1,4-Di-O-tert-alkyl-L-threitols as Chiral Auxiliaries in the Asymmetric Nucleophilic Addition of Alkyllithiums to Hydrazones

Article abstract of DOI:10.1021/jo971700y

The applications of 1,4-di-O-tert-alkyl-L-threitols as chiral auxiliaries in the asymmetric nucleophilic addition of alkyllithiums to hydrazones are investigated. Chiral acetal-hydrazones 9, obtained from the chiral acetals 8 by ozonolysis followed by treatment with dimethylhydrazine, are allowed to react with organolithium reagents in toluene at -78°C to give 15 with excellent diastereoselectivity. The stereochemical assignments were based on the X-ray crystal structure of 17a. The absolute configuration at C₂ of the major isomer of the adducts 15 was thereby determined to be S. The nucleophile thus attacked from the si face of the C=N moiety. The effect of solvent on the diastereoselectivity of the reactions of 9 with organolithium reagents is reported. Polar aprotic solvent shows poor diastereoselectivity, and the diastereoselectivity is reversed when the reaction is carried out in THF. Reaction of dl-14 with methyllithium has been studied for comparison purposes and the reaction shows the opposite selectivity. Chelation intermediates 18 and 26 are proposed for these reactions to account for the observed stereoselectivities.

Full text of DOI:10.1021/jo971700y

1484
J . Org. Chem. 1998, 63, 1484-1490
1,4-Di-O-ter t-a lk yl-L-th r eitols a s Ch ir a l Au xilia r ies in th e
Asym m etr ic Nu cleop h ilic Ad d ition of Alk yllith iu m s to
Hyd r a zon es†
Yu-Tsai Hsieh, Gene-Hsiang Lee, Yu Wang, and Tien-Yau Luh*
Department of Chemistry, National Taiwan University, Taipei, Taiwan 106, Republic of China
Received September 11, 1997
The applications of 1,4-di-O-tert-alkyl-L-threitols as chiral auxiliaries in the asymmetric nucleophilic
addition of alkyllithiums to hydrazones are investigated. Chiral acetal-hydrazones 9, obtained
from the chiral acetals 8 by ozonolysis followed by treatment with dimethylhydrazine, are allowed
to react with organolithium reagents in toluene at - 78 °C to give 15 with excellent diastereose-
lectivity. The stereochemical assignments were based on the X-ray crystal structure of 17a . The
absolute configuration at C2 of the major isomer of the adducts 15 was thereby determined to be
S. The nucleophile thus attacked from the si face of the CdN moiety. The effect of solvent on the
diastereoselectivity of the reactions of 9 with organolithium reagents is reported. Polar aprotic
solvent shows poor diastereoselectivity, and the diastereoselectivity is reversed when the reaction
is carried out in THF. Reaction of dl-14 with methyllithium has been studied for comparison
purposes and the reaction shows the opposite selectivity. Chelation intermediates 18 and 26 are
proposed for these reactions to account for the observed stereoselectivities.
Chiral amines, as a class of compounds, exhibit a
2).11-13 Excellent diastereoselectivities have been found
in the Simmons-Smith cyclopropanation13 and in ring
openings of acetals11a using these tunable chiral auxil-
iaries. The alkoxy side chain in 7 may serve either as a
variety of biological activities and have served as useful
reactive intermediates in organic synthesis.1 The reduc-
tions of ketimines and nucleophilic additions to aldimines
in a chiral environment provide a useful entry to the
corresponding asymmetric amines.3 To this end, there
has been increasing use of chiral hydrazones as precur-
sors of chiral amines.4-6 For example, reactions of 1 with
Grignard reagents lead to 2 as the major product (eq 1).5
The chelation intermediate 4 has been suggested to be
responsible for the selectivity. In contrast, 3 is obtained
predominantly when an organolithium reagent is em-
ployed as the alkylating agent. Presumably, the latter
reaction proceeds by nucleophilic attack from the si face
of the nonchelative imine 5.
(4) (a) Thiam, M.; Chastrette, F. Tetrahedron Lett. 1990, 31, 1429.
