2.44

and 2.78 (ABq, J ) 14.4, 2H, CH₂TMS), 3.26 (s, 1H, CHCH₃),

3.49 (s, 1H, CH₂OH), 3.89 (s, 1H, CH₂OH), 7.31 (s, 5H, Ar);

¹³C NMR -0.8 (TMS), 15.0 (CHCH₃), 32.0 (CH₂TMS), 56.1

(CHCH₃), 63.3 (CH₂OH), 126.7, 128.3, 129.0 and 137.0 (Ar),

172.3 (CdO); IR 3351, 2951, 1596, 1456; EIMS 265 (8), 264

(37), 250 (33), 105 (100), 77 (35); HRMS 265.1491, C₁₄H₂₃NO₂-

Si requires 265.1498.

(2S)-2-[N-Ben zoyl-N-[(t r im et h ylsilyl)m et h yl]a m in o]-

p r op ion a ld eh yd e (32). To a solution of DMSO (1.49 mL,

35.1 mmol) in 15 mL of CH₂Cl₂at -78 °C was added oxalyl

chloride (0.92 mL, 10.5 mmol), and the resulting solution was

stirred at -78 °C for 1 h. After addition of alcohol 31 (1.86 g,

7.0 mmol) in CH₂Cl₂(6 mL), the mixture was stirred at -78

°C for 2 h, diluted with triethylamine (4.89 mL, 35.1 mmol)

and stirred at 25 °C for 2 h, diluted with water, and extracted

with CH₂Cl₂. The extracts were washed with brine, dried, and

concentrated in vacuo to give 1.18 g (98%) of aldehyde 32 which

was used without further purification owing to its instability.

[R]²⁶-17.2° (c 1.90, CHCl₃); ¹H NMR (mixture of rotamers A/B

) 3:1) -0.08 (s, 9H, TMS, B), 0.05 (s, 9H, TMS, A), 1.21 (s,

3H, CHCH₃, A), 1.39 (s, 3H, CHCH₃, B), 2.36 and 2.68 (ABq,

J ) 13.8, 2H, CH₂TMS, A), 2.75 and 3.01 (ABq, J ) 13.8,

2H,CH₂TMS, B), 3.39 (s, 1H, CHCH₃, B), 4.24 (s, 1H, CHCH₃,

A), 7.26 (m, 5H, Ar, A and B), 9.50 (m, 1H, CHO, A and B);

¹³C NMR -1.4 (TMS, B), -1.1 (TMS, A), 11.1 (CH₃, B), 12.5

(CH₃, A), 35.7 (CH₂TMS, A), 41.6 (CH₂TMS, B), 63.2 (CH, B),

64.0 (CH, A), 126.1, 126.5, 128.2, 128.5, 129.4, 135.5 and 136.3

(Ar, A and B), 171.8 (CdO), 196.6 (CHO, B), 199.3 (CHO, A);

IR 2948, 1727, 1622, 1447; EIMS 263 (11), 262 (44), 248 (32),

234 (27), 105 (100); HRMS 263.1353, C₁₄H₂₁NO₂Si requires

263.1342.

C

₁₆H₂₁NO₂requires 259.1572.

En a n tiom er ic P u r ity Deter m in a tion of 22. P r ep a r a -

tion of Alcoh ol 23 a n d Mosh er Ester 24. A solution of 22

(11 mg, 0.04 mmol) and KCN (1.3 mg, 0.02 mmol) in MeOH

(2 mL) was stirred for 12 h at 25 °C, diluted with CHCl₃,

washed with brine and water, dried, and concentrated in vacuo

to give 12 mg (100%) of 23 which was used without further

purification: ¹H NMR 1.08 (d, J ) 6.5, 3H, CH₃), 2.08 (m, 2H,

CH₂CH₂N), 2.33 (m, 1H, Hb, CH₂N), 2.63 (m, 1H, CHCH₃),

2.67 (m, 1H, Ha, CH₂N), 3.25 and 3.82 (ABq, J ) 13.4, 2H,

CH₂Ph), 3.97 (br d, J ) 2.1, 1H, CHOH), 4.72 (s, 1H, CdCH₂),

4.81 (s, 1H, CdCH₂), 7.21 (m, 5H, Ar); ¹³C NMR 12.0 (CH₃),

31.4 (CH₂CH₂N), 50.4 (CH₂CH₂N), 57.5 (CH₂Ph), 60.8 (CHCH₃),

75.2 (CHOH), 107.9 (CdCH₂), 127.0, 128.3, 128.7, and 139.3

(Ar), 147.4 (CdCH₂).

A solution of 23 (13 mg, 0.06 mmol), the Mosher acid (R)-

MTPAcOH (70 mg, 0.30 mmol), DCC (80 mg, 0.40 mmol), and

4-DMAP (15 mg, 0.12 mmol) in CH₂Cl₂(3 mL) was stirred at

25 °C for 12 h and concentrated in vacuo, giving a residue

which was subjected to column chromatography (silica gel,

hexane:ether, 10:1) to give (R)-Mosher ester 24. The ee of 22

was determined to be ca. 4% by ¹H NMR analysis of 24.

Characteristic peaks in the ¹H and ¹³C NMR spectra are as

1

follows: H NMR 0.86 (d, J ) 6.6, 3H, CHCH₃), 1.01 (d, J )

6.6, 3H, CHCH₃), 3.56 (s, 3H, OCH₃), 3.57 (s, 3H, OCH₃), 4.77

(s, 1H, CdCH₂), 4.86 (s, 1H, CdCH₂), 4.92 (s, 1H, CdCH₂),

4.94 (s, 1H, CdCH₂), 5.64 (d, J ) 4.1, 2H, CHOCO); ¹³C NMR

8.5 (CHCH₃), 8.6 (CHCH₃), 109.8 (CdCH₂), 110.1 (CdCH₂);

IR 2935, 1745, 1714, 1665, 1493, 1248, 1181; EIMS 433 (M,

16), 418 (73), 216 (50), 189 (84), 126 (100); HRMS 433.1866,

C

₂₄H₂₆NO₃F₃requires 433.1865.

En a n tiom er ic P u r ity Deter m in a tion of 25. P r ep a r a -

tion of Alcoh ol 26 a n d Mosh er Ester 27. By the procedure

used to convert 22 to 23, the ester 25 was transformed

quantitativly to 26: ¹H NMR 0.90 (d, J ) 6.7, 3H, CHCH₃),

2.06 (m, 1H, CH₂CH₂N), 2.47 (m, 3H, CH₂CH₂N), 2.88 (dq, J

) 3.9, 6.7, 1H, CHCH₃), 3.48 and 3.56 (ABq, J ) 13.2, 2H,

CH₂Ph), 3.69 (d, J ) 3.9, 1H, CHOH), 4.79 (s, 1H, CdCH₂),

4.80 (s, 1H, CdCH₂), 7.26 (m, 5H, Ar); ¹³C NMR 9 (CH₃), 30

(CH₂CH₂N), 46 (CH₂CH₂N), 58 (CH₂Ph), 59.8 (CHCH₃), 75.6

(CHOH), 110.6 (CdCH₂), 127.1, 128.3, 128.7, and 138.9 (Ar),

145.1 (CdCH₂).

En a n tiom er ic P u r ity Deter m in a tion of Ald eh yd e 32.

P r ep a r a tion of Alcoh ol 30 a n d Its Mosh er Ester . To a

solution of crude aldehyde 32 (56 mg, 0.21 mmol) in Et₂O (2

mL) at 0 °C was added LiAH₄(24 mg, 0.63 mmol). The

mixture was stirred at 25 °C for 6 h, diluted with H₂O, and

extracted with Et₂O. The extracts were washed with brine,

dried, and concentrated in vacuo to give 41 mg (76%) of the

known¹⁶2-[N-benzyl-N-[(trimethylsilyl)methyl]amino]propan-

1-ol. This substance was esterified with (R)-MTPAcCl (Ald-

rich) to provide the Mosher ester which ¹H NMR analysis

showed to be >90% diastereomerically pure.

A mixture of 26 (22 mg, 0.20 mmol), 4-DMAP (2 mg), Et₃N

(0.03 mL, 0.20 mmol), and freshly prepared (see above) (S)-

MTPAcCl (5 mg, 0.20 mmol) in CH₂Cl₂(5 mL) was stirred for

12 h at 25 °C, diluted with CHCl₃, washed with brine and

water, dried, and concentrated in vacuo, giving a residue which

was subjected to column chromatography (silica gel, hexane:

ether, 5:1) to give 34 mg (77%) of (S)-Mosher ester 27. The ee

of 25 was determined to be ca. 24% by ¹H and ¹³C NMR

spectral analysis 27: [R]³⁰-10.4° (c 1.39); ¹H NMR 1.00 (d, J

) 6.8, 3H, CHCH₃, major), 1.02 (d, J ) 7.4, 3H, CHCH₃), 2.40

(m, 4H, CH₂CH₂), 3.09 (m, 1H, CHCH₃), 3.13-3.19 (m, 1H,

CHCH₃), 3.50 and 3.66 (ABq, J ) 13.8, 2H, CH₂Ph), 3.55 (s,

3H, OCH₃), 5.00 (br s, 1H, CdCH₂), 5.02 (s, 1H, CdCH₂), 5.23

(d, J ) 6.0, 1H, CHOCO, minor), 5.24 (d, J ) 5.9, 1H, CHOCO,

major), 7.30 (m, 10H, Ar); ¹³C NMR 9.5 (CHCH₃, major), 9.9

(CHCH₃, minor), 30.7 (CH₂CH₂N, minor), 30.8 (CH₂CH₂N,

major), 46.6 (CH₂CH₂N, major), 46.7 (CH₂CH₂N, minor), 55.4

(CHCH₃, major), 55.5 (CHCH₃, minor), 57.3 (CHOCO, minor),

57.7 (CHOCO, major), 57.9 (CH₂Ph, minor), 58.0 (CH₂Ph,

major), 79.8 (OCH₃), 114.3 (CdCH₂, major), 114.5 (CdCH₂,

minor), 122.0 (CdCH₂, minor), 124.8 (CdCH₂, major), 126.8,

126.9, 127.4, 127.5, 128.1, 128.2, 128.4, 128.5, 129.4, and 129.5

(aromatic), 132.4, 139.2, 139.3, 140.4, 140.7, 141.1, and 141.4

(quart), 165.8 (CdO, minor), 166.0 (CdO, major); IR 2955,

1743, 1455, 1261, 1177; EIMS 433 (12), 418 (64), 216 (42), 146

(7), 91 (100); HRMS 433.1859, C₂₄H₂₆NO₃F₃requires 433.1865.

(2S)-2-[N-Ben zoyl-N-[(tr im eth ylsilyl)m eth yl]a m in o]-1-

p r op a n ol (31). A solution of amine 30¹⁶(4.74 g, 29.4 mmol),

triethylamine (6.14 mL, 44.1 mmol), and benzoyl chloride (3.76

mL, 32.3 mmol) in CH₂Cl₂(100 mL) was stirred at 25 °C for 2

h and diluted with water. The CH₂Cl₂layer was washed with

(3R,4S)- a n d (3S,4S)-2-[(Tr im eth ylsilyl)m eth yl]-3-h y-

d r oxy-4-[N-[(tr im eth ylsilyl)m eth yl]-N-ben zoyla m in o]-1-

p en ten e (33 a n d 36). To a solution of (2-bromoallyl)-

trimethylsilane (1.63 g, 8.44 mmol) in THF (5 mL) was added

tert-BuLi (1.5 M in pentane, 5.4 mL, 8.16 mmol) at -78 °C

dropwise via a syringe. After stirring for 1 h, aldehyde 32 (0.74

g, 2.81 mmol) was added, and the mixture was stirred at -78

°C for 2 h, warmed to 25 °C, diluted with water, and extracted

with CH₂Cl₂. The extracts were washed with brine, dried, and

concentrated in vacuo to give a residue which was subjected

to flash column chromatography (silica gel, 4:1 hexanes-

EtOAc) to give 0.55 g (52%) of 33 and 0.07 g (6%) of 36.

33: [R]²⁵+0.68° (c 7.51, CHCl₃); ¹H NMR -0.13 (s, 9H,

TMS), 0.12 (s, 9H, TMS), 0.64 and 1.04 (ABq, J ) 14.1, 2H,

CH₂TMS), 1.12 (d, J ) 6.3, 3H, CH₃), 2.69 and 3.06 (ABq, J )

14.5, 2H, NCH₂), 3.79 (m, 2H, CH and CHOH), 4.57 (s, 1H,

dCH₂), 4.79 (s, 1H, dCH₂), 7.30 (m, 5H, Ar); ¹³C NMR (mixture

of rotamers A/B ) 10:1) -2.6 (TMS, B), -1.6 (TMS, A), -0.7

(TMS, A), 0.2 (TMS, B), 12.2 (CH₃, A), 13.8 (CH₃, B), 21.8 (CH₂-

TMS, A), 23.6 (CH₂TMS, B), 34.2 (NCH₂, A), 37.2 (NCH₂, B),

56.1 (CH, A), 59.0 (CH, B), 78.4 (CHOH, A), 78.9 (CHOH, B),

108.7 (dCH₂, A and B), 120.2, 126.5, 128.1, 128.5, 129.0, 132.3

and 137.3 (Ar, A and B), 147.4 (Cd, A and B), 171.1 (CdO);

IR 3351, 3074, 2951, 2362, 1598; CIMS 378 (M + 1, 1), 234

(91), 105 (100); HRMS 378.2273, C₂₀H₃₆NO₂Si₂requires

378.2284.

36: [R]²³+4.47° (c 0.75, CHCl₃); ¹H NMR -0.10 (s, 9H,

TMS), 0.16 (s, 9H, TMS), 1.00 (d, J ) 6.2, 3H, CH₃), 1.13 and

1.19 (ABq, J ) 14.3, 2H, CH₂TMS), 2.53 and 2.84 (ABq, J )

852 J . Org. Chem., Vol. 63, No. 3, 1998

Wu et al.

14.5, 2H, NCH₂), 3.81-3.87 (m, 2H, CHCH₃and CHOH), 4.65

(s, 1H, dCH₂), 4.79 (s, 1H, dCH₂), 7.35 (m, 5H, Ar); ¹³C NMR

(mixture of rotamers A/B ) 10:1) -2.3 (TMS, B), -1.6 (TMS,

A), -0.9 (TMS, A), -0.4 (TMS, B), 15.2 (CH₃, B), 15.4 (CH₃,

A), 20.9 (CH₂TMS, A), 26.0 (CH₂TMS, B), 32.3 (NCH₂, A), 33.6

(NCH₂, B), 57.4 (CH, A), 58.1 (CH, B), 75.8 (CHOH, B), 76.4

(CHOH, A), 111.3 (dCH₂, A and B), 126.3, 126.8, 128.0, 128.1,

128.3, 128.7 and 137.0 (Ar), 146.3 (Cd, A and B), 172.5 (CdO);

IR 3336, 3070, 2954, 1597; EIMS 377 (0.5), 234 (83), 105 (100),

77 (40); HRMS 377.2196, C₂₀H₃₅NO₂Si₂requires 377.2206.

En a n tiom er ic P u r ity Deter m in a tion of Alcoh ol 33.

P r ep a r a tion of Mosh er Ester 35. A mixture of 33 (24 mg,

0.064 mmol), 4-DMAP (2 mg, 0.016 mmol), (R)-MTPAcCl (32

mg, 0.127 mmol) in CH₂Cl₂(3 mL), and Et₃N (0.018 mL, 0.127

mmol) was stirred for 12 h at 25 °C, diluted with water, and

extracted with CH₂Cl₂. The extracts were washed with brine,

dried, and concentrated in vacuo to give the Mosher ester 35

as a 75:25 mixture (50 ee%) based upon ¹H NMR integration.

