Asymmetric conjugate additions of chiral phosphonamide anions to α,β-unsaturated carbonyl compounds. A versatile method for vicinally substituted chirons

Article abstract of DOI:10.1021/jo000388g

Reactions of anions derived from chiral nonracemic allyl, crotyl, and cinnamyl bicyclic C₂-symmetrical phosphonamides with α,β-unsaturated cyclic ketones, esters, lactones, and lactams take place at the γ-position of the reagents. The products are diastereomerically pure or enriched β-substituted carbonyl compounds. The method also provides easy access to vicinal substitution of as many as three stereogenic centers including in some cases quaternary carbon atoms, in a one-pot sequence.

Full text of DOI:10.1021/jo000388g

J . Org. Chem. 2000, 65, 5623-5631
5623
Asym m etr ic Con ju ga te Ad d ition s of Ch ir a l P h osp h on a m id e An ion s
to r,â-Un sa tu r a ted Ca r bon yl Com p ou n d s. A Ver sa tile Meth od for
Vicin a lly Su bstitu ted Ch ir on s
Stephen Hanessian,* Arthur Gomtsyan, and Nadia Malek
Department of Chemistry, Universite´ de Montre´al, C.P. 6128, Succursale Centreville,
Montre´al, Que´bec H3C 3J 7, Canada
Received March 17, 2000
Reactions of anions derived from chiral nonracemic allyl, crotyl, and cinnamyl bicyclic C2-
symmetrical phosphonamides with R,â-unsaturated cyclic ketones, esters, lactones, and lactams
take place at the γ-position of the reagents. The products are diastereomerically pure or enriched
â-substituted carbonyl compounds. The method also provides easy access to vicinal substitution of
as many as three stereogenic centers including in some cases quaternary carbon atoms, in a one-
pot sequence.
In tr od u ction
carbocyclic enones. Similar results were achieved by Fuji
and co-workers,7 who have used allyl and crotyl phos-
phonates prepared from 1,1′-binaphthalene-2,2′-diol in
the same type of reaction.
Asymmetric 1,4-addition reactions to R,â-unsaturated
carbonyl compounds are among the most frequently used
methods for stereoselective C-C bond construction.1 The
utilization of chiral sulfur- and phosphorus-based stabi-
lized allylic-type anions has shown great promise as a
powerful method in asymmetric Michael-type reactions.2-7
Individual enantiomers of allylic phosphine oxides
prepared by Haynes and co-workers4 were shown to
undergo 1,4-additions to cyclopentenones with good to
excellent stereoselectivity. Hua and co-workers5 reported
high levels of stereoselectivity in 1,4-additions of 2-allyl-
1,3,2-oxazaphospholidine 2-oxides to simple R,â-unsatur-
ated cyclic ketones and 3,4-dihydro-4-oxo-(2H)-pyridine-
L-carboxylate. Denmark and co-workers6 described high
levels of stereocontrol in 1,4-additions of anions derived
from 2-allyl-1,3,2-oxazaphosphorinane 2-oxide to simple
The majority of the above-cited examples consist of
additions to cyclic enones, and it remains unclear whether
other classes of R,â-unsaturated carbonyl compounds,
such as lactones, lactams, esters, etc., would provide the
same degree of stereo- and regiochemical efficiency.
Another practical problem associated with most of the
above-mentioned methods is the need to secure single
enantiomers of the phosphorus reagents, since diaster-
eomeric reagents have exhibited different levels of se-
lectivity.8 Separations of diastereomeric reagents are
usually done by fractional crystallization or by chroma-
tography.8
Our laboratory has had a long-standing interest in the
design, synthesis, and applications of phosphorus-
containing chiral reagents based on phosphonamides
derived from (R,R)- and (S,S)-N,N-dialkyl-1,2-diaminocy-
clohexanes.9 These can be easily prepared from the
corresponding commercially available trans-1,2-diami-
nocyclohexanes, which can be resolved with D- or L-
tartaric acid on a large scale.10 Like the alkyl ana-
logues,11,12 allylic phosphonamides13 are easily prepared
by condensation of allyl-, crotyl-, and cinnamylphosphonic
dichlorides, for example, with the corresponding (R,R)-
or (S,S)-N,N-dialkyl-1,2-diaminocyclohexane.14 Scheme 1
* To whom correspondence should be addressed. Phone: (514) 343-
6738. Fax: (514) 343-5728. E-mail: hanessia@ere.umontreal.ca.
(1) Leonard, J . Contemp. Org. Synth. 1994, 1, 387. Rossiter, B. E.;
Swingle, N. M. Chem. Rev. 1992, 92, 77. Perlmutter, P. Conjugate
Addition Reactions in Organic Synthesis; Pergamon: Oxford, 1992.
Tomioka, K.; Koga, K. In Asymmetric Synthesis; Morrison, J . D., Ed.;
Academic Press: New York, 1983; Vol. 2, p 201. See also: Oare, D. A.;
Heathcock, C. H. Top. Stereochem. 1991, 20, 87 and references therein.
(2) For a review on asymmetric conjugate additions with sulfoxide-
stabilized carbanions, see: Walker, A.-J . Tetrahedron: Asymmetry
1992, 3, 961. Posner, G. H. In The Chemistry of Sulfones and
Sulfoxides; Patai, S., Rappoport, Z., Striling, C. J . M., Eds.; Wiley-
Interscience: New York, 1988; p 823. Solladie´, G. In Asymmetric
Synthesis; Morrison, J . D., Ed.; Academic Press: New York, 1983; Vol.
2, p 157. Barbashyn, M. R., J ohnson, C. R. In Asymmetric Synthesis;
Morrison, J . D., Ed.; Academic Press: New York, 1983; Vol. 4, p 227.