(b) Thiam, M.; Chastrette, F. Bull. Soc. Chem. Fr. 1992, 129, 161. (d)
Enders, D.; Bettray, W. Pure Appl. Chem. 1996, 68, 569. (e) Itsuno,
S.; Sasaki, M.; Kuroda, S.; Ito, K. Tetrahedron: Asymmetry 1995, 6,
1507. (f) Lassaletta, J .-M.; Ferna´ndez, R.; Mart´ın-Zamora, E.; D´ıez,
E. J . Am. Chem. Soc. 1996, 118, 7002. (g) Enders, D.; Reinhold: U.
Liebigs Ann. 1996, 11.
(5) (a) Mangeney, P.; Alexakis, A.; Normant, J . F. Tetrahedron Lett.
1988, 29, 2677. (b) Alexakis, A.; Lensen, N.; Mangeney, P. Tetrahedron
Lett. 1991, 32, 1171. (c) Alexakis, A.; Lensen, N.; Tranchier, J .-P.
Mangeney, P. J . Org. Chem. 1992, 57, 4563. (d) Enders, D.; Funk, R.;
Klatt, M.; Raabe, G.; Hoverstreydt, E. H. Angew. Chem., Int. Ed. Int.
1993, 32, 418. (e) Denmark, S. E.; Edwards, J . P.; Nicaise, O. J . Org.
Chem. 1993, 58, 569. (f) For
a recent review, see: Alexakis, A.;
Mangeney, P.; Lensen, N.; Tranchier, J .-P.; Gosmini, R.; Raussou, S.
Pure Appl. Chem. 1996, 68, 531.
(6) (a) Claremon, D. A.; Lumma, P. K.; Philips, B. T. J . Am. Chem.
Soc. 1986, 108, 8265. (b) Alexakis, A.; Lensen, N.; Mangeney, P. Synlett
1991, 625. (c) Denmark, S. E.; Nicaise, O. Synlett 1993, 359.
(7) (a) Cainelli, G.; Giacomini, D.; Mezzina, E.; Panunzio, M.;
Zarantonello, P. Tetrahedron Lett. 1991, 32, 2967. (b) Cainelli, G.;
Giacomini, D.; Panunzio, M.; Zarantonello, P. Tetrahedron Lett. 1992,
33, 7783. (c) Reetz, M. T.; J aeger, R.; Drewlies, R.; Hubel, M. Angew.
Chem., Int. Ed. Engl. 1991, 30, 103.
(8) (a) Tamura, Y.; Ko, T.; Kondo, H.; Annoura, H. Tetrahedron Lett.
1986, 27, 2117. (b) Tamura, Y.; Annoura, H.; Yamamoto, H.; Kondo,
H.; Kita, Y.; Fujioka, H. Tetrahedron Lett. 1987, 28, 5709. (c) Tamura,
Y.; Annoura, H.; Fujioka, H. Tetrahedron Lett. 1987, 28, 5681. (d)
Tamura, Y.; Kondo, H.; Annoura, H. Tetrahedron Lett. 1986, 27, 81.
(e) Fujisawa, T.; Ichikawa, M.; Ukaji, Y.; Shimizu, M. Tetrahedron Lett.
1993, 34, 1307.
(9) (a) Mash, E. A.; Nelson, K. A. J . Am. Chem. Soc. 1985, 107, 8256.
(b) Mash, E. A.; Nelson, K. A. Tetrahedron 1987, 43, 679. (c) E. A.
Mash, D. S. Torok, J . Org. Chem. 1989, 54, 250. (d) Mash, E. A.;
Hemperly, S. B.; Nelson, K. A.; Heidt, P. C.; Van Deusen, S. J . Org.
Chem. 1990, 55, 2045. (e) Mash, E. A.; Hemperly, S. B. J . Org. Chem.
1990, 55, 2055.
We have recently reported a convenient synthesis of
tunable chiral C2-diols 7 derived from L-threitols 6 (eq
† Dedicated to Professor N. C. Yang on the occasion of his 70th
birthday.
(1) (a) J urczek, J .; Golebiowski, A. Chem. Rev. (Washington, D.C.)
1989, 89, 149. (b) Fisher, L. E.; Muchowski, J . M. Org. Prep. Proc. Int.
1990, 22, 399. (c) Ager, D. J .; Prakash, I.; Schaad, D. R. Chem. Rev.
(Washington, D.C.) 1996, 96, 835.
(2) Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley:
New York, 1994.
(10) (a) Compain, P.; Gore´, J .; Vate`le, J .-M. Tetrahedron 1996, 52,
6647. (b) Wu¨nsch, B.; Nerdinger, S. Tetrahedron Lett. 1995, 36, 8003.