Subjection to column chromatography (silica gel, 7:1 hexane/

EtOAc) did not alter the diastereomer ratio and gave pure 35

Mosher ester (35 mg, 92%). ¹H NMR (3:1 mixture of diaster-

omers, A/B) -0.06 (s, 9H, TMS, A and B), 0.04 (s, 9H, TMS,

B), 0.08 (s, 9H, TMS, A), 0.41 and 1.06 (ABq, J ) 14.4, 2H,

CH₂TMS, A), 0.51 and 1.13 (ABq, J ) 14.4, 2H, CH₂TMS, B),

1.15 (d, J ) 6.9, 3H, CH_3,B), 1.20 (d, J ) 6.9, 3H, CH_3,A),

2.41 and 2.83 (ABq, J ) 14.6, 2H, NCH₂, A), 2.43 and 2.87

(ABq, J ) 14.6, 2H, NCH₂, B), 3.41 (s, 3H, OCH₃, A), 3.50 (s,

3H, OCH₃, B), 4.15 (m, 1H, CHCH₃, A and B), 4.56 (s, 1H,

dCH₂, A), 4.60 (s, 1H, dCH₂, B), 4.66 (s, 1H, dCH₂, A and B),

5.02 (s, 1H, CHOCO, A), 5.14 (s, 1H, CHOCO, B), 7.38 (m,

10H, Ar, A and B); ¹³C NMR -1.5 (TMS, A), -1.2 (TMS, B),

-1.0 (TMS, A), -0.7 (TMS, B), 12.5 (CH_3,A), 12.7 (CH_3,B),

22.4 (CH₂TMS, A and B), 33.8 (NCH₂, A and B), 54.8 (OCH₃,

A), 55.1 (CH, A), 55.2 (OCH₃, B), 55.3 (CH, B), 81.7 (CHOCO,

B), 82.4 (CHOCO, A), 110.0 (CH₂d, A), 110.7 (CH₂d, B), 122.0

(COCH₃, A and B), 124.8 (CF₃, A and B), 126.5, 127.7, 127.9,

128.4, 128.6, 128.8, 129.5, 129.7, 129.8, 131.2, 131.6, 136.8 (Ar,

A and B), 142.2 (dC, A), 142.5 (dC, B), 165.0 (CHOCO, A and

B), 171.2 (NCdO, A and B); IR 2967, 1745, 1629; EIMS 593

(0.8), 360 (20), 234 (64), 130 (25), 105 (100); HRMS 593.2601,

TMS), 21.4 (COCH₃), 33.0 (NCH₂), 55.6 (CHCH₃), 78.1 (CHO-

COCH₃), 114.9 (dCH₂), 126.9, 128.5, 129.2 and 137.3 (Ar),

142.0 (Cd), 169.3 (COCH₃), 172.4 (NCdO); IR 2949, 1739,

1625; EIMS 419 (0.2), 234 (67), 105 (100), 7 (50); HRMS

419.2303, C₂₂H₃₇NO₃Si₂requires 419.2312.

CAN Oxid a tion of 34. P r ep a r a tion of tr a n s-4-Meth -

ylid en e Aceta te 38. A solution of CAN (0.51 g, 0.93 mmol)

and allylsilane 34 (0.13 g, 0.31 mmol) in MeCN (3 mL) was

stirred for 20 h at 25 °C, diluted with 2-propanol and water,

and extracted with CH₂Cl₂. The extracts were washed with

brine, dried, and concentrated in vacuo to give a residue which

was subjected to column chromatography (silica gel, 7:1

hexanes/EtOAc) to provide 0.041 g (48%) of 38. [R]²²-1.91°

1

(c 0.77, CHCl₃) H NMR (CD₃CN at 70 °C) 1.18 (d, J ) 7.1,

3H, CHCH₃), 1.99 (s, 3H, COCH₃), 2.19 (m, 1H, CH₂CH₂), 2.52

(td J ) 13.4, 5.8, 1H, CH₂CH₂), 3.00 (m, 1H, CH₂N), 4.15 (m,

1H, CHCH₃), 4.46 (m, 1H, CH₂N), 4.96 (s, 1H, CHOCOCH₃),

5.10 (t, J ) 1.7, 1H, dCH₂), 5.14 (t, J ) 1.7, 1H, dCH₂), 7.41

(m, 5H, Ar); ¹³C NMR (CD₃CN) 15.0 (CHCH₃), 21.2 (COCH₃),

29.9 (CH₂), 37.3 (CH₂), 54.9 (CH), 76.4 (CHO), 116.6 (dCH₂),

126.5, 128.5, 129.6 and 136.4 (Ar), 139.2 (Cd), 169.5 (COCH₃),

171.5 (NCdO); IR 2978, 1726, 1632, 1415; EIMS 273 (14), 213

(56), 105 (100), 77 (54); HRMS 273.1378, C₁₆H₁₉NO₃requires

273.1365.

CAN Oxid a tion of 37. P r ep a r a tion of cis-4-Meth -

ylid en e Aceta te 39. A solution of CAN (130 mg, 0.236 mmol)

and allylsilane 37 (33 mg, 0.079 mmol) in MeCN (3 mL) was

stirred for 22 h at 25 °C, diluted with 2-propanol and water,

and extracted with CH₂Cl₂. The extracts were washed with

brine, dried, and concentrated in vacuo to give a residue which

was subjected to column chromatography (silica gel, 7:1

hexanes/EtOAc) to provide 14 mg (67%) of 39. [R]²⁴-2.26° (c

1

0.60, CHCl₃); H NMR (C₆D₆, at 70 °C) 0.95 (d, J ) 6.7, 3H,

CHCH₃), 1.57 (s, 3H, COCH₃), 1.91 (m, 1H, CH₂), 1.99 (td J )

12.8, 5.5, 1H, CH₂), 2.66 (td, J ) 12.8, 3.5, 1H, CH₂N), 3.03

(m, 1H, CH₂N), 4.75 (d, J ) 1.4, 1H, dCH₂), 4.86 (d, J ) 1.4,

1H, dCH₂), 4.86 (m, 1H, CHCH₃), 5.47 (d, J ) 5.3, 1H, CHO),

7.21 (m, 5H, Ar); ¹³C NMR (C₆D₆, at 70 °C) 11.1 (CHCH₃), 20.0

(COCH₃), 33.9 (CH₂), 39.9 (CH₂N), 51.1 (CH), 73.1 (CHO),

108.5 (dCH₂), 128.6 128.7, 129.6 and 137.3 (Ar), 140.8 (Cd),

168.4 (COCH₃), 170.7 (NCdO); IR 2948, 1740, 1629; EIMS 273

(8), 213 (30), 105 (100); HRMS 273.1366, C₁₆H₁₉NO₃requires

273.1365.

C

₃₀H₄₂NO₄F₃Si₂requires 593.2604.

(3R,4S)-2-[(Tr im eth ylsilyl)m eth yl]-3-a cetoxy-4-[N-[(tr i-

m eth ylsilyl)m eth yl]-N-ben zoyla m in o]-1-p en ten e (34). A

solution of allylic alcohol 33 (0.28 g, 0.74 mmol), pyridine (3

mL), acetic anhydride (0.38 g, 3.72 mmol), and 4-DMAP (3 mg)

was stirred at 25 °C for 14 h, diluted with water, and extracted

with CH₂Cl₂. The extracts were dried and concentrated in

vacuo to give 0.30 g (95%) of 34. This material was used

without further purification. [R]²²-1.08° (c 7.91, CHCl₃); ¹H

NMR -0.10 (s, 9H, TMS), 0.12 (s, 9H, TMS), 0.72 and 1.02

(ABq, J ) 14.2, 2H, CH₂TMS), 1.18 (d, J ) 6.8, 3H, CHCH₃),

2.03 (s, 3H, COCH₃), 2.55 and 2.94 (ABq, J ) 14.6, 2H, NCH₂),

4.07 (dq, J ) 6.8, 4.0, 1H, CHCH₃), 4.61 (s, 1H, dCH₂), 4.75

(s, 1H, dCH₂), 5.08 (d, J ) 4.0, 1H, CHOCOCH₃), 7.35 (m,

5H, Ar); ¹³C NMR -1.5 (TMS), -0.7 (TMS), 13.5 (CHCH₃), 21.2

(COCH₃), 21.7 (CH₂TMS), 34.0 (NCH₂), 54.8 (CHCH₃), 79.1

(CHOCOCH₃), 110.9 (dCH₂), 126.6, 128.6, 129.3 and 136.9

(Ar), 142.4 (Cd), 169.3 (COCH₃), 171.5 (CdO); IR 2952, 1749,

1629; EIMS 419 (0.4), 234 (55), 105 (100); HRMS 419.2298,

En a n tiom er ic P u r ity Deter m in a tion of 38. P r ep a r a -

tion of Alcoh ol 26 a n d Mosh er Ester 27. To a solution of

acetate 38 (70 mg, 0.256 mmol) in anhydrous Et₂O (3 mL) at

0 °C was added LAH (29 mg, 0.769 mmol). The resulting

mixture was allowed to warm to 25 °C and stirred for 4 h,

diluted with H₂O, and extracted with Et₂O. The organic

extracts were washed with brine, dried over anhydrous MgSO₄,

and concentrated in vacuo to give 50 mg (90%) of alcohol 26.

The spectroscopic data for this compound were identical with

those reported above.

A solution of 26 (12 mg, 0.055 mmol), 4-DMAP (2 mg),

triethylamine (0.015 mL, 0.110 mmol), and (S)-MTPAcCl (28

mg, 0.110 mmol) in CH₂Cl₂(3 mL) was stirred at 25 °C for 18

h, diluted with H₂O, and extracted with CH₂Cl₂. The extracts

were washed with 5% HCl, saturated aqueous NaHCO₃and

H₂O, dried, and concentrated in vacuo to provide 24 mg (100%)

of the (S)-Mosher ester 27 as a 75:25 mixture (50% ee) based

upon ¹H NMR integration. Subjection to column chromatog-

raphy (silica gel, 8:1 hexane/EtOAc) did not alter the diaste-

reomer ratio and gave pure 27 (22 mg, 92%). [R]²⁸23.7° (c

0.88, CHCl₃). The spectroscopic properties of this subtance

were the same as those reported above.

En a n tiom er ic P u r ity Deter m in a tion of 39. P r ep a r a -

tion of Alcoh ol 23 a n d Mosh er Ester 24. To a solution of

acetate 39 (9 mg, 0.04 mmol) in Et₂O (2 mL) at 0 °C was added

LiAlH₄(6 mg, 0.15 mmol). The mixture was stirred for 4 h at

25 °C, diluted with H₂O, and extracted with Et₂O. The

extracts were washed with brine, dried, and concentrated in

vacuo to give 7 mg (88%) of alcohol 23. The spectroscopic data

for this compound were identical with those reported above.

A solution of 23 (5 mg, 0.02 mmol), 4-DMAP (1 mg),

triethylamine (0.006 mL, 0.046 mmol), and (S)-MTPAcCl (12

C

₂₂H₃₇NO₃Si₂requires 419.2312.

(3S,4S)-2-[(Tr im eth ylsilyl)m eth yl]-3-a cetoxy-4-[N-[(tr i-

m eth ylsilyl)m eth yl]-N-ben zoyla m in o]-1-p en ten e (37). To

a solution of allylic alcohol 36 (0.14 g, 0.37 mmol), pyridine (2

mL), acetic anhydride (0.19 g, 1.86 mmol), and 4-DMAP (3 mg)

was stirred at 25 °C for 16 h, diluted with water, and extracted

with CH₂Cl₂. The extracts were dried and concentrated in

vacuo to give a residue which was subjected to chromato-

graphic separation (silica gel, 9:1 hexanes/EtOAc) to afford 0.13

g (85%) of 37: [R]²⁴-2.65° (c 3.75, CHCl₃); ¹H NMR -0.14 (s,

9H, TMS), 0.13 (s, 9H, TMS), 1.19 (d, J ) 6.8, 3H, CHCH₃),

1.01 and 1.13 (ABq, J ) 14.5, 2H, CH₂TMS), 2.08 (s, 3H,

COCH₃), 2.36 and 2.85 (ABq, J ) 14.6, 2H, NCH₂), 4.06 (dq,

J ) 9.7, 6.8, 1H, CHCH₃), 4.75 (s, 1H, dCH₂), 4.94 (s, 1H,

dCH₂), 5.15 (d, J ) 9.7, 1H, CHOCOCH₃), 7.31 (m, 5H, Ar);

¹³C NMR -1.2 (TMS), -0.7 (TMS), 15.7 (CHCH₃), 20.4 (CH₂-

Oxidative Mannich Cyclizations

J . Org. Chem., Vol. 63, No. 3, 1998 853

mg, 0.046 mmol) in CH₂Cl₂(3 mL) was stirred at 25 °C for 18

h, diluted with H₂O, and extracted with CH₂Cl₂. The extracts

were washed with 5% HCl, saturated aqueous NaHCO₃, and

H₂O, dried, and concentrated to provide 10 mg of the Mosher

ester 24 as a 75:25 mixture of diastereomers (50% ee) based

upon ¹H NMR integration. Subjection of this material to

column chromatography (silica gel, 6:1 hexane/EtOAc) did not

effect diastereomeric ratios and gave 24 (8 mg, 85%). The

spectroscopic properties of this substance were the same as

those reported above.

(4S)-N-Ben zyl-N-[1(Z)-(tr im eth ylsilyl)-1-p en ten -4-yl]-

a m in e (40). (4S)-N-(p)-toluenesulfonyl)-N-[1(Z)-(trimethyl-

silyl)-1-penten-4-yl]amine (0.65 g, 2.1 mmol) and K₂CO₃(1.46

g, 10.6 mmol) in DMF (20 mL) was stirred at 25 °C for 15 min.

To this mixture was added benzyl bromide (0.47 g, 2.7 mmol)

and DMF (5 mL), and the resulting mixture was stirred at 25

°C for 12 h and concentrated in vacuo. The residue was

partitioned between water and CH₂Cl₂, and the CH₂Cl₂phase

was dried and concentrated in vacuo to give 0.76 g (92%) of

the N-benzyl analogue which was used without further purifi-

cation: [R]²⁵+12.9° (c 0.007, CHCl₃). ¹H NMR -0.08 (s, 9 H,

SiMe₃), 0.98 (d, J ) 6.9, 3 H, NCH), 2.00 (m, 2 H, dCCH₂),

2.41 (s, 3 H, CH₃), 3.98 (m, 1 H, NCHCH₃), 4.21 and 4.53 (ABq,

J ) 16.0, 2 H, NCH₂Ph), 5.40 (d, J ) 14.1, 1 H, CHdCH),

5.99 (m, 1 H, CHdCH), 7.35 (m, 9 H, Ar), 7.68 (m, 1 H, Ar);

¹³C NMR -0.1 (SiMe₃), 17.8 (NCHCH₃), 21.5 (CH₃), 39.8

(dCCH₂), 47.3 (NCH₂Ph), 54.3 (NCHCH₃), 127.1, 127.5, 128.4,

129.6 (Ar), 131.5 (CHdCHSiMe₃), 138.2, 138.4 (Ar-ipso), 143.0

(Ar-ipso), 144.4 (CHdCHSiMe₃); IR 3030, 2954, 1495, 1455,

(OMe, A), 55.9 (OMe, B), 56.1 (NCHCH₃, B), 56.4 (NCHCH₃,

A), 127.5, 128.0, 128.2, 128.3, 128.4, 128.5, 129.2, 129.3 (Ar,

A and B), 131.6 (Me₃SiCHdCH, B), 132.1 (Me₃SiCHdCH, A),

134.0 (Ar-ipso, A), 134.2 (Ar-ipso, B), 136.2 (Ar-ipso, B), 139.1

(Ar-ipso, A), 143.9 (CHdCH, A), 145.4 (CHdCH, B), 165.9

(NCdO, B), 166.1 (NCdO, A); IR 3010, 2955, 1652,; CIMS 464

(5), 351 (15), 350 (72), 189 (100); HRMS 464.2211; C₂₅H₃₄

NSiF₃O₂requires 464.2222.