(3) For 1,4-conjugate additions of chiral allylic sulfoxide anions,
see: (a) Hua, D. H.; Venkataraman, S.; Coulter, M. J .; Sinai-Zingde,
G. J . Org. Chem. 1987, 52, 719. (b) Hua, D. H. Bharati, S, N.;
Panagadan, J . A.; Isujimoto, A. J . Org. Chem. 1991, 56, 6998. (c) See
also: Hua, D. H.; Park, J .-G.; Katsuhira, T.; Bharati, S. N. J . Org.
Chem. 1993, 58, 2144.
(4) (a) Haynes, R. K.; Stokes, J . P.; Hambley, T. W. J . Chem. Soc.,
Chem. Commun. 1991, 58. (b) Binns, M. R.; Haynes, R. K.; Katsifis,
A. G.; Schober, P.; Vonwiller, S. C. J . Am. Chem. Soc. 1988, 110, 5411.
(c) See also: Haynes, R. K.; Vonwiller, S. C.; Hambley, T. W. J . Org.
Chem. 1989, 54, 5162. (d) Haynes, R. K.; Freeman, R. N.; Mitchell, C.
R.; Vonwiller, S. C. J . Org. Chem. 1994, 59, 2919 and previous papers.
(5) (a) Hua, D. H.; Chan-Yu-King, R.; Mckie, J .-A.; Myer, L. J Am.
Chem. Soc. 1987, 109, 5026. (b) Hua, D. H.; Chen, J . S.; Saha, S.; Wang,
H.; Roche, D.; Bharati, S. N.; Chan-Yu-King, R.; Robinson, P. D.; Iguchi,
S. Synlett 1992, 817.
(8) Hua, D. H.; Ostrander, R. A.; Chan-Yu-King, R.; Mckie, J .-A.
Org. Prep. Proc. Int. 1989, 21, 225. Freeman, R.; Haynes, R. K.;
Loughlin, W. A.; Mitchell, C.; Stokes, J . P. Pure Appl. Chem. 1993,
65, 647.
(9) For
a review on the design and applications of chiral 1,2-
diaminocyclohexane-based reagents in asymmetric synthesis, see:
Bennani, Y. L.; Hanessian, S. Chem. Rev. 1997, 97, 3161.
(10) Glasbol, F.; Steenbol, P.; Sorensen, S. B. Acta Chem. Scand.
1980, 26, 3605.
(11) (a) Hanessian, S.; Bennani, Y. L.; Delorme, D. Tetrahedron Lett.
1990, 31, 6461. (b) Bennani, Y. L.; Hanessian, S. Tetrahedron 1996,
52, 13837.
(12) For the alternative preparation see: Koeller, K. J .; Spilling, C.
D. Tetrahedron Lett. 1991, 32, 6297.
(13) Corey, E. J .; Cane, D. E. J . Org. Chem. 1969, 34, 3053. Corey,
E. J .; Kwiatkowski, G. T. J . Am. Chem. Soc. 1966, 88, 5652; 1968, 90,
6816.
(6) Denmark, S. E.; Kim, J .-H. J . Org. Chem. 1995, 60, 7535.
(7) Tanaka, K.; Ohta, Y.; Fuji, K. J . Org. Chem. 1995, 60, 8036.
(14) Hanessian, S.; Delorme, D.; Beaudoin, S.; Leblanc, Y. Chim.
Scr. 1985, 25, 5.
10.1021/jo000388g CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/17/2000

5624 J . Org. Chem., Vol. 65, No. 18, 2000
Hanessian et al.
Sch em e 1
shows the sequence of reactions leading to the formation
of stabilized allylic-type phosphonamide anions, and the
regiochemical issues15 resulting from reactions with an
R,â-unsaturated ketone. In addition, there is the chal-
lenge of stereochemical control, particularly with regard
to the synthesis of preparatively useful γ-1,4-adducts.
Phosphonamides 1a -c are crystalline, diastereomeri-
cally pure compounds which can be converted to their
anions with n-BuLi at -78 °C, and used directly in 1,4-
additions to R,â-unsaturated carbonyl compounds. We
have previously reported the utility of alkyl, allyl, and
related chiral bicyclic phosphonamides such as 1a and
1b in the asymmetric olefination of cyclohexanones.16
Other applications can be found in the asymmetric
synthesis of R,R′-dialkyl-,14 R-alkyl-R′-halo-,12 R-alkyl-R′-
amino-,17a,c and R-alkyl-â-aminophosphonic acids.17b Phos-
phonamide anion technology developed in our laboratory
has also been useful in natural product synthesis.18,19
Chiral nonracemic phosphonamides have been studied
in connection with carbanion-accelerated Claisen rear-
rangements.20
centers with high levels of diastereoselectivity. As a
logical extension of these results, we also reported the
asymmetric synthesis of acyclic motifs in which three or
more contiguous stereogenic centers were generated in
single-stage or sequential Michael-type reactions, respec-
tively.22,23 Utilizing anions derived from chiral bicyclic
γ-chloroallyl phosphonamides, we also reported the asym-
metric syntheses of enantiopure substituted cyclopro-
panes24 and aziridines.25
In this paper, we present a detailed account of the use
of allylic phosphonamide anions in asymmetric 1,4-
addition reactions to R,â-unsaturated cycloalkenones,
lactones, lactams, and esters (Scheme 2). The adducts
have been further transformed into chirons containing
contiguous functional groups that could find utility in
total syntheses.