(c) Chitkal, B.; Pinyopronpanich, Y.; Thebtaranonth, C.; Thebtara-
nonth, C. Tetrahedron Lett. 1994, 35, 1099. (d) Kato, K.; Suemune,
H.; Sakai, K. Tetrahedron 1994, 50, 3315. (e) Hasegawa, K.; Matsuda,
F.; Yanagiya, M.; Matsumoto, T. Tetrahedron Lett. 1987, 28, 1671. (f)
J ung, M. E.; Lew, W. Tetrahedron Lett. 1990, 31, 623. (g) Lange, G.
L.; Decicco, C. P. Tetrahedron Lett. 1988, 29, 2613.
(3) Seyden-Penne, J . Chiral Auxiliaries and Ligands in Asymmetric
Synthesis; Wiley: New York, 1995.
S0022-3263(97)01700-3 CCC: $15.00 © 1998 American Chemical Society
Published on Web 02/14/1998

1,4-Di-O-tert-alkyl-L-threitols as Chiral Auxiliaries
J . Org. Chem., Vol. 63, No. 5, 1998 1485
Ta ble 1. Syn th esis of Hyd r a zon e 9
Ta ble 2. Rea ction s of 9b (R1 ) Me, R2 ) H) w ith R3Li
u n d er Differ en t Con d ition s
R1
R2
8 (%yield)
9 (%yield)
R3
temp (reaction time)
2S/2R
H
H
H
H
Me
Me
Me
a (90)
b (86)
c (83)
d (81)
e (85)
f (85)
a (88)
b (92)
c (90)
d (75)
e (70)
f (88)
Me
i-Pr
H
Me
i-Pr
Me
25 °C (12 h)
-25 °C (12 h)
55/45
76/24
88/12
95/5
71/29
92/8
-78 °C (4 h) then 25 °C (8 h)
-78 °C (10 h)
n-Bu
-15 °C (10 h)
-78 °C (10 h)
bulky substituent or as an additional auxiliary ligand
Ta ble 3. Rea ction of Or ga n olith iu m Rea gen ts w ith 9 in
Tolu en e a t -78 °C
entry
9
R1
R2
R3
15 (%yield)
2S/2R
1
2
3
4
5
6
7
8
9
10
11
12
13
a
a
a
b
b
b
c
c
c
d
d
e
e
H
H
H
H
H
H
H
H
H
H
H
Me
n-Bu
Ph
Me
n-Bu
Ph
Me
n-Bu
Ph
Me
n-Bu
Me
a (88)
b (75)
c (71)
d (90)
e (83)
f (85)
g (86)
h (73)
i (70)
j (84)
k (68)
l (82)
m (70)
91:9
89:11
98:2
95:5
92:8
98:2
91:9
92:8
98:2
>99:1
98:2
>99:1
98:2
Me
Me
Me
i-Pr
i-Pr
i-Pr
H
H
Me
Me
H
Me
Me
Me
Me
n-Bu
during the formation of a chelating complex with a metal
catalyst in such a way that the stereoselectivity of these
reactions is enhanced. In this paper, we wish to report
the details of the use of these chiral diol auxiliaries in
the asymmetric nucleophilic addition of organolithium
reagents to hydrazones.
procedures (eqs 4 and 5).
Resu lts
Syn th esis of 9. Acid-catalyzed reaction of chiral diol
7 with an R,â-unsaturated carbonyl compound (R2 ) H
or Me) gave the corresponding acetal 8a or ketal 8b.13
Ozonolysis15 of 8 followed by treatment with dimethyl-
hydrazine afforded acetal-hydrazones 9 in good yield (eq
3). The results are tabulated in Table 1. Reference
Nu cleop h ilic Ad d ition to 9. In the beginning of this
investigation, we screened the conditions for the nucleo-
philic addition of alkyllithium to 9 to form 15 (eq 6).
Reaction at low temperature was essential to achieve
compounds 124,16 and 14 were prepared following similar
(14) Fujioka, H.; Fuji, M.; Okaichi, Y.; Yoshida, T.; Annoura, H.;
Kita, Y.; Tamura, Y. Chem. Pharm. Bull. 1989, 37, 602. See also:
Denmark, S. E.; Weber, T.; Piotrowski, D. W. J . Am. Chem. Soc. 1987,
109, 2224.