-

(4S)-N-Ben zyl-N-[(tr im eth ylsilyl)m eth yl]-N-[1(Z)-(tr i-

m eth ylsilyl)-1-p en ten -4-yl]a m in e (42). A solution of amine

40 (1.5 g, 6.03 mmol), (iodomethyl)trimethylsilane (6.5 g, 30

mmol) and K₂CO₃(3.3 g, 30 mmol) in MeCN (25 mL) was

stirred at reflux for 48 h, cooled to 25 °C, and partitioned

between water and ether. The ethereal layer was washed with

brine, dried, and concentrated in vacuo to provide a residue

which was subjected to column chromatography (Florisil, 20%

ether-hexane) to give 42 (1.07 g, 53%): [R]²⁵_D+27.1° (c 0.057,

CHCl₃). ¹H NMR 0.05 (s, 9 H, SiMe₃), 0.02 (s, 9 H, SiMe₃),

0.91 (d, J ) 6.5, 3 H, NCHCH₃), 1.92 and 1.88 (ABq, J ) 14.8,

2 H, NCH₂Si), 2.05 (m, 1 H, NCHCH), 2.20 (m, 1 H, NCHCH),

2.70 (m, 1 H, NCH), 3.39 and 3.61 (ABq, J ) 14.0, 2 H, NCH₂-

Ph), 5.46 (d, J ) 14.1, 1 H, CHdCH), 6.28 (m, 1 H, CHdCH),

7.15-7.23 (m, 5 H, Ar); ¹³C NMR -1.4 (SiMe₃), 0.2 (SiMe₃),

12.9 (NCHCH₃), 37.0 (NCH₂SiMe₃), 40.3 (NCHCH₂), 55.7

(NCH), 56.8 (NCH₂Ph), 126.5 (CHdCH), 128.0, 128.5129.2

(Ar), 141.0 (Ar-ipso), 147.5 (CHdCH); IR 3027, 2957, 1640;

CIMS 334 (M + 1, 14), 318 (32), 220 (100); HRMS 334.2388,

C

₁₉H₃₆NSi₂requires 334.2386.

CTAN Oxid a tion of Am in ovin ylsila n e 42. P r ep a r a tion

1388; CIMS 402 (M + 1, 2), 288 (100); HRMS 402.1959, C₂₂H₃₂

-

of Dim eth yltetr a h yd r op yr id in e 43. To a solution of ami-

novinylsilane 42 (100 mg, 0.3 mmol) in MeCN (5 mL) was

added (ⁿBu₄N)₂Ce(NO₃)₆(270 mg, 0.3 mmol) in anhydrous

MeCN (5 mL). After stirring at 25 °C for 6 h, another 1 equiv

of (ⁿBu₄N)₂Ce(NO₃)₆was added, and the resulting mixture was

stirred for 12 h, diluted with satd NaHCO₃, and extracted with

ether. The extracts were washed with brine and concentrated

in vacuo to give a residue which was subjected to preparative

TLC (50% ether-hexanes) to afford 34 mg (61%) of 43: [R]²⁵

+56° (c 0.02, CHCl₃). ¹H NMR 1.08 (d, J ) 6.5, 3 H, Me), 1.86

(m, 1 H, NCHCH), 2.30 (m, 1 H, NCHCH), 2.95 (m, 2 H,

CH₂N), 3.45 and 3.78 (ABq, J ) 13.3, 2 H, NCH₂Ph), 5.64 (m,

2 H, CHdCH), 7.27 (m, 5 H, Ar-H); ¹³C NMR 14.5 (Me), 32.6

(C-5), 48.9 (NCH₂Ph), 51.0 (C-6), 57.9 (C-2), 124.1, 124.9

(vinyl), 126.8, 128.2, 128.8 (Ar), 139.4 (Ar-ipso); IR 3028, 2962,

2923, 2793; EIMS 187 (8), 172 (28), 134 (69), 132; HRMS

187.1362, C₁₃H₁₇N requires 187.1360.

En a n tiom er ic P u r ity Deter m in a tion of 43. P r ep a r a -

tion of Mosh er Am id e 45. To a stirred suspension of 43 (110

mg, 0.54 mmol) and 10% Pd/C (110 mg) in dry methanol (3

mL) was added anhydrous ammonium formate (64 mg, 5.4

mmol). The resulting reaction mixture was stirred at reflux

for 10 min and filtered, and the filtrate was concentrated in

vacuo to afford 15 mg of 2,6-methyl-1,2,5,6-tetrahydropyridine

(44) whose spectroscopic properties matched those of the

commercial (Aldrich) substance.

NOSSi requires 402.1950.

A solution of this substance (750 mg, 1.88 mmol) in

anhydrous MeOH (100 mL) containing 6% Na/Hg (7.2 g) and

Na₂HPO₄(1.6 g, 7.62 mmol) was stirred at reflux for 12 h,

poured into water, decanted, and extracted with CH₂Cl₂. The

extracts were washed with aqueous satd NaHCO₃and brine,

dried, and concentrated in vacuo to provide a residue which

was subjected to flash column chromatography (silica, 20%

ether-hexanes) to give 40 (371 mg, 80%): [R]²⁵-17.7° (c 0.025,

1

CHCl₃); H NMR 0.10 (s, 9 H, SiMe₃), 1.08 (d, J ) 6.3, 3 H,

NCHCH₃), 1.58 (br singlet, 1 H, NH), 2.26 (m, 2 H, NCHCH₂),

2.75 (tq, J ) 6.3, 6.3, 1 H, NCH), 3.67 and 3.89 (ABq, J )

13.0, 2 H, NCH₂Ph), 5.57 (d, J ) 14.4, 1 H, Me₃SiCHdCH),

6.26 (ddd, J ) 7.2, 7.2, 14.4, 1 H, Me₃SiCHdCH), 7.30 (m, 5

H, Ar); ¹³C NMR 0.2 (SiMe₃), 20.2 (CH₃), 40.7 (NCHCH₂), 51.4

(NCH₂Ph), 52.6 (NCH), 126.8, 128.0, 128.4 (Ar), 131.4 (CHdCH),

140.7 (Ar-ipso), 145.6 (CHdCH); IR 3085, 3062, 3027, 2958,

2896, 1605; CIMS 338 (M + 1, 9), 134 (100); HRMS 248.1830,

C

₁₅H₂₆NSi requires 248.1835.

En a n tiom er ic P u r ity Deter m in a tion of 40. P r ep a r a -

tion of Mosh er Am id e 41. A mixture of (R)-MTPAcCl

(prepared by refluxing 150 mg of (R)-MTPAcOH and excess

thionyl chloride followed by removal of excess thionyl chloride

in vacuo), 40 (30 mg, 0.12 mmol), 4-DMAP (30 mg, 0.24 mmol),

and pyridine (0.5 mL) in CCl₄(3 mL) was stirred at reflux for

12 h, cooled to 25 °C, diluted with satd NaHCO₃, and extracted

with ether. The extracts were washed with brine, dried, and

concentrated in vacuo. The resulting residue was subjected

to preparative TLC (50% ether-hexanes) to give 20 mg (33%)

of the desired Mosher amide 41. The amine 40 was shown to

have an ee >99% by capillary GC and 400 MHz NMR analysis

of 41: ¹H NMR (2:1 mixture of rotamers A and B) -0.02 (s, 9

H, SiMe₃, A) 0.02 (s, 9 H, SiMe₃, B), 0.26 (d, J ) 6.7, 3 H,

NCHCH₃, A), 1.18 (d, J ) 6.8, 3 H, NCHCH₃, B), 2.10-2.25

(m, 2 H, NCHCH_a, A and B), 2.45 (m, 1 H, NCHCH₃, B), 2.74

(m, 1 H, NCHCH₃, B), 3.49 (m, 1 H, NCHCH_b, A), 3.74 (m, 6

H, OCH₃, A and B), 4.23 (m, NCHCH₃, 1 H, A), 4.84, 4.22 (ABq,

J ) 15.4, 2 H, NCH₂Ph, A), 4.72, 4.25 (AB, J ) 15, 2 H, NCH₂-

Ph, B), 5.48 (d, J ) 14.2, 1 H, Me₃SiCHdCH, A), 5.50 (d, J )

14.2, 1 H, Me₃SiCHdCH, B), 5.92 (ddd, J ) 5.0, 9.0 and 14.2,

1 H, Me₃SiCHdCH, A), 6.12 (ddd, J ) 7.1, 7.1 and 14.2, 1 H,

Me₃SiCHdCH, B), 6.60-7.78 (m, 10 H, Ar-H, A and B); ¹³C

NMR -0.03 (SiMe₃, A), 0.03 (SiMe₃, B), 16.5 (NCHCH₃, A),

16.7 (NCHCH₃, B) 37.8 (Me₃SiCHdCHCH₂, B), 40.6 (Me₃-

SiCHdCHCH₂, A), 45.5 (NCH₂Ph, A), 50.9 (NCH₂Ph, B), 52.4

A mixture of (R)-MTPAcCl (prepared by refluxing 150 mg

of (R)-MTPAcOH in excess thionyl chloride for 5 h), 44 (15

mg), 4-DMAP (30 mg, 0.24 mmol), and pyridine (0.5 mL) in

MeCN (2 mL) was stirred at reflux for 12 h, cooled to 25 °C,

diluted with satd NaHCO₃, and extracted with ether. The

extracts were washed with brine, dried, and concentrated in

vacuo, giving a residue which was subjected to preparative

TLC (50% ether-hexanes) to give 4 mg of the Mosher amide

45. The tetrahydropyridine 43 was shown to have an ee of

1

>98% by capillary GC and H NMR (500 MHz) analysis of the

Mosher amide 45. The assignments and validity of the

1

analysis were supported by comparisons of H NMR spectra

of both 45, and the Mosher amide was prepared from (R)-

MTPAcCl and racemic 2-methylpiperidine.

45: ¹H NMR (mixture of rotamers A/B ) 2:1) 0.28 (d, J )

7.0, 3 H, CH₃, B), 1.18 (d, J ) 7.0, 3 H, CH₃, A), 1.53 (m, 12 H,

A and B), 2.63 (ddd, J ) 3.0, 13.5 and 13.5, 1 H, B), 2.89 (ddd,

J ) 3.0, 10.3 and 10.3, 1 H, A), 3.61 (s, 3 H, OMe, A), 3.76 (s,

3 H, OMe, B). 3.72 (m, 1 H, A), 4.32 (m, 1 H, B), 4.54 (m, 1 H,

B), 5.01 (m, 1 H, A). 7.40 (m, 10 H, Ar, A and B); ¹³C NMR

854 J . Org. Chem., Vol. 63, No. 3, 1998

Wu et al.

14.3, 15.8, 18.3, 18.7, 24.0, 26.2, 29.6, 29.7, 30.9, 36.9, 39.5,

44.4, 47.8, 55.2, 126.8, 126.9, 128.1, 128.2, 129.1, 134.2, 163.9;

IR 3063, 2942, 2867, 1650, 1453, 1428; EIMS 315 (1), 125 (100);

HRMS 315.1456, C₁₆H₂₀NF₃O₂requires 315.1446.

(silica gel, hexane:EtOAc, 20:1) to give 21 mg (60%) of 50: ¹H

NMR 0.01 (s, 9H, TMS), 0.06 (s, 9H, TMS), 0.99 (d, J ) 6.6,

3H, CHCH₃), 1.97 (s, 3H, COCH₃), 1.95 and 2.01 (ABq, J )

14.7, 2H, CH₂TMS), 2.80 (m, 1H, CHCH₃), 3.32 and 3.68 (ABq,

J ) 13.9, 2H, CH₂Ph), 5.40 (dd, J ) 9.4, 9.3, 1H, TMSCHdCH),

5.68 (d, J ) 14.6, 1H, CHOAc), 6.17 (dd, J ) 14.6, 9.4, 1H,

TMSCHdCH), 7.20-7.31 (m, 5H, Ar); ¹³C NMR -1.2 (TMS),

0.00 (TMS), 7.9 (CHCH₃), 21.5 (COCH3), 41.5 (CH₂TMS),

57.7 (NCH₂Ph), 59.0 (CHCH₃), 76.2 (CHOAc), 126.8, 128.1,

128.8, and 140.2 (aromatic), 133.9 (TMSCHdCH), 144.2

(TMSCHdCH), 169.9 (COCH₃); IR 2951, 1731, 1241, 857;

CIMS 394 (M + 1, 1), 220 (100), 91 (82); HRMS 394.2606,

(3R,4S)-1-(Tr im eth ylsilyl)-4-[N-ben zyl-N-[(tr im eth ylsi-

lyl)m eth yl]a m in o]p en t-1-yn -3-ol (46). To a solution of

(trimethylsilyl)acetylene (6.6 mL, 46.0 mmol) in THF (20 mL)

was added BuLi (1.6 M solution, 22 mL, 36.0 mmol) at -78

°C. After stirring for 2 h at -78 °C, a solution of 19 (2.97 g,

12.0 mmol) in THF (10 mL) was added. The resulting solution

was stirred at -78 °C for 4 h, at 25 °C for 1 h, and diluted

with ether and water. The ethereal layer was washed with

brine, dried over anhydrous Na₂SO₄, and concentrated in

vacuo, giving a residue which was subjected to column chro-

matography (silica gel, hexane:EtOAc, 10:1) to give 3.36 g

C

₂₁H₄₀NO₂Si₂requires 394.2598.

CTAN Oxid a tion of Am in ovin ylsila n e 50. P r ep a r a tion

of Tetr a h yd r op yr id in yl Aceta te 53. To a solution of 50 (21

mg, 0.05 mmol) in MeCN (5 mL) was added a solution of

(ⁿBu₄N)₂Ce(NO₃)₆(107 mg, 0.11 mmol) in MeCN (5 mL)

through a cannula. The resulting solution was stirred for 12

h at 25 °C, diluted with CHCl₃, and washed with brine and

water. The CHCl₃layer was dried and concentrated in vacuo,

giving a residue which was subjected to column chromatog-

raphy (silica gel, hexane:ether, 10:1) to give 4 mg (30%) of 53

and 4 mg (25%) of secondary amine 54.

The same reaction was conducted by using CAN (160 mg,

0.029 mmol) as the oxidant and 50 (57 mg, 0.14 mmol) in dry

MeCN (5 mL) for 24 h at 25 °C. Workup and purification in

the same manner gave 25 mg (38%) of 53 and 12 mg (27%) of

54.

1

(79%) of 46 as a single diastereomer: [R]²⁵+9.0° (c 0.15); H

NMR 0.02 (s, 9H, TMS), 0.07 (s, 9H, TMS), 1.02 (d, J ) 6.8,

3H, Me), 1.88 and 2.51 (ABq, J ) 14.8, 2H, CH₂TMS), 2.82

(m, 1H, CH), 3.21 and 3.97 (ABq, J ) 13.3, 2H, PhCH₂), 4.02

(d, J ) 6.0, 1H, CHO), 7.28 (m, 5H, Ar); ¹³C NMR -1.3 (TMS),

-0.2 (TMS), 7.8 (CHCH₃), 41.4 (CH₂TMS), 57.2 (CHCH₃), 58.6

(CH₂Ph), 63.1 (CHOH), 90.7 (CtCTMS), 106.2 (CtCTMS),

127.2, 128.4, and 129.1 (Ar), 139.1 (Ar-ipso); IR 3018, 2960,

2400, 1251, 1216; CIMS 348 (M + 1, 1), 221 (28), 220 (99), 91

(100); HRMS 348.2174, C₁₉H₃₄NOSi₂requires 348.2179.

(3R,4S)-1-(Tr im eth ylsilyl)-4-[N-ben zyl-N-[(tr im eth ylsi-

lyl)m eth yl]a m in o]-1(Z)-p en ten -3-ol (47). A suspension

containing 46 (0.30 mmol) and 5 mg of 5% Pd/C in EtOAc at

-10 °C was evacuated by water aspirator and stirred under a

H₂atmosphere for 3 h, filtered, and concentrated in vacuo,

giving a residue which was subjected to column chromatog-

raphy (silica gel, hexane:EtOAc, 70:1) to give (Z)-allylic alcohol

47 (71%), (E)-allylic alcohol 48 (28%), and saturated product

49 (1%).

