An allyltitanium derived from acrolein 1,2-dicyclohexylethylene acetal and (η2-propene)Ti(o-i-Pr)2 as a chiral propionaldehyde homoenolate equivalent that reacts with imines with excellent stereoselectivity. An efficient and practical access to optically active γ-amino carbonyl compounds

Article abstract of DOI:10.1021/ja004140k

A chiral allyltitanium compound 2, prepared in situ by the reaction of optically active acrolein 1,2-dicyclohexylethylene acetal (3) with (η²-propene)Ti(O-i-Pr)₂ (1), reacts with a variety of acyclic and cyclic imines 4 in a regiospecific way to afford α-addition products 5 as a mixture of the E- and Z-isomers in good combined yield, where the former is predominant in a ratio of 92: 8 to >95:5. The mixture of (E)- and (Z)-5 and pure (E)-5 which could be isolated in several cases were respectively converted to the corresponding β-amino ester 6 to confirm the absolute configuration and enantiomeric purity. The ee of the newly formed asymmetric center of 5 is more than 78% for the mixture of (E)- and (Z)-5 and more than 96% for pure (E)-5. By taking advantage of the versatility of the vinyl ether moiety in 5, optically active γ-amino aldehydes 8, γ-amino aldehyde acetals 7 and 10, γ-amino acids 9, β-amino esters 6, and pyrrolidinoisoquinolines 12 were readily prepared. In the reaction of 2 with optically active α-silyloxyimine 4n, remarkable double stereodifferentiation was observed; thus, the reaction of 2 derived from (S,S)- or (R,R)-3 provided syn- and anti-5n in a ratio of 55:45 or 0:100, respectively. Meanwhile, the stereochemistry of the product in the reaction of 2 with β-silyloxyimine 4o was controlled mainly by 2. Thus, the reaction of β-silyloxyimine 14 with 2 derived from 1 and (R,R)-3 afforded γ-silyloxyimine 15 with 92% diastereoselectivity, from which 4-amino6-hydroxypentadecanal dimethyl acetal (13), a key intermediate for the synthesis of batzelladine D, was synthesized.

Full text of DOI:10.1021/ja004140k

3462
J. Am. Chem. Soc. 2001, 123, 3462-3471
An Allyltitanium Derived from Acrolein 1,2-Dicyclohexylethylene
Acetal and (η2-propene)Ti(O-i-Pr)2 as a Chiral Propionaldehyde
Homoenolate Equivalent that Reacts with Imines with Excellent
Stereoselectivity. An Efficient and Practical Access to Optically
Active γ-Amino Carbonyl Compounds
Sentaro Okamoto, Xin Teng, Shintaro Fujii, Yuuki Takayama, and Fumie Sato*
Contribution from the Department of Biomolecular Engineering, Tokyo Institute of Technology,
4259 Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa 226-8501, Japan
ReceiVed December 1, 2000
Abstract: A chiral allyltitanium compound 2, prepared in situ by the reaction of optically active acrolein
1,2-dicyclohexylethylene acetal (3) with (η2-propene)Ti(O-i-Pr)2 (1), reacts with a variety of acyclic and cyclic
imines 4 in a regiospecific way to afford R-addition products 5 as a mixture of the E- and Z-isomers in good
combined yield, where the former is predominant in a ratio of 92:8 to >95:5. The mixture of (E)- and (Z)-5
and pure (E)-5 which could be isolated in several cases were respectively converted to the corresponding
â-amino ester 6 to confirm the absolute configuration and enantiomeric purity. The ee of the newly formed
asymmetric center of 5 is more than 78% for the mixture of (E)- and (Z)-5 and more than 96% for pure (E)-5.
By taking advantage of the versatility of the vinyl ether moiety in 5, optically active γ-amino aldehydes 8,
γ-amino aldehyde acetals 7 and 10, γ-amino acids 9, â-amino esters 6, and pyrrolidinoisoquinolines 12 were
readily prepared. In the reaction of 2 with optically active R-silyloxyimine 4n, remarkable double
stereodifferentiation was observed; thus, the reaction of 2 derived from (S,S)- or (R,R)-3 provided syn- and
anti-5n in a ratio of 55:45 or 0:100, respectively. Meanwhile, the stereochemistry of the product in the reaction
of 2 with â-silyloxyimine 4o was controlled mainly by 2. Thus, the reaction of â-silyloxyimine 14 with 2
derived from 1 and (R,R)-3 afforded γ-silyloxyimine 15 with 92% diastereoselectivity, from which 4-amino-
6-hydroxypentadecanal dimethyl acetal (13), a key intermediate for the synthesis of batzelladine D, was
synthesized.
Introduction
corresponding reaction with aldehydes and ketones. This is due
to the inability of certain nucleophiles to add to imino
compounds, coupled with the propensity of basic reagents to
preferentially abstract protons R to the imino group. For
example, although many homoenolate synthons, including their
chiral form, which react selectively with carbonyl compounds,
have been reported and have been widely used in organic
synthesis,3 to the best of our knowledge, only one achiral
homoenolate equivalent has been reported to react with imines.4
Thus, Fang et al. generated a dithio-substituted crotyllithium
from 2-propenyl-1,3-dithiane and n-BuLi and showed that it
reacted with aldimines to afford the corresponding ketene
dithioacetals exclusively. However, the synthetic utility and
scope of the reaction have remained unexplored, and develop-
ment of the reagent to a chiral form seems difficult.
Chiral cyclic and acyclic amines bearing a stereogenic center
at the R-position are widely distributed in nature and include
many biologically important molecules, and thus, their asym-
metric synthesis has attracted much interest. Diastereo- or
enantioselective addition reaction of carbanions with imines and
imine derivatives affords an attractive access to these com-
pounds;1,2 however, the scope and a variety of this kind of
reaction have been considerably limited in comparison with the
(1) Reviews for the asymmetric nucleophilic addition reactions to
imines: Enders, D.; Reinhold: U. Tetrahedron: Asymmetry 1997, 8, 1895.
Denmark, S. E.; Nicaise, O. J.-C. Chem. Commun. 1996, 999. Bloch, R.
Chem. ReV. 1998, 98, 1407. Kobayashi, S.; Ishitani, H. Chem. ReV. 1999,
99, 1069. Kleinman, E. F. In ComprehensiVe Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 2, p 893.
Recently, we have reported a new efficient method for
preparing allyltitanium complexes by the reaction of allylic
alcohol derivatives with a divalent titanium reagent (η2-
(3) Reviews: Kuwajima, I.; Nakamura, E. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol.
2, p 441. Kuwajima, I.; Nakamura, E. Top. Curr. Chem. 1990, 155, 1. Ryu,
I.; Sonoda, N. Synth. Org. Chem., Jpn. 1985, 43, 112. Werstiuk, N. H.
Tetrahedron 1983, 39, 205. Katritzky, A. R.; Piffl, M.; Lang, H.; Anders,
E. Chem. ReV. 1999, 99, 665. See also: Hoppe, D. Angew. Chem., Int. Ed.
Engl. 1984, 23, 932. Review for chiral homoenolate equivalents: Ahlbrecht,
H.; Beyer, U. Synthesis 1999, 365.
(2) Most recent examples: Sato, I.; Kodaka, R.; Shibata, T.; Hirokawa,
Y.; Shirai, N.; Ohtake, K.; Soai, K. Tetrahedron: Asymmetry, 2000, 11,
2271. Saito, S.; Hatanaka, K.; Yamamoto, H. Org. Lett. 2000, 2, 1891.
Kobayashi, S.; Ishitani, H. Chirality 2000, 12, 540. Hamada, T.; Mizojiri,
R.; Urabe, H.; Sato, F. J. Am. Chem. Soc. 2000, 122, 7138. Hanessian, S.;
Griffin, A. M.; Cantin, L.-D. Chirality 2000, 12, 342. Garc´ıa Ruano, J. L.;
Alcudia, A.; del Prado, M.; Barros, D.; Maestro, M. C.; Ferna´ndez, I. J.
Org. Chem. 2000, 65, 2856. Alvaro, G.; Grepioni, F.; Grilli, S.; Maini, L.;
Martelli, G.; Savoia, D. Synthesis 2000, 581. Porter, J. R.; Wirschun, W.
G.; Kuntz, K. W.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000,
122, 2657. Vachal, P.; Jacobsen, E. N. Org. Lett. 2000, 2, 867. Roland, S.;
Mangeney, P. Eur. J. Org. Chem. 2000, 611. Cossy, J.; Pe´vet, I.; Meyer,
C. Synlett 2000, 122. Miyabe, H.; Ushiro, C.; Ueda, M.; Yamakawa, K.;
Naito, T. J. Org. Chem. 2000, 65, 176.
(4) Fang, J.-M.; Chen, S. T.; Chen, I.-H. J. Organomet. Chem. 1990,
398, 219.
10.1021/ja004140k CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/24/2001

Optically ActiVe γ-Amino Carbonyl Compounds
J. Am. Chem. Soc., Vol. 123, No. 15, 2001 3463
propene)Ti(O-i-Pr)2 (1),5 readily generated in situ from Ti(O-
i-Pr)4 and 2 equiv of i-PrMgX, which proceeds via an oxidative
addition pathway.6 The resulting allyltitaniums react with
aldehydes and ketones at the γ-position exclusively to provide
homoallylic alcohols. During these studies we found that the
allyltitanium 2 obtained from 1 and chiral acrolein 1,2-
dicyclohexylethylene acetal (3) reacts with aldehydes and
ketones at the R- rather than the γ-position highly selectively
as shown in eq 1.7 In all cases, the resulting R-addition product
Table 1.
afford 85% yield of the R-addition product 5c as a mixture of
E- and Z-enol ethers in a ratio of 94:6 (eq 2), and from which
consists of a mixture of inseparable E- and Z-enol ethers, and
the 13C NMR analysis of the mixture indicated that the chiral
induction at the newly generated asymmetric center was low
(see Supporting Information). These results strongly indicated
that 2 works as a convenient homoenolate equivalent, but not
as an efficient chiral homoenolate equivalent for the reaction
with carbonyl compounds.
As allyltitaniums also react with imines smoothly, we then
turned our attention to the reaction of 2 with imines, in
anticipation of developing for the first time a propionaldehyde
homoenolate equivalent that can react with imines. Furthermore,
we had some expectation of attaining high chiral induction
because the reaction of allyltitaniums with imines proceeds with
far better stereoselectivity than that of the reaction with
aldehydes.6b,d,h
pure (E)-5c was isolated in 70% yield by column chromatog-
raphy. The mixture of (E)- and (Z)-5c itself as well as the pure
(E)-5c was respectively converted into the known methyl
3-amino-4-methylpentanoate (6c) by conventional methods, and
the configuration of a stereogenic center bearing an amino group
as well as the enantiomeric excess (ee) was determined (vide
infra). To our surprise as well as to our delight, the ee of 6c
derived from the mixture was 88% and that of pure (E)-5c,
which has the structure depicted in eq 2, was very high, reaching
98%.
With this finding, to see whether 3 is the optimum acetal or
not, we investigated the reaction of 4c with allyltitaniums
derived from 1 and a few acrolein chiral acetals other than 3
such as 1,2-dimethyethylene and 1,2-diphenylethylene acetal,
and 1,3-dicyclohexylpropylene acetal.9 As revealed from Table
1, which summarizes the results, the allyltitanium 2 derived from
3 was found to work as the most efficient chiral propionaldehyde
We have now found that 2 works as an efficient chiral
homoenolate equivalent that reacts with a variety of imines, thus
opening an easy access to optically active γ-amino carbonyl
compounds.8
1
homoenolate equivalent; the diastereoselectivity judged by H
Results and Discussion
NMR analysis of the corresponding main product and the overall
ee value of 5 (shown in Table 1) were the highest for the reaction
with 3.
Reaction of 2 with Imines. The reaction of 2 derived from
(R,R)-3 with imine 4c, prepared from 2-methylpropanal and
benzylamine, proceeds smoothly and in a regiospecific way to
We then investigated the reaction of 2 with various imines
other than 4c, and the results are summarized in Table 2. It can
be seen from the table that a variety of acyclic and cyclic
aldimines reacted with 2 with excellent selectivity similarly to
secondary aldimine 4c. These aldimines involve methylimines
(entry 1), primary alkylimines (entry 2), arylimines (entries
5-7), five-membered cyclic imines (entry 9), and six-membered
cyclic imines including 3,4-dihydroisoquinolines (entries 10-
12). Tertiary alkylimines and acyclic ketimines, however, did
not react with 2, presumably due to their larger steric require-
ment (entries 4 and 8). In contrast to acyclic ketimines, cyclic
ketimine 4m reacted smoothly with 2 (entry 13), probably owing
to its strained dehydropiperidine structure. It is worth noting
that the ee of the product 5m was higher than that of 5l (entry
12), the reaction product of aldimines having a similar structure,
(5) Reviews for the synthetic utility of 1: Sato, F.; Urabe, H.; Okamoto,
S. Pure Appl. Chem. 1999, 71, 1511. Sato, F.; Urabe, H.; Okamoto, S. J.
Synth. Org. Chem. Jpn. 1998, 56, 424. Sato, F.; Urabe, H.; Okamoto, S.
Synlett 2000, 753. Sato, F.; Urabe, H.; Okamoto, S. Chem. ReV. 2000, 100,
2835.