(15) Heitz, M. P.; Grllinrty, F.; Mioskowski, C. Tetrahedron Lett.
1986, 27, 3859.
(11) (a) Yuan, T.-M.; Yeh, S.-M.; Hsieh, Y.-T.; Luh, T.-Y. J . Org.
Chem. 1994, 59, 8192. (b) Yuan, T.-M.; Hsieh, Y.-T.; Yeh, S.-M.; Shyue,
J .-J .; Luh, T.-Y. Synlett 1996, 53.
(12) For reviews, see: (a) Luh, T.-Y. Synlett 1996, 201. (b) Luh, T.-
Y. Pure Appl. Chem. 1996, 68, 635.
(13) Yeh, S.-M.; Huang, L.-H.; Luh, T.-Y. J . Org. Chem. 1996, 61,
3906.
(16) Takano, S.; Ohashi, K.; Sugihara, T.; Ogasawara, K. Chem. Lett.
1991, 203.

1486 J . Org. Chem., Vol. 63, No. 5, 1998
Hsieh et al.
Ta ble 5. Solven t Effect on th e Dia ster eoselectivity of
th e Ad d ition of RLi to 9 a t -78 °C
entry
substrate
RLi
solvent
product (2S/2R)
14
15
16
17
18
19
20
21
22
23
24
25
9a
n-BuLi
n-BuLi
PhLi
n-BuLi
n-BuLi
PhLi
n-BuLi
n-BuLi
MeLi
n-BuLi
n-BuLi
n-BuLi
ether
THF
THF
ether
THF
THF
ether
THF
ether
ether
toluene
THF
15b (76/24)
15b (31/69)
15c (33/67)
15e (83/17)
15e (35/65)
15f (37/63)
15h (60/40)
15h (32/68)
21a (80/20)a
21b (55/45)a
21c (78/22)
21d (36/64)
9b
9c
20a
20b
a
Reference 4.
from lithium may occur stereoselectively from the si face
of the CdN moiety. Similar intermediate has been
suggested in the CeCl3-mediated nucleophilic addition of
chiral oximes.14 Alternatively, conformers 19 and 55 are
similar and the nucleophilic attack may thus occur from
the less hindered si face of the imine moiety. To
differentiate these two possibilities, an investigation of
the solvent effect on the reaction of 9 with organolithium
reagents have been carried out.
F igu r e 1. ORTEP of (2S)-17a . Thermal ellipsoids are shown
in 30% probability.
Ta ble 4. Con ver sion of 15 to P h th a lim id e 17
16
R1
R2
R3
17 (%yield)
d
e
k
l
Me
Me
H
Me
Me
H
H
Me
Me
Me
Me
a (91)
b (85)
c (93)
d (82)
e (85)
n-Bu
n-Bu
Me
m
n-Bu
high diatereoselectivity (Table 2). Table 3 summarizes
representative examples of the nucleophilic addition of
organolithium reagents to 9. The diastereomeric ratio
was determined by 1H NMR spectroscopy of 15. The
signal for the proton at C2 of the 2S-isomer appeared at
a slightly higher field (∆δ ∼ 0.02-0.04) than that of the
corresponding 2R-isomer.17 Treatment of the major
stereoisomers (2S)-15 with Raney nickel followed by
phthalic anhydride yielded the corresponding phthalim-
ides (2S)-17 (eq 7) The results are outlined in Table 4.
Solven t Effect. Organolithium compounds are known
to form complexes with the oxygen donor solvents.
Accordingly, the stability of the chelation complex 18 in
a nonpolar hydrocarbon solvent and in a polar aprotic
solvent would be quite different. In other words, if
intermediate 18 is responsible for the formation of 15,
the selectivity might be changed when the reaction is
carried out in a polar solvent. Thus, the effect of solvent
on the diastereoselectivity of the reactions of 9 with
organolithium reagents is summarized in Table 5.
It is interesting to note that the reactions of 20a with
alkyllithium in ether yield 21a and 21b with poor
selectivity (entries 22 and 23).4 The reactions of related
methoxy derivative 20b with n-BuLi at -78 °C in toluene
as well as in THF were also examined (entries 24 and
25). These reactions were much less selective than those
with a bulky alkoxy substituent in the chiral auxiliary
under the same conditions (entry 24, cf Table 3).