53: [R]²⁵-57.4° (c 0.23); ¹H NMR 0.96 (d, J ) 6.8, 3H,

CHCH₃), 2.06 (s, 3H, COCH₃), 2.99 (dq, J ) 6.8, 2.0, 1H,

CHCH₃), 3.59 and 3.76 (ABq, J ) 13.4, 2H, CH₂Ph), 4.91 (br

t, J ) 2.0, 1H, CHCOCH₃), 5.76 (m, 1H, CHdCH), 6.01 (m,

1H, CHdCH), 7.28 (m, 5H, Ar); ¹³C NMR 8.6 (CHCH₃), 21.4

(COCH₃), 47.4 (CH₂N), 54.2 (CHCH₃), 57.7 (NCH₂Ph), 71.8

(CHOCOCH₃), 121.6 (CHdCH), 127.1, 128.3, 128.7, and 138.7

(Ar), 131.8 (CHdCH), 170.9 (COCH₃); IR 2926, 1728, 1454,

1371; CIMS 246 (M + 1, 17), 186 (38), 170 (68), 134 (72), 91

(100); HRMS 246.1503, C₁₅H₂₀NO₂requires 246.1494.

54: [R]²²+9.7° (c 0.17); ¹H NMR 0.13 (s, 9H, TMS), 1.08 (d,

J ) 6.5, 3H, CHCH₃), 2.04 (s, 3H, COCH₃), 2.83 (dq, J ) 3.9,

6.5, 1H, CHCH₃), 3.78 and 3.83 (ABq, J ) 13.2, 2H, CH₂Ph),

5.46 (ddd, J ) 14.6, 3.9, 0.4, 1H, CHOCOCH₃), 5.79 (dd, J )

14.6, 0.4, 1H, CHdCHTMS), 6.21 (dd, J ) 14.6, 9.2, 1H,

CHdCHTMS), 7.28 (m, 5H, Ar); ¹³C NMR 0.1 (TMS), 15.7

(CHCH₃), 21.3 (COCH₃), 51.2 (CH₂Ph), 55.5 (CHCH₃), 76.1

(CHOCOCH₃), 127.0, 128.1, 128.4, and 140.3 (aromatic), 135.3

(CHdCHTMS), 142.4 (CHdCHTMS), 170.1 (COCH3); IR 2916,

1735, 1451, 1235; CIMS 306 (M + 1, 3), 220 (28), 134 (99), 91

(100); HRMS 306.1889, C17H₂₈NO₂Si requires 306.1889.

En a n tiom er ic P u r ity Deter m in a tion of 53. P r ep a r a -

tion of Alcoh ol 55 a n d Mosh er Ester 56. A solution of

piperidine 53 (10 mg, 0.04 mmol) and KCN (1.5 mg, 0.02 mmol)

in MeOH (2 mL) was stirred for 12 h at 25 °C and concentrated

in vacuo. The residue was dissolved in CHCl₃and washed

with brine and water, dried, and concentrated in vacuo giving

a residue which was subjected to column chromatography

1

47: [R]³²+25.8° (c 0.12); H NMR 0.04 (s, 9H, TMS), 0.09

(s, 1H, TMS), 1.00 (d, J ) 6.8, 3H, CH₃), 1.96 and 2.03 (ABq,

J ) 14.8, 2H, CH₂TMS), 2.82 (m, 1H, CHCH₃), 3.29 and 3.74

(ABq, J ) 13.7, 2H, CH₂Ph), 4.03 (m, 1H, CHOH), 5.64 (dd, J

) 14.3, 0.8, 1H, CHdCHTMS), 6.32 (dd, J ) 14.3, 8.6, 1H,

CHdCHTMS), 7.19-7.29 (m, 5H, Ar); ¹³C NMR -1.2 (TMS),

0.5 (TMS), 7.9 (CHCH₃), 42.5 (CH₂TMS), 58.6 (NCH₂Ph), 59.8

(CHCH₃), 73.3 (CHOH), 127.0, 128.3, 128.8, and 139.8 (Ar),

132.1 (TMSCHdCH), 148.1 (TMSCHdCH); IR 2953, 1660,

1605; CIMS 350 (M + 1, 1), 220 (100), 91 (75); HRMS 350.2339,

C

₁₉H₃₆NOSi₂requires 350.2336.

48: [R]²⁵+15.2° (c 0.61); ¹H NMR 0.03 (s, 18H, 2TMS), 1.01

(d, J ) 6.8, 3H, CHCH₃), 1.91 and 2.02 (ABq, J ) 14.7, 2H,

CH₂TMS), 2.85 (dq, J ) 6.8, 4.6, 1H, CHCH₃), 3.25 and 3.75

(ABq, J ) 13.6, 2H, CH₂Ph), 3.89 (m, 1H, CHOH), 5.94 (dd, J

) 18.8, 1.6, 1H, CHdCHCHOH), 6.19 (dd, J ) 18.8, 4.6, 1H,

CHdCHCHOH), 7.12-7.34 (m, 5H, Ar); ¹³C NMR -1.3, and

-1.2 (2TMS), 7.7 (CHCH₃), 42.1 (CH₂TMS), 58.4 (NCH₂Ph),

59.6 (CHCH₃), 74.7 (CHOH), 127.0, 128.3, 128.8, and 139.8

(Ar), 129.3 (CHdCHCHOH), 146.9 (CHdCHCHOH); IR 2954,

1634, 1247.

49: [R]³¹+39.1° (c 0.24); ¹H NMR -0.04 (s, 9H, TMS), 0.04

(s, 9H, TMS), 0.26 (ddd, J ) 13.6, 13.6, 4.3, 1H, TMSCH₂CH₂),

0.60 (ddd, J ) 13.8, 13.8, 4.3, 1H, TMSCH₂CH₂), 0.99 (d, J )

6.7, 3H, CH₃), 1.16 (m, 1H, TMSCH₂CH₂), 1.79 (m, 1H,

TMSCH₂CH₂), 1.94 and 1.98 (ABq, J ) 14.8, 2H, CH₂TMS),

2.54 (dq, J ) 6.7, 6.8, 1H, CHCH₃), 3.32 (m, 1H, CHOH), 3.32

and 3.69 (ABq, J ) 13.7, 2H, CH₂Ph), 7.18-7.30 (m, 5H, Ar);

¹³C NMR -1.8 (TMS), -1.2 (TMS), 7.3 (CH₃), 12.3 (TMSCH₂-

CH₂), 28.6 (TMSCH₂CH₂), 41.8 (CH₂TMS), 58.3 (NCH₂Ph),

59.5 (CHCH₃), 76.3 (CHOH), 126.8, 128.2, 128.8, and 140.4

(Ar); IR 3420, 2953, 1651; EIMS 351 (1), 220 (100), 91 (88);

HRMS 351.2414, C₁₉H₃₇NOSi₂requires 351.2414.

(3R,4S)-1-(Tr im eth ylsilyl)-3-acetoxy-4-[N-ben zyl-N-[(tr i-

m eth ylsilyl)m eth yl]a m in o]-1(Z)-p en ten e (50). A solution

of (Z)-allylic alcohol 47 (31 mg, 0.09 mmol) in CHCl₃(10 mL)

containing Ac₂O (0.01 mL, 0.01 mmol), pyridine (0.01 mL, 0.01

mmol), and 4-DMAP (2 mg) was stirred for 12 h at 25 °C,

diluted with CHCl₃(10 mL), and washed with brine and water.

The CHCl₃layer was dried and concentrated in vacuo, giving

a residue which was subjected to column chromatography

(silica gel, hexane:ether, 1:1) to give 6.5 mg (78%) of 55: [R]²⁶

D

-26.0° (c 0.2); ¹H NMR 0.91 (d, J ) 6.8, 3H, CHCH₃), 2.87

(ddd, J ) 17.7, 1.9, 1.2, 1H, dCHCH₂N), 2.99 (dq, J ) 6.8,

1.9, 1H, CHCH₃), 3.05 (ddd, J ) 17.7, 4.1, 1.9, 1H, dCHCH₂N),

3.64 (s, 2H, CH₂Ph), 3.67 (br s, 1H, CHOH), 5.78 (ddd, J )

9.8, 4.1, 1.9, CHd), 5.86 (dddd, J ) 9.8, 4.0, 1.9, 1.2, 1H,

dCHCHO), 7.22-7.33 (m, 5H, Ar); ¹³C NMR 7.6 (CH₃), 47.4

(CHdCHCH₂N), 57.9 (CHCH₃), 58.8 (CH₂Ph), 68.8 (CHOH),

126.0 (CHd), 127.2 (dCHCHO), 128.4, 128.8, and 138.6 (Ar);

IR 3400, 2953, 2925, 1707, 1454, 1370, 1138; EIMS 203 (11),

134 (51), 91 (100); HRMS 203.1314, C₁₃H₁₇NO requires

203.1310.

To a mixture of piperidine alcohol 55 (20 mg, 0.10 mmol)

and 4-DMAP (2 mg) was added a solution of freshly made (S)-

MTPAcCl (52 mg, 0.20 mmol) in CH₂Cl₂(5 mL). The resulting

solution was treated with Et₃N (0.03 mL, 0.20 mmol) and

stirred for 12 h at 25 °C, diluted with CHCl₃, and washed with

brine and water. The CHCl₃layer was dried and concentrated

in vacuo, giving a residue which was subjected to column

Oxidative Mannich Cyclizations

J . Org. Chem., Vol. 63, No. 3, 1998 855

chromatography (silica gel, hexane:ether, 5:1) to give 40 mg

(95%) of the Mosher ester 56. The enantiomeric purity of 53

was determined to be >90% by analysis of the ¹H NMR

spectrum of 57: ¹H NMR 1.01 (d, J ) 6.8, 3H, CHCH₃), 2.94

and 2.99 (m, 1H, CHdCHCH₂N), 3.04 (m, 1H, CHdCHCH₂N),

3.08 (m, 1H, CHCH₃), 3.57 (s, 3H, OCH₃), 3.52 and 3.67 (ABq,

J ) 13.5, 2H, CH₂Ph), 5.11 (br s, 1H, dCHCHO), 5.86 (dddd,

J ) 10.0, 4.6, 2.5, 2.4, 1H, dCHCH₂N), 6.01 (dddd, J ) 10.0,

3.8, 2.5, 1.7, 1H, CHdCHCH₂N), 7.16-7.24 (m, 5H, Ar), 7.35-

7.38 (m, 3H, Ar), 7.57-7.59 (m, 2H, Ar); ¹³C NMR 9.6 (CHCH₃),

47.1 (dCHCH₂N), 55.1 (CHCH₃), 55.4 (OCH₃), 57.9 (CH₂Ph),

74.5 (dCHCHO), 120.4 (dCHCH₂N), 126.9, 127.4, 128.2, 128.3,

128.5, and 129.5 (Ar), 132.9 (CHd), 166.4 (CdO), 122.0, 124.8,

132.5, and 138.7; EIMS 419 (2), 189 (87), 170 (53), 104 (25),

91 (100); HRMS 419.1714, C₂₃H₂₄NO₃F₃requires 419.1708.

(3R,4S)-1-(Tr im et h ylsilyl)-3-h yd r oxy-4-[N-b en zyl-N-

[(tr im eth ylsilyl)m eth yl]a m in o]-1(E)-p en ten e (48). To a

solution of (E)-1-(trimethylsilyl)-2-(tri-n-butylstannyl)ethene

(1.5 g, 4.20 mmol) in THF (5 mL) was added n-BuLi (1.M in

hexane, 2.3 mL, 3.70 mmol) at -78 °C. The resulting solution

was warmed to 25 °C and stirred for 5 min, cooled to -78 °C,

and treated with aldehyde 19 (0.7 g, 2.80 mmol). The resulting

solution was stirred for 12 h, diluted with CHCl₃, washed with

brine and water, dried, and concentrated in vacuo, giving a

residue which was subjected to column chromatography (silica

gel, hexane:EtOAc, 20:1) to give 794 mg (81%) of 48: [R]²⁵

+15.2° (c 0.61); ¹H NMR 0.03 (s, 18H, 2TMS), 1.01 (d, J ) 6.8,

3H, CHCH₃), 1.91 and 2.02 (ABq, J ) 14.7, 2H, CH₂TMS), 2.85

(dq, J ) 6.8, 4.6, 1H, CHCH₃), 3.25 and 3.75 (ABq, J ) 13.6,

2H, CH₂Ph), 3.89 (m, 1H, CHOH), 5.94 (dd, J ) 18.8, 1.6, 1H,

CHd), 6.19 (dd, J ) 18.8, 4.6, 1H, dCHCHOH), 7.12-7.34 (m,

5H, Ar); ¹³C NMR -1.3, and -1.2 (2TMS), 7.7 (CHCH₃), 42.1

(CH₂TMS), 58.4 (NCH₂Ph), 59.6 (CHCH₃), 74.7 (CHOH), 127.0,

128.3, 128.8, and 139.8 (Ar), 129.3 (CHd), 146.9 (dCHCHOH);

IR 2954, 1634, 1247; CIMS 350 (M + 1, 1), 220 (100), 162 (2),

91 (75); HRMS 350.2339, C₁₉H₃₆NOSi₂requires 350.2336.

(3R,4S)-1-(Tr im eth ylsilyl)-3-acetoxy-4-[N-ben zyl-N-[(tr i-

m eth ylsilyl)m eth yl]a m in o-1(E)-p en ten e (52). A solution

of 48 (270 mg, 0.77 mmol), acetic anhydride (0.15 mL, 1.20

mmol), 4-DMAP (2 mg), and pyridine (0.1 mL, 1.20 mmol) in

CHCl₃(5 mL) was stirred for 12 h at 25 °C, washed with water,

dried, and concentrated in vacuo, giving a residue which was

subjected to column chromatography (silica gel, hexane:EtOAc,

20:1) to give 265 mg (88%) of 52: [R]³¹-22.6° (c 0.31); ¹H NMR

0.02 (s, 9H, TMS), 0.06 (s, 9H, TMS), 0.94 (d, J ) 6.6, 3H,

CHCH₃), 1.94 and 1.99 (ABq, J ) 14.7, 2H, CH₂TMS), 2.04 (s,

3H, COCH₃), 2.78 (dq, J ) 6.6, 8.3, CHCH₃), 3.35 and 3.69

(ABq, J ) 13.8, 2H, CH₂Ph), 5.29 (m, 1H, CHOCOCH₃), 5.73

(dd, J ) 18.8, 1.3, dCHTMS), 6.10 (dd, J ) 18.8, 5.3 Hz,

HCdCHTMS), 7.18-7.34 (m, 5H, Ar); ¹³C NMR -1.3 (TMS),

-1.2 (TMS), 7.9 (CHCH₃), 21.2 (COCH₃), 41.2 (CH₂TMS), 57.5

(NCH₂Ph), 58.4 (CHCH₃), 76.4 (CHOCOCH₃), 126.7, 128.1,

128.7, and 140.2 (Ar), 130.8 (dCHTMS), 143.4 (CHdCHTMS),

170.1 (COCH₃); IR 2955, 1739, 1668, 1373, 1247, 863, 839;

CIMS 392 (M + 1, 3), 220 (100), 134 (22), 91 (24), 73 (86);

HRMS 392.2442, C₂₁H₃₈NO₂SiO₂requires 392.4411.

(3R,4S)-1-(Tr im et h ylsilyl)-3-h yd r oxy-4-[N-b en zoyl-N-

[(tr im eth ylsilyl)m eth yl]a m in o]-1(E)-p en ten e (58). To a

solution of (E)-1-(trimethylsilyl)-2-(tri-n-butylstannyl)ethene

(0.51 g, 1.31 mmol) was added dropwise tert-BuLi (1.4 M in

pentane, 0.81 mL) at -78 °C. The solution was stirred at 25

°C for 2 h. Aldehyde 32 (0.23 g, 0.87 mmol) was added at -78

°C, and the mixture was stirred for 12 h at 25 °C, diluted with

water, and extracted with CH₂Cl₂. The extracts were washed

with brine, dried, and concentrated in vacuo to give a residue

which was subjected to column chromatography (silica gel,

hexanes:EtOAc, 5:1) to afford 0.15 g (47%) of 58: mp 151-

153 °C; [R]²⁰-2.17° (c 2.34, CHCl₃); ¹H NMR 0.05 (s, 9H, TMS),

0.12 (s, 9H, TMS), 1.22 (d, J ) 6.6, 3H, CH₃), 2.45 and 2.85

(ABq, J ) 14.4, 2H, NCH₂), 3.75 (dq, J ) 6.6, 5.0, 1H, CH),

4.00 (s, 1H, CHOH), 5.83 (s, 2H, dCH), 7.29 (m, 5H, Ar); ¹³C

NMR -1.4 (TMS), -0.6 (TMS), 15.1 (CH₃), 34.1 (NCH₂), 58.8

(CH), 76.4 (CHOH), 126.7, 128.5, 129.2, and 137.0 (Ar), 132.1

(CHd), 145.0 (dCH), 171.6 (CdO); IR 3327, 2952, 1592, 1244,

842; EIMS 363 (1), 234 (64), 105 (100); HRMS 363.2051,

C

₁₉H₃₃NO₂Si₂requires 363.2050.