(6) (a) Kasatkin, A.; Nakagawa, T.; Okamoto, S.; Sato, F. J. Am. Chem.
Soc. 1995, 117, 3881. (b) Gao, Y.; Sato, F. J. Org. Chem. 1995, 60, 8136.
(c) Kasatkin, A.; Sato, F. Angew. Chem., Int. Ed. Engl. 1996, 35, 2848. (d)
Hikichi, S.; Gao, Y.; Sato, F. Tetrahedron Lett. 1997, 38, 2867. (e) Teng,
X.; Kasatkin, A.; Kawanaka, Y.; Okamoto, S.; Sato, F. Tetrahedron Lett.
1997, 38, 8977. (f) Teng, X.; Okamoto, S.; Sato, F. Tetrahedron Lett. 1998,
39, 6927. (g) Matsuda, S.; An, D. K.; Okamoto, S.; Sato, F. Tetrahedron
Lett. 1998, 39, 7513. (h) Okamoto, S.; Fukuhara, K.; Sato, F. Tetrahedron
Lett. 2000, 41, 5561. (i) Okamoto, S.; Sato, F. J. Organomet. Chem. In
press.
(7) These results strongly indicate that the allyltitanium 2 is in equilibrium
with its internal titanium form (depicted in Scheme 1, vide infra) and the
reaction with the carbonyl compounds proceeds mainly through this internal
form.
(8) For a preliminary account of this work, see: Teng, X.; Takayama,
Y.; Okamoto, S.; Sato, F. J. Am. Chem. Soc. 1999, 121, 11916.
(9) Reviews for use of C2-symmetric diols as a chiral auxiliary:
Whitesell, J. K. Chem. ReV. 1989, 89, 1581. Alexakis, A.; Mangeney, P.
Tetrahedron: Asymmetry, 1990, 1, 477.

3464 J. Am. Chem. Soc., Vol. 123, No. 15, 2001
Okamoto et al.
Table 2. Asymmetric Addition Reaction of the Allyltitanium
Compound 2 Derived from 1 and 3 with Imines 4
Scheme 1
shown in Scheme 1, which has a trans-fused chair-chair
conformation.12
Reaction of 2 with r- and â-Alkoxy Imines. Properly
functionalized 1,2- and 1,3-alkoxyamines (â- or γ-alkoxyamines)
can serve as key intermediates for the synthesis of biologically
active compounds.13 We were, therefore, interested in the
reaction of 2 with optically active R- or â-alkoxyimines such
as 4n and 4o (eqs 3 and 4). In these reactions, since the
electrophile (imine) and the nucleophile (allyltitanium) are both
chiral, double asymmetric differentiation was expected.14 For
the reaction with R-silyloxyimine 4n remarkable double asym-
metric differentiation was observed. Thus, as shown in eq 3,
a No γ-addition product was observed. Absolute configuration was
determined for 5a-c,e,k,m (see Supporting Information), and, in other
cases, was speculated in analogy with them. b Determined by 1H NMR
analysis. c Unless otherwise indicated, 5 was isolated by column
chromatography. d Determined after conversion to 6 for entries 1-7
or to 10 for entries 9-13 (see Schemes 2 and 3). e Ee of 6 or 10 derived
from the mixture of (E)- and (Z)-5. f 4h was an 18:1 mixture of E and
Z isomers. g Isolated as the N-benzyloxycarbonyl derivative. h Isolated
by recrystallization after column chromatography. i Ee of 10k derived
from recrystallized (E)-5k.
although it is widely observed that the asymmetric nucleophilic
addition reaction with ketimines usually affords lower ee than
that attained with aldimines.1,10 In addition to 5c, pure (E)-5e
and -5k could be easily isolated by column chromatography or
recrystallization, respectively, and the corresponding ee of which
was more than 96%. For the other entries in Table 2, the
separation of (E)- and (Z)-5 is difficult or tedious; however,
even in these cases, use of the mixture for further elaboration
is synthetically attractive because of the high level of ee that is
attainable.
while the reaction of 4n15 having (S)-configuration with 2
derived from (S,S)-3 proceeded with complete diastereoselec-
(11) A similar stabilization of allyltitaniums by intramolecular chelation
or coordination has been reported, see: Hanko, R.; Hoppe, D. Angew. Chem.,
Int. Ed. Engl. 1982, 21, 372. Weidmann, B.; Seebach, D. Angew. Chem.,
Int. Ed. Engl. 1983, 22, 31. Roder, H.; Helmchen, G.; Peters, E.-M.; Peters,
K.; von Schnering, H.-G. Angew. Chem., Int. Ed. Engl. 1984, 23, 898.
Zubaidha, P. K.; Kasatkin, A.; Sato, F. Chem. Commun. 1996, 197. See
also ref 6f.
(12) Yamamoto, Y.; Nishii, S.; Maruyama, K.; Komatsu, T.; Ito, W. J.
Am. Chem. Soc. 1986, 108, 7778.
(13) Leading references: (a) Sakaitani, M.; Ohfune, Y. J. Am. Chem.
Soc. 1990, 112, 1150. (b) Ishimaru, K.; Tsuru, K.; Yabuta, K.; Wada, M.;
Yamamoto, Y.; Akiba, K. Tetrahedron 1996, 52, 13137.
The predominant production of (E)-5 with the absolute
configuration depicted in Table 2, the sense of which should
be noted to be different between acyclic and cyclic imines, can
be explained by assuming that the allyltitanium complex
generated from 1 and 3 would exist mostly as an internal
titanium derivative that can be stabilized by chelation, rather
than as the primary derivative,11 and the reaction with imines
proceeds preferentially via the most stable transition state, as
(10) For example, see: Hanessian, S.; Yang, R.-Y. Tetrahedron Lett.
1996, 37, 8997. Nakamura, K.; Hirai, A.; Nakamura, E. J. Am. Chem. Soc.
1996, 118, 8489.
(14) Double stereodifferentiation of the reaction of a chiral imine with
a chiral allylmetal reagent has been reported; see: Hallett, D. J.; Thomas,
E. J. J. Chem. Soc., Chem. Commun. 1995, 657.

Optically ActiVe γ-Amino Carbonyl Compounds
J. Am. Chem. Soc., Vol. 123, No. 15, 2001 3465
Scheme 2a
Scheme 3a
a Conditions: (i) Ac2O, pyridine; (ii) p-TsOH catalyst, MeOH; (iii)
(CF3CO)2O, Et3N, CH2Cl2.
a Conditions: (i) (Boc)2O, Et3N, THF; (ii) O3, Me2S, CH2Cl2; (iii)
NaClO2, NaH2PO4, 2-methyl-2-butene, t-BuOH-H2O; (iv) MeI, NaH-
CO3, DMF; (v) Ac2O, pyridine, DMAP catalyst; (vi) p-TsOH catalyst,
MeOH; (vii) TFA, CH2Cl2-H2O.
Scheme 4a
tivity to afford 5n with anti-stereochemistry exclusively, the
reaction with 2 derived from (R,R)-3 gave a diastereomeric
mixture of 5n in a ratio of 55:45.16 In contrast, as shown in eq
4, little double stereodifferentiation was observed for the
a Conditions: (i) (Boc)2O, Et3N, CH2Cl2; (ii) Ac2O, pyridine; (iii)
TFA, CH2Cl2-H2O; (iv) NaHBH4, EtOH; (v) MsCl, Et3N, CH2Cl2;
(vi) TFA, CH2Cl2 and then quenched with saturated aqueous NaHCO3.
converted into the corresponding γ-amino aldehyde dimethyl
acetal 7 by acidic methanolysis.18 Acidic hydrolysis of the
resulting 7 afforded the γ-amino aldehyde 8 which, in turn, was
converted to the γ-amino acid 9 by oxidation with sodium
chlorite. The compound 5 can also be converted to â-amino
ester 619 by conventional reaction sequence. Similarly, from the
cyclic amines 5i-m the corresponding N-protected γ-amino
aldehyde dimethyl acetals 10i-m20 were readily prepared
(Scheme 3).
From the compounds 5k and 5m, optically active pyrrolidi-
noisoquinolines, the structure of which exists in plant alkaloids,21
could be easily synthesized as shown in Scheme 4. Thus, the
N-Boc-O-acetyl derivatives of 5k and 5m were successively
treated with TFA and H2O in CH2Cl2 and then NaBH4 in EtOH
to provide the corresponding alcohols 11k and 11m which, in
turn, were converted to the corresponding known pyrrolidi-
noisoquinolines 12k and 12m,22 respectively, by deprotective
cyclization after mesylation.
reactions with a â-silyloxyimine 4o15 and the stereochemistry
was controlled mainly by 2; thus, the reaction affords either
syn- or anti-5o with more than 92% diastereoselectivity. As the
resulting products have an enol ether moiety that allows further
elaboration, a new efficient entry to optically active â-alkoxy-
amines with anti-stereochemistry and γ-alkoxyamines with
either syn- or anti-stereochemistry has conclusively been opened
up.
Synthetic Transformation of the Addition Products 5 and
Preparation of a Key Intermediate for the Synthesis of
Batzelladine D. By taking advantage of the reactivity of the
enol ether functionality, the products 5 could be readily
transformed into a variety of aminocarbonyl compounds.17 As
represented by the reaction of 5c shown in Scheme 2, after
protection of 5 as the N-Boc-O-acetyl derivative, it was readily
We also carried out the synthesis of 4-amino-6-hydroxypen-
tadecanal dimethyl acetal (13), which is a key intermediate for
the Overman synthesis of an anti-HIV polyguanidine alkaloid
Batzelladine D (Scheme 5).23 Thus, the optically active â-silyl-
(15) Imines 4n and 4o were prepared according to the reported
procedure: Yamamoto, Y.; Komatsu, T.; Maruyama, K. J. Chem. Soc.,
Chem. Commun. 1985, 814. Cainell, G.; Giacomini, D.; Mezzina, E.;
Panunzio, M.; Zarantonello, P. Tetrahedron Lett. 1991, 32, 2967. See also
ref 13b.
(16) The reaction of 4n with allyltitanium derived from acrolein 1,1,2,2-
tetramethylethylene acetal afforded the corresponding anti- and syn-adducts
in a ratio of 90:10.
(17) Recent reviews for syntheses of â-amino acids, see: (a) Juaristi,
E.; Lopez-Ruiz, H. Curr. Med. Chem. 1999, 6, 983. (b) Yamamoto, Y.;
Asao, N.; Tsukada, N. AdV. Asymmetric Synth. 1998, 3, 1. (c) Enantiose-
lectiVe Synthesis of â-Amino Acids; Juaristi, E., Ed.; Wiley-VCH: New
York, 1997. Synthesis of optically active γ-amino acids attracts current
interest; see: (d) Smrcina, M.; Majer, P.; Majerova´, E.; Guerassina, T. A.;
Eissenstat, M. A. Tetrahedron 1997, 53, 12867 and references therein. For
the biological importance of γ-amino acids, see: (e) Nanavati, S. M.;
Silverman, R. B. J. Am. Chem. Soc. 1991, 113, 9341. (f) Burke, J. R.;
Silverman, R. B. J. Am. Chem. Soc. 1991, 113, 9329. See also ref 17d.
(18) Treatment of a crude mixture including 7 and the monoacetate of
1,2-dicyclohexylethandiol with NaOH in MeOH followed by column
chromatography after extractive workup gave 7 in 70% yield and 1,2-
dicyclohexylethandiol in 63% yield.
1
(19) Ee of 6c was confirmed by H NMR analysis after conversion to
the corresponding MTPA amides. The absolute configuration was deter-
mined by conversion of the corresponding N-Cbz derivative and comparison
of its [R]D value with that reported. See Supporting Information.
(20) Ee of 10 thus obtained was determined by HPLC analysis with use
of a chiral column.
(21) Boekelheide, V. Alkaloids 1960, 7, 201. Hill, R. K. Alkaloids 1967,
9, 483.
(22) The spectroscopic data of 12k and 12m thus prepared were in good
agreement with those reported, and their absolute configuration was
determined by comparison of their [R]D values with those reported: (a)
Lee, Y. S.; Kang, D. W.; Lee, S. J.; Park, H. J. Org. Chem. 1995, 60,
7149. (b) Meyers, A. I.; Gonzalez, M. A.; Struzka, V.; Akahane, A.; Guiles,
J.; Warmus, J. S. Tetrahedron Lett. 1991, 32, 5501.

3466 J. Am. Chem. Soc., Vol. 123, No. 15, 2001
Okamoto et al.
Scheme 5a
solution from i-PrCl and magnesium turnings by the usual procedure,
titrated, and stocked under argon atmosphere. All reactions sensitive
to oxygen or moisture were conducted under an argon or nitrogen
atmosphere in a flame-dried flask.
Acrolein (R,R)-1,2-Dicyclohexylethylene Acetal (3). To a solution
of (1R,2R)-(-)-1,2-dicyclohexyl-1,2-ethanediol (2.26 g, 10 mmol,
Aldrich) and p-toluenesulfonic acid hydrate (30 mg) in dichloromethane
(40 mL) was added dropwise acrolein diethyl acetal (1.7 mL, 13 mmol)
at 0 °C. The resulting solution was stirred at room temperature for 2 h
and then quenched by addition of saturated aqueous NaHCO3 (40 mL).
