One-pot construction of multiple contiguous chiral centers using Michael addition of chiral amine

Article abstract of DOI:10.1021/jo1004586

Multiple contiguous chiral centers were constructed in one pot using three types of multistep reactions initiated with the Michael addition of N-benzyl-2(R)-methoxy-(+)-10-bornylamide to α,β-unsaturated esters, i.e., asymmetric Michael-aldol reaction, dou

Full text of DOI:10.1021/jo1004586

pubs.acs.org/joc
One-Pot Construction of Multiple Contiguous Chiral Centers Using
Michael Addition of Chiral Amine
Minoru Ozeki, Shunsuke Ochi, Noboru Hayama, Shinzo Hosoi, Tetsuya Kajimoto, and
Manabu Node*
Department of Pharmaceutical Manufacturing Chemistry, 21st COE Program, Kyoto Pharmaceutical
University, 1 Shichono-cho, Misasagi, Yamashina-ku, Kyoto 607-8412, Japan
node@mb.kyoto-phu.ac.jp
Received March 15, 2010
Multiple contiguous chiral centers were constructed in one pot using three types of multistep
reactions initiated with the Michael addition of N-benzyl-2(R)-methoxy-(þ)-10-bornylamide to
R,β-unsaturated esters, i.e., asymmetric Michael-aldol reaction, double Michael addition, and
double Michael-aldol reaction. The chiral 2-methoxy-10-bornyl group as well as the benzyl group
on the amino group of the products in the Michael-aldol reaction could be easily cleaved by
treatment with NIS (4 equiv), and β-amino esters with multiple contiguous chiral centers were
obtained in good yield. As an application, the β-amino-β0-hydroxy ester obtained in the asymmetric
Michael-aldol reaction was converted to the β-lactam derivative in good yield.
Introduction
by intramolecular Michael addition.2 Enders succeeded in
one-pot construction of eight contiguous chiral centers by
designing the double Michael-aldol reaction initiated by
adding Jørgensen’s catalyst3 to perform a subsequent in-
tramolecular Diels-Alder reaction.4 Moreover, other types
of domino reaction initiated by Michael addition have been
developed by other research groups.5-7
Recently, one-pot multistep reactions1 have been devel-
oped for the asymmetric synthesis of complex compounds
having several chiral centers. For instance, Davies achieved
one-pot construction of three contiguous chiral centers in a
cyclic amine, which was initiated by the Michael addition of
R-phenethyl amide to nona-2,7-diene-1,9-diate, followed
We also developed a tandem Michael addition-MPV
reduction, which was initiated with the Michael addition of
(1) See, e.g.: (a) Ley, S. V.; Baxendale, I. R.; Bream, R. N.; Jackson, P. S.;
Leach, A. G.; Longbottom, D. A.; Nesi, M.; Scott, J. S.; Storer, R. I.; Taylor,
S. J. J. Chem. Soc.. Perkin Trans. 1 2000, 3815–4195. (b) Alba, A.-N.;
Companyo, X.; Viciano, M.; Rios, R. Curr. Org. Chem. 2009, 13, 1432–1474.
(2) (a) Urones, J. G.; Garrido, N. M.; Diez, D.; El Hammoumi, M. M.;
Dominguez, S. H.; Casaseca, J. A.; Davies, S. G.; Smith, A. D. Org. Biomol.
Chem. 2004, 2, 364–372. (b) Davies, S. G.; Dıez, D.; Dominguez, S. H.;
Garrido, N. M.; Kruchinin, D.; Price, P. D.; Smith, A. D. Org. Biomol. Chem.
2005, 3, 1284–1301. (c) Davies, S. G.; Mujtabe, N.; Roberts, P. M.; Smith,
A. D.; Thomson, J. E. Org. Lett. 2009, 11, 1959–1962.
(3) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 2005, 44, 794–797.
€
(4) (a) Enders, D.; Huttl, M. R. M.; Grondal, C.; Raabe, G. Nature 2006,
441, 861–863. (b) Enders, D.; Huttl, M. R. M.; Runsink, J.; Raabe, G.;
€
€
Wendt, B. Angew. Chem., Int. Ed. 2007, 46, 467–469. (c) Enders, D.; Huttl,
M. R. M.; Raabe, G.; Bats, J. W. Adv. Synth. Catal. 2008, 350, 267–279.
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DOI: 10.1021/jo1004586
r
Published on Web 05/19/2010
J. Org. Chem. 2010, 75, 4201–4211 4201
2010 American Chemical Society

Ozeki et al.
JOCArticle
R,β-unsaturated carbonyls with (þ)-bornyl-10-mercapto al-
cohol to afford optically active β-mercapto alcohols with
three contiguous chiral centers.8 Encouraged by the success-
ful results in the reaction, the asymmetric Michael addition
of R,β-unsaturated esters with a chiral amine, N-benzyl-
2(R)-methoxy-(þ)-10-bornylamine (1), was investigated.9
In good contrast with the tandem Michael-Meerwein-
Prondorff-Verley (MPV) reduction, the Michael addition
using 1 as a nucleophile promoted no further reaction;
however, the Michael addition with 1 generated an enolate,
which could still be reacted with electrophiles. Thus, we tried
to apply the Michael addition of R,β-unsaturated esters with
1 to the tandem asymmetric Michael-aldol reaction, double
Michael reaction, and double Michael-aldol reaction.
Both phenethyl and benzyl groups on the amino group
employed in Davies’ tandem reactions2,10 were cleavable with
relative ease under the hydrogenolysis condition;11 however,
disposal of the chiral auxiliary reduced the utility in terms of
atom economy. Meanwhile, the chiral bornyl and benzyl
groups on the amino groups, which were incorporated in
thestep of theMichael additionof1, could be easily cleaved by
treatment with NIS.12 Moreover, the chiral amine 1 can be
regenerated by the reductive amination of bornyl aldehyde 2,
which resulted in oxidative cleavage of the C-N bonds with
NIS (Scheme 1).9 In addition, no requirement of hydrogena-
tion to cleave the benzyl group or of the products could
increase the availability of our method, which we report here.
SCHEME 1. Michael Addition of R,β-Unsaturated Esters with
the Chiral Amine 1
addition of 1, and the enolate intermediate was reacted with
benzaldehyde (4a) to complete the asymmetric Michael-
aldol reaction (Scheme 2).
Namely, n-butyllithium (1.5 equiv) was added to a solu-
tion of 1 in tetrahydrofuran (THF) at -50 °C to prepare the
corresponding amide, to which either 3a or 3b (1.0 equiv) was
added to complete the Michael addition. Successively, 4a
(3.0 equiv) was added dropwise to the reaction mixture while
maintaining the temperature. As a result, in spite that
diastereomers 5a, 6a, and 6a0 were obtained with the ratio
of 1:1:1.3 in the reaction of 3a, 5b and its isomers 6b were
obtained with high diastereoselectivity (89:11) in good yield
accompanied by a small amount of the nonaldol product 7b
in the reaction of 3b (Scheme 2) .
We investigated several conditions, in which substrates
3c-e, having a substitute on the aromatic ring of 3b, were
chosen as the Michael acceptor. As a result, aldol products
5c-e were afforded in good yield. Next, several aliphatic and
aromatic aldehydes 4b-g were subjected to the aldol reac-
tion, and products 5f-k were obtained in as good of yields as
5b-e (Table 1).
Results and Discussion
Initially, tert-butyl β-isopropylacrylate (3a) and tert-butyl
cinnamate (3b) were chosen as the substrates of the Michael
Stereochemistry of the major product 5b was determined
by X-ray diffraction analysis after debenzylation on the
amino group with formic acid in the presence of Pd/C,
followed by protection of the secondary hydroxyl group
with the Boc group, to afford 8b (see Table 3). In addition,
the stereochemistry of 5a and 6a was directly determined by
X-ray diffraction analysis.
Regarding the transition state of the aldol reaction to
afford the major products, it was speculated as shown in
Scheme 3. Namely, lithium ion coordinates the carbonyl
oxygen of the ester group to form a six-membered transition
state, where the Z-enolate intermediate is generated from the
s-cis conformer of R,β-unsaturated ester.13 The aldehyde
would approach preferentially from the bottom to the upper
face of the enolate due to steric hindrance caused by the
presence of the N-benzyl group. Addition of the aldehyde,
the Re face of which should be preferentially attacked to that
of the Si-face, affords the major product 5b. Higher selectiv-
ity in the reaction using 3b than 3a as the Michael acceptor
could be attributed to the π-π interaction between the
phenyl groups of 1 and the Michael acceptor, which stabilize
the Z-enolate intermediate (A, Scheme 3).
(5) (a) Reyes, E.; Vicario, J. L.; Carrillo, L.; Badıa, D.; Iza, A.; Uria, U.
Org. Lett. 2006, 8, 2535–2538. (b) Koutsaplis, M.; Andrews, P. C.; Bull, S. D.;
Duggan, P. J.; Fraser, B. H.; Jensen, P. Chem. Commun. 2007, 3580–3582.
(c) Zhu, D.; Lu, M.; Dai, L.; Zhong, G. Angew. Chem., Int. Ed. 2009, 48,
6089–6092.
(6) For recent examples of tandem Michael-aldol reactions, see: (a) Arai,
T.; Sasai., H.; Aoe, K.; Okamura, K.; Date, T.; Shibasaki, M. Angew. Chem.,
Int. Ed. 1996, 35, 104–106. (b) Schneider, C.; Reese, O. Chem.;Eur. J. 2002,
8, 2585–2594. (c) Nishimura, K.; Tsubouchi, H.; Ono, M.; Hayama, T.;
Nagaoka, Y.; Tomioka, K. Tetrahedron Lett. 2003, 44, 2323–2326.
(d) Makino, K.; Nagata, E.; Hamada, Y. Tetrahedron Lett. 2005, 46,
8159–8162. (e) Kinoshita, H.; Osamura, T.; Mizuno, K.; Kinoshita, S.;
Iwamura, T.; Watanabe, S.; Kataoka, T.; Muraoka, O.; Tanabe, G.
Chem.;Eur. J. 2006, 12, 3896–3904. (f) Zu, L.; Wang, J.; Li, H.; Xie, H.;
Jiang, W.; Wang., W. J. Am. Chem. Soc. 2007, 129, 1036–1037. (g) Chernega,
A.; Davies, S. G.; Elend, D. L.; Smethurst, C. A. P.; Roberts, P. M.; Smith,
A. D.; Smyth, G. D. Tetrahedron 2007, 63, 7036–7046. (h) Rueping, M.;
Kuenkel, A.; Tato, F.; Bats, J. W. Angew. Chem., Int. Ed. 2009, 48, 3699–
3702.
(7) For recent examples of double Michael reaction, see: (a) Hoashi, Y.;
Yabuta, T.; Takemoto, Y. Tetrahedron Lett. 2004, 45, 9185–9188. (b) Li, K.;
Alexakis, A. Tetrahedron Lett. 2005, 46, 8019–8022. (c) Li, H.; Zu, L.; Xie,
H.; Wang, J.; Jiang, W.; Wang, W. Org. Lett. 2007, 9, 1833–1835. (d) Zu, L.;
Li, H.; Xie, H.; Wang, J.; Jiang, W.; Tang, Y.; Wang, W. Angew. Chem., Int.
Ed. 2007, 46, 3732–3734. (e) Tan, B.; Shi, Z.; Chua, P. J.; Zhong, G. Org. Lett.
2008, 10, 3425–3428. (f) Wu, L.-Y.; Bencivenni, G.; Mancinelli, M.;
Mazzanti, A.; Bartoli, G.; Melchiorre, P. Angew. Chem., Int. Ed. 2009, 48,
7196–7199.
(8) Nishide, K.; Ozeki, M.; Kunishige, H; Shigeta, Y.; Patra, P. K.;
Hagimoto, Y.; Node, M. Angew. Chem., Int. Ed. 2003, 42, 4515–4517.
(9) Node, M.; Hashimoto, D.; Katoh, T.; Ochi, S.; Ozeki, M; Watanabe,
T.; Kajimoto, T. Org. Lett. 2008, 10, 2653–2656.
(10) (a) Davies, S. G.; Ichihara, O.; Walters, I. A. S. J. Chem. Soc., Perkin
Trans. 1 1994, 1141–1147. (b) Bunage, M. E.; Davies, S. G.; Goodwin, C. J.;
Walters, I. A. S. Tetrahedron: Asymmetry 1994, 5, 35–36. (c) Davies, S. G.;
Smith, A. D.; Cowley, A. R. Synlett 2004, 1957–1960.
Next, double Michael addition was applied to a substrate
with a pair of R,β-unsaturated esters in its molecule, i.e.,
di-tert-butyl nona-2,7-diene-1,9-diate (9a). When the reac-
tion was achieved at -50 °C, the desired product (10a) was
obtained in high yield (91%) with high diastereoselectivity
(11) Davies, S. G.; Smith, A. D.; Price, P. D. Tetrahedron 2005, 16,
2833–2891.