Resu lts a n d Discu ssion
Ad d it ion t o Cyclop en t en on es a n d Cycloh ex-
en on es. Treatment of 1a and 1b with 1.2 equiv of n-BuLi
at -78 °C for 1-2 min generated the corresponding
lithiated anions that reacted with cyclic ketones within
30 min. Depending on the substrate and quenching
electrophile, this methodology afforded substituted cy-
clopentanones having one, two, and three contiguous
asymmetric centers with high diastereomeric purity.
Methanol was a better quenching agent in the reactions
with 2-methylcyclopentenone (Table 1, entries 2 and 6),
since the use of NH4Cl resulted in a significant loss of
stereoselectivity at the R-position of the ketone. Entries
3, 4, and 7 represent examples of creating quaternary
stereogenic centers at R- and â-positions in the cyclopen-
tanone and cyclohexanone cores.26 Addition of 1a to
3-methylcyclohexenone under standard conditions was
not a regioselective process, leading to a ∼2:1 mixture of
γ-1,4- and γ-1,2-adducts with poor stereoselectivity (66%
de) for the desired γ-1,4-adduct. However, addition of 1
equiv of HMPA4 to the reaction mixture enhanced the
In a preliminary communication,21 we reported the
highly stereocontrolled 1,4-additions of allylic phospho-
namide anions 1a and 1b to a variety of R,â-unsaturated
carbonyl compounds. The option to trap the correspond-
ing enolates with a variety of electrophiles allowed the
generation of as many as three contiguous stereogenic
(15) For factors influencing the regioselectivity of phosphonamide-
stabilized allylic anion addition, see: (a) Denmark, S. E.; Cramer, C.
J . J . Org. Chem. 1990, 55, 1806. (b) Cramer, C. J .; Denmark, S. E.;
Miller, P. C.; Dorow, R. L.; Swiss, K. A.; Wilson, S. R. J . Am. Chem.
Soc. 1994, 116, 2437. See also: (a) Corey, E. J .; Cane, D. E. J . Org.
Chem. 1969, 34, 3053. (b) Ahlbrecht, H.; Farnung, W. Chem Ber. 1984,
117, 1. (c) Evans, D. A.; Takacs, J . M.; Hurst, K. M. J . Am. Chem. Soc.
1979, 101, 371. (d) Birse, E. F.; McKenzie, A.; Murray, A. W. J . Chem.
Soc., Perkin Trans. 1 1988, 1039. (e) Hata, T.; Nakajima, M.; Sekine,
M. Tetrahedron Lett. 1979, 2047; see also ref 29.
(16) (a) Hanessian, S.; Delorme, D.; Beaudoin, S.; Leblanc, Y. J . Am.
Chem. Soc. 1984, 106, 5754. (b) Hanessian, S.; Beaudoin, S. Tetrahe-
dron Lett. 1992, 33, 7655. (c) Hanessian, S.; Beaudoin, S. Tetrahedron
Lett. 1992, 33, 7659.
(17) (a) Hanessian, S.; Bennani, Y. L. Tetrahedron Lett. 1990, 31,
6465. (b) Hanessian, S.; Bennani, Y. L.; Herve, Y. Synlett 1993, 35. (c)
Hanessian, S.; Bennani, Y. L. Synthesis 1994, 1272.
(18) (a) Paquette, L. A.; Wang, T.-Z.; Pinard, E. J . Am. Chem. Soc.
1995, 117, 1455. (b) Wang, T.-Z.; Pinard, E.; Paquette, L. A. J . Am.
Chem. Soc. 1996, 118, 1309.
(22) Hanessian, S.; Gomtsyan, A. Tetrahedron Lett. 1994, 35, 7509.
(23) For a recent review on sequential reactions see: Bunce, R. A.
Tetrahedron 1995, 51, 13103.
(24) (a) Hanessian, S.; Andreotti, D.; Gomtsyan, A. J . Am. Chem.
Soc. 1995, 117, 10393. (b) Hanessian, S.; Cantin, L.-D.; Roy, S.;
Andreotti, D.; Gomtsyan, A. Tetrahedron Lett. 1997, 38, 1103.
(25) Hanessian, S.; Cantin, L.-D. Tetrahedron Lett. 2000, 41, 787.
(26) See for example: Corey, E. J .; Guzman-Perez, A. Angew. Chem.,
Int. Ed. 1998, 37, 388. Fuji, K. Chem. Rev. 1993, 93, 2037. Martin, S.
F. Tetrahedron 1980, 36, 419.
(19) Boyle, C. D.; Kishi, Y. Tetrahedron Lett. 1995, 36, 4579.
(20) Denmark, S. E.; Stadler, H.; Dorow, R. L.; Kim, J .-H. J . Org.
Chem. 1991, 56, 5063.
(21) (a) Hanessian, S.; Gomtsyan, A.; Payne, A.; Herve, Y.; Beaudoin,
S. J . Org. Chem. 1993, 58, 5032. (b) Hamme, A. T.; Paquette, L. A.
Chemtracts:Org. Chem. 1994, 7, 24.

Phosphonamide Anion Addition to Carbonyl Compounds
Sch em e 2
J . Org. Chem., Vol. 65, No. 18, 2000 5625
Ta ble 1. 1,4-Con ju ga te Ad d ition Rea ction s of 1a a n d 1b
Generally, diastereoselectivities were determined by
1
analysis of H, 13C, and 31P NMR spectra of the vinylic
w ith r,â-Un sa tu r a ted Cyclic Keton es
phosphonamide adducts, and further corroborated by
spectral analysis of cleavage products either as bisdiox-
olanes or as Mosher esters (Scheme 3).