The organic layer was separated and the aqueous layer was extracted
with ether (2 × 15 mL). The combined organic layers were dried over
anhydrous MgSO4, filtered, and concentrated under reduced pressure.
The residue was purified by passing through a short silica gel column
(hexanes/ether ) 3/1) to give 3 as a colorless oil (2.50 g, 95%): [R]26
D
+28.5 (c 1.10, CHCl3); IR (neat) 2924, 2852, 1449, 1346, 1103, 983,
933, 891 cm-1; 1H NMR δ 0.95-2.00 (m, 22H, C6H11), 3.62 (dd, J )
5.1, 6.6 Hz, 1H, C6H11CHO), 3.67 (t, J ) 5.3 Hz, 1H, C6H11CHO),
5.22 (d, J ) 6.6 Hz, 1H, CH2dCHCH), 5.34 (d, J ) 10.2 Hz, 1H,
CH2dCHCH), 5.46 (d, J ) 16.8 Hz, 1H, CH2dCHCH), 5.82 (ddd, J
) 6.6, 10.2, 16.8 Hz, 1H, CH2dCHCH); 13C NMR δ 25.77, 25.88,
26.05, 26.09, 26.33 (two carbons), 28.11, 28.40, 29.58, 29.68, 40.60,
41.46, 83.30, 83.63, 103.13, 120.31, 135.39. Anal. Calcd for
C17H28O2: C, 77.22; H, 10.67. Found: C, 77.45; H, 10.71.
a Conditions: (i) CbzCl, i-Pr2NEt, CH2H2; (ii) Ac2O, DMAP catalyst,
pyridine; (iii) p-TsOH catalyst, MeOH; (iv) NaH, THF; (v) Li, liquid
NH3-THF; (vi) KOH, H2O, EtOH.
Typical Procedure for the Reactions in Tables 1 and 2. (E)-(4S)-
4-(N-Benzyl)amino-1-[(1R,2R)-2-hydroxy-1,2-dicyclohexylethyl]oxy-
5-methyl-1-hexene (5c) (eq 2 and entry 3 in Table 2): To a solution
of the acetal 3 (305 mg, 1.153 mmol) and Ti(O-i-Pr)4 (443 µL, 1.50
mmol) in ether (3 mL) was added dropwise i-PrMgCl (2.34 mL, 1.28
M in ether, 3.0 mmol) at -50 °C and the resulting mixture was stirred
for 1.5 h at -50 to -40 °C. To this was added a solution of E-2-
methylpropanal N-benzylimine (4c) (242 mg, 1.5 mmol) in ether (2
mL) at -40 °C. The mixture was allowed to warm to room temperature
over 4 h and then quenched by addition of saturated aqueous NaHCO3
(ca. 100 µL). The mixture was filtered through a pad of Celite with
ether. The filtrate was concentrated under reduced pressure and the
residue was dried by azeotropical removal of water with THF to give
a crude mixture. On 1H NMR analysis of the crude mixture no
γ-addition product was observed. The crude residue was purified by a
rapid column chromatography on silica gel eluted with hexanes, ether,
and triethylamine to give a mixture of (E)- and (Z)-5c (total 405 mg,
85% yield) in a ratio of 94:6. Further purification by repeated column
chromatography gave pure (E)-5c (344 mg, 70% yield): IR (neat) 3447,
oxyimine 1424 reacted with 2 derived from (R,R)-3 to afford
anti-adduct 15 with 92% diastereoselectivity in 77% total yield,
which was then converted to 13 in 52% overall yield via 16 by
the conventional protection/deprotection reaction sequence.
Although the diastereoselectivity of the resulting 13 was 92%
due to the difficulty of separating each diastereomer of 15, the
synthesis seems to be attractive because the stereochemistry and
the functionalities required for the preparation of 13 can be
introduced by the one-step reaction.
Conclusions
We have now succeeded in developing, for the first time, a
chiral homoenolate equivalent that reacts with a variety of
acyclic and cyclic imines with excellent stereoselectivity, thus
allowing an efficient preparation of various kinds of optically
active γ-amino carbonyl compounds. Since the reagent is easy
to prepare from readily available and inexpensive starting
materials, the reaction is practical and will find numerous
applications in organic synthesis.
2926, 2853, 1666, 1450, 1384, 1261, 1166, 1041, 924, 734, 698 cm-1
;
1H NMR δ 0.89 (d, J ) 6.9 Hz, 3H, CH3CH), 0.91 (d, J ) 6.6 Hz, 3H,
CH3CH), 0.88-2.00 (m, 24H, C6H11, CH3CH, CH2CHdCH), 2.07
(dddd, J ) 1.2, 4.5, 6.6, 14.1 Hz, 1H, CH2CHdCH), 2.30 (dt, J ) 8.1,
4.5 Hz, 1H, CHN), 3.25-3.43 (m, 2H, C6H11CH), 3.72 (d, J ) 13.2
Hz, 1H, C6H5CH2), 3.77 (d, J ) 13.2 Hz, 1H, C6H5CH2), 4.81 (ddd, J
) 6.6, 8.1, 12.0 Hz, 1H, CH2CHdCH), 6.10 (d, J ) 12.0 Hz, 1H,
CH2CHdCH), 7.16-7.40 (m, 5H, C6H5); 13C NMR δ 17.86, 18.86,
26.10, 26.16, 26.18, 26.46, 26.49, 28.11, 28.25, 28.83, 29.63, 29.75,
29.77, 39.69, 40.44, 52.03, 62.27, 74.85, 85.70, 102.27, 126.64, 128.01,
128.18, 140.84, 149.46. Anal. Calcd for C28H45NO2: C, 78.64; H, 10.61;
Experimental Section
General. 1H and 13C NMR spectra were taken on a Varian Gemini-
2000 spectrometer at 300 and 75 MHz, respectively. CDCl3 was used
as the solvent. Chemical shifts are reported in parts per million (δ value)
from Me4Si (δ 0 ppm for 1H) or based on the middle peak of the solvent
(CDCl3) (δ 77.00 ppm for 13C NMR) as an internal standard. Signal
patterns are indicated as br s, broad singlet; s, singlet; d, doublet; t,
triplet; q, quartet; m, multiplet. Coupling constants (J) are given in
hertz. Analytical thin-layer chromatography (TLC) was performed on
aluminum sheets precoated with silica gel (Merck, Kieselgel 60 F254).
Visualization was accomplished by UV light (254 nm), KMnO4, and/
or vanillin. Infrared (IR) spectra were recorded on a JASCO A-230
spectrometer and are reported in wavenumbers (cm-1). Optical rotation
was measured on a JASCO DIP-370 digital polarimeter. Enantiomeric
excess values were determined by HPLC analysis with use of chiral
columns or by 1H NMR analysis of MTPA amides. Elemental analysis
was performed on a Elementar Vario-EL. Ti(O-i-Pr)4 was distilled and
stored under argon. i-PrMgCl was prepared as a 1.20-1.50 M ethereal
1
N, 3.28. Found: C, 78.27; H, 10.22; N, 3.40. The selected H NMR
data for (Z)-5c: (300 MHz, CDCl3) δ 4.23 (dt, J ) 6.3, 7.2 Hz, 1H,
CH2CHdCH), 6.07 (d, J ) 6.3 Hz, 1H, CHdCHO).
(E)-(4R)-4-(N-Benzyl)amino-1-[(1R,2R)-2-hydroxy-1,2-dicyclo-
hexylethyl]oxy-1-pentene (5a) [entry 1 in Table 2]: The reaction of
3 with 4a gave a mixture of (E)- and (Z)-5a (total 84% yield) in a
ratio of 92:8. The following data were selected for (E)-5a from the
spectra obtained with use of a mixture of E- and Z-isomers: 1H NMR
δ 0.88-2.08 (m, 24H, C6H11, CH2CHdCH), 1.07 (d, J ) 6.3 Hz, 3H,
CH3), 2.64 (sixtet, J ) 6.3 Hz, 1H, CH3CHN), 3.25-3.44 (m, 2H,
C6H11CH), 3.71 (d, J ) 12.9 Hz, 1H, C6H5CH2), 3.84 (d, J ) 12.9 Hz,
1H, C6H5CH2), 4.82 (dt, J ) 12.0, 7.8 Hz, 1H, CH2CHdCH), 6.12 (d,
J ) 12.0 Hz, 1H, CH2CHdCH), 7.15-7.38 (m, 5H, C6H5); 13C NMR
δ 20.15, 26.09, 26.16, 26.19, 26.44, 26.48, 28.22, 28.80, 29.76, 29.78,
35.06, 39.68, 40.41, 51.48, 52.48, 74.84, 85.72, 101.46, 126.71, 127.93,
128.27, 140.45, 149.77. The selected 1H NMR data for (Z)-5a: δ 4.17-
4.28 (m, 1H, CH2CHdCH). IR (neat) 3412, 2924, 2852, 1665, 1450,
(23) Cohen, F.; Overman, L. E.; Ly Sakata, S. K. Org. Lett. 1999, 1,
2169.
(24) Prepared from (S)-(+)-epichlorohydrine through a six-step reaction
sequence, see Supporting Information.

Optically ActiVe γ-Amino Carbonyl Compounds
J. Am. Chem. Soc., Vol. 123, No. 15, 2001 3467
1376, 1170, 1146, 924, 732, 697 cm-1. Anal. Calcd for C26H41NO2:
C, 78.15; H, 10.34; N, 3.51. Found: C, 77.93; H, 10.36; N, 3.57
(measured using a mixture of E- and (Z)-5a).
147.20, 150.24. The selected peaks for (Z)-5g: 1H NMR δ 4.17 (dt, J
) 6.3, 8.4 Hz, 1H, CH2CHdC), 6.04 (d, J ) 6.3 Hz, 1H, CdCHO).
IR (neat) 3410, 2926, 2853, 1664, 1602, 1502, 1450, 1316, 1263, 1164,
927, 748, 700 cm-1. The diastereoselectivity of the addition reaction
was determined by conversion of a mixture of (E)- and (Z)-5g to the
corresponding acetal, 4-phenyl-4-(N-phenyl)-amino-1-butanal (R,R)-
1,2-dicyclohexylethylene acetal, and its 1H and 13C NMR analyses: To
a stirred solution of 5g (60.0 mg, 0.134 mmol) in chloroform (1.34
mL) was added 1 N HCl (0.5 mL). After 1 h at room temperature, the
reaction mixture was quenched with saturated aqueous NaHCO3 and
extracted with Et2O (3 × 5 mL). The combined extracts were washed
with brine, dried over MgSO4, filtered, and concentrated in vacuo. The
residue was passed through a short silica gel column to give the cyclic
acetal as a colorless oil (52.7 mg, 88%). The diastereomeric ratio of
the resulting acetal was determined to be >85%: selected peaks for
major and minor isomers; 1H NMR δ 3.611 (s) vs 3.605 (s) [measured
by 1H-1H homo-decoupling experiments with irradiating allylic
methylene protons], and 13C NMR δ 83.524 vs 83.467, 83.077 vs
83.024.
(E)-3-[(2S)-N-Benzyloxycarbonyl-2-pyrrolidinyl]-1-[(1R,2R)-2-hy-
droxy-1,2-dicyclohexylethyl]oxy-1-propene (5i) [entry 9 in Table 2]:
1H NMR (65 °C) δ 0.93-2.40 (m, 28H, C6H11, CH2CH2, CH2CHd
CH), 3.24-3.54 (m, 4H, CH2N, C6H11CHO), 3.73-3.90 (m, 1H, CHN),
4.80 (dt, J ) 12.0, 8.1 Hz, 1H, CH2CHdCH), 5.10 (d, J ) 12.6 Hz,
1H, C6H5CH2), 5.16 (d, J ) 12.6 Hz, 1H, C6H5CH2), 6.07 (d, J ) 12.0
Hz, 1H, CH2CHdCH), 7.20-7.40 (m, 5H, C6H5); 13C NMR (65 °C) δ
26.24, 26.28, 26.35, 26.61, 26.63, 28.35, 28.91, 29.94, 40.07, 40.90,
46.94, 58.17, 66.62, 75.03, 85.55, 100.97, 127.72, 127.75, 128.33,
137.26, 149.64, 154.75; IR (neat) 3449, 3032, 2923, 2851, 1700, 1449,
1414, 1359, 1171, 1106, 923, 768, 732, 697 cm-1. Anal. Calcd for
C29H43NO4: C, 74.16; H, 9.23; N, 2.98. Found: C, 74.52; H, 9.25; N,
3.22.