(12) Katoh, T.; Watanabe, T.; Nishitani, M.; Ozeki, M.; Kajimoto, T.;
Node, M. Tetrahedron Lett. 2008, 49, 598–600.
(13) (a) Chamberlin, A. R.; Reich, S. H. J. Am. Chem. Soc. 1985, 107,
1440–1441. (b) Nishimura, K.; Tomioka, K. J. Org. Chem. 2002, 67, 431–434.
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SCHEME 2. Tandem Michael-Aldol Reaction Using 3a,b and Benzaldehyde (4a)
TABLE 1. Tandem Michael-Aldol Reaction
entry
R1
R2
Products (%)a
1
2
3
4
5
6
7
8
9
10
Ph
(3b)
(3c)
(3d)
(3e)
(3b)
(3b)
(3b)
(3b)
(3b)
(3b)
Ph
Ph
Ph
Ph
4-Cl-Ph
4-Me-Ph
4-MeO-Ph
i-Pr
c-Hex
n-Pen
(4a)
(4a)
(4a)
(4a)
(4b)
(4c)
(4d)
(4e)
(4f)
(4g)
5b(71)
5c (57)
5d(72)
5e (61)
5f (51)
5g(62)
5h(77)
5i (84)
5j (71)
5k(81)
6b(9)
7b (9)
7c (4)
4-Cl-Ph
4-Me-Ph
4-MeO-Ph
Ph
Ph
Ph
Ph
Ph
Ph
6c (12)
6d(10)
6e (8)
7d (11)
7e (17)
7b (15)
7b (14)
7b (1)
7b (2)
7b (17)
7b (4)
6f (9)
6g(11)
6h(10)
6i (9)
6j (16)
6k(12)
aIsolated yields.
(93:7) (Table 2, entry 1). Moreover, the double Michael
reaction was applied to the formation of trisubstituted
cyclopentane, where di-tert-butyl 2,6-octadien-1,8-diate
(9b) was chosen as the Michael acceptor. The desired
product 10b was isolated in excellent yield (96%) with high
diastereoselectivity (89: 11) (Table 2, entry 2). The stereo-
chemistry of 10a and 10b was confirmed by comparison
with the 13C NMR data in the literature14 after cleaving the
chiral auxiliary and the benzyl group with NIS (4.0 equiv).
Furthermore, the addition of aldehydes (4a-f) to the
double Michael adduct in situ was attempted to investigate
the possibility of constructing five contiguous chiral cen-
ters. Fortunately, the desired product 11a was afforded in
good yield (71%) with satisfactory diastereoselectivity
(84:16) when benzaldehyde (4a) was added to the dou-
ble Michael intermediate prepared from 1 and 9a (Table 2,
entry 3).
However, the double Michael addition-aldol reaction,
where the enolate anion of 10b generated in the double
Michael addition of 1 and 9b was reacted with benzaldehyde
(4a), gave an unsatisfactory result in terms of stereoselectiv-
ity. Reactions with other aromatic aldehydes 4b-d provided
11b-d in good yield with moderate stereoselectivity (Table 2,
entry 3-6).
Although low selectivities were observed in the reactions
with an aliphatic aldehyde 4e-f, it should be emphasized
that one isomer among 32 possible isomers was afforded in
40-42% (Table 2, entries 7 and 8).
The stereochemistry of the major product of 11a was
determined by X-ray diffraction analysis after deriving to
12 as well as 5b. The stereochemistries of 11b-f were pro-
posed by the comparison of their 1H NMR spectra with that
of 11a.
(14) The 13C NMR spectrum and the value of [R]D of the primary amine
obtained by the cleavage of the 2-methoxy-10-bornyl group and benzyl group
of 10b with NIS (4 equiv) completely coincided with those reported by
Davies. Meanwhile, the primary amine derived from 10a in the same way
provided a partially different 13C NMR spectrum from those reported by
Davies. Since the primary amines obtained from 10a were the enantiomers of
that synthesized by Davies, the values of those amines showed opposite signs
but showed almost the same values. See ref 2.
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SCHEME 3. Plausible Transition State of the Michael-Aldol Reaction
TABLE 2. Intramolecular Double Michael Addition and Tandem Double Michael-Aldol Reaction
time (h)
entry
substrate
R
Michael
aldol
major product
yielda (%)
minor productsa (%)
1
2
3
4
5
6
7
8
9a
9b
9a
9a
9a
9a
9a
9a
none of aldehyde
none of aldehyde
Ph
2.0
2.0
0.5
0.5
0.5
0.5
0.5
0.5
10a
10b
11a
11b
11c
11d
11e
11f
85
85
60
55
67
57
40
42
6
11
11
22
17
26
46
45
(4a)
(4b)
(4c)
(4d)
(4e)
(4f)
2.0
2.0
2.0
2.0
2.0
2.0
4-Cl-Ph
4-Me-Ph
4-MeO-Ph
i-Pr
c-Hex
aIsolated yields.
SCHEME 4. Plausible Transition State of the Double Michael-Aldol Reaction Affording 11a
A plausible transition state could be proposed, as shown in
Scheme 4, i.e., the intramolecular Michael addition would
advance via TS-B, as reported by Davies,2b and the subsequent
aldol reaction with 4a would proceed via TS-C to afford 11a.
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TABLE 4. Cleavage of C-N Bonds of 11 Utilizing NIS
FIGURE 1. Comparison of the enolate intermediates in the reac-
tions using 9a (D) and 9b (E) as substrates.
entry
substrate
R
yield (%)
1
2
3
4
11a
11b
11c
11d
Ph
4-Cl-Ph
4-Me-Ph
4-MeO-Ph
77a
78
76
72
A similar transition state would rationalize the low selec-
tivity of the tandem reaction using 9b (Figure 1). Standing
vertical in enolate D to avoid steric hindrance with the
equatorial orientated-amino group on the cyclohexane ring,
the tert-butoxy group of the nonenolated ester moiety could
effectively inhibit the access of the aldehyde from the Si face.
Meanwhile, the enolate generated by the Michael addition of
1 and 9b formed enolate E, in which the tert-butoxy group of
the nonenolated ester moiety would lie horizontally due to
steric repulsion with the bulky amino group. Both faces of
enolate E are exposed to allow the approach of the aldehyde.
Thus, satisfactory stereoselectivity of the product was not
observed in the double Michael-aldol reaction using 1, 9b,
and 4a.
Finally, conditions for removal of the chiral auxiliary were
scrutinized. We reported that the 2-methoxy-10-bornyl and
the benzyl groups on the amino group can be removed
by oxidative cleavage using N-iodosuccinimide (NIS) and,
if necessary, successive treatment with O-methylhydroxy-
lamine.9,12 Thus, the Michael-aldol product 5b was first
treated with NIS (4 equiv) in dichloromethane; however, the
desired β-amino ester was not obtained due to the neigh-
boring group participation of the hydroxyl group in 5b.
Next, the treatment with NIS was performed after protec-
tion of the hydroxyl group with acetyl, Boc, and silyl groups
(Table 3). Although OfN migration of the acetyl group
was observed during the reaction (Table 3, entry 1), Boc and
TES groups remained on the hydroxyl group (Table 3,
entries 2 and 3). Cleavage of the 2-methoxy-10-bornyl
and benzyl groups from amino group proceeded in satis-
factory yield and was a practical deprotection of the Boc
compound.
aBornyl aldehyde 2 was recoverd in 74% yield.
SCHEME 5. Preparation of the β-Lactam Derivative from 14c
Interestingly, the 2-methoxy-10-bornyl and the benzyl
group of 11a and 11b-d could be cleaved with NIS (4 equiv)
in satisfactory yield without protection of the hydroxyl
group generated in the aldol reaction (Table 4).
Finally, as an example of the application of the tandem
Michael-aldol reaction, β-lactam 17 was prepared from
amino ester 14c by treating with LDA (Scheme 5).
Conclusion
In conclusion, we have developed the stereocontrolled
one-pot synthesis of three or five contiguous chiral centers
using tandem asymmetric Michael-aldol, intramolecular
double-Michael, and double Michael-aldol reactions in-
itiated by the addition of chiral amide 1 to R,β-unsaturated
esters. This is the first method of the amination that can build
up the five contiguous chiral centers in one pot. The method
was shown to be applicable for the synthesis of β-lactam
antibiotics.
TABLE 3. Cleavage of C-N Bonds of 5b Utilizing NIS
entry
Ra
Ac
Boc
TES
13a-c yield (%)
R1
R2
14a-c yield (%)
8a-c yield (%)
1
2
3
96
93
100
Ac
H
H
H
Boc
TES
96b
81
42
40c
aAc = acetyl, Boc = tert-butoxycarbonyl, TES = triethylsilyl. bBornyl aldehyde 2 was recoverd in 95%yield. c8c could be converted to 14c in 81%
yield by treating with NIS (2.0 equiv).
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Experimental Section
3.07 (s, 3H), 2.38 (d, B part of AB, JAB =13.4 Hz, 1H), 2.07 (s,
3H), 1.76-1.53 (m, 6H), 1.35-1.19 (m, 1H), 1.24 (s, 9H),
1.04-1.00 (m, 1H), 0.94 (d, J = 7.1 Hz, 3H), 0.92 (s, 3H), 0.81
(s, 3H), 0.62 (d, J=5.9 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 172.0, 170.1, 141.1, 138.5, 130.8 (2C), 128.2 (2C), 127.6 (3C),
126.6, 126.4 (2C), 86.1, 80.6, 74.2, 60.7, 56.3, 54.7, 53.4, 51.6,
48.0, 46.9, 45.1, 37.6, 30.2, 29.4, 27.6 (3C), 27.3, 21.1, 21.1, 21.0,
A typical procedure for the tandem Michael-aldol reaction
was shown by representing the reaction of 1 and 3b. The major
products (5b-k) were isolated as a single diastereomer by
employing silica gel column chromatography or recycle HPLC.
(2S,3S)-tert-Butyl 2-[(R)-Hydroxy(phenyl)methyl]-3-[(1S,2R)-
2-methoxybornyl-10-benzylamino]-3-phenylpropanoate (5b). n-Buthy-
llithium (2.6 M in hexane solution, 1.1 mL, 2.91 mmol) was added
dropwise to a solution of chiral amine 1 (796 mg, 2.91 mmol) in THF
(20 mL) at -50 °C, and the solution was stirred for 5 min under an
argon atmosphere. A solution of R,β-unsaturated ester 3b (396.4 mg,
1.94 mmol) in THF (10 mL) was added dropwise to the lithium
amide solution at the same temperature, and the mixture was stirred
for 0.5 h. Then, benzaldehyde (591 μL, 5.82 mmol) was added
dropwise to the solution at the same temperature, and the mixture
was stirred for 2 h. The reaction mixture was quenched with a
saturated aqueous solution of sodium hydrogen carbonate and
extracted with diethyl ether. The organic layer was washed with
brine, dried over anhydrous sodium sulfate, and concentrated in
vacuo. The residue was purified by column chromatography on silica
gel (hexane/ethyl acetate=80/1) to afford 5b as a single diastereomer
(807 mg, 71%) as well as a mixture of minor diastereomers (102 mg,
20.4, 18.8; IR (CHCl3) 2955, 1732, 1719, 1454, 1369, 1151 cm-1
;
MS (20 eV) m/z 591 (Mþ, 0.2), 548 (55), 327 (100), 284 (45), 204
(20), 148 (43); HRMS calcd for C37H53NO5 (Mþ) 591.3923,
found 591.3919.