The X-ray structure of (2S)-17a is shown in Figure 1 and
the absolute configuration at C2 of the major isomer of
the adducts 15 was thereby determined.
Discu ssion
As can be seen from Table 3, good to excellent daste-
reoselectivities were obtained from the reaction of 9 with
organolithium reagents in toluene at -78 °C. Nucleo-
philic addition occurred preferentially from the si face of
the hydrazone moiety in 9. Two possible conformers 18
and 19 are proposed to rationalize the observed stereo-
selectivity. In 18, lithium can coordinate to the imino
nitrogen atom as well as to the two oxygen atoms to form
a chelation complex. Then direct transfer of R3 anion
(17) For the purpose of simplification, the numbering used through-
out text is based on the numbering for the corresponding unprotected
2-aminoalkanals. Hence, the postion of attachment the amino or the
hydrazino group in 15 is considered as C2. The nomenclature for 15
should be 4,5-Bis(alkoxymethyl)-2-[1-(N′,N′-dimethylhydrazino)alkyl]-
dioxolane.
As is evident from Table 5, the diastereoselectivity was
reversed when the reaction was carried out in THF as

1,4-Di-O-tert-alkyl-L-threitols as Chiral Auxiliaries
J . Org. Chem., Vol. 63, No. 5, 1998 1487
opposed to diethyl ether. Furthermore, when 9b was
treated with MeLi in toluene in the presence of 2 equiv
of TMEDA, a 33/67 (2S/2R) diastereomeric mixture of
15d was obtained. Again, this selectivity is opposite to
that obtained from the same reaction in the absence of
an amine ligand (entry 4, Table 3). Both THF and
TMEDA are good donor ligands for organolithium com-
pounds. The oxygen atoms of 9 may be less competitive
in the accommodation of lithium to form intermediate
18 when the reaction is carried out in THF or in the
presence of such a chelating amine. There might exist a
rapid conformational equilibrium between 19 and 22 (eq
8) making the nucleophilic addition less selective.
F igu r e 2. ORTEP of 25b. Thermal ellipsoids are shown in
30% probability.
Tables 3 and 5. Furthermore, the reaction assisted by
stilbene diol moiety 14 was much less selective than those
using tunable diols 6 as the chiral auxiliary. By compar-
ing 18 with 26, it is clear that the alkoxy side chain in 9
plays a pivotal role in directing the diastereoselective
addition of organolithium nucleophiles to the hydrazone
moiety.
Rea ction of d l-14 w ith MeLi. To show that 18 is
involved in the overall asymmetric nucleophilic addition
to 9, we examined the reaction of dl-14 with methyl-
lithium (eq 9). The hydrazines 23 were converted to 25
in a manner similar to that described in eq 7. The X-ray
structure of 25b was determined; hence the relative con-
figuration at C2 of 23b is established. The nucleophile
may attack preferentially from the re face (or si face if
the other enantiomeric form of 14 is considered) of the
carbon-nitrogen double bond of 14. The chelation inter-
mediate 26 appears to prevail, and the transfer of the
alkyl anion may occur from the less hindered face.
Con clu sion
In summary, we have demonstrated another useful
application of the tunable chiral auxiliary 6 in asym-
metric synthesis. Our results show that the bulky alkoxy
moiety in 9 may serve as an additional auxiliary ligand
to form a chelating complex with the metal catalyst. The
stereoselectivity of the nucleophilic addition reactions of
alkyllithiums to 9 in aromatic hydrocarbon solvent is
enhanced. The present results along with our earlier
work11-13 suggest that the bulky alkoxy group of 8 has a
demonstrated role as a chiral auxiliary in asymmetric
synthesis. The selectivities in these reactions are higher
than those in reactions employing simple methoxy or
even benzyloxy auxiliaries 6. Further applications of 8
are under study.
Exp er im en ta l Section
Gen er a l P r oced u r e for th e P r ep a r a tion of 4,5-Bis-
(a lk oxym eth yl)-2-(2-p h en yleth en yl)d ioxola n e (8). A ben-
zene solution of the R,â-unsaturated aldehyde or ketone (1
equiv), 7 (1 equiv), and PPTs (1 mol %) was refluxed overnight,
cooled, diluted with ether, washed with saturated NaHCO3 and
brine, and dried (MgSO4). The organic solution was evapo-
rated in vacuo to give the residue which was chromatographed
on silica gel (5% EtOAc in hexane) to give 8.