(E)-(4R)-4-(N-Benzyl)amino-1-[(1R,2R)-2-hydroxy-1,2-dicyclo-
hexylethyl]oxy-1-heptene (5b) [entry 2 in Table 2]: The reaction of
3 with 4b gave a mixture of (E)- and (Z)-5b (total 81% yield) in a
ratio of 94:6. The following data were selected for (E)-5b from the
spectra obtained by using a mixture of E- and Z-isomers: 1H NMR δ
0.90 (t, J ) 6.6 Hz, 3H, CH3CH2), 0.95-2.02 (m, 27H, C6H11,
CH3CH2CH2, CH2CHdCH), 2.04-2.16 (m, 1H, CH2CHdCH), 2.45-
2.56 (m, 1H, CHN), 3.27-3.44 (m, 2H, C6H11CH), 3.73 (d, J ) 12.9
Hz, 1H, C6H5CH2), 3.78 (d, J ) 12.9 Hz, 1H, C6H5CH2), 4.83 (ddd, J
) 6.9, 8.7, 12.0 Hz, 1H, CH2CHdCH), 6.11 (d, J ) 12.0 Hz, 1H,
CH2CHdCH), 7.15-7.40 (m, 5H, C6H5); 13C NMR δ 14.47, 19.02,
26.10, 26.12, 26.18, 26.21, 26.46, 26.49, 28.21, 28.80, 29.78, 31.81,
36.14, 39.72, 40.45, 51.28, 56.65, 74.86, 85.70, 101.38, 126.70, 127.99,
128.24, 140.59, 149.63. The selected 1H NMR data for (Z)-5b: δ 4.23
(dt, J ) 6.3, 7.5 Hz, 1H, CH2CHdCH), 6.09 (d, J ) 6.3 Hz, 1H, CHd
CHO). IR (neat) 3422, 2924, 2852, 1666, 1450, 1168, 924, 732, 698
cm-1. Anal. Calcd for C28H45NO2: C, 78.64; H, 10.61; N, 3.28.
Found: C, 78.71; H, 10.84; N, 3.16 (measured using the mixture of
(E)- and (Z)-5b).
(E)-(4S)-4-(N-Benzyl)amino-1-[(1R,2R)-2-hydroxy-1,2-dicyclo-
hexylethyl]oxy-4-phenyl-1-butene (5e) [entry 5 in Table 2]: The
reaction of 3 with 4e gave a mixture of (E)- and (Z)-5e (total 82%
yield) in a ratio of 93:7. Further purification of the mixture by repeated
column chromatography gave pure (E)-5e in 40% yield. For the
E-isomer: 1H NMR δ 0.90-1.90 (m, 22H, C6H11), 2.15 (dt, J ) 14.1,
8.7 Hz, 1H, CH2CHdCH), 2.26 (dt, J ) 14.1, 6.0 Hz, 1H, CH2CHd
CH), 3.22-3.40 (m, 2H, C6H11CH), 3.51 (d, J ) 13.5 Hz, 1H,
C6H5CH2), 3.58 (dd, J ) 5.4, 8.1 Hz, 1H, C6H5CHNH), 3.67 (d, J )
13.5 Hz, 1H, C6H5CH2), 4.78 (ddd, J ) 6.3, 9.3, 12.3 Hz, 1H, CH2CHd
CH), 6.09 (d, J ) 12.3 Hz, 1H, CH2CHdCH), 7.18-7.40 (m, 10H,
C6H5); 13C NMR δ 25.86, 25.90, 25.97, 26.26, 26.28, 27.97, 28.60,
29.56, 29.60, 36.84, 39.54, 40.23, 51.51, 62.42, 74.73, 85.68, 101.40,
126.84, 127.01, 127.33, 128.10, 128.37, 140.70, 144.04, 150.24. Anal.
Calcd for C31H43NO2: C, 80.65; H, 9.39; N, 3.03. Found: C, 80.53;
H, 9.26; N, 2.95. The selected 1H NMR data for (Z)-5e: δ 4.18 (dt, J
) 8.4, 6.3 Hz, 1H, CH2CHdCH), 6.04 (d, J ) 6.3 Hz, 1H, CHd
(E)-3-[(2S)-N-Benzyloxycarbonyl-2-piperidyl]-1-[(1R,2R)-2-hydroxy-
1,2-dicyclohexylethyl]oxy-1-propene (5j) [entry 10 in Table 2]: 1H
NMR (65 °C) δ 0.90-1.95 (m, 28H, C6H11, CH2CH2CH2), 2.10 (dt, J
) 7.2, 14.1 Hz, 1H, CH2CHdCH), 2.19 (dt, J ) 7.2, 14.1 Hz, 1H,
CH2CHdCH), 2.82 (dt, J ) 2.1, 12.9 Hz, 1H, CH2N), 3.27-3.43 (m,
2H, CHO), 3.95-4.30 (m, 2H, CH2N, CHN), 4.79 (dt, J ) 7.8, 12.0
Hz, 1H, CH2CHdCH), 5.09 (d, J ) 12.9 Hz, 1H, C6H5CH2), 5.14 (d,
J ) 12.9 Hz, 1H, C6H5CH2), 6.11 (d, J ) 12.0 Hz, 1H, CH2CHdCH),
7.20-7.41 (m, 5H, C6H5); 13C NMR (65 °C) δ 18.88, 25.51, 26.20,
26.30, 26.32, 26.37, 26.60, 26.62, 27.18, 28.15, 28.70, 30.00, 39.54,
40.00, 40.76, 51.67, 66.94, 75.08, 85.65, 101.55, 127.67, 127.69, 128.32,
137.23, 149.30, 155.62; IR (neat) 3448, 3033, 2925, 2853, 1685, 1423,
1352, 1258, 1172, 1040, 730, 697 cm-1. Anal. Calcd for C30H45NO4:
C, 74.50; H, 9.38; N, 2.90. Found: C, 74.58; H, 9.62; N, 3.09.
(E)-3-[(1R)-1,2,3,4-Tetrahydroisoquinol-1-yl]-1-[(1R,2R)-2-hydroxy-
1,2-dicyclohexylethyl]oxy-1-propene (5k) [entry 11 in Table 2]:
CHO). IR (neat) 3450, 2926, 2852, 1665, 1451, 1165, 926, 700 cm-1
.
(E)-(4S)-4-(N-Propyl)amino-1-[(1R,2R)-2-hydroxy-1,2-dicyclo-
hexylethyl]oxy-4-phenyl-1-butene (5f) [entry 6 in Table 2]: The
reaction of 3 with 4f gave a mixture of (E)- and (Z)-5f (total 85% yield)
in a ratio of 95:5. The following data were selected for (E)-5f from
spectra obtained by using a mixture of E- and Z-isomers: 1H NMR δ
0.86 (t, J ) 7.5 Hz, 3H, CH3), 0.90-1.95 (m, 24H, C6H11, CH3CH2),
2.14 (dt, J ) 13.8, 9.0 Hz, 1H, CH2CHdCH), 2.25 (dt, J ) 13.8, 5.7
Hz, 1H, CH2CHdCH), 2.39 (t, J ) 7.5 Hz, 2H, CH3CH2CH2N), 3.25-
3.42 (m, 2H, 2C6H11CH), 3.52 (dd, J ) 5.4, 7.8 Hz, 1H, C6H5CHN),
4.80 (ddd, J ) 6.6, 9.3, 12.3 Hz, 1H, CH2CHdCH), 6.11 (d, J ) 12.3
Hz, 1H, CH2CHdCH), 7.17-7.40 (m, 5H, C6H5); 13C NMR δ 11.65,
23.16, 25.89, 25.95, 26.01, 26.30, 28.04, 28.69, 29.57, 29.62, 36.80,
39.58, 40.29, 49.66, 63.33, 74.78, 85.69, 101.55, 126.89, 127.21, 128.31,
Recrystallized from hexanes-ether: mp 54-55 °C; [R]26 +63.9 (c
D
1.07, CHCl3) (98% ee); 1H NMR δ 0.90-2.23 (m, 24H, NH, OH,
C6H11), 2.31 (dt, J ) 8.7, 14.1 Hz, 1H, CH2CHdCH), 2.49 (ddd, J )
3.6, 7.2, 14.4 Hz, 1H, CH2CHdCH), 2.67-2.92 (m, 2H, ArCH2), 2.97
(ddd, J ) 6.0, 7.2, 12.3 Hz, 1H, CH2NH), 3.22 (dt, J ) 5.1, 12.3 Hz,
1H, CH2NH), 3.28-3.47 (m, 2H, C6H11CH), 3.93 (dd, J ) 3.3, 8.4
Hz, 1H, CHNH), 4.84 (ddd, J ) 7.2, 8.4, 12.0 Hz, 1H, CH2CHdCH),
1
144.41, 150.22. The selected H NMR data for (Z)-5f: δ 4.16-4.28
(m, 1H, CH2CHdCH). IR (neat) 3422, 2925, 2852, 1664, 1450, 1166,
926, 758, 701 cm-1. Anal. Calcd for C27H43NO2: C, 78.40; H, 10.48;
N, 3.39. Found: C, 78.25; H, 10.40; N, 3.65 (measured using the
mixture of (E)- and (Z)-5f).
6.19 (d, J ) 12.0 Hz, 1H, CH2CHdCH), 7.00-7.23 (m, 4H, Ar); 13
C
NMR δ 26.11, 26.18, 26.25, 26.44, 26.47, 28.15, 28.69, 29.76, 30.04,
34.13, 39.58, 40.42, 40.93, 55.53, 74.82, 85.99, 100.95, 125.56, 125.80,
125.93, 129.09, 135.23, 138.44, 150.37. Anal. Calcd for C26H39NO2:
C, 78.54; H, 9.89; N, 3.52. Found: C, 78.23; H, 10.13; N, 3.34.
(E)-3-[(1R)-6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinol-1-yl]-1-
[(1R,2R)-2-hydroxy-1,2-dicyclohexylethyl]oxy-1-propene (5l) [entry
12 in Table 2]: For the E-isomer: 1H NMR δ 0.90-1.90 (m, 22H,
C6H11), 2.28 (dt, J ) 8.7, 14.1 Hz, CH2CHdCH), 2.46 (ddd, J ) 3.0,
7.5, 14.1 Hz, 1H, CH2CHdCH), 2.60-2.82 (m, 2H, ArCH2), 2.93 (dt,
J ) 6.0, 12.6 Hz, 1H, CH2NH), 3.19 (dt, J ) 5.4, 12.6 Hz, 1H, CH2-
NH), 3.32 (dd, J ) 3.6, 6.3 Hz, 1H, C6H11CH), 3.40 (dd, J ) 3.6, 6.0
Hz, 1H, C6H11CH), 3.77-3.90 (m, 1H, CHNH), 3.85 (S, 6H, CH3O),
4.85 (ddd, J ) 7.5, 8.7, 12.3 Hz, 1H, CH2CHdCH), 6.20 (d, J ) 12.3
Hz, 1H, CH2CHdCH), 6.57 (s, 1H, Ar), 6.64 (s, 1H, Ar); 13C NMR δ
25.94, 26.00, 26.07, 26.26, 26.29, 27.88, 28.46, 29.41, 29.60, 29.63,
(E)-(4S)-4-(N-Phenyl)amino-1-[(1R,2R)-2-hydroxy-1,2-dicyclo-
hexylethyl]oxy-4-phenyl-1-butene (5g) [entry 7 in Table 2]: The
reaction of 3 with 4g gave a mixture of (E)- and (Z)-5g (total 71%
yield) in a ratio of 95:5. The following data were selected for (E)-5g
from the spectra obtained with use of a mixture of E- and Z-isomers:
1H NMR δ 0.90-1.95 (m, 22H, C6H11), 2.25-2.50 (m, 2H, CH2CHd
CH), 3.30-3.45 (m, 2H, C6H11CH), 4.20 (br s, 1H, NH), 4.27 (t, J )
6.2 Hz, 1H, CHN), 4.77 (dt, J ) 12.3, 7.8 Hz, 1H, CH2CHdCH), 6.16
(d, J ) 12.3 Hz, 1H, CH2CHdCH), 6.47 (d, J ) 7.8 Hz, 2H, C6H5N),
6.62 (t, J ) 7.5 Hz, 1H, C6H5N), 7.08 (t, J ) 7.5 Hz, 2H, C6H5N),
7.18-7.40 (m, 5H, C6H5C); 13C NMR δ 26.10, 26.14, 26.20, 26.29,
26.45, 26.49, 28.13, 28.73, 29.82, 37.00, 39.64, 40.47, 57.70, 74.88,
85.79, 100.02, 113.40, 117.20, 126.28, 126.77, 128.37, 128.94, 143.37,

3468 J. Am. Chem. Soc., Vol. 123, No. 15, 2001
Okamoto et al.
34.03, 39.47, 40.29, 40.83, 55.12, 55.73, 55.90, 74.80, 86.09, 100.96,
109.17, 111.79, 127.57, 130.60, 147.23, 147.40, 150.68. The selected
peaks for the Z-isomer: 1H NMR δ 4.21 (q, J ) 6.9 Hz, 1H, CH2CHd
CH), 6.12 (d, J ) 6.0 Hz, 1H, CH2CHdCH). IR (neat) 3204, 2924,
continued for an additional 10 h. The mixture was concentrated in
vacuo. The resulting residue was diluted with tert-butyl alcohol (10
mL) and 2-methyl-2-butene (2.5 mL). To this was added dropwise a
solution of NaClO2 (416 mg, 4.6 mmol) and NaH2PO4-2H2O (538
mg, 3.45 mmol) in water (4.2 mL). The mixture was stirred overnight
at room temperature and concentrated under reduced pressure. The
residue was diluted with ether (10 mL), acidified (pH 6) by addition
of aqueous 0.5 N HCl, and extracted with ether (3 × 10 mL). The
combined organic layers were dried over MgSO4, concentrated in vacuo,
and chromatographed on silica gel (hexanes-ether) to give 3-(N-Boc-
N-benzyl)amino-4-methylpentanoic acid (113 mg), which was converted
into its methyl ester 6c (100 mg, 60% yield) by treatment with MeI
(0.11 mL) in the presence of NaHCO3 (59 mg) in DMF (3.5 mL) at
room temperature for 12 h: [R]D25 -34.9 (c 0.88, CHCl3) for 6c derived
from the 94:6 mixture of (E)- and (Z)-5c; [R]D25 -40.7 (c 1.32, CHCl3)
2845, 1663, 1509, 1449, 1258, 1166, 1113, 1038, 923, 853, 729 cm-1
.