(2S,3R)-tert-Butyl 2-[(S)-hydroxy(phenyl)methyl]-3-[(1S,2R)-
2-methoxybornyl-10-benzylamino]-4-methylpentanoate (6a: min-
or isomer-2): colorless crystal; mp 196-198 °C (diethyl ether);
[R]22D = þ49.2 (c 0.8, CHCl3); H NMR (400 MHz, CDCl3)
1
δ 7.46 (br d, J=8.2 Hz, 2H), 7.37-7.20 (m, 8H), 5.30 (dd, J=
2.0, 10.2 Hz, 1H), 4.63 (br, 1H), 3.88 (s, 2H), 3.43 (d, A part of
AB, JAB=14.8 Hz, 1H), 3.42 (dd, J=3.1, 7.3 Hz, 1H), 3.28 (dd,,
J=3.5, 10.3 Hz, 1H), 3.21 (s, 3H), 3.05 (dd, J=3.5, 9.9 Hz, 1H),
2.62 (d, B part of AB, JAB =14.8 Hz, 1H), 2.31-2.22 (m, 1H),
1.75 (dq, J=3.3, 12.8 Hz, 1H), 1.55 (t, J=4.2 Hz, 1H), 1.47 (dd,
J = 7.3, 12.8 Hz, 1H), 1.37-1.30 (m, 1H), 1.27 (d, J = 6.6 Hz,
3H), 1.19 (d, J = 6.2 Hz, 3H), 1.09 (s, 9H), 0.97-0.87 (m, 1H),
0.92 (s, 3H), 0.82-0.76 (m, 1H), 0.56 (s, 3H), 0.49 (br, 1H); 13C
NMR (100 MHz, CDCl3): δ 172.7, 142.9, 141.2, 130.7 (2C),
128.0 (2C), 127.8 (2C), 127.7 (2C), 127.6, 126.7, 85.7, 80.3, 73.2,
65.5, 56.5, 55.9, 54.2, 53.4, 48.2, 47.7, 45.4, 37.1, 30.3, 29.9, 27.5
(3C), 26.9, 23.1, 22.5, 20.6, 20.4; IR (CHCl3) 3396, 2951, 1715,
1603, 1456, 1367, 1148 cm-1; MS (20 eV) m/z 549 (Mþ, 0.1), 344
(22), 328 (44), 106 (92), 91 (100); HRMS calcd for C35H51NO4
(Mþ) 549.3818, found 549.3824. Anal. Calcd for C35H51NO4: C,
76.46; H, 9.35; N, 2.55. Found: C, 76.19; H, 9.19; N, 2.54.
(2S,3S)-tert-Butyl 3-(4-chlorophenyl)-2-[(R)-hydroxy(phenyl)-
methyl]-3-[(1S,2R)-2-methoxybornyl-10-benzylamino]propanoate
(5c): colorless oil; [R]20D = -66.0 (c 0.6, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 7.39-7.18 (m, 14H), 4.50 (d, J=11.5 Hz,
1H), 4.44 (dd, J=2.4, 11.0 Hz, 1H), 4.00 (d, J=11.0 Hz, 1H),
3.88 (d, A part of AB, JAB=13.9 Hz, 1H), 3.55 (dd, J=2.6, 11.5
Hz, 1H), 3.40 (d, B part of AB, JAB = 13.9 Hz, 1H), 3.23 (d,
A part of AB, JAB = 14.3 Hz, 1H), 3.26-3.21 (br, 1H), 2.99
(s, 3H), 2.18 (d, B part of AB, JAB=14.3 Hz, 1H), 1.72-1.66 (m,
1H), 1.62-1.49 (m, 3H), 1.45 (dd, J=7.3, 12.6 Hz, 1H), 1.24 (s,
9H), 1.21-1.15 (m, 1H), 0.96-0.91 (m, 1H), 0.87 (s, 3H), 0.80 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 174.3, 142.2, 140.1, 135.3,
133.0, 131.0 (2C), 129.5 (2C), 128.3 (2C), 127.9 (2C), 127.8 (2C),
126.9, 126.8, 125.3 (2C), 84.9, 82.2, 71.7, 63.7, 57.6, 54.5, 53.5,
53.0, 47.6, 46.1, 45.0, 37.2, 29.7, 27.9 (3C), 27.3, 20.9, 20.3; IR
(CHCl3) 3690, 3020, 2936, 1697, 1603, 1495 cm-1; MS (20 eV)
m/z 617 (Mþ, 0.6), 396 (100), 272 (6), 182 (11), 106 (32); HRMS
calcd for C38H48ClNO4 (Mþ) 617.3272, found 617.3265.
9%): colorless oil; [R]22D = -64.3 (c 1.0, CHCl3); H NMR (400
1
MHz, CDCl3) δ 7.42-7.17 (m, 15H), 4.53 (d, J=11.7 Hz, 1H), 4.49
(dd,J=2.6, 10.8 Hz, 1H), 4.03 (d, J=10.8 Hz, 1H), 3.92 (d, A part of
AB, JAB =13.7 Hz, 1H), 3.61 (dd, J=2.6, 11.7 Hz, 1H), 3.40 (d, B
part of AB, JAB=13.7 Hz, 1H), 3.21 (d, A part of AB, JAB=14.3 Hz,
1H), 3.23-3.19 (br, 1H), 2.95 (s, 3H), 2.24 (d, B part of AB, JAB
=
14.3 Hz, 1H), 1.69-1.55 (m, 4H), 1.43 (dd, J = 7.3, 12.6 Hz, 1H),
1.26-1.16 (m, 1H), 1.24 (s, 9H), 0.94-0.90 (m, 1H), 0.86 (s, 3H), 0.81
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 174.6, 142.6, 140.4, 136.5,
129.8, 129.6 (2C), 128.1 (2C), 127.9 (2C), 127.7 (2C), 127.3 (2C),
126.8, 126.7, 125.3 (2C), 84.9, 82.0, 71.6, 64.5, 57.5, 54.5, 53.6, 53.0,
47.6, 46.3, 45.0, 37.3, 29.7, 28.0 (3C), 27.3, 20.9, 20.3; IR (CHCl3)
3479, 2934, 1695, 1603, 1452, 1369, 1150 cm-1; MS (20 eV) m/z:
583 (Mþ, 2), 362 (100), 272 (13), 242 (10), 204 (12), 148 (63), 131 (17),
106 (99); HRMS calcd for C38H49NO4 (Mþ) 583.3661, found
583.3653.
tert-Butyl 2-[Hydroxy(phenyl)methyl]-3-[(1S,2R)-2-methoxy-
bornyl-10-benzylamino]-4-methylpentanoate (5a, 6a). H NMR
1
spectra of 6a0, 5a (major isomer and minor isomer-1) were
broad. Therefore compound data of 6a0, 5a (major isomer and
minor isomer-1) were collected as acetyl form of hydroxyl group
(6a0-Ac, 5a-Ac).
6a0-Ac: major isomer: colorless oil; [R]20 = þ11.1 (c 1.0,
D
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.37-7.27 (m, 5H), 7.09
(m, 3H), 6.81 (m, 2H), 6.09 (d, J=9.5 Hz, 1H), 3.69 (d, A part of
AB, JAB=14.3 Hz, 1H), 3.44 (dd, J=2.7, 9.5 Hz, 1H), 3.24 (br
d, J=3.8 Hz, 1H), 3.12 (br, B part of AB, 1H), 3.04 (s, 3H), 2.97
(d, A part of AB, JAB = 13.6 Hz, 1H), 2.32 (br, 1H), 2.28 (d, B
part of AB, JAB=13.6 Hz, 1H), 2.12-2.04 (m, 1H), 1.99 (s, 3H),
1.72-1.40 (m, 6H), 1.45 (s, 9H), 1.13 (d, J = 6.2 Hz, 3H),
0.97-0.93 (m, 1H), 0.96 (d, J=6.2 Hz, 3H), 0.93 (s, 3H), 0.74 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 171.8, 169.5, 140.5, 139.2,
129.4 (2C), 128.6 (2C), 128.1, 127.7 (2C), 127.5 (2C), 126.2, 85.4,
80.6, 76.5, 65.1, 55.6, 54.6, 53.1, 52.2, 48.0, 47.8, 45.1, 37.4, 31.0,
29.6, 28.0 (3C), 27.3, 22.4 (2C), 21.2, 20.9, 20.5; IR (CHCl3)
2953, 2936, 1734, 1456, 1369, 1240, 1146 cm-1; MS (20 eV) m/z
591 (Mþ, 0.2), 548 (90), 327 (100), 284 (61), 204 (38), 148 (81);
HRMS calcd for C37H53NO5 (Mþ) 591.3923, found 591.3925.
(2S,3R)-tert-Butyl 2-[(R)-acetoxy(phenyl)methyl]-3-[(1S,2R)-
2-methoxybornyl-10-benzylamino]-4-methylpentanoate (5a-Ac:
minor isomer-1): colorless oil; [R]19D = þ16.2 (c 0.9, CHCl3);
1H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 7.4 Hz, 2H),
7.32-7.20 (m, 8H), 5.97 (d, J = 5.1 Hz, 1H), 3.68 (s, 2H), 3.39
(dd, J=3.4, 7.2 Hz, 1H), 3.30 (dd, J=5.1, 9.0 Hz, 1H), 3.25 (d,
A part of AB, JAB=13.4 Hz, 1H), 3.17 (dd, J=4.6, 9.0 Hz, 1H),
(2S,3S)-tert-Butyl 2-[(R)-hydroxy(phenyl)methyl]-3-[(1S,2R)-
2-methoxybornyl-10-benzylamino]-3-p-tolylpropanoate (5d): col-
orless oil; [R]20D = -59.9 (c 0.9, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 7.35 (d, J=7.6 Hz, 2H), 7.31-7.16 (m, 12H), 4.49 (d,
J = 11.7 Hz, 1H), 4.49 (dd, J = 2.6, 10.8 Hz, 1H), 3.99 (d, J =
10.8 Hz, 1H), 3.92 (d, A part of AB, JAB = 13.7 Hz, 1H), 3.58
(dd, J=2.6, 11.7 Hz, 1H), 3.35 (d, B part of AB, JAB=13.7 Hz,
1H), 3.20-3.16 (br, 1H), 3.18 (d, A part of AB, JAB =15.0 Hz,
1H), 2.92 (s, 3H), 2.37 (s, 3H), 2.22 (d, B part of AB, JAB=15.0
Hz, 1H), 1.68-1.55 (m, 4H), 1.43 (dd, J=7.4, 12.5 Hz, 1H), 1.23
(s, 9H), 1.25-1.18 (m, 1H), 0.95-0.90 (m, 1H), 0.86 (s, 3H), 0.82
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 174.6, 142.6, 140.4,
136.8, 133.1, 129.8 (2C), 129.6 (2C), 128.8 (2C), 127.8 (2C), 127.6
(2C), 126.7, 126.6, 125.3 (2C), 84.9, 81.9, 71.6, 64.3, 57.6, 54.4,
53.9, 53.0, 47.6, 46.4, 45.0, 37.3, 29.7, 28.0 (3C), 27.4, 21.1, 20.9,
20.3; IR (CHCl3) 3690, 2934, 1695, 1603, 1452, 1367 cm-1; MS
(20 eV) m/z 597 (Mþ, 0.6), 376 (100), 162 (9), 106 (19); HRMS
calcd for C39H51NO4 (Mþ) 597.3818, found 597.3810.
4206 J. Org. Chem. Vol. 75, No. 12, 2010

Ozeki et al.
JOCArticle
(2S,3S)-tert-Butyl 2-[(R)-hydroxy(phenyl)methyl]-3-[(1S,2R)-
2-methoxybornyl-10-benzylamino]-3-(4-methoxyphenyl)propano-
ate (5e): colorless oil; [R]14D = -61.5 (c 1.0, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 7.36 (d, J = 7.6 Hz, 2H), 7.31-7.16 (m,
10H), 6.94 (d, J = 8.8 Hz, 2H), 4.49 (d, J = 11.7 Hz, 1H), 4.48
(dd, J=2.6, 10.8 Hz, 1H), 4.00 (d, J=10.8 Hz, 1H), 3.91 (d, A
part of AB, JAB =13.7 Hz, 1H), 3.83 (s, 3H), 3.56 (dd, J=2.6,
11.7 Hz, 1H), 3.36 (d, B part of AB, JAB = 13.7 Hz, 1H),
3.21-3.16 (br, 1H), 3.19 (d, A part of AB, JAB =16.7 Hz, 1H),
2.94 (s, 3H), 2.20 (d, B part of AB, JAB = 16.7 Hz, 1H),
1.69-1.56 (m, 4H), 1.43 (dd, J = 7.4, 12.5 Hz, 1H), 1.23 (s,
9H), 1.22-1.18 (m, 1H), 0.96-0.90 (m, 1H), 0.86 (s, 3H), 0.82 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 174.6, 158.7, 142.6, 140.4,
130.9 (2C), 129.6 (2C), 128.4, 127.8 (2C), 127.7 (2C), 126.7,
126.6, 125.3 (2C), 113.5 (2C), 84.9, 81.9, 71.7, 63.9, 57.6, 55.2,
54.5, 54.0, 53.0, 47.5, 46.3, 45.0, 37.3, 29.7, 28.0 (3C), 27.3, 20.9,
1H), 1.61-1.56 (m, 3H), 1.43 (dd, J=7.5, 12.6 Hz, 1H), 1.28 (s,
9H), 1.20-1.13 (m, 1H), 0.94-0.90 (m, 1H), 0.86 (s, 3H), 0.80 (s,
3H); 13C NMR (100 MHz, CDCl3): δ 174.7, 158.5, 140.4, 136.6,
134.8, 129.8 (2C), 129.6 (2C), 128.1 (2C), 127.7 (2C), 127.2,
126.6, 126.4 (2C), 113.3 (2C), 85.0, 82.0, 71.3, 64.4, 57.5, 55.3,
54.5, 53.6, 53.0, 47.6, 46.2, 45.0, 37.3, 29.7, 28.0 (3C), 27.3, 20.9,
20.3; IR (CHCl3) 3690, 2936, 1695, 1603, 1512, 1367, 1150 cm-1
;
MS (20 eV) m/z 613 (Mþ, 1), 362 (100), 272 (11), 106 (16);
HRMS calcd for C39H51NO5 (Mþ) 613.3767, found 613.3760.