(3R,4S)-1-(Tr im et h ylsilyl)-3-a cet oxy-4-[N-b en zoyl-N-

[(tr im eth ylsilyl)m eth yl]a m in o]-1(E)-p en ten e (59). A so-

lution of alcohol 58 (84 mg, 0.23 mmol), Ac₂O (118 mg, 1.16

mmol), and 4-DMAP (5 mg) in pyridine (2 mL) was stirred at

25 °C for 18 h, diluted with water, and extracted with CH₂-

Cl₂. The extracts were dried and concentrated in vacuo to give

88 mg (95%) of 59 which was used without further purification.

[R]²²-5.29° (c 2.52, CHCl₃); ¹H NMR -0.03 (s, 9H, TMS), 0.11

(s, 9H, TMS), 1.18 (d, J ) 6.7, 3H, CH₃), 1.98 (s, 3H, COCH₃),

2.45 and 2.85 (ABq, J ) 14.5, 2H, NCH₂), 3.95 (dq, J ) 6.7,

6.0, 1H, CH), 5.22 (dd, J ) 6.0, 5.7, 1H, CHO), 5.67 (dd, J )

18.7, 5.7, 1H, CHd), 5.84 (d, J ) 18.7, 1H, dCH), 7.26-7.34

(m, 5H, Ar); ¹³C NMR -1.5 (TMS), -0.6 (TMS), 15.5 (CHCH₃),

21.1 (CH₃), 34.1 (NCH₂), 57.1 (CH), 77.0 (CHOCOCH₃), 126.8,

128.5, 129.4, and 136.8 (Ar), 134.7 (dCH), 139.9 (CHd), 169.6

(COCH₃), 171.7 (NCdO); IR 2954, 1743, 1629, 1232, 840; EIMS

405 (5), 390, 234 (61), 105(100); HRMS 405.2136, C₂₁H₃₅NO₃-

Si₂requires 405.2156.

En a n tiom er ic P u r ity Deter m in a tion of 58. P r ep a r a -

t ion of Mosh er E st er 60. A mixture of 58 (14 mg, 0.037

mmol), 4-DMAP (3 mg), triethylamine (0.03 mL, 0.074 mmol),

and (R)-MTPAcCl (Aldrich) (19 mg, 0.074 mmol) in CH₂Cl₂(3

mL) was stirred for 12 h at 25 °C, diluted with water, and

extracted with CH₂Cl₂. The extracts were washed with brine,

dried, and concentrated, giving a residue which was subjected

to column chromatography (silica gel, hexanes:EtOAc, 5:1) to

give 19 mg (89%) of Mosher ester 60. The alcohol 58 was

1

shown to have an enantiomeric excess of ca. 90% by H NMR

analysis of the 60: ¹H NMR (mixture of diasteromers, A/B )

ca. 10:1); 0.03 (s, 9H, TMS), 0.05 (s, 9H, TMS, B), 0.12 (s, 9H,

TMS, A and B), 1.06 (d, J ) 6.7, 3H, CH₃, B), 1.24 (d, J ) 6.6,

3H, CH₃, A), 2.38 and 2.81 (ABq, J ) 14.2, 2H, NCH₂, B), 2.40

and 2.84 (ABq, J ) 14.5, 2H, NCH₂, A), 3.45 (s, 3H, OCH₃, A

and B), 4.02 (m, 1H, CH, A and B), 5.41 (m, 1H, CHOCO, A

and B), 5.53 (dd, J ) 8.7, 7.1, 1H, CHd, A), 5.63 (dd, J ) 8.7,

7.1, 1H, CHd, B), 5.94 (d, J ) 8.7, 1H, dCH, A), 6.05 (d, J )

8.7, 1H, dCH, B), 7.23-7.39 (m, 10H, Ar, A and B); ¹³C NMR

-2.8 (TMS, B), -1.6 (TMS, A), -1.4 (TMS, B), -0.6 (TMS, A),

15.3 (CH₃, B), 15.7 (CH₃, A), 33.5 (TMSCH₂, B), 33.8 (TMSCH₂,

A), 55.4 (OCH₃, B), 55.6 (OCH₃, A), 56.7 (CH, A), 56.8 (CH,

B), 79.4 (CHOC, B), 79.6 (CHOC, A), 121.7 (CO), 124.6 (CF₃),

126.7, 127. 2, 127.3, 127.8, 128.4, 128.6, 129.6, 129.7, 131.7,

and 136.5 (Ar, A and B), 137.9 (dCH, A and B), 138.6 (dCH,

A and B), 165.6 (CHOCO), 171.6 (NCdO); IR 2944, 1745, 1629,

1241, 1163, 841; EIMS 579 (6), 234 (34), 130 (50), 105 (100);

HRMS 579.2471, C₂₉H₄₀NO₄F₃Si₂requires 579.2448.

CTAN Oxid a tion of Am in ovin ylsila n e 52. P r ep a r a tion

of Secon d a r y Am in e 57. A solution of (Bu₄N)₂Ce(NO₃)₆(1

g, 1.20 mmol) and 52 (231 mg, 0.60 mmol) in dry MeCN (20

mL) was stirred for 12 h at 25 °C and concentrated in vacuo,

giving a residue which was diluted with CHCl₃, washed with

water and brine, and concentrated in vacuo, giving a residue

which was subjected to column chromatography (silica gel,

hexane:EtOAc, 10:1) to give 19 mg (11%) of 57. [R]³²+41.6°

(c 0.25); ¹H NMR (CD₃CN) 0.02 (s, 9H, TMS), 1.47 (d, J ) 7.0,

3H, CH₃), 1.97 (s, 3H, COCH₃), 4.53 and 4.95 (ABq, J ) 15.2,

2H, CH₂Ph), 4.64 (dq, J ) 5.1, 7.0, 1H, CHCH₃), 5.49 (dd,

J ) 5.1, 4.3, 1H, CHOCO), 5.91 (s, 1H, TMSCHd), 5.93 (d,

J ) 4.3, 1H, TMSCHdCH), 7.08 (m, 2H, Ar), 7.24-7.37 (m,

3H, Ar); ¹³C NMR (CD₃CN) -1.5 (TMS), 15.3 (CHCH₃),

21.1 (COCH₃), 48.5 (CH₂PH), 61.9 (CHCH₃), 77.6 (CHCO),

128.3, 128.4, 129.6, and 136.2 (Ar), 134.8 (TMSCHd), 141.1

(TMSCHdCH), 170.5 (COCH₃); IR 2955, 1746, 1446, 1372;

EIMS 304 (M - 1, 6), 134 (61), 91 (100), 75 (33); HRMS

305.1816, C₁₇H₂₇NO₂Si requires 305.1811.

CAN Oxid a tion of 59. P r ep a r a tion of Tetr a h yd r op y-

r id in yl Aceta te 66. A solution of CAN (325 mg, 0.59 mmol)

and 59 (80 mg, 0.20 mmol) in MeCN (3 mL) was stirred for 24

h at 25 °C, diluted with 2-propanol and water, and extracted

with CH₂Cl₂. The extracts were washed with brine, dried, and

concentrated to give a residue which was subjected to column

chromatography (silica gel, hexanes:EtOAc, 3:1) to provide 18

1

mg (43%) of 66. [R]²⁵+6.57° (c 0.65, CHCl₃); H NMR 1.14

D

(d, J ) 6.5, 3H, CH₃), 2.02 (s, 3H, CH₃), 3.61 (d, J ) 19.9, 1H,

856 J . Org. Chem., Vol. 63, No. 3, 1998

Wu et al.

CH₂N), 4.04 (dq, J ) 6.5, 6.0, 1H, CH), 4.86 (s, 1H, CHO), 4.95

(d, J ) 19.9, 1H, CH₂N), 4.87 (m, 1H, dCH), 6.12 (m, 1H,

dCH), 7.30 (m, 5H, Ar); ¹³C NMR 15.9 (CH₃), 21.0 (CH₃), 38.2

(NCH₂), 52.6 (CH), 69.4 (CHO), 120.4 (dCH), 126.6 128.5,

129.6, and 136.1 (Ar), 130.0 (CHd), 170.1 (COCH₃), 171.3

(NCdO); IR 1729, 1625, 1418, 1233; EIMS 259 (1), 105 (100),

77 (34); HRMS 259.1200, C₁₅H₁₇NO₃requires 259.1209.

En a n tiom er ic P u r ity Deter m in a tion of 66. P r ep a r a -

tion of Tetr a h yd r op yr id in yl Alcoh ol 55 a n d Mosh er

Ester 56. To a solution of 66 (22 mg, 0.085 mmol) in Et₂O (2

mL) at 0 °C was added LiAlH₄(10 mg, 0.255 mmol). The

mixture was stirred at 25 °C and for 4 h, diluted with H₂O,

and extracted with Et₂O. The extracts were washed with

brine, driedn and concentrated in vacuo to give 14 mg (82%)

of alcohol 55. A solution of 55 (7 mg, 0.035 mmol), 4-DMAP

(1 mg), (R)-MTPAcCl (Aldrich) (18 mg, 0.069 mmol), and

triethylamine (0.010 mL, 0.069 mmol) in CH₂Cl₂(3 mL) was

stirred at 25 °C for 21 h, diluted with H₂O, and extracted with

CH₂Cl₂. The extracts were washed with 5% HCl, satd NaH-

CO₃, and H₂O, dried, and concentrated to provide 14 mg of

the Mosher ester 56 as an ca. 95:5 diastereomeric mixture (90

29.6 (CH₂), 33.0 (NCH₂), 61.3 (CH), 74.2 (CHOAc), 135.0

(dCH), 137.9 (TMSCHd), 169.6 (CH₃CO), 174.2 (NCO); IR

2954, 2900, 1744, 1685, 1231, 842; CIMS 342 (M + 1, 3), 170

(100); HRMS 342.1938, C₁₆H₃₁O₃NSi₂requires 342.1921.

CAN Oxid a tion of Vin ylsila n e 63. P r ep a r a tion of

Acetoxyin d olizid in on e 67. To a solution of CAN (472 mg,

0.86 mmol) in MeCN (1 mL) was added a solution of acetoxy-

vinylsilane 63 (91 mg, 0.27 mmol) in MeCN (2 mL). The

resulting mixture was stirred at 25 °C for 2 d, diluted with

2-propanol and water, and extracted with CH₂Cl₂. The

extracts were dried and concentrated in vacuo to provide a

residue which was subjected to column chromatography (silica

gel, 100% Et₂O to 3:2 Et₂O/acetone) (resulting in significant

product loss) to provide 13 mg (25%) of indolizidine 67: [R]²⁷

1

+190° (c 0.003, CHCl₃); H NMR 1.86 (m, 1 H, CH₂), 2.03 (s,

3 H, CH₃OCO), 2.16 (m, 1 H, CH₂), 2.42 (m, 2 H, CH₂), 3.53

and 4.42 (ABq, J ) 18.8, 2 H, NCH₂), 3.83 (ddd, J ) 3.0, 3.6,

and 8.6, CH), 5.15 (q, J ) ca. 3, 1 H, CHOAc), 6.12 (d, J ) 3.1,

2 H, dCH); ¹³C NMR 19.8 (CH₂), 21.0 (CH₃CO), 30.1 (CH₂),

40.2 (NCH₂), 55.9 (C₂CH), 67.0 (CHOAc), 123.0 (CHd), 130.1

(dCH), 170.6 (OCO), 174.4 (NCO); IR 3234, 3090, 3035, 1934,

1854, 1618; EIMS 195 (M, 2), 155 (24), 126 (25), 84 (100);

HRMS 195.0886, C₁₀H₁₃NO₃requires 195.0895.

En a n tiom er ic P u r ity Deter m in a tion of 67. P r ep a r a -

tion of Alcoh ol 68 a n d Mosh er Ester 69. A mixture of

acetoxyindolizidone 67 (6 mg, 0.03 mmol) and KCN (2 mg, 0.03

mmol) in MeOH (2 mL) was stirred at 25 °C for 18 h and

concentrated in vacuo providing a residue which was triturated

with acetone. The triturate was concentrated in vacuo to

provide 3 mg (60%) of hydroxyindolizidine 68: [R]²⁶+66° (c

0.002, CHCl₃); ¹H NMR 2.12 (m, 1 H, CH₂), 2.28 (m, 1 H, CH₂),

2.36 (m. 1 H, CH₂), 2.50 (m, 1 H, CH₂), 3.53 (d, J ) 19.7, 1 H,

CH₂), 3.68 (ddd, J ) 8.9, 4.2, 2.4, 1 H, CH), 3.98 (dd, 1 H, J )

5.1, 2.4, CHOH), 4.38 (ddd, J ) 19.7, 3.2, 2.7, 1 H, NCH₂),

5.92 (ddd, J ) 9.6, 3.2, 1.9, CHd), 6.10 (m, 1 H, dCH); ¹³C

NMR 19.0 (CH₂), 29.7 (CH₂), 40.3 (NCH₂), 58.0 (CH), 64.9

(CHOH), 127.1 (CHd), 128.2 (dCH), 175.4 (NCO); IR 3373,

2929, 2840, 1687, 1679, 1650; EIMS 153 (M, 7), 84 (100);

HRMS 153.0783, C₈H₁₁NO₂requires 153.0790.

1

ee%) based upon H NMR analysis. Subjection of this material

to column chromatography (silica gel, hexane:EtOAc, 6:1) did

not alter the diastereomeric ratio and gave pure 56 Mosher

ester (11 mg, 77%).

(5S,6R)- a n d (5S,6S)-1-[(Tr im eth ylsilyl)m eth yl]-5-[3-

h yd r oxy-1-(t r im et h ylsilyl)-1(E)-p r op en -3-yl]-2-p yr r oli-

d on e 62 a n d 64. To a solution of (E)-1-(trimethylsilyl)-2-(tri-

n-butylstannyl)ethylene (4.4 mL, 4.6 g, 12 mmol) in THF (10

mL) at -78 °C was added n-BuLi (7.5 mL of 1.6 M hexane

solution). The mixture was stirred at -78 °C for 2 h and at

25 °C for 11 h and cooled to -78 °C, and aldehyde 61 (1.1 g,

5.5 mmol) in THF (20 mL) was added. The mixture was

stirred at 25 °C for 15 h, diluted with water, and extracted

with CH₂Cl₂. The extracts were washed with brine and water,

dried, and concentrated in vacuo to give a residue which was

subjected to column chromatography (silica gel, ether:acetone,

4:1) to provide 495 mg (30%) of 62 and 150 mg (9%) of 64.