(E)-3-[(1R)-6,7-Dimethoxy-1-methyl-1,2,3,4-tetrahydroisoquinolyl]-
1-[(1R,2R)-2-hydroxy-1,2-dicyclohexylethyl]oxy-1-propene (5m) [en-
try 13 in Table 2]: For the E-isomer: 1H NMR δ 0.90-2.10 (m, 22H,
C6H11), 1.37 (s, 3H, CH3C), 2.15 (dd, J ) 9.3, 14.1 Hz, 1H, CH2CHd
CH), 2.53 (dd, J ) 6.0, 14.1 Hz, 1H, CH2CHdCH), 2.56-2.72 (2H,
m, ArCH2), 2.93-3.18 (m, 2H, CH2NH), 3.27-3.42 (m, 2H, C6H11CH),
3.85 (s, 6H, CH3O), 4.65 (ddd, J ) 6.9, 9.0, 12.0 Hz, 1H, CH2CHd
CH), 6.15 (d, J ) 12.0 Hz, 1H, CH2CHdCH), 6.53 (s, 1H, Ar), 6.65
(s, 1H, Ar); 13C NMR δ 25.87, 25.89, 26.00, 26.26, 28.05, 28.65, 29.21,
29.54, 29.60, 30.03, 38.08, 38.79, 39.51, 40.30, 40.58, 54.73, 55.65,
56.02, 74.75, 85.70, 99.91, 109.08, 111.65, 127.39, 134.80, 147.20,
147.32, 150.71. The selected peak for the Z-isomer: 1H NMR δ 6.08
(d, J ) 6.9 Hz, 1H, CH2CHdCH).
1
for 6c derived from pure (E)-5c; H NMR (65 °C) δ 0.76 (d, J ) 6.6
Hz, 3H, (CH3)2CHCH), 0.87 (d, J ) 6.9 Hz, 3H, (CH3)2CHCH), 1.45
(s, 9H, C(CH3)3), 1.90-2.10 (m, 1H, (CH3)2CHCH), 2.54 (dd, J )
5.1, 15.6 Hz, 1H, CH2COOCH3), 2.64 (dd, J ) 8.4, 15.6 Hz, 1H, CH2-
COOCH3), 3.52 (s, 3H, COOCH3), 3.70-3.87 (m, 1H, CHN), 4.29 (d,
J ) 15.6 Hz, 1H, C6H5CH2), 4.45 (d, J ) 15.6 Hz, 1H, C6H5CH2),
7.15-7.35 (m, 5H, C6H5); 13C NMR (65 °C) δ 20.12, 20.30, 28.56,
31.69, 37.28, 50.89, 51.37, 61.65, 79.87, 126.83, 127.99, 128.10, 139.24,
155.70, 172.15; IR (neat) 2965, 2874, 1741, 1688, 1453, 1435, 1365,
(E)-(4R,5S)-5-(tert-Butyldimethylsilyl)oxy-4-benzylamino-1-[(1S,2S)-
1
2-hydroxy-1,2-dicyclohexylethyl]oxy-1-hexene (anti-5n) [eq 3]: H
NMR δ 0.02 (s, 3H, SiCH3), 0.04 (s, 3H, SiCH3), 0.87 (s, 9H, t-Bu),
0.92-2.17 (m, 24H, C6H11, allylic CH2), 1.14 (d, J ) 6.3 Hz, 3H, CH3),
2.49 (dt, J ) 4.2, 6.6 Hz, 1H, CHN), 3.30-3.42 (m, 2H, CHC6H11),
3.74-3.91 (m, 3H, CH2Ph, CHOSi), 4.85 (dt, J ) 12.0, 8.1 Hz, 1H,
CH2CHdCHO), 6.10 (d, J ) 12.0 Hz, 1H, CHdCHO), 7.19-7.34 (m,
5H, Ph); 13C NMR δ -4.99, -4.70, 17.86, 18.18, 25.72, 25.87, 25.90,
25.98, 26.26, 28.06, 28.64, 29.56, 39.51, 40.33, 52.18, 62.86, 69.91,
74.75, 85.55, 101.79, 126.75, 128.16, 128.31, 140.94, 149.36; IR (neat)
3430, 2926, 1666, 1450, 1386, 1254, 1166, 1004, 836, 775 cm-1. Anal.
Calcd for C33H57NO3Si: C, 72.87; H, 10.56; N, 2.58. Found: C, 72.95;
H, 10.90; N, 2.69.
(E)-(4R,6R)-6-(tert-Butyldimethylsilyl)oxy-4-benzylamino-1-[(1S,2S)-
2-hydroxy-1,2-dicyclohexylethyl]oxy-1-heptene (anti-5o) [eq 4]: Data
for the anti-E-isomer: 1H NMR δ 0.03 and 0.04 (2s, 6H, SiCH3), 0.86
(s, 9H, t-Bu), 0.94-1.98 (m, 24H, C6H11, CH2), 1.10 (d, J ) 6.0 Hz,
3H, CH3), 1.99-2.45 (m, 2H, allylic CH2), 2.64-2.73 (m, 1H, CHN),
3.31-3.43 (m, 2H, C6H11CH), 3.69 (d, J ) 12.9 Hz, 1H, CH2Ph), 3.80
(d, J ) 12.9 Hz, 1H, CH2Ph), 3.97-4.08 (m, 1H, CHOSi), 4.83 (dt, J
) 12.3, 7.5 Hz, 1H, CH2CHdCH), 6.11 (d, J ) 12.3 Hz, 1H,
CHdCHO), 7.18-7.41 (m, 5H, Ph); 13C NMR δ -4.98, -4.51, 17.86,
23.77, 25.74, 25.88, 25.92, 26.00, 26.28, 28.03, 28.63, 29.58, 32.16,
39.56, 40.32, 43.80, 51.18, 54.04, 66.51, 74.81, 85.56, 101.36, 126.80,
128.13, 128.25, 128.34, 140.91, 149.75.
(E)-(4S,6R)-6-(tert-Butyldimethylsilyl)oxy-4-benzylamino-1-
[(1R,2R)-2-hydroxy-1,2-dicyclohexylethyl]oxy-1-heptene (syn-5o) [eq
4]: Data for the syn-E-isomer: 1H NMR δ 0.02 and 0.04 (2s, 6H,
SiCH3), 0.86 (s, 9H, t-Bu), 0.92-2.22 (m, 26H, C6H11, CH2), 1.11 (d,
J ) 6.0 Hz, 3H, CH3), 2.56-2.74 (m, 1H, CHN), 3.32-3.44 (m, 2H,
C6H11CHO), 3.72 (d, J ) 13.5 Hz, 1H, CH2Ph), 3.77 (d, J ) 13.5 Hz,
1H, CH2Ph), 3.88-3.98 (m, 1H, CHOSi), 4.75-4.88 (m, 1H, CH2CHd
CH), 6.10 (d, J ) 12.0 Hz, 1H, CHdCHO), 7.16-7.34 (m, 5H, Ph);
13C NMR δ -4.86, -4.34, 17.85, 24.29, 25.73, 25.90, 25.97, 26.25,
26.27, 28.01, 28.62, 29.58, 31.70, 39.57, 40.28, 44.11, 51.01, 54.11,
66.45, 74.78, 85.76, 101.15, 126.77, 128.12, 128.27, 128.33, 140.89,
150.00.
Typical Procedure for the Conversion of 5 to the â- and γ-Amino
Carbonyl Compounds 6, 7, 8, and 9 (Scheme 2). Methyl (S)-3-(N-
tert-butyloxycarbonyl-N-benzyl)amino-4-methylpentanoate (6c): A
mixture of 5c (215 mg, 0.504 mmol), Et3N (0.14 mL), Boc2O (0.23
mL, 1.0 mmol), and THF (5 mL) was stirred at 50 °C for 12 h. After
addition of water (15 mL), the mixture was extracted with ether (2 ×
10 mL). The combined extracts were washed with brine (15 mL), dried
over MgSO4, filtered, and concentrated under reduced pressure. The
residue was passed through a short silica gel column with hexanes and
ether and concentrated in vacuo. The resulting residue was dissolved
in CH2Cl2 (methanol-free, 10 mL). Ozone gas (1.5 g/(h‚air)) was passed
at a rate of gentle bubbling through the solution at -78 °C. After
consumption of the substrate was checked by TLC analysis, ozone was
stopped and argon was bubbled for 20 min at -78 °C to remove excess
ozone, and then dimethyl sulfide (0.5 mL) was added. The mixture
was allowed to warm to room temperature over 2 h and stirring was
1252, 1163, 982, 868, 771, 733, 701 cm-1
.
Methyl (R)-3-(N-tert-butyloxycarbonyl-N-benzyl)aminobutanoate
(6a): 61% yield from a mixture of (E)- and (Z)-5a; [R]23 -22.5 (c
D
1.03, CHCl3); 1H NMR (65 °C) δ 1.16 (d, J ) 6.9 Hz, 3H, CH3CHN),
1.45 (s, 9H, C(CH3)3), 2.43 (dd, J ) 7.2, 15.0 Hz, 1H, CH2COOCH3),
2.68 (dd, J ) 6.9, 15.0 Hz, 1H, CH2COOCH3), 3.61 (s, 3H, COOCH3),
4.12-4.32 (m, 1H, CHN), 4.30 (d, J ) 15.6 Hz, 1H, C6H5CH2), 4.49
(d, J ) 15.6 Hz, 1H, C6H5CH2), 7.15-7.38 (m, 5H, C6H5); 13C NMR
(65 °C) δ 19.28, 28.76, 40.26, 49.68, 50.75, 51.60, 80.18, 127.02,
127.47, 128.44, 139.67, 155.51, 171.84; IR (neat) 2975, 2975, 1739,
1689, 1451, 1407, 1365, 1253, 1165, 1029, 866, 736, 701 cm-1
.
Methyl (R)-3-(N-tert-butyloxycarbonyl-N-benzyl)aminohexanoate
(6b): 65% yield from a mixture of (E)- and (Z)-5b; [R]28 -22.8 (c
D
1
1.42, CHCl3); H NMR (65 °C) δ 0.80 (t, J ) 7.2 Hz, 3H, CH3CH2),
1.11-1.27 (m, 2H, CH3CH2), 1.35-1.68 (m, 2H, CH3CH2CH2), 1.45
(s, 9H, C(CH3)3), 2.42 (dd, J ) 6.6, 15.0 Hz, 1H, CH2COOCH3), 2.60
(dd, J ) 7.5, 15.0 Hz, 1H, CH2COOCH3), 3.58 (s, 3H, COOCH3),
4.07-4.24 (m, 1H, CHN), 4.30 (d, J ) 15.6 Hz, 1H, C6H5CH2), 4.44
(d, J ) 15.6 Hz, 1H, C6H5CH2), 7.16-7.38 (m, 5H, C6H5); 13C NMR
(65 °C) δ 13.76, 19.76, 28.56, 35.73, 38.89, 49.66, 51.38, 54.72, 79.91,
126.85, 127.64, 128.17, 139.42, 155.64, 171.77; IR (neat) 2960, 2872,
1739, 1691, 1454, 1408, 1365, 1247, 1164, 1016, 868, 734, 701 cm-1
.
Methyl (S)-3-(N-tert-butyloxycarbonyl-N-benzyl)amino-3-phenyl-
26
propionate (6e): 52% yield from a mixture of (E)- and (Z)-5e; [R]D
-79.2 (c 1.18, CHCl3) for 6e derived from pure (E)-5e; [R]26 -70.8
D
(c 1.28, CHCl3) for 6e derived from the mixture of (E)- and (Z)-5e; 1H
NMR (65 °C) δ 1.41 (s, 9H, C(CH3)3), 2.89 (dd, J ) 7.8, 15.9 Hz, 1H,
CH2COOCH3), 2.95 (dd, J ) 7.8, 15.9 Hz, 1H, CH2COOCH3), 3.55
(s, 3H, COOCH3), 4.14 (d, J ) 15.6 Hz, 1H, C6H5CH2), 4.46 (d, J )
15.6 Hz, 1H, C6H5CH2), 5.61 (t, J ) 7.5 Hz, 1H, CHN), 7.05-7.35
(m, 10H, C6H5); 13C NMR (65 °C) δ 28.49, 37.68, 49.10, 51.57, 56.65,
80.38, 126.78, 127.39, 127.45, 127.49, 128.13, 128.33, 139.22, 139.71,
155.66, 171.06; IR (neat) 2975, 1741, 1689, 1453, 1402, 1365, 1252,
1163, 975, 867, 743, 699 cm-1
.