Accordingly, all the adducts listed in Table 1 resulting
from addition of allyl reagent 1a (entries 1-4 and 7) were
converted to bisdioxolanes via δ-keto aldehydes (Scheme
3), and their diastereomeric ratios were determined by
13C NMR according to Hiemstra and Wynberg.30 For the
adducts from the crotyl reagent 1b (Table 1, entries 5
and 6) a different cleavage procedure was devised to avoid
possible racemization at the aldehyde side chain (Scheme
4). Thus, the carbonyl group in 5 and 6 was reduced and
the mixture of alcohols protected as a silyl ether. Ozo-
nolysis of the vinyl phosphonamide segment gave an
alcohol which was converted to the corresponding Mosher
esters 8a and 8b in each case after the carbonyl group
in the cyclopentane ring was reinstalled by removal of
the silyl group followed by oxidation with PDC. It should
be noted that, in the majority of examples shown in Table
1, the degrees of diastereoselectivity obtained from 1H,
13C, and 31P NMR spectra of 1,4-adducts were in close
agreement with the values obtained from 19F NMR of
Mosher esters. In isolated instances when de values for
products before and after cleavage were not concordant,
the value determined for the cleavage product was chosen
to determine the stereoselectivity of the particular 1,4-
addition reaction.
a
Determined from 1H, 13C, and 31P NMR parameters (all
entries) and further substantiated from 13C NMR spectra of cyclic
ketal-acetal derivatives with (R,R)-2,3-butanediol after oxidative
cleavage (entries 1-4 and 7) and Mosher esters of products after
The newly created asymmetric center on the cyclopen-
tanone ring in 2a (Table 1, entry 1) was assigned an (S)-
b
oxidative cleavage and reduction (entries 5 and 6). Yield of
isolated product after flash chromatography. c Reaction done in
the presence of HMPA (1 equiv).
(27) Binns, M. R.; Haynes, R. K. J . Org. Chem. 1981, 46, 3790. Ager,
D. J . East, M. B. J . Org. Chem. 1986, 51, 3983. Binns, M. R.; Haynes,
R. K.; Katsifis, A. G.; Schober, P. A.; Vonwiller, S. C. J . Org. Chem.
1989, 54, 1960.
(28) Park, Y.-S.; Weisenburger, G. A.; Beak, P. J . Am. Chem. Soc.
1997, 119, 10537.
(29) For a review on regioselectivity in the additions of heteroatom-
stabilized allylic anions, see: Katritsky, A. R.; Piffl, M.; Lang, H.;
Anders, E. Chem. Rev. 1999, 99, 665.
stereochemical purity of 7 to 80% de with an increase in
yield to 62% (Table 1, entry 7). The reaction between
3-methylcyclopentenone and 1b afforded a mixture of 1,2-
addition products only. The nature of the solvent, addi-
tives, and external ligands is known to affect the regi-
oselectivity in conjugate addition reactions.27-29
(30) Hiemstra, H.; Wynberg, H. Tetrahedron Lett. 1977, 2183.

5626 J . Org. Chem., Vol. 65, No. 18, 2000
Hanessian et al.
Sch em e 3a
a
Reagents and conditions: (a) O3, CH2Cl2, -78 °C, then Me2S; (b) 3 equiv of (2R,3R)-2,3-butanediol, 0.05 equiv of p-TsOH; (c) O3,
CH2Cl2-MeOH, -78 °C, then NaBH4; (d) (+)-Mosher acid chloride, Py-CCl4, 1 h, rt, then 3-dimethylamino-1-propylamine.
Sch em e 4a
a
Reagents and conditions: (a) NaBH4; (b) TBDMS-Cl; (c) O3, CH2Cl2-MeOH, -78 °C, then NaBH4; (d) Mosher reagent; (e) TBAF,
AcOH; (f) PDC.
F igu r e 1. “Cleft” concept for the reaction transition state.
configuration on the basis of a comparison of the optical
rotation value with that reported for a degradation
product.
states to explain selectivities of 1,4-addition reactions
with related reagents.
5a
Ad d ition to La cton es a n d La cta m s. To the best of
our knowledge there are no precedents in the literature
for the successful asymmetric conjugate reactions be-
tween allylic phosphonamide anions and R,â-unsaturated
lactones and lactams. In the only reported attempt7 of
the addition of an allyl binaphthylphosphonate to a five-
membered R,â-unsaturated lactone, a mixture of products
resulting from R- and γ-attack by the reagent with poor
stereoselectivity was observed.
To rationalize the high levels of stereocontrol in the
additions of lithiated allyl and crotyl phosphonamides to
R,â-unsaturated cyclic ketones, we propose an approach
of the enone component from the “left cleft” 21a of the Li-
coordinated reagent, resulting in a re-face attack (Figure
1). An approach from the “right cleft” is less favorable
due to the steric interaction between the N-Me group of
the phosphonamide and H atoms of the enone. A key
requirement for the correct relative positioning of the
reagent and substrate is the anchoring of a lithium cation
on polarized PdO and CdO groups. Haynes31 has pro-
posed cis- and trans-decalinoid Li-chelated transition
Allyl, crotyl, and cinnamyl phosphonamides 1a -c
undergo remarkably stereoselective 1,4-additions to lac-
tones and lactams (Table 2). Diastereoselection in most
examples with five- and six-membered lactones is virtu-
ally complete. Little if any erosion of stereoselectivity was
observed when the intermediate enolates were quenched
with alkyl halides to provide lactones with up to three
contiguous stereogenic centers. In the case of benzylated
lactone 9b , prepared from allyl reagent 1a (entry 1),
(31) For discussions about relevant 10-membered transition states,
see: (a) Binns, M. R.; Haynes, R. K.; Katsifis, A. G.; Schober, P. A.;
Vonwiller, S. C. J . Am. Chem. Soc. 1988, 110, 5411. (b) Haynes, R. K.;
Katsifis, A. G.; Vonwiller, S. C.; Hambley, T. W. J . Am. Chem. Soc.