62: mp 133-134 °C, Et₂O/hexane; [R]²²-11.5° (c 0.012,

1

CHCl₃); H NMR 0.03 (s, 9 H, Si(CH₃)₃), 1.93 (m, 2 H, CH₂),

A solution of 100 mg (0.40 mmol) of (R)-MTPAcCl (Aldrich),

4-DMAP (4 mg, 0.03 mmol), and indolizidine 68 (3 mg, 0.02

mmol) in 1:1 CH₃CN-pyridine (1 mL) was stirred at 75 °C

for 12.5 h, cooled to 25 °C, diluted with satd NaHCO₃, and

extracted with Et₂O. The extracts were washed with brine,

dried, and concentrated in vacuo to provide a 4:1 mixture (63%

de) of (R)-Mosher esters 69 (¹H NMR analysis). Subjection to

preparative TLC (silica, Et₂O:acetone, 4:1) provided 7 mg (97%)

of 69 again as a 4:1 diastereomeric mixture: [R]²⁶-8.3° (c

0.003, CHCl₃); ¹H NMR (mixture of (R)-Mosher diastereomers

A/B) 1.1 (m, 2 H, CH₂, A and B), 2.17 (m, 2 H, CH₂, A and B),

2.25 (m, 4 H, CH₂, A and B), 3.36 (d, J ) 0.9, 3 H, OCH₃, A),

3.42 (buried signal, 1 H, NCH₂, B), 3.49 (d, J ) 1.4, 3 H, OCH₃,

B), 3.54 (d, J ) 19.6, 1 H, NCH₂, A), 3.83 (ddd, J ) 7.4, 4.4, 3,

1 H, CH, B), 3.87 (ddd, J ) 8.8, 3.9, 2.9, 1 H, CH, A), 4.37

(ddd, J ) 19.6, 3.2, 1 Hz, 1 H, NCH₂, A), 4.44 (ddd, J ) 20.6,

3, 1, 1 H, NCH₂, B), 5.21 (ddd, J ) 5.9, ca. 3, 1, 1 H, CHOCO,

B), 5.27 (ddd, J ) 7.3, 2.9, 1, 1 H, CHOCO, A), 6.10 (m, 2 H,

NCH₂CH, A and B), 6.16 (m, 2 H, CH, A and B), 7.40 (m, 6 H,

Ar, A and B), 7.45 (m, 4 H, Ar, A and B); ¹³C NMR 19.8 (CH₂,

A), 19.9 (CH₂, B), 29.3 (CH₂, B), 29.4 (CH₂, A), 40.1 (NCH₂, A

and B), 55.1 (CH, A and B), 55.6 (OCH₃, A), 55.7 (OCH₃, B),

69.8 (CHOCO, B), 70.0 (CHOCO, A), 121.8 (NCH₂CHd, A),

122.1 (NCH₂CHd, B), 126.8 (NCH₂CHCH, B), 127.7 (NCH₂-

CHCH, A), 128.4 (B), 128.6 (A), 129.8 (A and B), 131.7 (A),

131.8 (B), 131.3 (A and B), 166.4 (OCO, A), 168.8 (OCO, B),

174.1 (NCO, B), 174.2 (NCO, A); IR 2954, 2849, 1755, 1729,

1695, 1654; EIMS 369 (2), 189 (100), 135 (24); HRMS 369.1183,

2.19 (m, 2 H, CH₂), 2.44 and 3.26 (ABq, J ) 15.3, and 2), 2.58

(s, 1 H, OH), 3.67 (ddd, J ) 5.3, 4.1, and 2.9, 1 H, CH), 4.31

(d, J ) 4.1, 1 H, CHOH), 5.97 (s, 2 H, CHdCH); ¹³C NMR -1.3

(Si(CH₃)₃), -1.5 (Si(CH₃)₃), 20.0 (CH₂CH₂CH), 29.9 (CH₂CH₂-

CH), 33.4 (NCH₂Si), 63.4 (CH₂CH₂CH), 74.2 (CHOH), 132.6

(CHdCH), 143.6 (CHdCH), 174.6 (NCO); IR 3220, 2994, 2955,

2898, 1652; CIMS 300 (M + 1, 0.8), 170 (100); HRMS 300.1788,

C

₁₄H₂₉O₂NSi₂requires 300.1815.

64: mp 124-126 °C, Et₂O/acetone; [R]²²-13° (c 0.035,

1

CHCl₃); H NMR 0.06 (s, 9 H, TMS), 0.08 (s, 9 H, TMS), 1.69

(s, 1 H, OH), 1.85 (m, 1 H, CH₂), 1.95 (m, 1 H, CH₂), 2.123 (m,

1 H, CH₂), 2.40 (m, 1 H, CH₂), 2.37 and 3.33 (ABq, J ) 15.2,

2 H, NCH₂), 3.56 (ddd, J ) 9.3, 3.8, 2.1, 1 H, CH), 4.48 (dd, J

) 4.3 and 2.1, 1 H, CHOH), 5.92 (dd, J ) 18.9 and 4.3, 1 H,

dCH), 6.04 (dd, J ) 18.9 and 1.3, 1 H, TMSCH); ¹³C NMR

-1.4 (TMS), -1.3 (TMS), 17.9 (CH₂), 30.1 (CH₂), 32.0 (NCH₂),

63.7 (CH), 71.5 (CHOH), 132.4 (dCH), 143.5 (TMSCHd), 175.1

(NCO); IR 3322, 2954, 2896, 1651; CIMS 300 (M + 1, 2), 170

(100); HRMS 300.1813, C₁₄H₂₉O₂NSi₂requires 300.1815.

(5S,6R)-1-[(Tr im eth ylsilyl)m eth yl]-5-[3-a cetoxy-1-(tr i-

m eth ylsilyl)-1(E)-p r op en -3-yl]-2-p yr r olid on e (63). A solu-

tion of hydroxy-vinylsilane 62 (50 mg, 0.17 mmol), 4-DMAP

(10 mg, 0.08 mmol), and acetic anhydride (0.20 mL, 0.22 g,

2.1 mmol) in pryridine (4 mL) was stirred at 25 °C for 16 h,

diluted with water, and extracted with CH₂Cl₂. The extracts

were washed with water, dried, and concentrated in vacuo to

provide a residue which was subjected to column chromatog-

raphy (silica gel, Et₂O:hexane, 1:3) to yield 45 mg (79%) of

C

₁₈H₁₈NO₃F₃requires 369.1182.

1

acetoxy-vinylsilane 63: [R]²³-7.3° (c 0.06, CHCl₃); H NMR

(Tr im eth ylsilyl)m eth yl N-[(Tr im eth ylsilyl)m eth yl]ser i-

0.01 (s, 9 H, TMS), 0.05 (s, 9 H, TMS), 1.96 (m, 2 H, CH₂),

2.07 (s, 3 H, CH₃CO), 2.18 (m, 2 H, CH₂), 2.36 and 3.26 (ABq,

J ) 15.3, 2 H, NCH₂Si), 3.68 (ddd, J ) 8.1, 3.1, and 2.9, 1 H,

CH), 5.44 (dd, J ) 4.6 and 3.1, 1 H, CHOH), 5.83 (dd, J )

18.8 and 4.6, 1 H, dCH), 5.91 (d, J ) 18.8, 1 H, TMSCHd);

¹³C NMR -1.6 (TMS), -1.4 (TMS), 19.6 (CH₂), 21.1 (CH₃CO),

n a te (70). To a slurry of ^D-serine (5.25 g, 50 mmol) and K₂-

CO₃(6.91 g, 50 mmol) in anhydrous DMF (150 mL) at 100 °C

was added (trimethylsilyl)methyl iodide (21.4 g, 100 mmol).

After stirring at 100 °C for 17 h, the reaction mixture was

cooled to 25 °C, filtered, diluted with 5% NaHCO₃, and

extracted with Et₂O. The extracts were washed with brine,

Oxidative Mannich Cyclizations

J . Org. Chem., Vol. 63, No. 3, 1998 857

dried, and concentrated in vacuo to give a residue which was

subjected to flash column chromatography (silica gel, hexane:

EtOAc, 4:1) providing 70 (4.29 g, 31%): [R]²⁶+0.71° (c 0.05,

°C was added oxalyl chloride (0.72 mL, 8.21 mmol). After

stirring the resulting mixture at -78 °C for 1 h, a solution of

alcohol 73 (2.16 g, 5.48 mmol) in CH₂Cl₂(10 mL) was added,

and the resulting mixture was stirred at -78 °C for 2.5 h,

diluted with triethylamine (3.82 mL, 27.4 mmol), stirred at

25 °C for 2.5 h, diluted with H₂O, and extracted with CH₂Cl₂.

The extracts were washed with brine, dried, and concentrated

in vacuo to provide aldehyde 74 (2.11 g, 98%, ca. 85% pure by

¹H NMR) which was used without purification: ¹H NMR

(mixture of rotamers A/B ) 2:1) 0.11 (s, 9H, TMS, A and B),

0.13 (s, 6H, Si(CH₃)₂, A and B), 0.87 (s, 9H, C(CH₃)₃, A), 0.92

(s, 9H, C(CH₃)₃, B), 2.62 and 2.72 (ABq, J ) 14.5, 2H, NCH₂,

A), 3.08 and 3.25 (ABq, J ) 14.6, 2H, NCH₂, B), 4.20 (m, 3H,

CH₂O and CHN, A and B), 7.41 (m, 5H, Ar, A and B), 9.55 (s,

1H, CHO, A), 9.59 (s, 1H, CHO, A); ¹³C NMR -5.6 (Si(CH₃)₂,

A and B), -1.7 (TMS, B), -0.7 (TMS, A), 18.4 (C(CH₃)₃, A and

B), 25.8 (C(CH₃)₃, A and B), 36.6 (NCH₂, A), 43.9 (NCH₂, B),

60.0 (CH₂O, A), 60.8 (CH₂O, B), 69.5 (CHN, B), 70.5 (CHN,

A), 127.1, 128.5, 129.7, and 135.5 (Ar, A and B), 170.3 (NCdO,

B), 172.7 (NCdO, A), 195.9 (CHO, B), 1985.7 (CHO, A); EIMS

393 (M, 10), 378 (37), 206 (28), 105 (100); HRMS 393.2159,

1

CHCl₃); H NMR 0.04 (s, 9H, TMS), 0.06 (s, 9H, TMS), 1.95

and 2.05 (ABq, J ) 13.2, 2H, NCH₂TMS), 3.29 (dd, J ) 7.1,

4.5, 1H, CHNH), 3.49 (dd, J ) 10.5, 7.1, 1H, CH₂OH), 3.75

(dd, J ) 10.5, 4.5, 1H, CH₂OH), 3.79 and 3.88 (ABq, J ) 14.1,

2H, TMSCH₂O); ¹³C NMR -3.2 (TMS), -2.8 (TMS), 38.3

(NCH₂TMS), 58.4 (TMSCH₂O), 61.8 (CH₂OH), 66.4 (CHNH),

173.6 (NCdO); IR 3431, 2955, 2901, 1730, 1244, 1169, 850;

FABMS 278 (M + 1, 100), 246 (2), 190 (1); HRMS 277.1535,

C

₁₁H₂₇O₃Si₂N requires 277.1530.

(Tr im eth ylsilyl)m eth yl N-[(Tr im eth ylsilyl)m eth yl]-O-

(ter t-bu tyld im eth ylsilyl)ser in a te (71). To a solution of

primary alcohol 70 (0.44 g, 1.59 mmol) in DMF (2 mL) were

added imidazole (0.27 g, 3.98 mmol) and tert-butyldimethylsilyl

chloride (0.29 g, 1.91 mmol) at 25 °C. The resulting mixture

was stirred at 25 °C for 18 h, diluted with water, and extracted

with CH₂Cl₂. The combined organic extracted was washed

with brine, dried over MgSO₄, and concentrated in vacuo to

give a residue which was subjected to column chromatography

(silica gel, hexane:EtOAc, 5:1) to provide 0.54 g (100%) product

71: [R]²²_D+1.43° (c 0.09, CHCl₃); ¹H NMR 0.00 (s, 3H, SiCH₃),

0.01 (s, 3H, SiCH₃), 0.02 (s, 9H, TMS), 0.06 (s, 9H, TMS), 0.84

(s, 9H, C(CH₃)₃), 1.92 and 2.07 (ABq, J ) 13.1 Hz, 2H, NCH₂-

TMS), 3.26 (t, J ) 4.8 Hz, 1H, CHN), 3.78 (d, J ) 4.8 Hz, 2H,

CH₂OTBDMS), 3.79 (s, 2H, TMSCH₂O); ¹³C NMR -5.5 (Si-

(CH₃)₂), -3.0 (TMS), -2.7 (TMS), 18.2 (C(CH₃)₃), 25.8 (C(CH₃)₃),

38.1 (NCH₂TMS), 57.7 (TMSCH₂O), 64.2 (CH₂OTBDMS), 67.0

(CHN); IR 3389 (br), 2956, 2840, 1733, 1464, 1242, 1110; CIMS

m/z 392 (M + 1, 12), 376 (18), 362 (21), 334 (20), 261 (25), 260

(100), 246 (72); HRMS 392.2462, C₁₇H₄₂NO₃Si₃requires

392.2473.

C

₂₀H₃₅NO₃Si₂requires 393.2156.

En a tiom er ic P u r ity Deter m in a tion of 74. P r ep a r a tion

of Alcoh ol 73 a n d Its Mosh er Ester . A solution of aldehyde

74 (72 mg, 0.183 mmol) and NaBH₄(10 mg, 0.275 mmol) in

absolute ethanol (1 mL) was stirred at 25 °C for 5 h, diluted

with H₂O, and extracted with CH₂Cl₂. The extracts were

washed with brine, dried, and concentrated in vacuo to provide

67 mg (92%) of alcohol 73. A solution of 73 (32 mg, 0.081

mmol), 4-DMAP (1 mg), and triethylamine (0.055 mL, 0.396

mmol) and (R)-MTPAcCl (100 mg, 0.396 mmol) in CH₂Cl₂(3

mL) was stirred at 25 °C for 18 h, diluted with H₂O, and

extracted with CH₂Cl₂. The extracts were washed with 5%

HCl, saturated aqueous NaHCO₃, and H₂O, dried, and con-

centrated to provide 41 mg (84%) of the (R)-Mosher ester

(Tr im eth ylsilyl)m eth yl N-[(Tr im eth ylsilyl)m eth yl]-N-

ben zoyl-O-(ter t-bu tyld im eth ylsilyl)ser in a te (72). To a

solution of 71 (2.08 g, 5.31 mmol) and triethylamine (0.50 mL,

5.31 mmol) in CH₂Cl₂(50 mL) at 0 °C was added benzoyl

chloride (0.62 mL, 5.31 mmol), and the resulting mixture was

stirred at 0 °C for 15 min, diluted with H₂O, and extracted

with CH₂Cl₂. The extracts were washed with brine, dried, and

concentrated in vacuo to give a residue which was subjected

to flash column chromatography (silica gel, hexane:EtOAc, 4:1)

1

diastereomer as a 85:15 mixture (70% ee) based upon H NMR

integration. Subjection of this substance to column chroma-

tography (silica gel, hexane:EtOAc, 5:1) did not effect the

diastereomeric ratios and gave pure esters: [R]³⁰-12.4° (c

1

9.67, CHCl₃); H NMR (mixture of R-A/B ) 85:15) -0.05 (s,

3H, SiCH₃, A and B), -0.02 (s, 3H, SiCH₃, A and B), 0.07 (s,

9H, TMS, A), 0.12 (s, 9H, TMS, B), 0.83 (s, 9H, C(CH₃)₃, A),

0.87 (s, 9H, C(CH₃)₃, B), 2.55 and 2.69 (ABq, J ) 14.5, 2H,

NCH₂, A), 2.57 and 2.68 (ABq, J ) 14.6, 2H, NCH₂, B), 3.45

(s, 3H, OCH₃, A), 3.51 (s, 3H, OCH₃, B), 3.63 (m, 2H, CH₂O, A

and B), 4.17 (m, 2H, CH₂O, A and B), 4.52 (m, 1H, CHN, A

and B), 7.27 (m, 10H, Ar, A and B); ¹³C NMR -5.7 (Si(CH₃)₂,

A and B), -5.6 (Si(CH₃)₂, A and B), -0.7 (TMS, A), -0.6 (TMS,

B), 18.2 (C(CH₃)₃, A and B), 25.8 (C(CH₃)₃, A and B), 33.4

(NCH₂, B), 33.6 (NCH₂, A), 55.5 (OCH₃, A), 55.7 (OCH₃, B),

58.8 (CHN, B), 59.0 (CHN, A), 61.5 (CH₂O, A), 61.6 (CH₂O,

B), 63.6 (CH₂O, B), 63.7 (CH₂O, A), 121.8 (CCF₃, A and B),

124.7 (CCF₃, A and B), 126.9, 127.0, 127.1, 128.3, 128 5, 128.6,

129.1, 129.2, 129.7, 129.8, 131.8, 132.0, and 136.3 (Ar), 166.4

(OCdO, A), 166.5 (OCdO, B), 172.3 (NCdO, A and B); IR 2952,

2851, 1750, 1628; EIMS 611 (M, 32), 596 (60), 189 (48), 105

(100); HRMS 611.2711, C₃₀H₄₄F₃NO₅Si₂requires 611.2710.