4,5-Bis(isop r op oxym et h yl)-2-(2-p h en ylet h en yl)d iox-
ola n e (8a ): 90%: [R]20 ) +13.3 (c 11.1, CHCl3); 1H NMR
D
(CDCl3, 300 MHz) δ 1.16 (d, J ) 6.1 Hz, 12 H), 3.51-3.70 (m,
6 H), 3.98 (dt, J ) 4.9, 6.5 Hz, 1 H), 4.05 (dt, J ) 6.4, 6.5 Hz,
1 H), 5.56 (d, J ) 6.3 Hz, 1 H), 6.16 (dd, J ) 6.3, 16.0 Hz, 1
H), 6.74 (d, J ) 16.0 Hz, 1 H), 7.21-7.34 (m, 3 H), 7.35-7.41
(m, 2 H); 13C NMR (CDCl3, 75 MHz) δ 21.9, 22.0, 68.5, 68.8,
72.3, 72.3, 77.4, 78.5, 104.2, 125.4, 126.9, 128.2, 128.5, 135.1,
135.8; HRMS calcd for C19H28O4 320.1988, found 320.1988.
4,5-Bis(ter t-b u t oxym et h yl)-2-(2-p h en ylet h en yl)d iox-
ola n e (8b): 86%; mp 43-44 °C; [R]27D ) +15.6 (c 2.1, CHCl3);
1H NMR (CDCl3, 300 MHz) δ 1.22 (s, 18 H), 3.46-3.63 (m, 4
H), 3.93 (dt, J ) 5.1, 6.5 Hz, 1 H), 4.00 (q, J ) 6.5 Hz, 1 H),
5.55 (d, J ) 6.1 Hz, 1 H), 6.16 (dd, J ) 6.1, 16.1 Hz, 1 H), 6.73
(d, J ) 16.1 Hz, 1 H), 7.18-7.32 (m, 3 H), 7.33-7.40 (m, 2 H);
It is important to note that the diastereoselectivity
shown in eq 9 was opposite to those summarized in

1488 J . Org. Chem., Vol. 63, No. 5, 1998
Hsieh et al.
13C NMR (CDCl3, 75 MHz) δ 27.4, 62.6, 63.0, 73.1, 73.2, 78.4,
79.1, 104.1, 125.6, 126.9, 128.2, 128.4, 134.9, 135.9; HRMS
calcd for C21H32O4 348.2301, found 348.2304.
6.27 (d, J ) 6.0 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ 17.4,
17.5, 21.9, 22.0, 35.7, 35.7, 42.2, 61.7, 62.1, 77.3, 77.4, 78.5,
78.7, 103.6, 129.3; HRMS calcd for C20H40O4N2 372.2988, found
372.2995.
4,5-Bis(isop r op oxym e t h yl)-2-for m yl-2-m e t h yld iox-
ola n e N,N-Dim eth ylh yd r a zon e (9d ): 75%; [R]27D ) +5.8 (c
4.6, CHCl3); IR (neat) ν 1617 cm-1; 1H NMR (300 MHz, CDCl3)
δ 1.11 (d, J ) 6.0 Hz, 12 H), 1.52 (s, 3 H), 2.74 (s, 6 H), 3.46-
3.64 (m, 6 H), 3.90-4.01 (m, 2 H), 6.45 (s, 1 H); 13C NMR (75
MHz, CDCl3) δ 21.8, 21.9, 23.7, 42.5, 68.7, 68.8, 72.1, 72.2,
78.3, 78.3, 108.3, 134.5; HRMS calcd for C15H30O4N2 302.2206,
found 302.2206.