1988, 110, 5423.

Phosphonamide Anion Addition to Carbonyl Compounds
J . Org. Chem., Vol. 65, No. 18, 2000 5627
Ta ble 2. 1,4-Con ju ga te Ad d ition Rea ction s of 1a -c w ith r,â-Un sa tu r a ted La cton es a n d La cta m sa
a
The reaction mixture was quenched with NH4Cl or with MeI (10a , 12b, and 13b), BnBr (9b and 10c), or allyl bromide (10a ).
Determined from 1H, 13C, and 31P NMR parameters (all entries) and further substantiated from 13C NMR spectra of cyclic ketal-acetal
b
derivatives with (R,R)-2,3-butanediol after oxidative cleavage (entry 1) and Mosher esters of products after oxidative cleavage and reduction
(entries 2, 3, and 7-9). c Yield of isolated product after flash chromatography. After DBU equilibration. e Toluene as solvent, NaHMDS
d
as base. f Toluene as solvent.
Sch em e 5a
a
Reagents and conditions: (a) O3, CH2Cl2, -78 °C, then Me2S, 95%; (b) MeP(Ph3)Br, n-BuLi, THF, -50 °C, 58%; (c) H2, Pd/C, CHCl3,
99%.
followed by treatment with benzyl bromide, it was
necessary to equilibrate the product with DBU to obtain
a single isomer. In contrast, reactions with crotyl reagent
1b, followed by addition of an electrophile to the corre-
sponding enolates, proved to be highly stereoselective
(Table 2, entries 2 and 4, adducts 10b-d and 12b). The
1,4-additions and trapping of lactone enolates with
cinnamyl phosphonamide reagent 1c were also highly
stereoselective (Table 2, entries 5 and 6). The adducts
13a , 14a and 13b, 14b have two and three contiguous
stereocenters, including a phenyl appendage on the
acyclic chain. Easy access to highly functionalized chiral
nonracemic lactones made this technology a method of
choice for the key step in the total synthesis of (+)-
acetoxycrenulide by Paquette and co-workers.18
As in the case of ketones, initial assessment of stereo-
1
selectivity was done by the analysis of H, 13C, and 31P
NMR of addition products. In addition, Mosher ester and
bisdioxolane adducts of the lactone aldehydes obtained
after ozonolytic cleavage were used to confirm the initial
diastereoselectivities. To establish the absolute stereo-
chemistry for conjugate addition to lactones, compound
9a was converted to the known compound 1932 in three
steps (Scheme 5). It is noteworthy to point out that the
ozonolytic cleavage and subsequent reduction of the
lactone adducts 9, 10, and 13 (Table 2) did not result in
ring expansion to δ-lactones (see later); the product of
(32) Mukayama, T.; Fujimoto, K.; Hirose, T.; Takeda, T. Chem. Lett.
1980, 635.

5628 J . Org. Chem., Vol. 65, No. 18, 2000
Hanessian et al.
Ch a r t 1
Sch em e 6a
a
Reagents and conditions: (a) O3, CH2Cl2-MeOH, -78 °C, then NaBH4; (b) (R)-OAc-mandelic acid, DCC; (c) CAN, MeCN-H2O.
oxidative cleavage and reduction was found to be the
racemic δ-lactone as a result of equilibration between two
ω-hydroxy lactones of symmetrical structures. It was
possible to isolate the corresponding aldehydes (see Chart
1, compound 40).
the six-membered lactam (Table 2, entry 9) the diaster-
eomeric ratio of conjugate addition adducts dropped to
75:25. Diastereoselectivities were determined by analyz-
ing 19F NMR spectra of Mosher esters after oxidative
cleavage, reduction to the primary alcohol, and esterifi-
cation. To validate the reliability of assignments of
absolute configuration of the newly formed centers in the
lactam series, we prepared the mandelate 20 (Scheme
6) in four steps by ozonolysis of 16, followed by reductive
workup with NaBH4, condensation with (R)-(-)-O-acetyl-
mandelic acid, and deprotection of the PMB group. X-ray
crystallographic analysis confirmed the structure and
absolute stereochemistry of 20, and of the lactone adducts
in Table 2 by analogy.
Ad d ition to r,â-Un sa tu r a ted Ester s. Anions of al-
lylic phosphonamides undergo highly stereocontrolled
conjugate additions to R,â-unsaturated esters. In our
initial studies, we found that the reaction of 1a with
methyl or benzyl trans-cinnamates gave a mixture of
γ-1,4-adducts with only a 80:20 ratio of diastereomers
(Scheme 7). The stereoselectivity of the process improved
to 92:8 by employing secondary alkyl esters such as
The nature of the N-protecting group in R,â-unsatur-
ated lactams exhibits a significant effect on the stereo-
selectivity of the process. Initially, we observed very poor
stereocontrol with N-Boc and N-Ts protecting groups
(Scheme 6). We attributed these results to a possible
coordination of the N-protecting groups to the lithium
cation, which presumably alters the favored approach
from the left cleft of the (R,R)-reagent as discussed above
(Figure 1). To substantiate this assumption, we found
that stereoselectivity was markedly increased with the
use of the noncomplexing p-methoxybenzyl (PMB) group.