(3S,4R)- a n d (3R,4R)-1-(Tr im eth ylsilyl)-4-[N-[(tr im eth -

ylsilyl)m eth yl]-N-ben zoyla m in o]-5-(ter t-bu tyld im eth yl-

siloxy)-1(E)-p en ten -3-ol (75 a n d 79). To a solution of (E)-

1-(trimethylsilyl)-2-(tri-n-butylstannyl)ethene (4.18 g, 10.7

mmol) in THF (7 mL) was added a hexane solution of n-BuLi

(6.24 mL, 1.55 M) at -78 °C. The resulting solution was

stirred at -78 °C for 1 h and at 25 °C for 3 h and then cooled

again to -78 °C before addition of a solution of aldehyde 74

(2.11 g, 5.37 mmol) in THF (15 mL). The mixture was stirred

at -78 °C for 2 h, at 25 °C for 0.5 h, diluted with H₂O, and

extracted with CH₂Cl₂. The extracts were washed with brine

and H₂O, dried, and concentrated in vacuo to give a residue

containing diastereomeric alcohols 75 and 79 (ca. 3.6:1) which

was subjected to column chromatography (silica gel, hexane:

EtOAc, 8:1) providing 1.24 g (47%) of 75 and 0.35 g (13%) of

79.

to give 1.83 g (88%) of benzamide 72 (11.2 g, 96%): [R]²²

D

1

+0.60° (c 0.04, CHCl₃); H NMR 0.00 (s, 3H, SiCH₃), 0.00 (s,

3H, SiCH₃), 0.05 (s, 9H, TMS), 0.12 (s, 9H, TMS), 0.84 (s, 9H,

C(CH₃)₃), 2.63 (s, 2H, NCH₂), 3.74 and 3.84 (ABq, J ) 14.1,

2H, CH₂O), 3.87 (d, J ) 6.8, 2H, CH₂O), 4.60 (t, J ) 6.8, 1H,

CHN), 7.38 (m, 5H, Ar); ¹³C NMR -5.6 (Si(CH₃)₂), -3.1 (TMS),

-0.7 (TMS), 18.2 (C(CH₃)₃), 25.8 (C(CH₃)₃), 35.0 (NCH₂), 58.8

(CH₂O), 60.4 CH₂O), 64.4 (CHN), 127.4, 128.2, 129.4, and 136.1

(Ar), 169.9 (OCdO), 172.6 (NCdO); IR 2952, 2931, 2858, 1734,

1641; EIMS 495 (M, 37), 480 (88), 438 (30), 348 (25), 206 (84),

105 (100); HRMS 495.2652, C₂₄H₄₅NO₄Si₃requires 495.2657.

(2S)-3-(ter t-Bu t yld im et h ylsiloxy)-2-[N-[(t r im et h ylsil-

yl)m eth yl]-N-ben zoyla m in o]-1-p r op a n ol (73). A solution

of ester 72 (1.02 g, 2.05 mmol) and NaBH₄(0.16 g, 4.20 mmol)

in absolute ethanol (5 mL) was stirred at 25 °C for 6 h, cooled

to 0 °C, diluted with H₂O, and extracted with CHCl₃. The

extracts were washed with brine, dried, and concentrated in

vacuo to give 0.77 g (95%) of alcohol 73 which was used without

further purification. Column chromatography (silica gel,

hexane:EtOAc, 3:1) of this substance gave 73: mp 91-92 °C

(CH₂Cl₂/hexane); [R]²³-2.44° (c 0.05, CHCl₃); ¹H NMR -0.03

(s, 3H, SiCH₃), -0.01 (s, 3H, SiCH₃), 0.13 (s, 9H, TMS), 0.84

(s, 9H, C(CH₃)₃), 2.67 and 2.72 (ABq, J ) 14.5, 2H, NCH₂),

3.60 (m, 4H, CH₂O and CH₂OH), 3.98 (m, 1H, CHN), 7.37 (m,

5H, Ar); ¹³C NMR -5.6 (Si(CH₃)₂), -0.7 (TMS), 18.2 (C(CH₃)₃),

25.8 (C(CH₃)₃), 33.5 (NCH₂), 61.0 (CH₂), 61.7 (CH₂), 61.9

(CHN), 127.2, 128.3, 129.1, and 136.8 (Ar), 172.8 (NCdO); IR

3368, 2951, 2931, 2890, 2857, 1615; EIMS 395 (M, 14), 380

(58), 208 (65), 105 (100); HRMS 395.2316, C₂₀H₃₇NO₃Si₂

requires 395.2312.

(2S)-3-(ter t-Bu t yld im et h ylsiloxy)-2-[N-[(t r im et h ylsil-

yl)m eth yl]-N-ben zoyla m in o]-1-p r op a n ol (74.) To a solu-

tion of DMSO (1.17 mL, 16.4 mmol) in CH₂Cl₂(10 mL) at -78

75: mp 139-141 °C, (CH₂Cl₂/hexane); [R]²⁶+2.48° (c 0.02,

CHCl₃); ¹H NMR 0.04 (s, 3H, SiCH₃), 0.07 (s, 3H, SiCH₃), 0.07

858 J . Org. Chem., Vol. 63, No. 3, 1998

Wu et al.

(s, 9H, TMS), 0.13 (s, 9H, TMS), 0.88 (s, 9H, C(CH₃)₃), 2.57

and 2.83 (ABq, J ) 14.3, 2H, NCH₂), 3.87 (m, 3H, CH₂O and

CHN), 4.26 (dd, J ) 6.4, 4.6, 1H, CHOH), 5.87 (dd, J ) 18.7,

4.6, 1H, dCH), 5.94 (d, J ) 18.7, 1H, CHd), 7.40 (m, 5H, Ar);

¹³C NMR -5.5 (Si(CH₃)₂), -1.4 (TMS), -0.4 (TMS), 18.2

(C(CH₃)₃), 25.9 (C(CH₃)₃), 34.8 (NCH₂), 62.5 (CH₂O), 63.9

(NCH), 74.5 (CHOH), 127.4, 128.2, 129.2, and 136.7 (Ar), 132.3

(dCH), 144.4 (CHd), 172.4 (NCdO); IR 3323, 2952, 2852,

1592; EIMS 493 (M, 0.8), 364 (82), 105 (100); HRMS 493.2867,

J ) 18.5, 5.3, 1H, dCH, B), 7.33 (m, 5H, Ar); ¹³C NMR -1.8

(TMS, B), -1.4 (TMS, A and B), -0.5 (TMS, B), 35.1 (NCH₂,

A), 46.1 (NCH₂, B), 62.0 (CH₂OH, B), 62.4 (CH₂OH, A), 63.7

(NCH, A), 68.3 (NCH, B), 72.1 (CHOH, B), 74.4 (CHOH, A),

126.7, 127.1, 128.4, 128.5, 129.3, 129.6, 136.5, and 136.6 (Ar),

132.6 (dCH, A), 133.0 (dCH, B), 144.4 (CHd, A), 145.0 (CHd,

B), 172.6 (NCdO, A), 172.8 (NCdO, B); IR 3359, 2949, 2892,

1593; EIMS 379 (M, 2), 250 (57), 105 (100); HRMS 379.1996,

C

₁₉H₃₃NO₃Si₂requires 379.1999.

C

₂₅H₄₇NO₃Si₃requires 493.2864.

(3S,4R)-1-(Tr im eth ylsilyl)-3,5-diacetoxy-4-[N-[(tr im eth -

79: mp 134-136 °C, (CH₂Cl₂/hexane); [R]²⁶+2.31° (c 0.05,

ylsilyl)m eth yl]-N-ben zoyla m in o]-1(E)-p en ten e (77).

A

CHCl₃); ¹H NMR -0.02 (s, 3H, SiCH₃), 0.00 (s, 3H, SiCH₃),

0.02 (s, 9H, TMS), 0.14 (s, 9H, TMS), 0.85 (s, 9H, C(CH₃)₃),

2.72 and 2.85 (ABq, J ) 14.4, 2H, NCH₂TMS), 3.59 (dd, J )

10.9, 3.9, 1H, CH₂O), 3.67 (dd, J ) 10.9, 7.9, 1H, CH₂O), 3.82

(ddd, J ) 7.9, 3.9, and undetermined, 1H, CHN), 4.11 (t, J )

5.8, 1H, CHOH), 5.81 (dd, J ) 18.7, 5.8, 1H, dCH), 5.89 (d, J

) 18.7, 1H, CHd), 7.38 (m, 5H, Ar); ¹³C NMR -5.6 (Si(CH₃)₂),

-1.5 (TMS), -0.5 (TMS), 18.2 (C(CH₃)₃), 25.9 (C(CH₃)₃), 34.0

(NCH₂), 63.1 (CH₂O), 64.7 (NCH), 73.2 (CHOH), 127.7, 128.1,

129.0, and 136.9 (Ar), 133.8 (dCH), 144.4 (CHd), 173.3

(NCdO); IR 3302, 2951, 2858, 1590; EIMS 493 (M, 1), 478 (23),

364 (100), 105 (58); HRMS 493.2853, C₂₅H₄₇NO₃Si₃requires

493.2864.

solution of diol 76 (1.45 g, 3.82 mmol), 4-DMAP (8 mg), and

acetic anhydride (2.16 mL, 22.9 mmol) in pyridine (6 mL) was

stirred at 25 °C for 17 h, diluted with H₂O, and extracted with

CH₂Cl₂. The extracts were washed with brine, dried, and

concentrated in vacuo to give a residue which was subjected

to flash column chromatography (silica gel, hexane:EtOAc, 6:1)

to provide 1.64 g (93%) 77: [R]²⁶-3.87° (c 6.00, CHCl₃); ¹H

NMR 0.06 (s, 9H, TMS), 0.12 (s, 9H, TMS), 2.02 (s, 3H,

COCH₃), 2.09 (s, 3H, COCH₃), 2.55 and 2.75 (ABq, J ) 14.3,

2H, NCH₂), 4.08 (dd, J ) 11.5, 2.9, 1H, CH₂O), 4.18 (td, J )

7.8, 2.9, 1H, CHN), 4.27 (dd, J ) 11.5, 9.2, 1H, CH₂O), 5.37 (t,

J ) 6.3, 1H, CHO), 5.72 (dd, J ) 18.7, 6.3, 1H, dCH), 5.90 (d,

J ) 18.7, 1H, CHd), 7.36 (m, 5H, Ar); ¹³C NMR -1.6 (TMS),

-0.6 (TMS), 20.8 (COCH₃), 21.0 (COCH₃), 34.5 (NCH₂), 60.1

(CHN), 61.3 (CH₂O), 74.2 (CHO), 127.2, 128.5, 129.6, and 136.3

(Ar), 135.6 (dCH), 138.9 (CHd), 169.3 (OCdO), 170.2 (OCdO),

172.6 (NCdO); IR 2950, 2898, 1741, 1635; EIMS 463 (M, 1),

448 (28), 292 (28), 105 (100); HRMS 463.2213, C₂₃H₃₇NO₅Si₂

requires 463.2210.

En a n tiom er ic P u r ity Deter m in a tion of 75. P r ep a r a -

tion of Mosh er Ester s 78. A solution of alcohol 75 (35 mg,

0.071 mmol), 4-DMAP (1 mg), triethylamine (0.06 mL, 0.426

mmol), and (R)-MTPAcCl (100 mg, 0.396 mmol) in CH₂Cl₂(2

mL) was stirred at 25 °C for 17 h, diluted with H₂O, and

extracted with CH₂Cl₂. The extracts were washed with satd

NaHCO₃and H₂O, dried, and concentrated in vacuo to give

33 mg of Mosher ester 78 as an 85:15 mixture (70% ee) based

upon ¹H NMR integration. Subjection of this material to

column chromatography (silica gel, hexane:EtOAc, 6:1) did not

affect diastereomeric ratios and provided 78 (30 mg, 60%):

[R]³⁰+1.90° (c 6.33, CHCl₃); ¹H NMR 0.03 (s, 3H, Si(CH₃)₂,

A), 0.04 (s, 6H, Si(CH₃)₂, B), 0.04 (s, 9H, TMS, A), 0.06 (s, Si-

(CH₃)₂, A), 0.06 (s, 9H, TMS, B), 0.12 (s, 9H, TMS, B), 0.13 (s,

9H, TMS, A), 0.86 (s, 9H, C(CH₃)₃, B), 0.90 (s, 9H, C(CH₃)₃,

A), 2.45 and 2.61 (ABq, J ) 14.3, 2H, NCH₂, B), 2.48 and 2.64

(ABq, J ) 14.2, 2H, NCH₂, A), 3.40 (s, 3H, OCH₃, A), 3.43 (s,

3H, OCH₃, B), 3.48 (dd, J ) 10.8, 3.8, 1H, CH₂O, B), 3.66 (dd,

J ) 10.3, 9.3, 1H, CH₂O, B), 3.78 (m, 2H, CH₂O, A), 4.15 (m,

1H, CHN, B), 4.18 (m, 1H, CHN, A), 5.42 (t, J ) 7.5, 1H,

CHOH, A), 5.43 (t, J ) 7.5, 1H, CHOH, B), 5.59 (dd, J ) 18.6,

7.5, 1H, dCH, A), 5.67 (dd, J ) 18.6, 7.5, 1H, dCH, B), 5.96

(d, J ) 18.6, 1H, CHd, A), 6.04 (d, J ) 18.6, 1H, CHd, B),

7.44 (m, 10H, Ar, A and B); ¹³C NMR -5.6 (Si(CH₃)₂, B), -5.5

(Si(CH₃)₂, A and B), -1.7 (TMS, A and B), -0.3 (TMS, A and

B), 18.3 (C(CH₃)₃, A and B), 25.9 (C(CH₃)₃, A and B), 33.6

(NCH₂, B), 33.9 (NCH₂, A), 55.3 (OCH₃, A and B), 59.9 (CH₂O,

B), 60.3 (CH₂O, A), 62.5 (NCH, A and B), 77.2 (CHO, A and

B), 121.7 (CCF₃, A), 121.8 (CCF₃, B), 124.5 (CCF₃, A), 124.7

(CCF₃, B), 127.2, 127.4, 127.7, 127.9, 128.2, 128.5, 129.4, 129.8,

131.4, 131.8, 136.2, and 136.3 (Ar), 138.1 and 138.3 (CHdCH,

A), 138.4 and 139.2 (CHdCH, B), 165.4 (CCdO, A), 165.5

(CCdO, B), 172.7 (NCdO, B), 172.8 (NCdO, A); IR 2955, 2857,

1744, 1627; EIMS 709 (M, 1), 694 (20), 364 (23), 260 (42), 105

(100); HRMS 709.3275, C₃₅H₅₄NO₅F₃Si₃requires 709.3262.