(2S,3S)-tert-Butyl 3-hydroxy-2-[(S)-[(1S,2R)-2-methoxybornyl-
10-benzylamino](phenyl)methyl]-4-methylpentanoate (5i): color-
1
less oil; [R]21D = -60.2 (c 1.0, CHCl3); H NMR (400 MHz,
CDCl3) δ 7.36-7.18 (m, 10H), 4.48 (d, J = 11.7 Hz, 1H), 3.91
(d, A part of AB, JAB=13.9 Hz, 1H), 3.44 (dd, J=2.2, 11.5 Hz,
1H), 3.31 (d, B part of AB, JAB =13.9 Hz, 1H), 3.17 (br d, J=
4.0 Hz, 1H), 3.10 (d, A part of AB, JAB=14.5 Hz, 1H), 3.06 (d,
J = 11.0 Hz, 1H), 2.91 (s, 3H), 2.71 (dt, J = 2.2, 11.0 Hz, 1H),
2.24 (d, B part of AB, JAB =14.5 Hz, 1H), 1.69-1.53 (m, 5H),
1.63 (s, 9H), 1.51-1.44 (m, 1H), 1.43 (dd, J=7.3, 12.5 Hz, 1H),
1.18 (m, 1H), 0.91 (d, J=6.6 Hz, 3H), 0.86 (s, 3H), 0.84 (s, 3H),
0.80 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 175.0, 140.6, 136.7,
129.7 (2C), 129.7 (2C), 128.0 (2C), 127.6 (2C), 127.0, 126.5, 85.2,
82.0, 76.7, 64.8, 57.1, 54.5, 53.0, 49.0, 47.6, 46.6, 45.0, 37.3, 33.5,
29.8, 28.4 (3C), 27.3, 20.9, 20.3, 20.2, 19.1; IR (CHCl3) 3690,
2936, 1692, 1601, 1454, 1367, 1150 cm-1; MS (20 eV) m/z 549
(Mþ, 0.6), 362 (100), 272 (4), 135 (5), 106 (5); HRMS calcd for
C35H51NO4 (Mþ) 549.3818, found 549.3812.
20.3; IR (CHCl3) 3690, 3034, 2936, 1695, 1609, 1512, 1367 cm-1
;
MS (20 eV) m/z 613 (Mþ, 0.3), 392 (100), 234 (19), 178 (65), 106
(88); HRMS calcd for C39H51NO5 (Mþ) 613.3767, found
613.3764.
(2S,3S)-tert-Butyl 2-[(R)-(4-chlorophenyl)(hydroxy)methyl]-
3-[(1S,2R)-2-methoxybornyl-10-benzylamino]-3-phenylpropano-
ate (5f): colorless oil; [R]21D = -55.6 (c 1.0, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 7.42-7.19 (m, 14H), 4.51 (d, J=11.7 Hz,
1H), 4.45 (dd, J=2.6, 10.6 Hz, 1H), 4.07 (d, J=10.6 Hz, 1H),
3.90 (d, A part of AB, JAB=13.7 Hz, 1H), 3.56 (dd, J=2.6, 11.7
Hz, 1H), 3.41 (d, B part of AB, JAB = 13.7 Hz, 1H), 3.22 (d, A
part of AB, JAB=15.0 Hz, 1H), 3.25-3.20 (br, 1H), 2.96 (s, 3H),
2.23 (d, B part of AB, JAB = 15.0 Hz, 1H), 1.71-1.51 (m, 4H),
1.44 (dd, J=7.4, 12.7 Hz, 1H), 1.28 (s, 9H), 1.26-1.12 (m, 1H),
0.95-0.88 (m, 1H), 0.86 (s, 3H), 0.80 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 174.4, 141.2, 140.2, 136.4, 132.5, 129.7 (2C),
129.6 (2C), 128.2 (2C), 128.0 (2C), 127.7 (2C), 127.4, 126.8 (2C),
126.7, 84.9, 82.3, 71.2, 64.4, 57.5, 54.5, 53.4, 53.0, 47.6, 46.3,
45.0, 37.2, 29.7, 28.0 (3C), 27.3, 20.9, 20.3; IR (CHCl3) 3692,
3032, 2936, 1693, 1601, 1491, 1369 cm-1; MS (20 eV) m/z 617
(Mþ, 0.8), 396 (100), 272 (7), 182 (10), 148 (29), 140 (18), 106
(45); HRMS calcd for C38H48ClNO4 (Mþ) 617.3272, found
617.3263.
(2S,3S)-tert-Butyl 3-cyclohexyl-3-hydroxy-2-[(S)-[(1S,2R)-2-
methoxybornyl-10-benzylamino](phenyl)methyl]propanoate (5j):
colorless oil; [R]20 = -60.0 (c 0.9, CHCl3); 1H NMR (400
D
MHz, CDCl3) δ 7.35-7.17 (m, 10H), 4.59 (d, J=11.5 Hz, 1H),
3.91 (d, A part of AB, JAB=13.7 Hz, 1H), 3.45 (dd, J=2.2, 11.5
Hz, 1H), 3.30 (d, B part of AB, JAB =13.7 Hz, 1H), 3.15 (br d,
1H), 3.08 (d, A part of AB, JAB=14.1 Hz, 1H), 2.94 (d, J=11.0
Hz, 1H), 2.89 (s, 3H), 2.81 (dt, J=2.2, 11.2 Hz, 1H), 2.25 (d, B
part of AB, JAB =14.1 Hz, 1H), 1.99 (d, J=13.4 Hz, 1H), 1.92
(d, J=12.3 Hz, 1H), 1.79-1.53 (m, 7H), 1.63 (s, 9H), 1.42 (dd,
J=7.3, 12.6 Hz, 1H), 1.24-1.04 (m, 5H), 0.92 (t, J=8.4 Hz, 1H),
0.84 (s, 3H), 0.82-0.81 (m, 1H), 0.80 (s, 3H), 0.78-0.65 (m, 1H);
13C NMR (100 MHz, CDCl3) δ 175.0, 140.6, 136.7, 129.7 (2C),
129.7 (2C), 127.9 (2C), 127.6 (2C), 127.0, 126.5, 85.2, 81.9, 75.3,
64.7, 57.1, 54.5, 53.0, 48.6, 47.6, 46.6, 45.0, 42.9, 37.3, 30.0, 29.8,
29.2, 28.4 (3C), 27.4, 26.3, 26.0, 25.9, 21.0, 20.3; IR (CHCl3)
2930, 2853, 1697, 1452, 1367, 1150 cm-1; MS (20 eV) m/z 589
(Mþ, 1), 362 (100), 272 (8), 148 (13), 106 (40); HRMS calcd for
C38H55NO4 (Mþ) 589.4131, found 589.4140.
(2S,3S)-tert-Butyl 2-[(R)-hydroxy(p-tolyl)methyl]-3-[(1S,2R)-
2-methoxybornyl-10-benzylamino-3-phenylpropanoate (5g): col-
orless oil; [R]24D = -61.5 (c 1.0, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 7.42-7.21 (m, 10H), 7.14 (d, J=7.9 Hz, 2H), 7.07 (d,
J=8.1 Hz, 2H), 4.52 (d, J=11.5 Hz, 1H), 4.45 (dd, J=1.8, 10.8
Hz, 1H), 4.00 (d, J=10.8 Hz, 1H), 3.92 (d, A part of AB, JAB
=
13.9 Hz, 1H), 3.59 (dd, J=2.7, 11.7 Hz, 1H), 3.40 (d, B part of
AB, JAB =13.9 Hz, 1H), 3.22-3.18 (br, 1H), 3.20 (d, A part of
AB, JAB=14.8 Hz, 1H), 2.95 (s, 3H), 2.30 (s, 3H), 2.24 (d, B part
of AB, JAB=14.8 Hz, 1H), 1.69-1.52 (m, 4H), 1.43 (dd, J=7.3,
12.6 Hz, 1H), 1.26 (s, 9H), 1.20-1.16 (m, 1H), 0.94-0.90 (m,
1H), 0.86 (s, 3H), 0.80 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
174.6, 140.4, 139.5, 136.6, 136.2, 129.8 (2C), 129.6 (2C), 128.5
(2C), 128.1 (2C), 127.7 (2C), 127.2, 126.6, 125.2 (2C), 85.0, 81.9,
71.5, 64.4, 57.5, 54.5, 53.5, 53.0, 47.6, 46.2, 45.1, 37.3, 29.7, 28.0
(3C), 27.3, 21.0, 20.9, 20.3; IR (CHCl3) 3692, 3028, 2936, 1695,
1603, 1454, 1367, 1150 cm-1; MS (20 eV) m/z 597 (Mþ, 1), 362
(100), 162 (31), 148 (70), 120 (67), 106 (98), 91 (35); HRMS calcd
for C39H51NO4 (Mþ) 597.3818, found 597.3810.
(2S,3S)-tert-Butyl 3-hydroxy-2-[(S)-[(1S,2R)-2-methoxybornyl-
10-benzylamino](phenyl)methyl]octanoate (5k): colorless oil;
1
[R]20D = -64.6 (c 1.1, CHCl3); H NMR (400 MHz, CDCl3)
δ 7.36-7.20 (m, 10H), 4.44 (d, J=11.7 Hz, 1H), 3.90 (d, A part
of AB, JAB = 13.7 Hz, 1H), 3.31 (d, B part of AB, JAB = 13.7
Hz, 1H), 3.23 (dd, J = 2.4, 11.5 Hz, 1H), 3.23-3.16 (m, 2H),
3.12 (d, A part of AB, JAB=14.3 Hz, 1H), 2.94 (d, J=10.8 Hz,
1H), 2.92 (s, 3H), 2.22 (d, B part of AB, JAB = 14.3 Hz, 1H),
1.68-1.54 (m, 4H), 1.63 (s, 9H), 1.46-1.16 (m, 10H),
0.95-0.90 (m, 1H), 0.85 (d, J = 14.1 Hz, 3H), 0.85 (s, 3H),
0.80 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 174.8, 140.6,
136.6, 129.7 (2C), 129.7 (2C), 127.9 (2C), 127.7 (2C), 127.0,
126.5, 85.1, 82.0, 70.7, 64.6, 57.3, 54.5, 53.0, 51.5, 47.6, 46.6,
45.0, 37.3, 36.4, 31.8, 29.8, 28.4 (3C), 27.4, 25.7, 22.5, 20.9,
20.3, 14.0; IR (CHCl3) 3543, 2934, 1699, 1601, 1454, 1367,
1150 cm-1; MS (20 eV) m/z 577 (Mþ, 0.4), 362 (100), 272 (6),
242 (6), 148 (26), 106 (73); HRMS calcd for C37H55NO4 (Mþ)
577.4131, found 577.4137.
(2S,3S)-tert-Butyl 3-[(1S,2R)-2-methoxybornyl-10-benzylamino]-
2-[(R)-(4-methoxyphenyl)(hydroxy)methyl]-3-phenylpropanoate
(5h): colorless oil; [R]21 = -63.2 (c 1.0, CHCl3); 1H NMR
D
(400 MHz, CDCl3) δ 7.41-7.20 (m, 10H), 7.18 (d, J = 8.8 Hz,
2H), 6.82 (d, J=8.8 Hz, 2H), 4.52 (d, J=11.7 Hz, 1H), 4.44 (dd,
J=2.4, 10.8 Hz, 1H), 4.00 (d, J=10.8 Hz, 1H), 3.92 (d, A part of
AB, JAB=13.9 Hz, 1H), 3.77 (s, 3H), 3.58 (dd, J=2.6, 11.7 Hz,
1H), 3.40 (d, B part of AB, JAB =13.9 Hz, 1H), 3.22-3.18 (br,
1H), 3.20 (d, A part of AB, JAB=15.2 Hz, 1H), 2.95 (s, 3H), 2.25
(d, B part of AB, JAB=15.2 Hz, 1H), 1.67 (dq, J=2.9, 12.5 Hz,
(1R,2R,6R)-tert-Butyl 2-(2-tert-Butoxy-2-oxoethyl)-6-[(1S,2R)-
2-methoxybornyl-10-benzylamino]cyclohexanecarboxylate (10a).
n-Buthyllithium (2.6 M in hexane solution, 107 μL, 0.279 mmol)
was added dropwise to a solution of chiral amine 1 (76 mg,
J. Org. Chem. Vol. 75, No. 12, 2010 4207

Ozeki et al.