Thus, reaction of N-PMB R,â-unsaturated pyrrolidinone
with allyl and crotyl reagents 1a and 1b led to adducts
15 and 16 with excellent stereochemical outcome (Scheme
6, Table 2, entries 7 and 8). Toluene was a solvent of
choice in both cases, and NaHMDS replaced BuLi in the
synthesis of 15 to provide a higher yield. In the case of

Phosphonamide Anion Addition to Carbonyl Compounds
Sch em e 7a
J . Org. Chem., Vol. 65, No. 18, 2000 5629
a
Reagents and conditions: (a) n-BuLi, THF, -78 °C, then aq NH4Cl; (b) O3, CH2Cl2-MeOH, -78 °C, then NaBH4; (c) CBr4, Ph3P,
THF; (d) Bu3SnH, AlBN; (e) KOH, MeOH, 55% for three steps.
Ta ble 3. 1,4-Con ju ga te Ad d ition Rea ction s of 1a w ith
workup, gave the alcohol, which was brominated with
CBr4/Ph3P; the product was reduced with Bu3SnH and
then hydrolyzed with aq KOH to produce 23 in 55%
overall yield.
r,â-Un sa tu r a ted ester s
As in the cyclic enone series, we were successful in
quenching the intermediate enolates with electrophiles
for the acyclic series as well. A sequential conjugate
addition of 1a to tert-butyl trans-cinnamate, followed by
addition of methyl iodide (Table 3, entry 2), led to a 2:1
mixture of anti- and syn-adducts 21a and 21b, which
were separated by chromatography. The structure of the
major isomer 21a was unequivocally assigned by X-ray
analysis.
Conjugate addition of the crotyl reagent 1b to tert-butyl
trans-cinnamate afforded a single adduct, 26 (Table 3,
entry 3). Trapping the enolate with methyl iodide was
equally stereocontrolled to give 26a with three contiguous
stereogenic centers, essentially in one operation (Scheme
8, Table 3, entry 4). Structural and stereochemical
assignments were conclusively established by NOE data
on the corresponding lactone 29a and an X-ray structural
analysis of 29b (Scheme 8).
We were pleased to find that the reaction of 1a with
tert-butyl sorbate was highly regio- and stereoselective
to give the 1,4-adduct 27 as the major isomer (Table 3,
entry 5). Boyle and Kishi19 have used adduct 27 in their
structural studies of the natural product fumonisin B.
Finally, in an extension of the 1,4-addition reactions
in the acyclic series, we reacted 1a with isopropyl
crotonate to give the 1,4-adduct in excellent stereoselec-
tivity, albeit in 38% yield. The 1,4-additions of allyl
phosphonamide anions are more efficient with cinnama-
tes compared to crotonates, possibly due to a more
favorable reduction potential at the â-carbon atom when
an aromatic group is present, as well as to the prevalence
of a favored s-trans conformation.34 The stereochemical
outcome of phosphonamide anion additions to acyclic R,â-
unsaturated esters (Scheme 7, Table 3) can be rational-
ized by considering the proposed alignment of Li-
coordinated reactants to approximate favorable transition
a
Determined from 1H, 13C, and 31P NMR parameters (all
entries) and further substantiated from Mosher esters of products
b
after oxidative cleavage and reduction (entries 1-5). Yield of
isolated product after flash chromatography. c The γ-1,6-addition
product (7%) was also found.
2-propyl or diphenylmethyl. Remarkably, addition to tert-
butyl trans-cinnamate afforded a single diastereomer 21
(Table 3, entry 1). Oxidative cleavage and reduction
under standard conditions led to 22a , which gave a single
Mosher ester, 22b (Scheme 7). Since the Mosher ester
group in 22b is separated from the newly formed asym-
metric center by two carbon atoms, we chose to confirm
the stereochemical purity by an alternative route. Thus,
we synthesized the achiral vinyl phosphonamide 24
(Scheme 7), and converted it to a racemic Mosher ester,
25. Two well-separated peaks with a 1:1 ratio in the 19F
NMR spectrum ultimately confirmed the stereochemical
purity of the adduct 22b. The (S)-absolute configuration
at the benzylic carbon atom of adduct 21 was established
by converting it to the known acid 2333 in four steps
(Scheme 7). Thus, ozonolysis of 21, followed by reductive
(33) Brienne, M.-J .; Ouannes, C.; J acques, J . Bull. Soc. Chim. Fr.
1967, 613.
(34) For a discussion of enone conformations in conjugate reduction,
see: Chamberlin, A. R.; Reich, S. H. J . Am. Chem. Soc. 1985, 107,
1441.

5630 J . Org. Chem., Vol. 65, No. 18, 2000
Hanessian et al.
Sch em e 8a
a
Reagents and conditions: (a) O3, CH2Cl2-MeOH, -78 °C, then NaBH4; (b) CF3CO2H, CH2Cl2, rt.
F igu r e 2. (i) Disfavored left cleft trans-dacalinoid chair-chair-type TS. (ii) Disfavored right cleft trans-decalinoid chair-chair-
type TS. (iii) Disfavored left cleft cis-decalinoid boat-boat-type TS. (iv) Favored right cleft cis-decalionoid boat-boat-type TS.
states (Figure 2). Adopting a pictorial expression accord-
ing to Haynes,31 we can explain the stereochemical
outcome of the additions to tert-butyl cinnamate, for
example, by a favored si-face approach of the stabilized
γ-stabilized anion as in panel iv.
easily accessible (S,S)-reagents can lead to compounds
in the enantiomeric series.
Exp er im en ta l Section
1
Gen er a l P r oced u r es. H and 13C NMR spectra were
recorded at 300 and 75 MHz, respectively, and the
chemical shifts are reported in parts per million on the
δ scale with CHCl3 as reference. 31P NMR spectra were
recorded at 121 MHz with 85% H3PO4 as reference. 19F
spectra were recorded in CDCl3 at 282.2 MHz. IR spectra
were recorded as films. MS and HRMS spectra were
recorded using electron ionization or by the FAB tech-
nique. Organic solvents were dried by standard methods.