(3S,4R)-1-(Tr im eth ylsilyl)-4-[N-[(tr im eth ylsilyl)m eth yl]-

N-ben zoyla m in o]-1(E)-p en ten e-3,5-d iol (76). A solution of

allylic alcohol 75 (0.302 g, 0.613 mmol) and 0.2 mL of 48%

HF-H₂O in CH₃CN (3 mL) was stirred at 25 °C for 0.5 h, made

basic with NaHCO₃, and extracted with CHCl₃. The extracts

were washed with brine, dried, and concentrated in vacuo to

give a residue which was subjected to flash column chroma-

tography (silica gel, hexane:EtOAc, 2:1) to provide 76 (0.202

g, 87%): [R]²⁴-1.46° (c 2.27, CHCl₃); ¹H NMR (mixture of

rotamers A/B ) 2.5:1) -0.04 (s, 9H, TMS, B); 0.05 (s, 9H, TMS,

A), 0.11 (s, 9H, TMS, A and B), 2.53 and 2.80 (ABq, J ) 14.3,

2H, NCH₂, A), 2.69 and 3.03 (ABq, J ) 15.7, 2H, NCH₂, B),

3.71-3.85 (m, 2H, CH₂OH, A), 4.02 (m, 2H, CH₂OH, B), 4.16

(m, 1H, CHN, A and B), 4.79 (m, 1H, CHOH, A), 4.91 (m, 1H,

CHOH, B), 5.80 (dd, J ) 18.8, 4.4, 1H, dCH, A), 5.87 (d, J )

18.8, 1H, CHd, A), 6.07 (d, J ) 18.5, 1H, CHd, B), 6.15 (dd,

CAN Oxid a tion of 77. P r ep a r a tion of Tetr a h yd r op y-

r id in yl Dia ceta te 81. To a solution of CAN (0.533 g, 0.972

mmol) in dry MeCN (2 mL) was added a solution of 77 (0.225

g, 0.486 mmol) in MeCN (2 mL) at 25 °C. The mixture was

stirred for 20 h at 40 °C, diluted with H₂O, and extracted with

CHCl₃. The extracts were washed with brine, dried, and

concentrated in vacuo to give a residue which was subjected

to flash column chromatography (silica gel, hexane:EtOAc, 2:1)

1

to provide 81 (71 mg, 46%): [R]²⁵+16.9° (c 1.63, CHCl₃); H

NMR 2.03 (s, 3H, COCH₃), 2.06 (s, 3H, COCH₃), 3.63 (d, J )

19.8, 1H, NCH₂), 3.91 (dd, J ) 11.2, 5.1, 1H, CH₂O), 4.12 (dd,

J ) 11.2, 9.4, 1H, CH₂O), 4.30 (m, 1H, CHN), 4.86 (d, J )

19.8, 1H, NCH₂), 4.99 (d, J ) 2.4, 1H, CHO), 5.91 (m, 1H,

CHd), 6.16 (m, 1H, CHd), 7.39 (m, 5H, Ar); ¹³C NMR 20.7

(COCH₃), 20.9 (COCH₃), 38.9 (NCH₂), 55.6 (NCH), 60.8

(CH₂O), 65.6 (CHO), 120.8 (CHd), 127.2, 128.4, 129.9, and

135.5 (Ar), 130.9 (dCH), 170.1 (COCH₃), 172.2 (NCdO); IR

1732, 1634; EIMS 317 (M, 0.2), 184 (22), 105 (100), 77 (48);

HRMS 317.1264, C₁₇H₁₉NO₅requires 317.1263.

(3R,4R)-1-(Tr im eth ylsilyl)-4-[N-[(tr im eth ylsilyl)m eth yl]-

N-ben zoyla m in o]-1(E)-p en ten e-3,5-d iol (80). A solution of

silyl ether 79 (0.413 g, 0.838 mmol) and 0.3 mL of 48% HF-

H₂O in MeCN (4.5 mL) was stirred at 25 °C for 0.5 h, made

basic with NaHCO₃, and extracted with CHCl₃. The extracts

were washed with brine, dried, and concentrated in vacuo to

give a residue which was subjected to flash column chroma-

tography (silica gel, hexane:EtOAc, 2:1) to provide 0.264 g

(83%) of 80: mp 139-141 °C (CH₂Cl₂/hexane); [R]²⁴-2.93° (c

1

2.87, CHCl₃); H NMR 0.03 (s, 9H, TMS), 0.15 (s, 9H, TMS),

2.77 and 2.85 (ABq, J ) 14.3, 2H, NCH₂), 3.65 (m, 1H, CH₂-

OH), 3.88 (m, 1H, CH₂OH), 4.13 (m, 1H, CHN), 4.68 (s, 1H,

CHOH), 5.80 (dd, J ) 18.5, 5.1, 1H, dCH), 5.89 (d, J ) 18.5,

1H, CHd), 7.34 (m, 5H, Ar); ¹³C NMR -1.5 (TMS), -0.5 (TMS),

34.0 (NCH₂), 60.4 (CH₂OH), 64.4 (CHN), 73.6 (CHOH), 127.4,

128.4, 129.1, and 136.8 (Ar), 134.0 (dCH), 144.2 (CHd), 173.7

(NCdO); IR 3342, 2951, 2899, 1591, 1568; EIMS 379 (M, 1),

250 (24), 105 (100); HRMS 379.2001, C₁₉H₃₃NO₃Si₂requires

379.1999.

Tetr a d yd r op yr id in yl Diol 82. A solution of diacetate 81

(99 mg, 0.31) and KCN (13 mg, 0.20 mmol) in MeOH (2 mL)

was stirred for 18 h at 25 °C, concentrated, diluted with CHCl₃,

and washed with brine and H₂O. The CHCl₃layer was dried

and concentrated in vacuo to give 55 mg (76%) of the trans-

diol 82 as a crystalline substance which was used without

further purification: mp 173-174 °C (acetone/hexane); [R]²⁴

Oxidative Mannich Cyclizations

J . Org. Chem., Vol. 63, No. 3, 1998 859

-44.3° (c 3.0, MeOH); ¹H NMR (d₆-acetone) 3.53 (m, 3H, CH₂-

OH and CH₂N), 3.97 (t, J ) 5.6, 1H, CHOH), 4.11 (s, 1H,

CHCH₂O), 4.66 (d, J ) 18.9, 1H, CH₂N), 5.91 (m, 2H, CHdCH),

7.37 (s, 3H, Ar), 7.57 (s, 2H, Ar); ¹³C NMR 39.6 (CH₂N), 60.7

(CH₂OH), 62.6 (NCH or CHOH), 64.1(NCH or CHOH), 126.5

and 128.0 (CHdCH), 128.6, 129.0, 129.6, and 138.2 (Ar), 172.5

(NCdO); IR 3329, 1598, 1436; EIMS 233 (M, 1), 105 (100) 77

(39); HRMS 233.1046, C₁₃H₁₅NO₃requires 233.1052.

X-r a y Cr ysta llogr a p h ic Da ta for 80 a n d 82. A crystal

was placed and optically centered on the Enraf-Nonius CAD-4

diffractometer. The crystals’ final cell parameters and crystal

orientation matrix were determined from 25 reflections and

were confirmed with axial photographs. Data were collected

[Mo KR] with ω/2θ scans over the range 2.34 < θ < 22.5° with

each scan recorded in 96 steps with the outermost 16 steps on

each end of the scan being used for background determination.

The diffractometer was controlled with a Digital Equipment

Corporation MicroVAX II (MVII) computer and the Enraf-

Nonius VAX\ VMS CAD4 Express control program. Six stan-

dard reflections well dispersed in reciprocal space were

monitored at 1 h intervals of X-ray exposure. Minor variations

in intensity were observed; data were not corrected. An

absorption correction was applied based upon six ψ-scans,

each collected. Two forms of data were collected: the indices

(h-k-l and their Friedel mates (hkl.

(silica gel, hexane:EtOAc, 2:1) to provide 85 (less polar, 33%)

and 87 (more polar, 49%).

85: [R]³⁰-17° (c 8.0, CHCl₃); ¹H NMR (70 °C, CD₃CN) 1.95

(s, 3H, COCH₃), 2.02 (s, 3H, COCH₃), 2.07 (s, 3H, COCH₃),

2.11 (s, 3H, COCH₃), 3.33 (t, J ) 12.3, 1H, CH₂N), 4.22 (m,

1H, CHN), 4.28 (dd, J ) 11.7, 5.4, 1H, CH₂O), 4.51 (s, 1H,

CH₂N), 4.64 (dd, J ) 11.7, 9.0, 1H, CH₂O), 4.95 (d, 1H, J )

3.3, 1H, CHO), 5.06 (ddd, J ) 11.3, 5.2, 3.3, 1H, NCH₂CHO),

5.32 (t, J ) 3.3, 1H, NCHCHO), 7.45 (m, 5H, Ar); ¹³C NMR

21.0 (COCH₃), 21.1 (COCH₃), 21.1 (COCH₃), 21.2 (COCH₃),

61.3 (CH₂O), 66.6 (CHO), 68.4 (CHO), 69.8 (CHO), 128.2, 129.7,

131.1, and 137.0 (Ar), 170.4 (OCdO), 170.4 (OCdO), 170.7

(OCdO), 171.4 (OCdO), 173.1 (NCdO); IR 1746, 1644; CIMS

436 (M + 1, 8), 302 (39), 242 (41), 105 (100) 77 (43); HRMS

436.1615, C₂₁H₂₆NO₉requires 436.1608.

87: [R]³⁰-6.8° (c 9.3, CHCl₃); ¹H NMR (70 °C, CD₃CN) 1.95

(s, 3H, COCH₃), 2.04 (s, 3H, COCH₃), 2.05 (s, 3H, COCH₃),

2.07 (s, 3H, COCH₃), 3.44 (dd, J ) 15.4, 1.3, 1H, CH₂N), 4.23

(dd, J ) 11.8, 5.7, 1H, CH₂O), 4.43 (dd, J ) 11.8, 8.1, 1H,

CH₂O), 4.31 (m, 1H, CHN). 4.77 (s, 1H, CH₂N), 5.13 (m, 1H,

NCH₂CHO), 5.18 (t, J ) 2.8, 1H, NCHCHO), 5.21 (m, 1H,

CHO), 7.43 (m, 5H, Ar); ¹³C NMR 20.9 (COCH₃), 21.1 (COCH₃),

21.2 (COCH₃), 21.2 (COCH₃), 44.2 (CH₂N), 56.0 (NCHCH₂O),

61.9 (CH₂O), 68.1 (CHO), 68.1 (CHO), 68.4 (CHO), 128.1, 129.7,

130.8, and 137.3 (Ar), 170.7 (OCdO), 171.1 (OCdO), 171.2

(OCdO), 171.3 (OCdO), 173.3 (NCdO); IR 1740, 1641, 1421;

CIMS 436 (M + 1, 1), 105 (100); HRMS 436.1594, C₂₁H₂₆NO₉

requires 436.1608.

All crystallographic calculations were performed on a per-

sonal computer (PC) with a 486 DX2/66 processor and 20 Mb

of extended memory. Data were corrected for Lorentz and

2

polarization factors and reduced to F_oand σ(F_o²) using the

(-)-1-Deoxym a n n ojir im ycin Hyd r och lor id e (90). A

program XCAD4 (data reduction program written for a PC by

Klaus Harms, 1993). Intensity statistics and systematic

absences clearly determined the centrosymmetric monoclinic

space group P2₁/c (no. 14). The structure was determined by

direct methods with the successful location of several oxygen,

nitrogen, and carbon atoms using the program XS.²The

structure was refined with XL (Siemens SHELXTL, version

5).

Summary of results for 80: (C₁₉H₃₃NO₃SI₂O₃), M_r) 379.64,

orthorhombic, crystal dimensions 0.55 × 0.275 × 0.125 mm,

scan width (0.95 + 0.75 tan θ)°, variable scan speed of 4.1-

5.1° min^-1, transmission factor range 0.9576 ) 0.9800, 3637

reflections with 3099 unique [R(int) ) 0.658], P2₁2₁2₁, a )

7.3246(6) Å, b ) 10.5921(7) Å, c ) 30.685(6) Å, V ) 2380.7(5)

Å³, Z ) 4, D_x) 1.059 g cm^-3, λ(Mo KR) ) 0.71073 Å, µ(Mo

KR) ) 0.164 mm^-1, F(000) ) 824, T ) 153(2) K, R(F) ) 9.08%,

R(wF²) ) 16.16% (for all 3099 independent reflections) R(F)

) 6.45%, R(wF²) ) 14.44% (for the 2462 reflections with F_o>

4σ(F_o).

Summary of results for 82: (C₁₃H₁₅N₁O₃), M_r) 233.26,

monoclinic, crystal dimensions 0.325 × 0.150 × 0.050 mm, scan

width (0.52 + 0.45 tan θ)°, variable scan speed of 2.0-3.3°

min^-1, transmission factor range 0.9359)1.0000, 3189 reflec-

tions with 1511 unique [R(int) ) 0.0597], P2₁/c, a ) 9.0412(12)

Å, b ) 10.3876(12) Å, c ) 12.3801(14) Å, b ) 96.854(10)°, V )

1154.4(2) Å³, Z ) 4, D_x) 1.342 g cm^-3, λ(Mo KR) ) 0.71073 Å,

µ(Mo KR) ) 0.096 mm^-1, F(000) ) 496, T ) 153 K, R(F) )

10.19%, R(wF²) ) 8.24% for all 1511 independent reflections.

P ip er id in yl Tetr a ceta tes 85 a n d 87. To a stirred solution

of diol 82 (0.01 mmol) and hydroquinidine 1,4-phthalazinediyl

diether (0.01 mmol) in a 10:1 acetone:water mixture at 0 °C

was added NMO (0.012 mmol) followed by 0.01 equiv of a 4

wt % solution of OsO₄in water. The mixture was stirred for

17 h at 0 °C, quenched by addition of solid Na₂S₂O₅, stirred

for 0.5 h, dried with Na₂SO₄, and filtered. The filtrate was

concentrated in vacuo to give a residue, shown by ¹H NMR

analysis to contain the tetrols 88 and 89. A solution of this

mixture, 4-DMAP (2 mg), and acetic anhydride (0.01 mL, 0.10

mmol) in pyridine (3 mL) was stirred at 25 °C for 17 h, diluted

with H₂O, and extracted with CHCl₃. The extracts were

washed with brine, dried, and concentrated in vacuo to give a

residue which was subjected to flash column chromatography

solution of the teraacetate 85 (47 mg, 0.11 mmol) in 6 N HCl

(2 mL) was stirred at reflux for 5 h and concentrated, and the

residue was washed with ether, giving 24 mg (100%) of

deoxymannojirimycin hydrochloride (90). The free amine of

90: The spectroscopic data for this substance were the same

as the previously reported.^27a-p[R]²⁶-7.7° (c 6.0, MeOH);

D

¹H NMR 3.01 (ddd, J ) 10.2, 6.7, 3.3, 1H, NCH), 3.09 (dd, J )

13.6, 0.9 Hz, 1H, NCH₂), 3.27 (dd, J ) 13.6, 2.9, 1H, NCH₂),

3.55 (dd, J ) 9.5, 2.9, 1H), 3.68 (dd, J ) 12.5, 6.7, 1H, CH₂-

OH), 3.71 (dd, J ) 10.2, 9.5, 1H, CHOH), 3.83 (dd, J ) 12.5,

3.3, 1H, CH₂OH), 4.10 (ddd, J ) 2.9, 2.9, 0.9, 1H, CHOH); ¹³

C

NMR 48.2 (NCH₂), 58.8 (CH₂OH), 61.0 (CHN), 66.4, 66.6 and

73.1 (CHOH); CIMS 164 (M + 1, 100), 130 (19), 102 (18), 60

(26); HRMS 164.0923, C₆H₁₄NO₄requires 164.0923.

(+)-1-Deoxya llon ojir im ycin (91). A solution of tetraac-

etate 87 (44 mg, 0.10 mmol) in 6 N HCl (2 mL) was stirred at

reflux for 5 h and concentrated, and the residue was washed

with ether, giving 21 mg of the hydrochloride salt of deoxyal-

lonojirimycin. Ion-exchange chromatography provided deoxy-

allonojirimycin (91). 91‚HCl: [R]²⁹_D+10.9° (c 6.3, MeOH); ¹H

NMR 2.96 (t, J ) 11.8, 1H, NCH₂), 3.10 (dd, J ) 11.8, 4.9,

NCH₂), 3.17 (ddd, J ) 10.8, 5.1, 3.2, 1H, NCH), 3.67 (dd, J )

10.8, 2.3, 1H, CHOH), 3.70 (dd, J ) 12.8, 5.1, 1H, CH₂OH),

3.77 (dd, J ) 12.8, 3.2, 1H, CH₂OH), 3.85 (ddd, J ) 11.8, 4.9,

2.5, 1H, CHOH), 4.01 (dd, J ) 2.5, 2.3, 1H, CHOH); ¹³C NMR

44.0 (CH₂N), 57.2 (CHN), 60.1 (CH₂OH), 67.0, 67.8 and 72.4

(CHOH); CIMS 164 (M + 1, 6), 133 (30), 132 (81), 86 (18), 60

(100); HRMS 164.0923, C₆H₁₄NO₄requires 164.0923.

Ack n ow led gm en t. This research was supported by

a grant from the NIH (GM-27251).

Su p p or tin g In for m a tion Ava ila ble: ¹H NMR spectro-

scopic data for the new substances described in this publica-

tion, the X-ray crystallographic data for 80 and 82 (91 pages).

This material is contained in libraries on microfiche, im-

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J O971706N

Article Doi

An Oxidative Mannich Cyclization Methodology for the Stereocontrolled Synthesis of Highly Functionalized Piperidines

DOI: 10.1021/jo971706n

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