JOCArticle
0.279 mmol) in THF (2 mL) at -50 °C, and the solution was
stirred for 5 min under an argon atmosphere. A solution of
substrate 9a (55 mg, 0.186 mmol) in THF (1 mL) was added
dropwise to the lithium amide solution at the same temperature,
and the mixture was stirred for 2.0 h. The reaction mixture was
quenched with a saturated aqueous solution of sodium hydrogen
carbonate and extracted with diethyl ether. The organic layer
was washed with brine, dried over anhydrous sodium sulfate,
and concentrated in vacuo. The residue was purified by column
chromatography on silica gel (hexane/ethyl acetate =20/1) to
hexane solution, 110 μL, 0.285 mmol) was added dropwise to a
solution of chiral amine 1 (78 mg, 0.285 mmol) in THF (2 mL) at
-50 °C, and the solution was stirred for 5 min under an argon
atmosphere. A solution of substrate 9a (57 mg, 0.192 mmol) in
THF (1 mL) was added dropwise to the lithium amide solution
at the same temperature, and the mixture was stirred for 0.5 h.
Then, benzaldehyde (4a) (58 μL, 0.576 mmol) was added drop-
wise to the reaction mixture at the same temperature, and the
mixture was stirred for 2 h. The reaction mixture was quenched
with a saturated aqueous solution of sodium hydrogen carbo-
nate and extracted with diethyl ether. The organic layer was
washed with brine, dried over anhydrous sodium sulfate, and
concentrated in vacuo. The residue was purified by column
chromatography on silica gel (hexane/ethyl acetate =20/1) to
afford 11a as a single diastereomer (77 mg, 60%) as well as the
mixture of minor diastereomers (15 mg, 11%): colorless oil;
afford 10a as a single diastereomer (89 mg, 85%) as well as a
20
mixture of minor diastereomer (7 mg, 6%): colorless oil; [R]D
=
-29.3 (c 0.9, CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.34 (d,
J=7.4 Hz, 2H), 7.27 (t, J=7.4 Hz, 2H), 7.19 (br t, J=7.4 Hz,
1H), 3.78 (d, A part of AB, JAB=14.7 Hz, 1H), 3.72 (d, B part of
AB, JAB =14.7 Hz, 1H), 3.19 (d, A part of AB, JAB =14.1 Hz,
1H), 3.19-3.18 (m, 1H), 3.07 (s, 3H), 2.96-2.92 (m, 1H), 2.30 (d,
B part of AB, JAB=14.1 Hz, 1H), 2.30-2.21 (m, 2H), 1.98-1.91
(m, 2H), 1.86-1.84 (m, 1H), 1.73-1.67 (m, 3H), 1.62-1.55 (m,
2H), 1.53 (s, 9H), 1.46 (dd, J=7.4, 12.7 Hz, 1H), 1.48-1.44 (m,
1H), 1.43 (s, 9H), 1.40-1.12 (m, 3H), 0.94-0.86 (m, 2H), 0.92 (s,
3H), 0.76 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 174.6, 171.8,
141.8, 129.0 (2C), 127.8 (2C), 126.2, 85.3, 80.4, 80.1, 62.0, 55.8,
54.7, 53.8, 53.3, 47.4, 45.3, 40.3, 38.1, 37.4, 30.8, 30.5, 29.6, 28.2
(3C), 28.1 (4C), 27.3, 24.8, 20.8, 20.5; IR (CHCl3) 3030, 2936,
1717, 1603, 1456, 1367, 1153 cm-1; MS (20 eV) m/z 569 (Mþ,
45), 312 (87), 284 (61), 135 (22), 91 (100); HRMS calcd for
C35H55NO5 (Mþ) 569.4080, found 569.4083.
1
[R]23D = -16.2 (c 0.4, CHCl3); H NMR (400 MHz, CDCl3)
δ 7.36-7.17 (m, 10H), 4.82 (dd, J = 6.0, 10.4 Hz, 1H), 3.85 (d,
A part of AB, JAB =14.5 Hz, 1H), 3.81 (d, B part of AB, JAB =
14.5 Hz, 1H), 3.28 (d, A part of AB, JAB = 13.7 Hz, 1H), 3.18
(dd, J=3.1, 7.3 Hz, 1H), 3.09 (s, 3H), 3.04-2.99 (m, 2H), 2.71
(br d, J=9.9 Hz, 1H), 2.33 (d, B part of AB, JAB=13.7 Hz, 1H),
2.05-1.80 (m, 3H), 1.72-1.53 (m, 4H), 1.64 (s, 9H), 1.49-1.21
(m, 6H), 1.17-1.10 (m, 1H), 1.12 (s, 9H), 0.92-0.88 (m, 1H),
0.92 (s, 3H), 0.73 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 176.4,
171.6, 142.9, 142.0, 129.0 (2C), 128.2 (2C), 127.8, 127.8 (2C),
127.0 (2C), 126.2, 85.5, 81.1, 80.3, 72.8, 63.6, 55.3, 54.7, 53.5,
53.0, 48.4, 47.4, 45.4, 41.8, 37.4, 30.7 (2C), 28.2 (4C), 27.8 (4C),
27.3, 25.2, 20.8, 20.5; IR (CHCl3) 3692, 2934, 1715, 1603, 1456,
1367, 1151 cm-1; MS (20 eV) m/z 675 (Mþ, 34), 568 (32), 455
(81), 312 (78), 284 (55), 272 (51), 135 (50), 91 (100); HRMS calcd
for C42H61NO6 (Mþ) 675.4499, found 675.4496.
(1R,2R,5R)-tert-Butyl 2-(2-tert-Butoxy-2-oxoethyl)-5-[(1S,2R)-
2-methoxybornyl-10-benzylamino]-cyclopentanecarboxylate(10b).
n-Buthyllithium (2.6 M in hexane solution, 202 μL, 0.533 mmol)
was added dropwise to a solution of chiral amine 1 (146 mg,
0.533 mmol) in THF (4 mL) at -50 °C, and the solution was
stirred for 5 min under an argon atmosphere. A solution of
substrate 9b (100 mg, 0.355 mmol) in THF (10 mL) was added
dropwise to the lithium amide solution at the same temperature,
and the mixture was stirred for 2.0 h. The reaction mixture was
quenched with a saturated aqueous solution of sodium hydro-
gen carbonate and extracted with diethyl ether. The organic
layer was washed with brine, dried over anhydrous sodium
sulfate, and concentrated in vacuo. The residue was purified
by column chromatography on silica gel (hexane/ethyl acetate=
30/1 f 20/1 f 10/1 f ethyl acetate) to afford 10b as a single
diastereomer (168 mg, 85%) as well as a mixture of minor dia-
stereomers (21 mg, 11%): colorless oil; [R]25D = -40.0 (c 0.4,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.34 (d, J=6.8 Hz, 2H),
7.29-7.24 (m, 2H), 7.18 (br t, J=7.4 Hz, 1H), 3.74 (d, A part of
AB, JAB =15.2 Hz, 1H), 3.66 (d, B part of AB, JAB =15.2 Hz,
1H), 3.54 (dt, J=8.4, 8.7 Hz, 1H), 3.30 (dd, J=7.1, 7.3 Hz, 1H),
3.11 (s, 3H), 2.99 (d, A part of AB, JAB =13.7 Hz, 1H), 2.49 (t,
J=8.7 Hz, 1H), 2.40 (dd, A part of AB, JAB =14.5 Hz, J=8.8
Hz, 1H), 2.34 (m, 1H), 2.27 (d, B part of AB, JAB=13.7 Hz, 1H),
2.10 (dd, B part of AB, JAB = 14.5 Hz, J = 9.5 Hz, 1H),
1.92-1.18 (m, 10H), 1.45 (s, 9H), 1.42 (s, 9H), 1.00-0.88 (m,
1H), 0.96 (s, 3H), 0.82 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
175.1, 171.7, 141.4, 128.0 (2C), 127.9 (2C), 126.2, 85.3, 80.1,
79.9, 67.1, 57.4, 54.8, 53.1, 52.3, 47.4, 47.3, 45.3, 40.3, 37.4, 30.7,
30.2, 28.1 (7C), 27.2, 27.1, 20.8, 20.4; IR (CHCl3) 3030, 2951,
1717, 1456, 1367, 1198, 1148 cm-1; MS (70 eV) m/z 555 (Mþ,
10), 402 (18), 312 (100), 284 (15), 272 (56), 135 (26), 91 (79);
HRMS calcd for C34H53NO5 (Mþ) 555.3923, found 555.3915.
A typical procedure for the tandem double Michael-aldol
reaction was shown by representing the reaction of 1, 9a, and 4a.
The major products (11a-f) were isolated as a single diastereomer
by employing silica gel column chromatography or recycle HPLC.
(1R,2S,6R)-tert-Butyl 2-[(2S,3S)-1-tert-Butoxy-3-hydroxy-1-
oxo-3-phenylpropan-2-yl]-6-[(1S,2R)-2-methoxybornyl-10-benzyl-
amino]cyclohexanecarboxylate (11a). n-Buthyllithium (2.6 M in
(1R,2S,6R)-tert-Butyl 2-[(2S,3S)-1-tert-butoxy-3-(4-chlorophenyl)-
3-hydroxy-1-oxopropan-2-yl]-6-[(1S,2R)-2-methoxybornyl-10-
benzylamino]cyclohexanecarboxylate (11b): colorless oil; [R]24
-25.7 (c 0.6, CHCl3); H NMR (400 MHz, CDCl3) δ 7.34 (d,
J=7.8 Hz, 2H), 7.30-7.23 (m, 6H), 7.19 (br t, J=7.2 Hz, 1H),
4.79 (dd, J = 5.5, 10.3 Hz, 1H), 3.85 (d, A part of AB, JAB =
=
D
1
15.0 Hz, 1H), 3.81 (d, B part of AB, JAB=15.0 Hz, 1H), 3.28 (d,
A part of AB, JAB=14.1 Hz, 1H), 3.19 (dd, J=3.1, 7.3 Hz, 1H),
3.10 (s, 3H), 3.04-2.90 (br, 2H), 2.62 (br d, J=10.4 Hz, 1H), 2.33
(d, B part of AB, JAB = 14.1 Hz, 1H), 2.14-1.96 (br, 1H),
1.96-1.76 (br m, 3H), 1.76-1.51 (m, 4H), 1.63 (s, 9H), 1.50-1.02
(m, 6H), 1.21 (s, 9H), 0.96-0.86 (m, 1H), 0.92 (s, 3H), 0.73 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 176.5, 171.3, 141.9, 141.6,
133.4, 128.9 (2C), 128.4 (4C), 127.8 (2C), 126.3, 85.5, 81.3, 80.5,
72.0, 63.6, 55.0, 54.7, 53.5, 52.4, 48.0, 47.4, 45.3, 41.4, 37.3, 30.7
(2C), 28.2 (4C), 27.8 (4C), 27.3, 25.2, 20.8, 20.5; IR (CHCl3) 3690,
2936, 1715, 1601, 1456, 1369, 1151 cm-1; MS (70 eV) m/z 709
(Mþ, 14), 568 (6), 455 (13), 312 (29), 282 (17), 272 (12), 135 (23),
91 (100); HRMS calcd for C42H60ClNO6 (Mþ) 709.4109, found
709.4114.
(1R,2S,6R)-tert-Butyl 2-[(2S,3S)-1-tert-butoxy-3-hydroxy-1-
oxo-3-(p-tolyl)propan-2-yl]-6-[(1S,2R)-2-methoxybornyl-10-ben-
zylamino]cyclohexanecarboxylate (11c): colorless oil; [R]28
=
D
1
-27.7 (c 1.1, CHCl3); H NMR (400 MHz, CDCl3) δ 7.34 (d,
J=7.2 Hz, 2H), 7.29-7.23 (m, 2H), 7.22-7.15 (m, 1H), 7.19 (d, J=
8.0 Hz, 2H), 7.09 (d, J=8.0 Hz, 2H), 4.78 (dd, J=5.5, 10.3 Hz,
1H), 3.85 (d, A part of AB, JAB=14.3 Hz, 1H), 3.79 (d, B part of
AB, JAB =14.3 Hz, 1H), 3.27 (d, A part of AB, JAB =14.5 Hz,
1H), 3.17 (dd, J = 3.0, 7.2 Hz, 1H), 3.08 (s, 3H), 3.06-2.90
(br, 2H), 2.69 (d, J=10.1 Hz, 1H), 2.32 (d, B part of AB, JAB
=
14.5 Hz, 1H), 2.30 (s, 3H), 2.11-1.76 (m, 4H), 1.74-1.06 (m,
10H), 1.63 (s, 9H), 1.17 (s, 9H), 0.96-0.84 (m, 1H), 0.92 (s, 3H),
0.72 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 176.3, 171.6, 141.9,
140.0, 137.4, 128.8 (4C), 127.7 (2C), 126.9 (2C), 126.2, 85.5, 81.0,
80.1, 72.6, 63.6, 55.4, 54.7, 53.5, 53.2, 48.2, 47.3, 45.3, 41.7, 37.3,
30.6 (2C), 28.2 (4C), 27.7 (4C), 27.2, 25.2, 21.1, 20.8, 20.5; IR
4208 J. Org. Chem. Vol. 75, No. 12, 2010

Ozeki et al.