Methyl (S)-3-(N-tert-butyloxycarbonyl-N-propyl)amino-3-phen-
ylpropionate (6f): 60% yield from a mixture of (E)- and (Z)-5f; [R]24
D
1
-62.5 (c 1.32, CHCl3); H NMR (65 °C) δ 0.73 (t, J ) 7.5 Hz, 3H,
CH3CH2), 1.20-1.60 (m, 2H, CH3CH2), 1.44 (s, 9H, C(CH3)3), 2.99
(t, J ) 7.8 Hz, 2H, CH3CH2CH2N), 3.01 (d, J ) 7.5 Hz, 2H, CH2-
COOCH3), 3.65 (s, 3H, COOCH3), 5.51 (t, J ) 7.5 Hz, 1H, C6H5CHN),
7.15-7.45 (m, 5H, C6H5); 13C NMR (65 °C) δ 11.41, 22.69, 28.52,
37.74, 47.66, 51.62, 56.55, 79.74, 127.06, 127.32, 128.29, 140.20,
155.37, 171.26; IR (neat) 2970, 2874, 1741, 1686, 1453, 1405, 1365,
1250, 1154, 966, 864, 770, 700 cm-1
.
Methyl (3R,4S)-3-(N-tert-butyloxycarbonyl-N-benzyl)amino-4-
(tert-butyldimethylsiloxy)pentanoate (anti-6n): a white solid; mp
1
66.0-67.0 °C; [R]27 +46.2 (c 0.216, CHCl3); H NMR (65 °C) δ
D

Optically ActiVe γ-Amino Carbonyl Compounds
J. Am. Chem. Soc., Vol. 123, No. 15, 2001 3469
0.02 (s, 6H, SiCH3), 0.86 (s, 9H, Si-t-Bu), 0.96 (d, J ) 6.0 Hz, 3H,
CH3), 1.46 (s, 9H, O-t-Bu), 2.65 (dd, J ) 7.8, 15.9 Hz, 1H, CH2CO2),
2.79 (dd, J ) 4.2, 15.9 Hz, 1H, CH2CO2), 3.52 (s, 3H, OCH3), 3.84-
4.12 (m, 2H, CHO, CHN), 4.37 and 4.49 (2d, J ) 15.6, 15.6 Hz, 2H,
CH2Ph), 7.15-7.30 (m, 5H, Ph); 13C NMR (65 °C) δ -4.52, -3.91,
18.05, 21.26, 25.97, 28.60, 35.30, 51.29, 51.54, 61.76, 70.20, 80.10,
126.89, 128.13 (four carbons), 139.15, 155.66, 172.18; IR 2925, 2854,
1730, 1696, 1410, 1366, 1251, 1171, 1133, 1072, 1053, 1000, 834,
777 cm-1. Anal. Calcd for C24H41NO5Si: C, 63.82; H, 9.15; N, 3.10.
Found: C, 63.75; H, 9.26; N, 3.09. The selected peaks for syn-6n: 1H
NMR (65 °C) δ 1.19 (d, J ) 6.3 Hz, 3H, CH3), 2.46-2.64 (m, 2H,
CH2CO2), 3.51 (s, 3H, OCH3), 4.05-4.21 (m, 1H, CHO), 4.38 (q, J )
5.9 Hz, 1H, CHN), 4.54 (d, J ) 15.9 Hz, 1H, CH2Ph), 4.63 (d, J )
15.9 Hz, 1H, CH2Ph). The relative stereochemistries were confirmed
by conversion to â-(BnNH)-γ-valerolactone by sequential treatment
with TFA, CH2Cl2 and then NaH, THF and its NOE experiments on
1H NMR: 1H NMR δ 1.40 (d, J ) 6.3 Hz, 3H, CH3), 2.37 (dd, J )
6.0, 17.7 Hz, 1H, CH2CO2), 2.57 (dd, J ) 7.5, 17.7 Hz, 1H, CH2CO2),
3.18-3.26 (m, 1H, CHN), 3.80 (s, 2H, CH2Ph), 4.33-4.50 (m, 1H,
CHO), 7.22-7.38 (m, 5H, Ph).
gel to give 7 (128 mg, 70% yield) and (R,R)-1,2-dicyclohexyl-1,2-
ethandiol (72 mg, 63% recovered). 7: [R]25 -14.6 (c 0.70, CHCl3)
D
for 7 prepared from a mixture of (E)- and (Z)-5c (overall 88% ee.); 1H
NMR (65 °C) δ 0.81 (d, J ) 6.3 Hz, 3H, (CH3)2CH), 0.92 (d, J ) 6.3
Hz, 3H, (CH3)2CH), 1.44 (s, 9H, C(CH3)3), 1.20-1.90 (m, 5H,
(CH3)2CH, CH2CH2), 3.18 (s, 3H, OCH3), 3.22 (s, 3H, OCH3), 3.40-
3.80 (br, 1H, CHN), 4.07 (br s, 1H, CH(OCH3)2), 4.24 (d, J ) 13.5
Hz, 1H, C6H5CH2), 4.37 (d, J ) 13.5 Hz, 1H, C6H5CH2), 7.18-7.40
(m, 5H, C6H5); IR (neat) 2964, 2829, 1688, 1454, 1408, 1388, 1365,
1250, 1166, 1064, 951, 735, 701 cm-1
.
(S)-4-[N-(tert-Butyloxycarbonyl)-N-benzyl]amino-5-methylhexa-
nal (8): The acetal 7 (94 mg, 0.258 mmol) prepared above was treated
with trifluoroacetic acid (0.074 mL) in CH2Cl2 (0.3 mL) and water
(0.074 mL) at room temperature for 2 h. After addition of aqueous
saturated NaHCO3 (2 mL), the mixture was extracted with hexanes (3
× 5 mL).The combined extracts were washed with brine, dried over
MgSO4, filtered, and concentrated under reduced pressure to give the
crude aldehyde 8 (90 mg), which was subjected to the next reaction
without further purification. The 1H NMR date observed with the crude
product: 1H NMR (65 °C) δ 0.84 (d, J ) 6.6 Hz, 3H, CH3), 0.96 (d,
J ) 6.6 Hz, 3H, CH3), 1.46 (s, 9H, t-Bu), 1.55-2.30 (m, 5H, CH,
CH2), 3.20-3.70 (br s, 1H, CHN), 4.24 (d, J ) 14.7 Hz, 1H, CH2Ph),
4.39 (d, J ) 14.7 Hz, 1H, CH2Ph), 7.15-7.40 (m, 5H), 9.45 (s, 1H,
Ph).
(S)-4-[N-(tert-Butyloxycarbonyl)-N-benzyl]amino-5-methylhex-
anoic Acid (9): The aldehyde 8 obtained above was diluted with tert-
butyl alcohol (5.4 mL) and 2-methyl-2-butene (1.3 mL). To this was
added dropwise a solution of NaClO2 (214 mg, 2.37 mmol) and NaH2-
PO4-2H2O (271 mg, 1.78 mmol) in water (2.2 mL). The mixture was
stirred overnight at room temperature and concentrated under reduced
pressure. The residue was diluted with ether (6 mL), acidified (pH 4)
by addition of aqueous 0.5 N HCl, and extracted with ether (3 × 8
mL). The combined organic layers were dried over MgSO4, concen-
trated in vacuo, and purified by column chromatography on silica gel
Methyl (3S,5R)-3-(N-tert-butyloxycarbonyl-N-benzyl)amino-5-
(tert-butyldimethylsiloxy)hexanoate (anti-6o): 1H NMR (65 °C) δ
0.02 and 0.03 (2s, 6H, SiCH3), 0.88 (s, 9H, Si-t-Bu), 1.07 (d, J ) 6.0
Hz, 3H, CH3), 1.47 (s, 9H, O-t-Bu), 1.62-1.88 (m, 2H, CH2), 2.51
(dd, J ) 5.7, 15.3 Hz, 1H, CH2CO2), 2.68-2.80 (m, 1H, CH2CO2),
3.58 (s, 3H), 3.67-3.77 (m, 1H, CHO), 4.09-4.22 (m, 1H, CHN),
4.28 (d, J ) 15.6 Hz, 1H, CH2Ph), 4.53 (d, J ) 15.6 Hz, 1H, CH2Ph),
7.16-7.34 (m, 5H, Ph); 13C NMR (65 °C) δ -4.97, -4.53, 17.89,
23.28, 25.80, 28.40, 38.38, 43.23, 51.22, 52.69, 66.10, 80.00, 127.08,
127.87, 128.40, 139.46, 155.50, 172.07. The relative stereochemistries
were confirmed by conversion to the corresponding â-(BnNH)-δ-
caprolactone by sequential treatment with TFA, CH2Cl2 and then NaH,
1
THF and its NOE experiments on H NMR: 1H NMR δ 1.37 (d, J )
6.3 Hz, 3H, CH3), 1.72 (ddd, J ) 4.8, 10.8, 14.4 Hz, 1H, CH2), 1.89
(dt, J ) 14.4, 3.6 Hz, 1H, CH2), 2.45 (ddd, J ) 1.2, 5.4, 16.8 Hz, 1H,
CH2CO2), 2.69 (dd, J ) 5.1, 16.8 Hz, 1H, CH2CO2), 3.23-3.31 (m,
1H, CHN), 3.77 (s, 2H, CH2Ph), 4.72-4.85 (m, 1H, CHO), 7.21-
7.39 (m, 5H, Ph).
(hexanes-ether) to afford the γ-amino acid 9 (75 mg) in 87% overall
1
yield (two steps): [R]25 -19.5 (c 1.38, CHCl3); H NMR (65 °C) δ
D
0.81 (d, J ) 6.6 Hz, 3H, (CH3)2CH), 0.94 (d, J ) 6.3 Hz, 3H, (CH3)2-
CH), 1.45 (s, 9H, C(CH3)3), 1.60-2.30 (m, 5H, (CH3)2CH, CH2CH2),
3.20-3.80 (br, 1H, CHN), 4.23 (d, J ) 15.0 Hz, 1H, C6H5CH2), 4.39
(d, J ) 15.0 Hz, 1H, C6H5CH2), 7.12-7.40 (m, 5H, C6H5); 13C NMR
(65 °C) δ 20.30, 20.54, 25.79 (br), 28.55, 31.21, 31.46, 48.52 (br),
63.50 (br), 80.05, 126.98, 128.22, 139.40, 156.67, 177.95; IR (neat)
3189, 2973, 1724, 1686, 1454, 1411, 1366, 1252, 1163, 1006, 910,
734, 701 cm-1. Anal. Calcd for C19H29NO4: C, 68.03; H, 8.71; N, 4.18.
Found: C, 67.92; H, 8.79; N, 3.96.
Methyl (3R,5R)-3-(N-tert-butyloxycarbonyl-N-benzyl)amino-5-
(tert-butyldimethylsiloxy)hexanoate (syn-6o): 1H NMR (65 °C) δ 0.02
and 0.04 (2s, 6H, SiCH3), 0.88 (s, 9H, Si-t-Bu), 0.96 (d, J ) 6.0 Hz,
3H, CH3), 1.48 (s, 9H, O-t-Bu), 1.54-1.76 (m, 2H, CH2), 2.51 (dd, J
) 6.3, 15.0 Hz, 1H, CH2CO2), 2.69 (dd, J ) 8.1, 15.0 Hz, 1H, CH2-
CO2), 3.59 (s, 3H, OCH3), 3.53-3.67 (m, 1H, CHO), 4.15 (br s, 1H,
CHN), 4.35-4.52 (m, 2H, CH2Ph), 7.17-7.35 (m, 5H, Ph); 13C NMR
(65 °C) δ -4.72, -4.23, 17.90, 23.83, 25.85, 28.42, 39.29, 43.98, 50.46,
51.25, 53.00, 66.85, 80.04, 127.12, 127.90, 128.43, 139.65, 155.75,
172.03. The relative stereochemistries were confirmed by conversion
to the corresponding â-(BnNH)-δ-caprolactone by sequential treatment
with TFA, CH2Cl2 and then NaH, THF and its NOE experiments on
1H NMR: 1H NMR δ 1.40 (d, J ) 6.3 Hz, 3H, CH3), 1.33-1.56 (m,
1H, CH2), 2.14-2.24 (m, 1H, CH2), 2.33 (dd, J ) 9.0, 17.1 Hz, 1H,
CH2CO2), 2.84 (ddd, J ) 1.5, 6.0, 17.1 Hz, 1H, CH2CO2), 3.09-3.22
(m, 1H, CHN), 3.81 (s, 2H, CH2Ph), 4.36 (ddq, J ) 3.0, 12.9, 6.3 Hz,
1H, CHO), 7.23-7.40 (m, 5H, Ph).