R,â-Unsaturated ketones and lactones were distilled
before use. Other commercially obtained reagents were
used without further purification. Flash chromatography
was performed on 230-400 mesh silica gel. Thin-layer
chromatography (TLC) was performed on glass plates
coated with a 0.02 mm layer of silica gel 60 F-254. Optical
rotations were measured in CHCl3 at 23 °C.
(3a R,7a R)-2-Allylocta h yd r o-1H-1,3-d im eth yl-1,3,2-
ben za d ia za p h osp h ole 2-Oxid e, 1a . To a cooled solu-
tion of (1R, 2R)-N,N′-dimethyl-1,2-cyclohexanediamine9
(3 g, 21.1 mmol) and Et3N (4.7 g, 46.6 mmol) in benzene
(80 mL) was added allylphosphonic dichloride according
to Corey and Cane13 (3.7 g, 23 mmol) in benzene (80 mL)
within 1 h at 0 °C. The reaction mixture was stirred at
ambient temperature for 18 h, and the salts were filtered
and washed with ethyl acetate (100 mL). The filtrate was
concentrated, and the residue was purified by silica gel
Con clu sion
Asymmetric 1,4-addition reactions using anions of
enantiomerically pure allyl phosphonamide reagents
1a -c offer practical routes to a variety of enantiopure
or highly enriched branched carbocyclic, heterocyclic, and
acyclic compounds (Chart 1). Some of the acyclic chirons
obtained by oxidative cleavage of the adducts can be
viewed as products of effective chemical asymmetrization
(Chart 1, 36b, and 37), as opposed to enzymatic asym-
metrization accomplished with esterases and dialkyl
3-substituted glutarates.35 Good to excellent stereoselec-
tivity was achieved in generating stereogenic centers in
one-pot addition-alkylation sequences. Of particular
preparative significance is the successful adaptation of
these reactions to acyclic R,â-unsaturated esters, with the
generation of three contiguous stereogenic centers in one
operation. The unique structural, topological, and sym-
metry-related features of the allylic phosphonamide
reagents are mostly responsible for the excellent stereo-
and regiocontrol in these 1,4-addition reactions. The
(35) (a) Lam, L. K. P.; Hui, R. A. H. F.; J ones, J . B. J . Org. Chem.
1986, 51, 2047. (b) See also: Ohno, M.; Otsuka, M. Org. React. 1989,
37, 1.

Phosphonamide Anion Addition to Carbonyl Compounds
J . Org. Chem., Vol. 65, No. 18, 2000 5631
chromatography (95:5 ethyl acetate-MeOH) to give 4.50
g (92%) of the product: mp 45-46 °C (hexane); [R]D
-51.1° (c 1.85; CHCl3); 1H NMR δ 5.85-5.70 (1H, m
CHdCH2), 5.20-5.10 (2H, m, CHdCH2), 2.59 (3H, d, J
) 12.0 Hz, NCH3), 2.56 (3H, d, J ) 13.4 Hz, NCH3), 2.85-
2.45 (4H, M, 2CHN, PCH2), 2.15-1.80 (4H, m, cyclohex-
ane), 1.40-1.00 (4H, m, cyclic); 13C NMR δ 129.2 (d, J )
10 Hz), 118.5 (d, J ) 13.1 Hz), 64.2 (d, J ) 7.9 Hz), 64.2
(d, J ) 4.9 Hz), 33.6 (d, J ) 109.6 Hz), 29.4, 28.3 (d, J )
9.9 Hz), 27.9 (d, J ) 4.7 Hz), 27.8; HRMS calcd for
C11H21N2OP 228.1391, found 228.1384.
(3aR,7aR)-2-Cr otyloctah ydr o-1H-1,3-dim eth yl-1,3,2-
ben za d ia za p h osp h ole 2-Oxid e, 1b. The crotyl phos-
phonamide was prepared from (1R,2R)-N,N′-dimethyl-
1,2-cyclohexanediamine(2.1g,14.8mmol)andcrotylphosphonic
dichloride13 (2.9 g, 16.9 mmol) by using the procedure
described above for the synthesis of 1a : yield 3.33 g
(93%); mp 29-30 °C; [R]D -68.0° (c 0.94; CHCl3); 1H NMR
δ 5.55 (1H, m, 10.3, 11.7 Hz, 2NCH3), 2.09-1.73 (4H, m,
cyclohexane), 1.70 (3H, m, CHCH3), 1.40-1.05 (4H, m,
cyclic); 13C NMR, δ 129.1, 121.0, 64.0, 31.7, 30.3, 29.3,
28.2, 27.9, 27.7, 23.8, 17.5; 31P δ 42.90; HRMS calcd for
C12H23N2OP 242.1546, found 242.1530.