JOCArticle
(CHCl3) 3690, 2936, 1715, 1603, 1456, 1369, 1151 cm-1; MS (70
eV) m/z 689 (Mþ, 11), 568 (15), 455 (47), 312 (57), 282 (42), 272
(39), 135 (45), 91 (100); HRMS calcd for C43H63NO6 (Mþ)
689.4655, found 689.4662.
reaction was quenched with methanol at 0 °C, and the solvent
was removed in vacuo. The residue was added saturated aqu-
eous solution of ammonium chloride and extracted with ethyl
acetate. The organic layer was washed with brine, dried over
sodium sulfate, and concentrated in vacuo. The residue was
purified by column chromatography on silica gel (hexane/ethyl
(1R,2S,6R)-tert-Butyl 2-[(2S,3S)-1-tert-butoxy-3-hydroxy-3-
(4-methoxyphenyl)-1-oxopropan-2-yl]-6-[(1S,2R)-2-methoxybor-
nyl-10-benzylamino]cyclohexanecarboxylate (11d): colorless oil;
acetate =10/1) to afford 13a (449 mg, 96%):colorlessoil;[R]22
=
D
1
[R]19D = -38.3 (c 1.0, CHCl3); H NMR (400 MHz, CDCl3)
-65.8 (c 1.1, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.39-7.10
(m, 15H), 5.58 (d, J=4.4 Hz, 1H), 4.39 (d, J=11.2 Hz, 1H), 3.89
(d, A part of AB, JAB=13.9 Hz, 1H), 3.63 (dd, J=4.6, 11.2 Hz,
1H), 3.33 (d, B part of AB, JAB=13.9 Hz, 1H), 3.24 (d, A part of
AB, JAB =14.3 Hz, 1H), 3.27-3.22 (br, 1H), 2.97 (s, 3H), 2.18
(d, B part of AB, JAB=14.3 Hz, 1H), 1.91 (s, 3H), 1.71-1.54 (m,
4H), 1.44 (dd, J=7.3, 12.6 Hz, 1H), 1.31-1.20 (m, 1H), 1.25 (s,
9H), 0.97-0.92 (m, 1H), 0.87 (s, 3H), 0.82 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 170.7, 169.1, 140.2, 138.4, 135.4, 129.9
(2C), 129.6 (2C), 128.0 (2C), 128.0 (2C), 127.7 (2C), 127.4, 127.3,
126.7, 125.8 (2C), 84.7, 80.6, 73.6, 64.7, 57.9, 54.4, 53.3, 53.1,
47.6, 46.9, 45.0, 37.2, 29.6, 28.0 (3C), 27.4, 20.9, 20.7, 20.3; IR
(CHCl3) 2936, 1726, 1603, 1494, 1452, 1369, 1148 cm-1; MS (20
eV) m/z 625 (Mþ, 1), 362 (100), 272 (7), 148 (10), 106 (6); HRMS
calcd for C40H51NO5 (Mþ) 625.3767, found 625.3761.
δ 7.35 (d, J = 7.2 Hz, 2H), 7.29-7.16 (m, 3H), 7.24 (d, J =
8.8 Hz, 2H), 6.83 (d, J=8.8 Hz, 2H), 4.77 (dd, J=4.8, 9.9 Hz,
1H), 3.85 (d, A part of AB, JAB=14.5 Hz, 1H), 3.80 (d, B part of
AB, JAB = 14.5 Hz, 1H), 3.77 (s, 3H), 3.27 (d, A part of AB,
JAB =14.1 Hz, 1H), 3.18 (dd, J=3.1, 7.1 Hz, 1H), 3.09 (s, 3H),
3.30-2.90 (br, 2H), 2.68 (br d, J=10.6 Hz, 1H), 2.33 (d, B part
of AB, JAB = 14.1 Hz, 1H), 2.08-1.78 (m, 4H), 1.76-1.50 (m,
4H), 1.64 (s, 9H), 1.50-1.10 (m, 6H), 1.18 (s, 9H), 0.94-0.85 (m,
1H), 0.92 (s, 3H), 0.73 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 176.4, 171.6, 159.2, 142.0, 135.3, 129.1 (2C), 128.2, 128.1, 127.8
(2C), 126.2, 113.6 (2C), 85.4, 81.0, 80.2, 72.2, 63.6, 55.3, 55.2,
54.7, 54.0, 53.5, 48.0, 47.4, 45.3, 41.8, 37.3, 30.6 (2C), 28.2 (4C),
27.8 (4C), 27.2, 25.2, 20.8, 20.5; IR (CHCl3) 3692, 2936, 1715,
1611, 1456, 1369, 1151 cm-1; MS (70 eV) m/z 705 (Mþ, 26), 568
(22), 455 (88), 312 (77), 284 (56), 272 (59), 135 (56), 91 (100);
HRMS calcd for C43H63NO7 (Mþ) 705.4604, found 705.4601.
(1R,2S,6R)-tert-Butyl 2-[(2S,3R)-1-tert-butoxy-3-hydroxy-4-
methyl-1-oxopentan-2-yl]-6-[(1S,2R)-2-methoxybornyl-10-benz-
(2S,3R)-tert-Butyl 3-(tert-Butoxycarbonyloxy)-2-[(S)-[(1S,2R)-
2-methoxybornyl-10-benzylamino](phenyl)methyl]-3-phenylpro-
panoate (13b). Compound 13b was prepared in the same way as
in the case of 8b: colorless oil; [R]25D=-51.9 (c 1.2, CHCl3); 1H
NMR (400 MHz, CDCl3) δ 7.36 (d, J=7.5 Hz, 2H), 7.32-7.12
(m, 11H), 7.11 (br d, J=7.6 Hz, 2H), 5.38 (d, J=4.9 Hz, 1H),
4.45 (d, J=11.0 Hz, 1H), 3.92 (d, A part of AB, JAB=14.1 Hz,
ylamino]cyclohexanecarboxylate (11e): colorless oil; [R]21
=
D
1
-35.3 (c 1.1, CHCl3); H NMR (400 MHz, CDCl3) δ 7.32 (d,
J=7.2 Hz, 2H), 7.26 (t, J=7.2 Hz, 2H), 7.18 (br t, J=7.2 Hz,
1H), 3.81 (d, A part of AB, JAB=14.5 Hz, 1H), 3.77 (d, B part of
AB, JAB=14.5 Hz, 1H), 3.74 (br, 1H), 3.24 (br d, A part of AB,
1H), 3.60 (dd, J=4.9, 11.0 Hz, 1H), 3.34 (d, B part of AB, JAB
14.1 Hz, 1H), 3.22-3.16 (br, 1H), 3.18 (d, A part of AB, JAB
=
=
JAB =14.1 Hz, 1H), 3.15 (dd, J=3.1, 7.3 Hz, 1H), 3.08 (s, 3H),
14.7 Hz, 1H), 2.94 (s, 3H), 2.21 (d, B part of AB, JAB=14.7 Hz,
1H), 1.68-1.57 (m, 4H), 1.42 (dd, J = 7.3, 12.6 Hz, 1H),
1.32-1.22 (m, 1H), 1.28 (s, 9H), 1.27 (s, 9H), 0.96-0.90 (m,
1H), 0.86 (s, 3H), 0.82 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
170.5, 152.2, 140.4, 138.7, 135.7, 130.0 (2C), 129.5 (2C), 128.0
(2C), 127.9 (2C), 127.7 (2C), 127.2, 127.2, 126.6, 125.9 (2C),
84.8, 81.6, 80.6, 76.4, 65.1, 57.7, 54.4, 53.7, 53.1, 47.6, 47.2, 45.0,
37.2, 29.7, 28.0 (3C), 27.7 (3C), 27.4, 20.9, 20.3; IR (CHCl3)
2936, 1742, 1603, 1495, 1454, 1369, 1286, 1148, 1097 cm-1; MS
(20 eV) m/z 683 (Mþ, 1), 362 (100), 272 (8), 204 (4), 148 (21), 106
(22); HRMS calcd for C43H57NO6 (Mþ) 683.4186, found
683.4191.
2.91 (br, 2H), 2.39 (dd, J=1.5, 11.2 Hz, 1H), 2.30 (d, A part of
AB, JAB =14.1 Hz, 1H), 1.96-1.03 (m, 15H), 1.59 (s, 9H), 1.44
(s, 9H), 0.98 (d, J=6.9 Hz, 3H), 0.95-0.82 (m, 1H), 0.91 (s, 3H),
0.83 (d, J = 6.9 Hz, 3H), 0.71 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 176.2, 172.5, 142.0, 128.9 (2C), 127.8 (2C), 126.2, 85.4,
81.1, 80.2, 73.0, 63.4, 55.0, 54.6 (2C), 53.5, 47.4, 45.3 (2C), 37.3
(2C), 31.4, 30.7, 28.1 (8C), 27.2 (2C), 25.3, 20.8, 20.5, 20.4, 14.0;
IR (CHCl3) 2935, 1715, 1603, 1457, 1367, 1157 cm-1; MS (70
eV) m/z 641 (Mþ, 39), 598 (13), 568 (25), 455 (38), 312 (85), 284
(56), 272 (47), 135 (52), 91 (100); HRMS calcd for C39H63NO6
(Mþ) 641.4655, found 641.4646.
(1R,2S,6R)-tert-Butyl 2-[(2S,3R)-1-tert-butoxy-3-cyclohexyl-
3-hydroxy-1-oxopropan-2-yl]-6-[(1S,2R)-2-methoxybornyl-10-
=
(2S,3R)-tert-Butyl 2-[(S)-[(1S,2R)-2-Methoxybornyl-10-ben-
zylamino](phenyl)methyl]-3-phenyl-3-(triethylsilyloxy)propanoate
(13c). Triethylchlorosilane (251 μL, 1.492 mmol) and imidazole
(127 mg, 1.865 mmol) were added to a solution of 5b (218 mg,
0.373 mmol) in dichloromethane (5 mL) at 0 °C, and the reaction
mixture was stirred for 28 h at room temperature under an argon
atmosphere. The reaction mixture was poured into saturated
aqueous solution of ammonium chloride and extracted with
ethyl acetate. The organic layer was washed with brine, dried
over sodium sulfate, and concentrated in vacuo. The residue was
purified by column chromatography on silica gel (hexane/ethyl
acetate =20/1) to afford 13c (262 mg, 100%): colorless oil;
benzylamino]cyclohexanecarboxylate (11f): colorless oil; [R]21
D
-33.7 (c 0.9, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.32 (d, J=
7.8 Hz, 2H), 7.28-7.23 (m, 2H), 7.18 (br t, J=7.2 Hz, 1H), 3.81
(d, A part of AB, JAB=14.8 Hz, 1H), 3.77 (d, B part of AB, JAB=
14.8 Hz, 1H), 3.68 (br, 1H), 3.23 (br d, A part of AB, JAB=14.0
Hz, 1H), 3.14 (dd, J=3.2, 7.2 Hz, 1H), 3.07 (s, 3H), 2.89 (br, 2H),
2.45 (dd, J=1.2, 10.8 Hz, 1H), 2.30 (d, A part of AB, JAB=14.0
Hz, 1H), 1.90-1.02 (m, 25H), 1.59 (s, 9H), 1.45 (s, 9H), 0.94-0.82
(m, 1H), 0.91 (s, 3H), 0.71 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 176.4, 172.5, 142.0, 128.9 (2C), 127.8 (2C), 126.2, 85.4, 81.1,
80.2, 73.2, 63.4, 55.0, 54.6 (2C), 53.5, 47.4, 45.3 (2C), 41.9 (2C),
37.3, 30.67 (2C), 30.64, 28.15 (5C), 28.11 (4C), 27.2, 26.7, 26.4,
25.3, 24.6, 20.8, 20.5; IR (CHCl3): 3692, 2932, 1715, 1603, 1452,
1367, 1153 cm-1; MS (70 eV) m/z 681 (Mþ, 23), 624 (8), 455 (47),
312 (77), 284 (58), 272 (52), 135 (54), 91 (100); HRMS calcd for
C42H67NO6 (Mþ) 681.4968, found 681.4959.