(S)-4-[N-(tert-Butyloxycarbonyl)-N-benzyl]amino-5-methylhexa-
nal dimethyl acetal (7): To a solution of the crude N-Boc derivative
of 5c (215 mg, 0.504 mmol), prepared by the procedure described above
for the synthesis of 6c, in pyridine (5 mL) were added DMAP (ca. 15
mg) and Ac2O (0.24 mL) and the resulting mixture was stirred at room
temperature overnight. After addition of brine (20 mL), the mixture
was extracted with hexanes (2 × 15 mL). The combined organic layers
were dried over MgSO4, filtered, concentrated, and chromatographed
by passing through a short silica gel column to give an N-Boc-O-Ac
derivative of 5c, which was treated with a catalytic amount of p-TsOH
(ca. 15 mg) in MeOH (6.3 mL) to afford a mixture of the titled
compound and (R,R)-1,2-dicyclohexyl-1,2-ethandiol monoacetate. The
resulting mixture was refluxed with aqueous 3 N NaOH (0.5 mL) in
MeOH (2.5 mL) for 6 h. After cooling to room temperature, the mixture
was extracted with hexanes (2 × 15 mL), dried over MgSO4,
concentrated under reduced pressure, and chromatographed on silica
(S)-2-(3,3-Dimethoxypropyl)pyrrolidine benzylcarbamate (10i):
1
[R]25 -30.8 (c 0.84, CHCl3) (78% ee); H NMR (65 °C) δ 1.35-
D
2.02 (m, 8H, CH2), 3.28 (s, 6H, OCH3), 3.30-3.55 (m, 2H, CH2N),
3.80-3.93 (m, 1H, CHN), 4.30 (br s, 1H, CHOCH3), 5.10 (d, J )
12.6 Hz, 1H, C6H5CH2), 5.15 (d, J ) 12.6 Hz, 1H, C6H5CH2), 7.22-
7.40 (m, 5H, C6H5); 13C NMR (65 °C) δ 23.60, 29.49, 29.60, 30.58,
46.57, 52.79, 53.03, 57.52, 66.64, 104.81, 127.69, 127.75, 128.31,
137.21, 154.88; IR (neat) 2952, 2882, 2829, 1701, 1451, 1412, 1359,
1190, 1102, 1076, 919, 753, 698 cm-1. Anal. Calcd for C17H25NO4:
C, 66.43; H, 8.20; N, 4.56. Found: C, 66.07; H, 8.11; N, 4.80. Ee was
determined to be 78% by HPLC analysis (CHIRALCEL OD-H, Hexane/
i-PrOH 95/5, 0.60 mL/min, retention times, 15.4/17.2 min, respectively).
(S)-2-(3,3-Dimethoxypropyl)piperidine benzylcarbamate (10j):
1
[R]27 -31.6 (c 0.74, CHCl3) (89.5% ee); H NMR (65 °C) δ 1.50-
D
1.85 (m, 10H, CH2), 2.84 (dt, J ) 2.7, 13.2 Hz, 1H, CH2N), 3.27 (s,
6H, OCH3), 4.05 (dd, J ) 3.3, 13.2 Hz, 1H, CH2N), 4.20-4.37 (m,
1H, CHN), 4.32 (t, J ) 5.4 Hz, 1H, CH(OMe)2), 5.12 (s, 2H, PhCH2),
7.20-7.42 (m, 5H, Ph); 13C NMR (65 °C) δ 19.09, 24.77, 25.69, 28.70,
29.65, 39.28, 50.94, 52.87, 53.05, 67.00, 104.61, 127.70, 127.72, 128.33,
137.18, 155.51; IR (neat) 2936, 2870, 2829, 1697, 1425, 1354, 1259,
1125, 1070, 912, 733, 698 cm-1. Ee was determined to be 89.5% by
HPLC analysis (CHIRALCEL OD-H, Hexane/i-PrOH 95/5, 0.52 mL/
min, retention times, 13.3/14.8 min, respectively).
(R)-1-(3,3-Dimethoxypropyl)-1,2,3,4-tetrahydroisoquinoline tri-
fluoroacetylamide (10k): A mixture of rotamers was obtained in a
ratio of 83:17. For a major rotamer: 1H NMR δ 1.54-2.03 (m, 4H,

3470 J. Am. Chem. Soc., Vol. 123, No. 15, 2001
Okamoto et al.
CH2), 2.87 (dt, J ) 16.2, 3.6 Hz, 1H, ArCH2), 3.04 (ddd, J ) 5.7,
11.1, 16.8 Hz, 1H, ArCH2), 3.31 (s, 3H, OCH3), 3.32 (s, 3H, OCH3),
3.64 (ddd, J ) 5.2, 11.4, 15.3 Hz, 1H, CH2N), 3.95-4.10 (m, 1H,
CH2N), 4.39 (t, J ) 5.4 Hz, 1H, CHOMe), 5.55 (t, J ) 7.5 Hz, 1H,
CHN), 7.10-7.30 (m, 4H, Ar); 13C NMR δ 29.12, 31.25, 39.48, 39.53,
52.99, 53.31, 53.91, 104.00, 116.50 (q, 1J (C,F) ) 285.8 Hz), 126.55,
combined organic layers were dried over MgSO4, filtered, concentrated,
and purified by column chromatography to give 11k (170 mg, 77%)
1
as a colorless oil: [R]27 -60.7 (c 0.42, CHCl3); H NMR (65 °C) δ
D
1.47 (s, 9H, C(CH3)3), 1.55-1.92 (m, 4H, CH2CH2CH2OH), 2.72 (dt,
J ) 16.2, 4.2 Hz, 1H, ArCH2), 2.90 (ddd, J ) 6.0, 9.9, 15.9 Hz, 1H,
ArCH2), 3.27 (ddd, J ) 4.2, 9.9, 13.8 Hz, 1H, CH2N), 3.69 (dt, J )
1.5, 6.6 Hz, 2H, CH2OH), 3.86-4.14 (m, 1H, CH2N), 5.12 (br s, 1H,
CHN), 7.02-7.20 (m, 4H, Ar); 13C NMR (65 °C) δ 28.65, 28.69, 29.65,
33.66, 38.24, 54.43, 62.78, 79.81, 125.98, 126.42, 127.09, 128.76,
134.25, 138.20, 155.04; IR (neat) 3436, 2976, 2929, 2867, 1691, 1422,
2
127.00, 127.22, 128.66, 132.25, 135.89, 156.07 (q, J (C,F) ) 35.3
Hz). The selected peaks of a minor rotamer: 1H NMR δ 4.33 (t, J )
5.4 Hz, 1H, CHOMe), 4.47 (ddd, J ) 2.4, 6.6, 13.2 Hz, 1H, CH2N),
4.92 (t, J ) 6.9 Hz, 1H, CHN). IR (neat) 2953, 2832, 1685, 1458,
1386, 1269, 1198, 1141, 1068, 948, 930, 765, 744, 675 cm-1. Anal.
Calcd for C16H20F3NO3: C, 58.00; H, 6.08; N, 4.23. Found: C, 58.37;
H, 4.42; N, 6.00. Ee was determined to be 80.2% (minor rotamer) and
79.8% (major rotamer) by HPLC analysis (CHIRALCEL OD-H,
Hexane/i-PrOH 95/5, 0.60 mL/min, retention times, 8.6/9.2 min (minor)
and 12.7/15.5 min (major), respectively).
(R)-1-(3,3-Dimethoxypropyl)-6,7-dimethoxy-1,2,3,4-tetrahydroiso-
quinoline trifluoroacetylamide (10l): A mixture of rotamers was
obtained in a ratio of 84:16. For a major rotamer: 1H NMR δ 1.52-
2.00 (m, 4H, CH2), 2.77 (ddd, J ) 2.7, 3.6, 15.9 Hz, 1H, ArCH2), 3.04
(ddd, J ) 5.4, 11.4, 15.9 Hz, 1H, ArCH2), 3.32 (s, 3H, OCH3), 3.33 (s,
3H, OCH3), 3.60 (ddd, J ) 4.5, 11.7, 15.3 Hz, 1H, CH2N), 3.85 (s,
3H, OCH3), 3.86 (s, 3H, OCH3), 3.95-4.10 (m, 1H, CH2N), 4.40 (t, J
) 5.4 Hz, 1H, CHOMe), 5.48 (t, J ) 7.8 Hz, 1H, CHN), 6.58 (s, 1H,
Ar), 6.61 (s, 1H, Ar); 13C NMR δ 28.77, 29.08, 31.10, 39.41 (q, J
(C,F) ) 3.7 Hz), 52.91, 53.44, 53.47, 55.92, 56.05, 104.00, 109.79,
111.02, 116.50 (q, 1J (C,F) ) 285.9 Hz), 124.16, 127.86, 147.70,
147.96, 156.00 (q, 2J (C,F) ) 35.2 Hz). The selected peaks of a minor
rotamer: 1H NMR δ 4.34 (t, J ) 5.4 Hz, 1H, CHOMe), 4.49 (ddd, J
) 2.4, 6.6, 13.2 Hz, 1H, CH2N), 4.85 (t, J ) 6.9 Hz, 1H, CHN). IR
(neat) 2935, 2835, 1684, 1612, 1520, 1465, 1371, 1254, 1198, 1119,
1069, 921, 858, 755 cm-1. Ee was determined to be 81% for 10l derived
from a mixture of E- and Z-5l by HPLC analysis (CHIRALCEL OD-
H, Hexane/i-PrOH 95/5).
1365, 1295, 1166, 1121, 1065, 1039, 945, 757 cm-1
.
(R)-1-Methyl-1-(3-hydroxypropyl)-6,7-dimethoxy-1,2,3,4-tetrahy-
droisoquinoline tert-butyl carbamate (11m): 71% yield from 5m; a
colorless oil; [R]26D +60.1 (c 1.52, CHCl3); 1H NMR (65 °C) δ 0.98-
1.80 (m, 3H, CH2CH2CH2OH), 1.51 (s, 9H, C(CH3)3), 1.69 (S, 3H,
CH3C), 2.59 (dt, J ) 15.9, 3.9 Hz, 1H, ArCH2), 2.76 (ddd, J ) 3.6,
9.6, 14.7 Hz, 1H, ArCH2), 2.98-3.14 (m, 1H, CH2CH2CH2OH), 3.31
(ddd, J ) 3.0, 9.9, 12.6 Hz, 1H, CH2N), 3.40-3.54 (m, 2H, CH2OH),
3.84 (s, 6H, CH3O), 4.00 (dt, J ) 12.6, 4.2 Hz, 1H, CH2N), 6.52 (s,
1H, Ar), 6.75 (s, 1H, Ar); 13C NMR (65 °C) δ 27.79, 28.76, 30.41,
38.31, 42.37, 56.06, 56.61, 61.85, 63.04, 79.86, 110.54, 111,17, 129.04,
134.80, 147.62, 148.22, 155.01; IR (neat) 3447, 2974, 2935, 2870, 1677,
1518, 1465, 1366, 1257, 1164, 1075, 1021, 913, 859, 798, 773, 732
cm-1
.
Pyrrolidino[a]-1,2,3,4-tetrahydroisoquinoline (12k): To a solution
of 11k prepared above and Et3N (162µL, 1.17 mmol) in CH2Cl2 (1.20
mL) was added MsCl (90.3 µL, 1.17 mmol) at 0 °C. The mixture was
stirred at room temperature for 6 h. After addition of aqueous saturated
NaHCO3, the mixture was extracted with Et2O (3 × 15 mL). The
combined organic layers were dried over MgSO4, filtered, and
concentrated to afford a crude oil that was treated with trifluoroacetic
acid (1.5 mL) in CH2Cl2 (1.5 mL) at room temperature for 1 h. After
neutralization with aqueous saturated NaHCO3, the mixture was
extracted with CH2Cl2 (3 × 10 mL), and the combined organic layers
were dried over MgSO4, filtered, and concentrated. The residue was
chromatographed on silica gel to give 12k (70 mg, 70%) as a colorless
oil: 1H NMR δ 1.65-2.04 (m, 3H, CH2CH2CHN), 2.28-2.42 (m, 1H,
CH2CHN), 2.51 (q, J ) 8.4 Hz, 1H, CH2N), 2.63 (dt, J ) 4.8, 10.2
Hz, 1H, CH2N), 2.82 (dt, J ) 16.2, 3.0 Hz, 1H, ArCH2), 3.02-3.27
(3H, CH2N, ArCH2), 3.40 (dd, J ) 7.5, 8.7 Hz, 1H, CHN), 7.00-7.20
(m, 4H, Ar); 13C NMR δ 22,24, 28.74, 30.21, 48.57, 53.41, 63.46,
125.45, 125.58, 125.82, 128.29, 134.08, 138.87; IR (neat) 3018, 2938,
2872, 2784, 2731, 1492, 1451, 1376, 1323, 1284, 1162, 1116, 1039,
911 cm-1. The absolute configuration of 12k thus obtained was
(R)-1-Methyl-1-(3,3-dimethoxypropyl)-6,7-dimethoxy-1,2,3,4-tet-
rahydroisoquinoline trifluoroacetylamide (10m): 1H NMR δ 1.00-
1.40 (m, 2H, CH2CH(OCH3)2), 1.72 (dt, J ) 3.9, 14.1 Hz, 1H,
CH2CH2CH(OCH3)2), 1.79 (s, 3H, CH3C), 2.70 (1H, ddd, J ) 3.0, 4.5,
15.9 Hz, ArCH2), 2.88 (1H, ddd, J ) 3.9, 7.5, 15.6 Hz, ArCH2), 3.06
(s, 3H, CH(OCH3)2), 3.12-3.31 (m, 1H, CH2CH2CH(OCH3)2), 3.20
(s, 3H, CH(OCH3)2), 3.41 (ddd, J ) 2.7, 10.2, 13.5 Hz, 1H, CH2N),
3.80-3.95 (m, 1H, CH2N), 3.87 (s, 6H, ArOCH3), 4.21 (dd, J ) 4.8,
6.9 Hz, 1H, CH(OCH3)2), 6.56 (s, 1H, Ar), 6.74 (s, 1H, Ar); 13C NMR
δ 26.04, 26.41, 29.78, 34.73, 42.87, 51.54, 52.54, 55.85, 56.11, 64.75,
103.47, 108.75, 110.28, 116.39 (q, 1J (C,F) ) 287.4 Hz), 127.30,
confirmed to be R by comparison of its [R]D value ([R]28 +112.8 (c
D
0.96, MeOH)) with that reported for the (S)-isomer [lit.22a for 100%
2
132.37, 147.38, 148.08, 155.89 (q, J (C,F) ) 34.4 Hz). Anal. Calcd
ee: [R]22 -101.7 (c 2.0, MeOH)].
for C28H43NO4: C, 56.29; H, 6.46; N, 3.45. Found: C, 56.27; H, 6.49;
N, 3.41. Ee was determined to be 94% ee by HPLC analysis
(CHIRALCEL OD-H, Hexane/i-PrOH 95/5, 0.51 mL/min, retention
times, 15.6/16.3 min, respectively).