(3a R,7a R)-2-Cin n a m ylocta h yd r o-1H-1,3-d im eth yl-
1,3,2-ben za d ia za p h osp h ole 2-Oxid e, 1c. 1c was pre-
pared according to the method described for 1b, from the
diamine (0.46 g, 3.2 mmol) and cinnamylphosphonic
dichloride34 (0.8 g, 3.5 mmol) in benzene. Purification of
the crude product by silica gel chromatography gave the
title compound 1c (0.84 g, 87%) as a white solid: mp 57-
58 °C; [R]D +76° (c 1.25, CHCl3); 1H NMR δ 7.45 (5H, m,
Ph), 6.53 (1H, m, CHsCHpH), 6.23 (1H, m, CHdCHPh),
2.90 (4H, m P(O)CH2, CHN), 2.54 (6H, 2d, J ) 11.15 Hz,
NMe), 2.09-1.73 (4H, m, cyclohexane); 13C NMR δ 137,
129.5, 127.13, 126.91, 134, 121, 64.75, 32.13, 31.5, 30.7,
29.7, 28.5, 27.87, 27.56, 23.7, 20.21; 31P δ 42.10; HRMS
calcd for C17H25N2OP 304.1880, found 304.1878.
could not be detected by TLC (∼20-30 min). The reaction
flask was flushed with argon to remove residual O3, and
then Me2S (0.5 mL) was added. The mixture was allowed
to warm to ambient temperature and stirred for 1 h. The
mixture was diluted with CH2Cl2 (10 mL) and washed
with water (5 mL). The organic layer was separated,
dried (MgSO4), and concentrated in vacuo. Purification
of the reaction mixture by silica gel chromatography
(hexane -EtOAc) provided an aldehyde. Corresponding
ketal-acetals were prepared by the reaction of the
aldehyde with (R,R)-2,3-butanediol and TsOH according
to the literature.5a (b) This procedure was the same as
(a) except instead of CH2Cl2 a mixture of CH2Cl2-MeOH
(1.5:1) was used and instead of Me2S NaBH4 (5 equiv)
was used. Resulting alcohols were transformed to Mosher
esters according to the literature.36
(3S)-Allyl Bu tyr ola cton e, 18. A 2.5 M solution of
n-BuLi in hexanes (0.19 mL, 0.475 mmol) was added
dropwise to a suspension of methyltriphenylphosphonium
bromide (0.17 g, 0.475 mmol) in THF (4 mL) at 0 °C. The
mixture was stirred at 0 °C for 20 min and then cooled
to -50 °C. The ylide was added dropwise by cannula to
a -50 °C solution of the aldehyde formed from the
ozonolysis of 9a (0.058 g, 0.452 mmol) in THF (3 mL).
The mixture was stirred at -50 °C for 1 h and then
stirred at ambient temperature overnight. The reaction
mixture was quenched with glacial AcOH, stirred for 30
min, and extracted with dichloromethane. The organic
layer was dried (MgSO4) and concentrated and the
residue purified by flash chromatography (hexanes-
EtOAc, 3:1) to give volatile olefin 18 (0.033 g, 58%); [R]D
-3.20° (c ) 0.25); IR (film) 1775 cm-1; 1H NMR δ 5.80-
5.67 (m, 1H), 5.15-5.08 (m, 2H), 4.40 (dd, J ) 9.0 and
7.2 Hz, 1H), 4.00 (dd, J ) 9.0 and 5.7 Hz, 1H), 2.70-
2.17 (m, 5H).
19. Compound 18 (0.033 g, 0.262 mmol) was dissolved
in chloroform (3 mL) and hydrogenated over 10% pal-
ladium on carbon for 30 min. The catalyst was removed
by filtration and the solvent evaporated at ambient
temperature to give pure lactone 19 (0.033 g, 99%). [R]D
-5.6° (c 0.90, EtOH) (lit.30 [R]D -7.3° for the (S)-lactone);
IR (film) 1775 cm-1; 1H NMR δ 4.42 (dd, J ) 9.0 and 7.5
Hz, 1H), 3.92 (dd, J ) 9.0 and 7.0 Hz, 1H), 2.67-2.50
(m, 2H), 2.23-2.14 (m, 1H), 1.48-1.28 (m, 4H), 0.94 (t,
J ) 7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 177.0, 73.2,
35.3, 35.1, 34.4, 20.4, 13.7; HRMS calcd for C7H12O2
129.0924, found 129.0921 (M + H)+.
Gen er a l P r oced u r e for 1,4-Ad d ition . To a solution
of allyl phosphonamide (1 mmol) in THF (10 mL) was
added n-BuLi (1.2 mmol, 1.6 or 2.5 M solution in hexane)
at -78 °C under argon. A solution of R,â-unsaturated
carbonyl compound (1.2 mmol) in THF (5 mL) at -78 °C
was added immediately via cannula. The reaction mix-
ture was stirred at -78 °C for 30 min, slowly quenched
with saturated aqueous NH4Cl or with MeOH, with MeI
(10 equiv), with BnBr (5 equiv), and with allyl bromide
(5 equiv) and allowed to warm to ambient temperature.
The mixture was diluted with EtOAc (50 mL) and washed
with brine (20 mL) and water (20 mL). The organic layer
was separated, dried (MgSO4), and concentrated in vacuo.
The resulting crude product was purified by column
chromatography (EtOAc-MeOH). Individual yields are
Ack n ow led gm en t. We thank the NSERCC for
general financial assistance. We also thank Dr. Michel
Simard for the X-ray analyses.
Su p p or tin g In for m a tion Ava ila ble: 1H, 13C, and 31P
NMR data, IR data, mass spectral data, [R]D values, copies of
1H, 13C, 31P, and 19F NMR spectra, and X-ray structural data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
1
listed in Tables 1-3; physical constants (IR and H, 13C,
and 31P NMR data and copies of spectra) can be found in
the Supporting Information.
Gen er a l P r oced u r e for th e Oxid a tive Clea va ge of
1,4-Ad d ition P r od u cts. (a) A -78 °C solution of 1,4-
addition product (0.3 mmol) in dry CH2Cl2 (13 mL) was
treated with a stream of O3 in O2 until starting material
J O000388G
(36) Dale, J . A.; Dull, D. L.; Mosher, H. S. J . Org. Chem. 1969, 34,
2543.