(2S,3R)-tert-Butyl 3-Acetoxy-2-[(S)-[(1S,2R)-2-methoxybor-
nyl-10-benzylamino](phenyl)methyl]-3-phenylpropanoate (13a).
Acetic anhydride (2.8 mL, 29.9 mmol), pyridine (3.0 mL, 37.4
mmol), and 4-dimethylaminopyridine (9 mg, 0.07 mmol) were
added to a solution of 5b (437 mg, 0.75 mmol) in THF (8 mL) at
room temperature, and the resulting mixture was stirred for 5 h
at the same temperature under a nitrogen atmosphere. The
1
[R]25D = -47.9 (c 0.9, CHCl3); H NMR (400 MHz, CDCl3)
δ 7.40 (d, J=7.6 Hz, 2H), 7.34 (t, J=7.6 Hz, 2H), 7.31-7.12 (m,
11H), 4.70 (d, J=3.1 Hz, 1H), 4.42 (d, J=11.4 Hz, 1H), 3.89 (d,
A part of AB, JAB = 13.9 Hz, 1H), 3.35 (dd, J = 3.1, 11.4 Hz,
1H), 3.34 (d, B part of AB, JAB=13.9 Hz, 1H), 3.20 (dd, J=3.1,
7.3 Hz, 1H), 3.11 (d, A part of AB, JAB =14.3 Hz, 1H), 2.87 (s,
3H), 2.25 (d, B part of AB, JAB=14.3 Hz, 1H), 1.64 (dq, J=3.6,
12.5 Hz, 1H), 1.57-1.45 (m, 3H), 1.41 (dd, J=7.2, 12.7 Hz, 1H),
1.35 (s, 9H), 1.25-1.19 (m, 1H), 0.93-0.87 (m, 1H), 0.85 (s, 3H),
0.78 (s, 3H), 0.64 (t, J = 8.0 Hz, 9H), 0.15 (dq, A part of AB,
J
AB =14.9 Hz, J=8,0 Hz, 3H), 0.10 (dq, B part of AB, JAB =
14.9 Hz, J=8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 170.3,
143.5, 140.8, 137.2, 130.2 (2C), 129.9 (2C), 127.7 (2C), 127.6
J. Org. Chem. Vol. 75, No. 12, 2010 4209

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JOCArticle
(2C), 127.5 (2C), 126.8, 126.7, 126.4 (3C), 84.8, 79.7, 73.6, 63.8,
57.6, 56.0, 54.4, 53.0, 47.7, 46.3, 45.1, 37.3, 29.7, 28.2 (3C), 27.3,
20.9, 20.3, 6.7 (3C), 4.6 (3C); IR (CHCl3) 2955, 1724, 1603, 1495,
1452, 1367, 1146 cm-1; MS (20 eV) m/z 697 (Mþ, 0.7), 362 (100),
272 (7), 106 (12); HRMS calcd for C44H63NO4Si (Mþ) 697.4526,
found 697.4521.
(s, 3H), 0.43 (dq, A part of AB, JAB=15.0 Hz, J=8.0 Hz, 3H), 0.39
(dq, B part of AB, JAB=15.0 Hz, J=8.0 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 172.1, 143.3, 141.6, 127.9 (2C), 127.9 (2C), 127.5,
127.5 (2C), 127.0(2C), 126.2, 86.2, 79.8, 75.1, 63.2, 61.2, 55.7, 53.1,
46.4, 45.8, 45.7, 37.5, 32.3, 27.9 (3C), 27.3, 20.5, 20.5, 6.7 (3C), 4.8
(3C); IR (CHCl3) 3032, 2954, 1717, 1454, 1367, 1198, 1151 cm-1
;
(2S,3R)-tert-Butyl 2-[(S)-Acetamido(phenyl)methyl]-3-hydro-
xy-3-phenylpropanoate (14a). N-Iodosuccinimide (NIS) (36 mg,
0.161 mmol) was added to a solution of 13a (25 mg, 0.04 mmol)
in dichloromethane (1.0 mL) at room temperature under an
argon atmosphere, and the reaction mixture was stirred for 6 h
at the same temperature. The reaction mixture was poured into
saturated aqueous solution of sodium hydrogen carbonate and
extracted with chloroform. The organic layer was washed with a
saturated aqueous solution of sodium thiosulfate followed by
brine, dried over potassium carbonate, and concentrated in
vacuo. The residue was purified by column chromatography on
silica gel (hexane/ethyl acetate=5/1 f chloroform/methanol=
20/1) to afford 14a (14 mg, 96%) and 29 (6.9 mg, 95%): colorless
plate; mp 145-147 °C (diethyl ether); [R]23D = þ27.5 (c 0.5,
MS (20 eV) m/z 607 (Mþ, 0.8), 272 (100), 240 (11), 106 (13);
HRMS calcd for C37H57NO4Si (Mþ) 607.4057, found 607.4049.
(1R, 2R, 6S)-tert-Butyl 2-Amino-6-[(2S,3S)-1-tert-butoxy-3-
hydroxy-1-oxo-3-phenylpropan-2-yl]cyclohexanecarboxylate (16a).
N-Iodosuccinimide (NIS) (26 mg, 0.117 mmol) was added to
a solution of 11a (20 mg, 0.029 mmol) in dichloromethane
(1.5 mL) at room temperature under an argon atmosphere,
and the reaction mixture was stirred for 6 h at the same
temperature. The reaction mixture was poured into a saturated
aqueous solution of sodium hydrogen carbonate and extracted
with chloroform. The organic layer was washed with saturated
aqueous solution of sodium thiosulfate followed by brine, dried
over potassium carbonate, and concentrated in vacuo. The residue
was purified by column chromatography on silica gel (hexane/
ethyl acetate =10/1 f 0/100 f chloroform/methanol =20/1) to
afford 16a (9.3 mg, 76%) and 29 (3.9 mg, 74%): colorless oil;
[R]21D =þ19.4 (c 0.5, CHCl3); 1H NMR (400 MHz, CDCl3) H
of OH and NH2 were not detected. δ 7.36-7.20 (m, 5H), 4.76 (d,
J=11.1 Hz, 1H), 2.79 (dt, J=3.7, 11.1 Hz, 1H), 2.71 (dd, J=
2.1, 11.1 Hz, 1H), 2.48 (t, J = 11.1 Hz, 1H), 2.18-2.10 (br m,
1H), 1.98-1.88 (m, 2H), 1.87-1.79 (m, 1H), 1.59 (s, 9H),
1.44-1.38 (m, 2H), 1.16 (s, 9H), 1.15-1.07 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ 176.0, 171.3, 142.4, 128.3 (2C),
127.9, 127.1 (2C), 81.6, 80.4, 72.7, 58.0, 57.5, 54.3, 39.4, 35.7,
28.2, 28.1 (3C), 27.7 (3C), 24.6; IR (CHCl3) 2934, 1715, 1458,
1369, 1151 cm-1; MS (70 eV) m/z 419 (Mþ, 1), 362 (7), 288 (16),
244 (12), 201 (14), 140 (100); HRMS calcd for C24H37NO5 (Mþ)
419.2671, found 419.2676.
1
CHCl3); H NMR (400 MHz, CDCl3) δ 7.40-7.16 (m, 10H),
7.14 (br, 1H), 4.97 (dd, J=5.3, 8.7 Hz, 1H), 4.84 (dd, J=5.5, 8.1
Hz, 1H), 3.04 (dd, J=5.3, 8.1 Hz, 1H), 2.72 (d, J=5.7 Hz, 1H),
2.08 (s, 3H), 1.26 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 173.0,
169.0, 141.2, 139.8, 128.8 (2C), 128.5 (2C), 128.4, 127.4, 126.2
(4C), 82.4, 73.7, 58.6, 52.0, 27.8 (3C), 23.4; IR (CHCl3) 3404,
3034, 1703, 1674, 1506, 1369, 1153 cm-1; MS (CIþ) m/z 370 (Mþ þ
H, 62); HRMS calcd for C22H28NO4 (Mþ þ H) 370.2018, found
370.2016.
(2S,3R)-tert-Butyl 2-[(S)-amino(phenyl)methyl]-3-(tert-butoxy-
carbonyloxy)-3-phenylpropanoate (14b): colorless plate; mp
1
138-141 °C (diethyl ether); [R]24D = -8.4 (c 0.3, CHCl3); H
NMR (400 MHz, CDCl3) δ 7.49-7.47 (m, 2H), 7.39-7.16 (m,
8H), 5.94 (d, J=9.5 Hz, 1H), 3.78 (d, J=5.3 Hz, 1H), 3.11 (dd,
J=5.3, 9.7 Hz, 1H), 1.70 (br, 2H), 1.40 (s, 9H), 1.26 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ 170.9, 152.4, 143.6, 137.9, 128.5
(2C), 128.4, 128.3 (2C), 127.3 (2C), 127.1, 126.2 (2C), 82.0, 81.1,
78.3, 59.0, 54.2, 27.7 (3C), 27.7 (3C); IR (CHCl3) 3032, 1742,
1369, 1234, 1157 cm-1; MS (CIþ) m/z 428 (Mþ þ H, 100);
HRMS calcd for C25H34NO5 (Mþþ H): 428.2437, found 428.2444.
Anal. Calcd for C25H33NO5: C, 70.23; H, 7.78; N, 3.28. Found:
C, 69.99; H, 7.80; N, 3.11.
(1R,2R,6S)-tert-Butyl 2-amino-6-[(2S,3S)-1-tert-butoxy-3-(4-
chlorophenyl)-3-hydroxy-1-oxopropan-2-yl]cyclohexanecarboxylate
1
(16b): colorless oil; [R]20D = þ11.8 (c 0.7, CHCl3); H NMR
(400 MHz, CDCl3): H of OH was not detected. δ 7.30-7.23 (m,
4H), 4.73 (d, J = 11.0 Hz, 1H), 2.78 (dt, J = 3.5, 10.7 Hz, 1H),
2.62 (dd, J = 2.1, 11.0 Hz, 1H), 2.44 (t, J = 10.7 Hz, 1H),
2.18-2.10 (br m, 1H), 1.96-1.86 (m, 2H), 1.86-1.80 (m, 1H),
1.60-1.25 (br, 2H), 1.58 (s, 9H), 1.44-1.35 (m, 2H), 1.20 (s, 9H),
1.17-1.05 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 176.1, 171.1,
141.1, 133.5, 128.44 (2C), 128.37 (2C), 81.7, 80.7, 71.9, 57.8,
54.3, 39.3, 35.7, 29.7, 28.4, 28.1 (3C), 27.8 (3C), 24.6; IR (CHCl3)
2934, 1715, 1477, 1369, 1151 cm-1; MS (20 eV) m/z 453 (Mþ, 5),
396 (14), 380 (7), 201 (24), 140 (100); HRMS calcd for
C24H36ClNO5 (Mþ) 453.2282, found 453.2285.
(2S,3R)-tert-Butyl 2-[(S)-amino(phenyl)methyl]-3-phenyl-3-
(triethylsilyloxy) propanoate (14c): colorless oil; [R]21D =þ19.3
(c 0.8, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.48 (br d, J =
7.1 Hz, 2H), 7.34 (br t, J = 7.1 Hz, 2H), 7.29 (br t, J = 7.1 Hz,
1H), 7.25 (br t, J=7.5 Hz, 2H) 7.19-7.13 (m, 3H), 5.14 (d, J=
9.2 Hz, 1H), 3.60 (d, J=4.6 Hz, 1H), 2.96 (dd, J=4.6, 9.2 Hz,
1H), 1.73 (br, 2H), 1.22 (s, 9H), 0.81 (t, J=8.0 Hz, 9H), 0.44 (dq,
A part of AB JAB=15.0 Hz, J=8.0 Hz, 3H), 0.39 (dq, B part of
AB JAB = 15.0 Hz, J = 8.0 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 172.1, 144.3, 142.7, 128.2 (2C), 128.0 (2C), 127.8,
127.2 (2C), 126.7, 126.2 (2C), 80.4, 75.0, 62.1, 54.3, 27.9 (3C), 6.7
(3C), 4.8 (3C); IR (CHCl3) 3015, 2955, 1709, 1454, 1367, 1234,
1198, 1151 cm-1; MS (20 eV) m/z 441 (Mþ, 0.6), 356 (5), 233
(10), 208 (6), 164 (10), 106 (100); HRMS calcd for C26H39NO3Si
(Mþ) 441.2699, found 441.2695.