D
Pyrroridino[a]-1-methyl-1,2,3,4-terahydroisoquinoline (12m): 74%
yield from 11m; a colorless oil; 1H NMR δ 1.42 (s, 3H, CH3C), 1.58-
1.92 (m, 2H, CH2CH2CH2N), 2.00-2.18 (m, 2H, CH2CH2CH2N), 2.45
(ddd, J ) 2.7, 4.2, 15.9 Hz, 1H, CH2N), 2.80-3.12 (m, 4H, ArCH2,
CH2CH2CH2N), 3.22 (ddd, J ) 5.1, 11.1, 13.5 Hz, 1H, CH2N), 3.84
(s, 3H, CH3O), 3.86 (s, 3H, CH3O), 6.53 (s, 1H, Ar), 6.65 (s, 1H, Ar);
13C NMR (75 MHz, CDCl3) δ 22.34, 23.46, 30.09, 40.31, 42.94, 50.34,
55.78, 56.05, 62.29, 109.63, 110.98, 125.64, 135.67, 146.83, 147.34;
IR (neat) 2962, 2931, 2862, 16.9, 1510, 1464, 1357, 1254, 1211, 1167,
1078, 996, 858, 770 cm-1. The absolute configuration of 12m thus
Synthesis of Pyrrolidinoisoquinolines 12 (Scheme 4). (R)-1-(3-
Hydroxypropyl)-1,2,3,4-tetrahydroisoquinoline tert-butyl carbamate
(11k): A mixture of 5k (300 mg, 0.754 mmol), Et3N (210 µL, 1.51
mmol), Boc2O (347 µL, 1.51 mmol), and THF (7.5 mL) was stirred at
room temperature for 12 h. After addition of water (20 mL), the mixture
was extracted with ether (2 × 15 mL). The combined extracts were
washed with brine (20 mL), dried over MgSO4, filtered, and concen-
trated under reduced pressure. The residue was passed through a short
silica gel column (hexanes-ether) and concentrated in vacuo. To a
solution of the residue in pyridine (7.5 mL) were added DMAP (ca.
20 mg) and Ac2O (356 µL, 3.77 mmol), and the resulting mixture was
stirred at room temperature overnight. After addition of brine (25 mL),
the mixture was extracted with hexanes (2 × 15 mL). The combined
organic layers were dried over MgSO4, filtered, concentrated, and
chromatographed by passing through a short silica gel column to give
the N-Boc-O-Ac derivative of 5k which was treated with trifluoroacetic
acid (0.27 mL) in CH2Cl2 (1.1 mL) and H2O (0.27 mL) at room
temperature for 2 h to afford a crude residue of aldehyde. To this in
EtOH (1.5 mL) was added NaBH4 (57 mg, 1.50 mmol) at 0 °C. After
1 h at room temperature, the solution was quenched by addition of
water (5 mL). The mixture was extracted with Et2O (3 × 15 mL). The
obtained was confirmed to be R by comparison of its [R]D value ([R]26
D
+40.1 (c 1.36, CHCl3); [R]28 +40.6 (c 1.32, THF); [R]29 +43.1 (c
D
D
1.20, EtOH)) with that reported for the (R)-isomer [lit.22b for 74% ee;
[R]D +42].
Preparation of Overman’s Intermediate (13) for Synthesizing
Batzelladine D [Scheme 4]. (R,R)-1,2-Dicyclohexyl-2-hydroxyethyl
(1E,4S,6S)-4-N-benzylamino-6-(tert-butyldimethylsilyl)oxypentadec-
1-enyl ether (15): To a solution of acrolein (R,R)-1,2-dicyclohexyl-
ethylene acetal (3) (153 mg, 0.58 mmol) and Ti(O-i-Pr)4 (0.257 mL,
0.87 mmol) in ether (2.5 mL) was added i-PrMgCl (2.18 mL, 0.80 M
in ether, 1.74 mmol) at -50 °C and the resulting mixture was stirred
for 1.5 h at -50 to -40 °C. To this was added (S)-3-(tert-butyl-
dimethylsilyl)oxydodecanal N-benzylimine (14)24 (1.15 mL, 0.4 M in
ether, 0.46 mmol) at -40 °C and the mixture was allowed to warm to

Optically ActiVe γ-Amino Carbonyl Compounds
J. Am. Chem. Soc., Vol. 123, No. 15, 2001 3471
room temperature over 3 h. After addition of saturated aqueous NaHCO3
(0.3 mL), NaF (1 g), and Celite (1 g), the mixture was filtered through
a pad of Celite, concentrated in vacuo, and chromatographed on silica
Hz, 3H), 1.12-1.88 (m, 22H), 3.16-3.26 (m, 1H), 3.29 and 3.30 (2s,
6H), 4.09 (d, J ) 15.3 Hz, 1H), 4.26 (t, J ) 5.1 Hz, 1H), 4.32 (m,
1H), 5.11 (d, J ) 15.3 Hz, 1H), 7.18-7.40 (m, 5H); 13C NMR (65 °C)
δ 13.8, 22.4, 24.7, 27.2, 29.1, 29.2, 29.3, 29.4, 30.7, 31.7, 35.3, 50.3,
52.4, 53.1, 53.2, 73.4, 104.4, 126.9, 127.5, 128.0, 128.5, 128.6, 137.6,
154.2; IR (neat) 2925, 2854, 1686, 1448, 1362, 1253, 1227, 1129, 1075,
1
gel to provide 15 (240 mg) in 77% yield. H NMR δ 0.02 and 0.03
(2s, 6H), 0.86 (s, 9H), 0.88 (t, J ) 4.5 Hz, 3H), 0.92-2.14 (m, 42H),
2.62-2.70 (m, 1H), 3.29-3.43 (m, 2H), 3.68 (d, J ) 12.9 Hz, 1H),
3.72-3.90 (m, 1H), 3.80 (d, J ) 12.9 Hz, 1H), 4.82 (dt, J ) 12.0, 7.5
Hz, 1H), 6.10 (d, J ) 12.0 Hz, 1H), 7.17-7.35 (m, 5H); the selected
peaks of 13C NMR δ -4.8, -4.6, 13.9, 17.8, 22.5, 25.0, 29.6, 31.7,
32.2, 37.0, 39.5, 40.2, 40.7, 51.1, 53.8, 70.5, 74.7, 85.5, 101.3, 126.7,
128.1, 128.3, 140.8, 149.7. Selected peak for syn-diastereomer: 1H
NMR δ 6.22 (d, J ) 12.3 Hz, 1H).
756 cm-1
.
(4S,6S)-4-Amino-6-hydroxypentadecanal dimethyl acetal (13): A
solution of 16 (107 mg, 0.255 mmol) in THF (3.5 mL) was cooled to
-78 °C and to this was introduced NH3 until the total volume reached
ca. 7 mL. To the mixture was added metal Li (16 mg) and the resulting
blue solution was stirred for 1 h at -78 °C. After addition of methanol
(0.2 mL) and then saturated aqueous NaHCO3 (2 mL), the mixture
was extracted with ethyl acetate (2 × 5 mL), dried over MgSO4,
concentrated, and passed through a pad of silica gel to give (4S,6S)-
4-(3,3-dimethoxy)propyl-6-nonyltetrahydro-1,3-oxazin-2-one (78 mg)
in 93% yield: 1H NMR (65 °C) δ 0.84 (t, J ) 6.6 Hz, 3H), 1.10-1.89
(m, 22H), 3.29 and 3.30 (2s, 6H), 3.43 (m, 1H), 4.27 (m, 1H), 4.32 (t,
J ) 5.1 Hz, 1H), 6.62 (br s, 1H); 13C NMR (65 °C) δ 13.9, 22.4, 24.8,
28.5, 29.1, 29.2, 29.3, 29.5, 30.8, 31.3, 31.7, 34.5, 47.9, 53.0, 53.4,
74.1, 104.3, 154.7. A mixture of (4S,6S)-4-(3,3-Dimethoxy)propyl-6-
nonyltetrahydro-1,3-oxazin-2-one (78 mg, 0.236 mmol) and KOH (120
mg), H2O (0.5 mL), and EtOH (2 mL) was heated to reflux for 12 h.
After being cooled to room temperature, the mixture was concentrated
in vacuo and diluted with THF (4 mL). After addition of Et3N (0.5
mL) and solid NH4Cl (100 mg), the mixture was filtered through a
pad of Celite. The filtrate was concentrated and diluted with THF (3
mL). The mixture was passed through a pad of Chromatorex NH-gel
(DM1020, Fuji Silysia Chemical Ltd.) and concentrated in vacuo to
give 13 (68 mg) in 95% yield. The spectroscopic data (1H and 13C
NMR) of compound 13 thus obtained were in good agreement with
those reported in the literature.23
N-Cbz-O-Ac derivative of 15: To a solution of 15 (422 mg, 0.63
mmol) in CH2Cl2 (2.5 mL) were added i-Pr2NEt (0.33 mL) and benzyl
chloroformate (0.77 mL, 30% in toluene, 1.26 mmol) and the mixture
was stirred for 1 h at ambient temperature. After addition of saturated
aqueous NaHCO3 (10 mL), the mixture was extracted with ether (1 ×
10 mL), dried over MgSO4, concentrated in vacuo, and chromato-
graphed on silica gel to afford the N-Cbz derivative of 15 (396 mg) in
78% yield. The mixture of this compound (273 mg, 0.34 mmol) thus
obtained, pyridine (3.4 mL), Ac2O (0.232 mL), and 4-N,N-(dimethy-
lamino)pyridine (12 mg) was stirred for 20 h at room temperature. After
addition of brine (16 mL), the mixture was extracted with hexanes (2
× 15 mL), dried over MgSO4, concentrated in vacuo, and chromato-
graphed on silica gel to give the N-Cbz-O-Ac derivative of 15 (272
1
mg) in 95% yield. H NMR (65 °C) δ -0.01 (s, 6H), 0.86 (s, 9H),
0.82-2.24 (m, 45H), 2.04 (s, 3H), 3.42 (t, J ) 5.4 Hz, 1H), 3.48 (m,
1H), 3.82 (m, 1H), 4.40 (d, J ) 15.9 Hz, 1H), 4.48 (dm J ) 15.9 Hz,
1H), 4.75 (dt, J ) 12.3, 7.2 Hz, 1H), 4.93 (t, J ) 5.4 Hz, 1H), 5.13 (d,
J ) 12.3 Hz, 1H), 5.22 (d, J ) 12.3 Hz, 1H), 5.95 (d, J ) 12.3 Hz,
1H), 7.16-7.41 (m, 10H).
(4S,6S)-3-Benzyl-4-(3,3-dimethoxy)propyl-6-nonyltetrahydro-1,3-
oxazin-2-one (16): The mixture of the N-Cbz-O-Ac derivative of 15
(272 mg, 0.322 mmol), p-TsOH (10 mg), and methanol (3.1 mL) was
stirred for 2 h at ambient temperature. After addition of saturated
aqueous NaHCO3 (6 mL), the mixture was extracted with hexanes (2
× 6 mL), dried over MgSO4, concentrated, and chromatographed on
silica gel to provide (4R,6S)-4-(N-benzyl-N-benzyloxycarbonyl)amino-
6-hydroxypentadecanal dimethyl acetal (146 mg) in 86% yield. To a
solution of the resulting dimethyl acetal (146 mg, 0.277 mmol) in THF
(0.5 mL) was added NaH (20 mg, 50% in oil, 0.42 mmol) at 0 °C and
the mixture was stirred for 1.5 h at room temperature. After addition
of brine (2 mL), the mixture was extracted with hexanes (2 × 5 mL),
dried over MgSO4, concentrated, and chromatographed on silica gel to
Acknowledgment. We thank the Ministry of Education,
Culture, Sports, Science and Technology (Japan) for financial
support.
Supporting Information Available: Experimental proce-
dure for the reaction of eq 1, spectral data of cyclic acetals and
adducts shown in Table 1, procedure for determination of ee
and absolute configuration of 6, and procedure for preparation
of imine 14 (PDF). This material is available free of charge via
the Internet at http://pubs.acs.org.
1
provide 16 (107 mg, 92% yield). H NMR (65 °C) δ 0.88 (t, J ) 6.3
JA004140K