(2S,3R)-tert-Butyl 2-[(S)-[(1S,2R)-2-methoxybornyl-10-amino]-
(phenyl)methyl]-3-phenyl-3-(triethylsilyloxy)propanoate (8c): colo-
rless plate; mp 80-82 °C (diethyl ether); [R]19D = -26.8 (c 0.6,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.52 (br d, J = 7.3 Hz,
2H), 7.34 (br t, J=7.3 Hz, 2H), 7.28 (br t, J=7.3 Hz, 1H), 7.23 (t,
J=7.3 Hz, 2H), 7.14 (br t, J=7.3 Hz, 1H), 7.05 (br d, J=7.3 Hz,
2H), 5.37 (d, J=9.7Hz, 1H), 3.52 (dd, J=3.4, 7.4Hz, 1H), 3.34(s,
3H), 3.13 (d, J=3.9 Hz, 1H), 2.79 (dd, J=4.0, 9.7 Hz, 1H), 2.70
(d, A partof AB, JAB=10.6 Hz, 1H), 2.26 (br, 1H), 1.82-1.54 (m,
6H), 1.71 (d, B part of AB, JAB = 10.6 Hz, 1H), 1.21 (s, 9H),
1.13-1.07 (m, 1H), 0.91 (s, 3H), 0.81 (t, J = 8.0 Hz, 9H), 0.77
(1R,2R,6S)-tert-Butyl 2-amino-6-[(2S,3S)-1-tert-butoxy-3-
hydroxy-1-oxo-3-(p-tolyl)propan-2-yl]cyclohexanecarboxylate
1
(16c): colorless oil; [R]22D = þ13.3 (c 0.7, CHCl3); H NMR
(400 MHz, CDCl3) H of OH and NH2 were not detected. δ 7.20
(d, J=8.0 Hz, 2H), 7.10 (d, J=8.0 Hz, 2H), 4.73 (d, J=11.0 Hz,
1H), 2.79 (dt, J=3.5, 11.2 Hz, 1H), 2.70 (dd, J=2.0, 11.0 Hz,
1H), 2.48 (t, J = 11.2 Hz, 1H), 2.31 (s, 3H), 2.16-2.08 (br m,
1H), 1.98-1.87 (m, 2H), 1.86-1.79 (m, 1H), 1.59 (s, 9H),
1.44-1.37 (m, 2H), 1.17 (s, 9H), 1.17-1.07 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ 176.1, 171.5, 139.7, 137.7, 129.1
(2C), 127.1 (2C), 81.7, 80.5, 72.6, 58.4, 57.6, 54.5, 39.7, 35.9,
29.9, 28.3 (3C), 28.0 (3C), 24.8, 21.3; IR (CHCl3) 2936, 1715,
1458, 1369, 1151 cm-1; MS (20 eV) m/z 433 (Mþ, 3), 376 (9), 360
(5), 201 (29), 140 (100); HRMS calcd for C25H39NO5 (Mþ)
433.2828, found 433.2824.
(1R,2R,6S)-tert-Butyl 2-amino-6-[(2S,3S)-1-tert-butoxy-3-hy-
droxy-3-(4-methoxyphenyl)-1-oxopropan-2-yl]cyclohexanecarboxylate
(16d): colorless oil; [R]20 = þ7.4 (c 0.7, CHCl3); 1H NMR
D
(400 MHz, CDCl3) H of OH was not detected, δ 7.24 (d, J =
8.8 Hz, 2H), 6.84 (d, J=8.8 Hz, 2H), 4.72 (d, J=11.0 Hz, 1H),
4210 J. Org. Chem. Vol. 75, No. 12, 2010

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JOCArticle
3.78 (s, 3H), 2.78 (br t, J=10.8 Hz, 1H), 2.69 (dd, J=2.0, 11.0
Hz, 1H), 2.47 (t, J = 10.8 Hz, 1H), 2.17-2.08 (br m, 1H),
1.98-1.87 (m, 2H), 1.86-1.76 (m, 1H), 1.60-1.30 (br, 2H), 1.59
(diethyl ether); [R]14 = -52.2 (c 0.7, CHCl3); 1H NMR
D
(400 MHz, CDCl3) δ 7.55 (br d, J = 7.3 Hz, 2H), 7.38 (br t,
J=7.3 Hz, 2H), 7.33 (br t, J=7.3 Hz, 1H), 7.25 (t, J=7.3 Hz,
2H), 7.17 (br t, J=7.3 Hz, 1H), 7.07 (d, J=7.3 Hz, 2H), 6.14 (d,
J=10.4 Hz, 1H), 3.55 (dd, J=3.4, 7.4 Hz, 1H), 3.34 (s, 3H), 3.26
(d, J = 4.2 Hz, 1H), 2.97 (dd, J = 4.4, 10.4 Hz, 1H), 2.70 (d, A
part of AB, JAB = 10.6 Hz, 1H), 2.27 (br, 1H), 1.81-1.58 (m,
6H), 1.71 (d, B part of AB, JAB=10.6 Hz, 1H), 1.38 (s, 9H), 1.26
(s, 9H), 1.10-1.04 (m, 1H), 0.89 (s, 3H), 0.74 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 170.9, 152.5, 140.9, 138.5, 128.3 (2C),
128.2, 128.1 (2C), 127.6 (2C), 126.8 (2C), 126.7, 86.1, 81.7, 80.5,
79.0, 61.0, 59.8, 55.6, 53.0, 46.5, 45.9, 45.8, 37.3, 32.3, 27.8 (3C),
27.7 (3C), 27.2, 20.5, 20.4; IR (CHCl3) 2953, 1742, 1603, 1456,
1275, 1157 cm-1; MS (20 eV) m/z 593 (Mþ, 1.2), 272 (100), 240
(8), 148 (7), 106 (11); HRMS calcd for C36H51NO6 (Mþ)
593.3716, found 593.3710. Anal. Calcd for C36H51NO6: C,
72.82; H, 8.66; N, 2.36. Found: C, 73.11; H, 8.63; N, 2.38.
(1R,2S,6R)-tert-Butyl 2-[(2S,3S)-1-tert-Butoxy-3-(tert-buto-
xycarbonyloxy)-1-oxo-3-phenylpropan-2-yl]-6-[(1S,2R)-2-meth-
oxybornyl-10-amino]cyclohexanecarboxylate (12). Compound
12 was prepared in the same way as debenzylation of 5b.
(s, 9H), 1.45-1.36 (m, 2H), 1.18 (s, 9H), 1.17-1.07 (m, 1H); 13
C
NMR (100 MHz, CDCl3) δ 175.8, 171.3, 159.2, 134.8, 128.2
(2C), 113.6 (2C), 81.0, 80.4, 72.2, 57.8 (br), 57.4 (br), 55.3, 54.2,
39.5, 35.4, 29.7, 28.1 (3C), 27.8 (3C), 24.6; IR (CHCl3) 2934,
1715, 1460, 1369, 1151 cm-1; MS (70 eV) m/z 449 (Mþ, 5), 392
(6), 376 (6), 320 (13), 313 (67), 257 (45), 201 (100), 140 (64);
HRMS calcd for C25H39NO6 (Mþ) 449.2777, found 449.2771.
(3S,4S)-4-Phenyl-3-[(R)-phenyl(triethylsilyloxy)methyl]azetidin-
2-one (17). A solution of 14c (30 mg, 0.067 mmol) in THF (1 mL)
was added dropwise to a solution of lithium diisopropylamide
(1.09 M in THF solution, 186 μL, 0.202 mmol) in THF (2 mL) at
-78 °C, and the reaction mixture was stirred for 3 h at the same
temperature under an argon atmosphere. The reaction mixture
was poured into saturated aqueous solution of sodium hydrogen
carbonate and extracted with ethyl acetate. The organic layer
was washed with brine, dried over sodium sulfate, and concen-
trated in vacuo. The residue was purified by column chroma-
tography on silica gel (hexane/ethyl acetate = 3/1) to afford 17
(20 mg, 82%): colorless oil; [R]19 = þ25.9 (c 0.5, CHCl3);
12: colorless plate; mp 133-134 °C (methanol); [R]18
=
D
D
1H NMR (400 MHz, CDCl3) δ 7.49 (br d, J = 7.0 Hz, 2H),
7.37-7.23 (m, 8H), 5.96 (br, 1H), 5.17 (d, J=4.5 Hz, 1H), 4.51
(d, J=2.4 Hz, 1H), 3.38 (ddd, J=0.5, 2.4, 4.4 Hz, 1H), 0.87 (t,
J=7.7 Hz, 9H), 0.55 (q, J=7.7 Hz, 6H); 13C NMR (100 MHz,
CDCl3) δ 167.9, 141.0, 139.9, 128.6 (2C), 128.1 (2C), 127.8,
127.8, 126.7 (2C), 125.5 (2C), 71.7, 68.8, 53.1, 6.7 (3C), 4.7 (3C);
IR (CHCl3) 3410, 3032, 1759, 1495, 1456, 1234, 1198, 1096
cm-1; MS (CIþ) m/z 368 (MþþH, 0.4); HRMS calcd for
C22H30NO2Si (Mþ þ H) 368.2046, found 368.2053.
-47.0 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ
7.38-7.35 (m, 2H), 7.31-7.23 (m, 3H), 5.70 (d, J = 11.2 Hz,
1H), 3.33 (dd, J=3.3, 7.5 Hz, 1H), 3.21 (s, 3H), 3.08 (d, A part of
AB, JAB=10.8 Hz, 1H), 2.91 (dd, J=0.7, 11.4 Hz, 1H), 2.56 (dt,
J =3.7, 11.1 Hz, 1H), 2.43 (t, J =10.9 Hz, 1H), 2.20-2.03 (m,
3H), 2.17 (d, B part of AB, JAB =10.8 Hz, 1H), 1.86-1.81 (m,
1H), 1.75 (dq, J = 3.7, 12.8 Hz, 1H), 1.71-1.60 (m, 2H),
1.58-1.52 (m, 1H), 1.55 (s, 9H), 1.50-1.43 (m, 1H), 1.41 (s,
9H), 1.36-1.17 (m, 4H), 1.13 (s, 9H), 1.02-0.96 (m, 1H), 0.99 (s,
3H), 0.91-0.84 (m, 1H), 0.81 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 174.0, 171.1, 152.6, 139.2, 128.2, 128.1 (2C), 127.9
(2C), 86.0, 81.9, 80.5, 79.9, 77.1, 60.6, 56.6, 55.9, 53.6, 52.8, 46.5,
45.7, 44.9, 41.5, 37.4, 32.0, 31.4, 28.3 (3C), 27.8 (3C), 27.6 (3C),
27.1, 26.6, 24.4, 20.6, 20.5; IR (CHCl3) 3030, 2936, 1732, 1717,
1458, 1369, 1277, 1153, 1097 cm-1; MS (20 eV) m/z 685 (Mþ, 1),
568 (4), 478 (7), 364 (7), 222 (8), 182 (13), 107 (10), 57 (100);
HRMS calcd for C40H63NO8 (Mþ) 685.4553, found 685.4549.
Anal. Calcd for C40H63NO8: C, 70.04; H, 9.26; N, 2.04. Found:
C, 70.17; H, 9.19; N, 2.06.
(2S,3R)-tert-Butyl 3-(tert-Butoxycarbonyloxy)-2-[(S)-[(1S,2R)-
2-methoxybornyl-10-amino](phenyl)methyl]-3-phenylpropanoate
(8b). A mixture of 5b (25.0 mg, 0.043 mmol), 10% Pd/C (3.0 mg),
and formic acid (2 drops) in methanol (2.0 mL) was stirred for
15 h at room temperature under a hydrogen atmosphere. The
reaction mixture was filtrated with Celite (washing with
methanol), and the filtrate was concentrated in vacuo to remove
the solvent. The residue was purified with preparative TLC
(hexane/ethyl acetate = 5/1) to afford debenzylated compound
(21.0 mg, 99%). Di-tert-butyl pirocarbonate (114 μL, 0.50 mmol)
and 4-dmimethylaminopyridine (20 mg, 0.17 mmol) were added
to a solution of the debenzylated compound (41 mg, 0.083 mmol)
in dichloromethane (1 mL) at room temperature, and the
solution was stirred for 24 h under a nitrogen atmosphere.
The reaction mixture was poured into saturated aqueous solu-
tion of sodium hydrogen-carbonate and extracted with ethyl
acetate. The organic layer was washed with brine, dried over
sodium sulfate, and concentrated in vacuo to remove the
solvent. The residue was purified by column chromatography
on silica gel (hexane/ethyl acetate =40/1) to afford 8b (28 mg,
58%). 8b was recrystallized from diethyl ether to give a suitable
crystal for X-ray analysis: colorless plate; mp 174-176 °C
Acknowledgment. This research was financially sup-
ported in part by the Frontier Research Program of the
Ministry of Education, Culture, Sports, Science and Tech-
nology, Japan.
Supporting Information Available: 1H NMR and 13C NMR
spectra for all new compounds, ORTEPs for 5a, 6a, 8b, and 12,
and complete experimental details following the general proce-
dures. This material is available free of charge via the Internet at
http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 12, 2010 4211