4,5-Bis(t h e xyloxym e t h yl)-2-(2-p h e n yle t h e n yl)d iox-
ola n e (8c): 83%; [R]25 ) +16.8 (c 3.8, CHCl3); 1H NMR
D
(CDCl3, 300 MHz) δ 0.86 (d, J ) 6.7 Hz, 3 H), 0.87 (d, J ) 6.7
Hz, 3 H), 0.88 (d, J ) 6.7 Hz, 6 H), 1.08 (s, 12 H), 1.78 (septet,
J ) 6.7 Hz, 1 H), 1.79 (septet, J ) 6.7 Hz, 1 H), 3.41-3.60 (m,
4 H), 3.97 (dt, J ) 4.6, 6.4 Hz, 1 H), 4.05 (q, J ) 6.4 Hz, 1 H),
5.55 (d, J ) 6.2 Hz, 1 H), 6.15 (dd, J ) 6.2, 15.9 Hz, 1 H), 6.73
(d, J ) 15.9 Hz, 1 H), 7.21-7.32 (m, 3 H), 7.34-7.40 (m, 2 H);
13C NMR (CDCl3, 75 MHz) δ 17.5, 17.5, 22.0, 22.1, 35.7, 35.9,
61.9, 62.3, 77.5, 78.7, 78.9, 104.2, 125.8, 126.9, 128.2, 128.5,
4,5-Bis(t er t -b u t oxym e t h yl)-2-for m yl-2-m e t h yld iox-
ola n e N,N-Dim eth ylh yd r a zon e (9e): 70%; [R]25D ) +9.7 (c
0.3, CHCl3); IR (neat) ν 1601 cm-1; 1H NMR (300 MHz, CDCl3)
δ 1.17 (s, 18 H), 1.55 (s, 3 H), 2.76, (s, 6 H), 3.42-3.59 (m, 4
H), 3.88-4.00 (m, 2 H), 6.49 (s, 1 H); 13C NMR (75 MHz, CDCl3)
δ 23.5, 27.3, 42.4, 62.9, 63.1, 72.9, 72.9, 78.5, 78.9, 108.1, 134.6;
HRMS calcd for C17H34O4N2 330.2519, found 330.2504.
4,5-B is (t h e x y lo x y m e t h y l)-2-fo r m y l-2-m e t h y ld io x -
134.9, 136.0; HRMS calcd for
404.2922.
C25H40O4 404.2927, found
4,5-Bis(isop r op oxym eth yl)-2-m eth yl-2-(2-p h en yleth e-
1
n yl)d ioxola n e (8d ): 81%; [R]24 ) +2.2 (c 10.0, CHCl3); H
D
NMR (CDCl3, 200 MHz) δ 1.13 (d, J ) 6.1 Hz, 3 H), 1.14 (d, J
) 6.1 Hz, 3 H), 1.16 (d, J ) 6.1 Hz, 6 H), 1.56 (s, 3 H), 3.39-
3.76 (m, 6 H), 3.90-4.02 (m, 2 H), 6.24 (d, J ) 16.0 Hz, 1 H),
6.72 (d, J ) 16.0 Hz, 1 H), 7.15-7.44 (m, 5 H); 13C NMR
(CDCl3, 50 MHz) δ 21.8, 21.9, 26.3, 68.7, 69.0, 72.0, 72.2, 78.3,
78.4, 108.4, 126.6, 127.7, 128.4, 129.2, 131.3, 136.3; HRMS
calcd for C20H30O4 334.2144, found 334.2147.
ola n e N,N-Dim eth ylh yd r a zon e (9f): 88%; [R]27 ) +7.4 (c
D
2.7, CHCl3); IR (neat) ν 1603 cm-1; 1H NMR (200 MHz, CDCl3)
δ 0.83 (d, J ) 6.8 Hz, 12 H), 1.05 (s, 12 H), 1.53 (s, 3 H), 1.77
(septet, J ) 6.8 Hz, 2 H), 2.75 (s, 6 H), 3.38-3.57 (m, 4 H),
3.90-4.01 (m, 2 H), 6.47 (s, 1 H); 13C NMR (50 MHz, CDCl3)
δ 17.4, 17.5, 21.9, 22.0, 23.7, 35.5, 42.5, 62.0, 62.2, 77.3, 77.4,
78.8, 78.9, 108.1, 135.0; HRMS calcd for C21H42O4N2 386.3145,
found 386.3145.
4,5-Bis(ter t-bu toxym eth yl)-2-m eth yl-2-(2-p h en yleth e-
n yl)d ioxola n e (8e): 85%; [R]27 ) +2.1 (c 5.0, CHCl3); 1H
D
NMR (CDCl3, 300 MHz) δ 1.16 (s, 9 H), 1.18 (s, 9 H), 1.55 (s,
3 H), 3.47-3.58 (m, 4 H), 3.86-3.92 (m, 2 H), 6.25 (d, J )
16.1 Hz, 1 H), 6.72 (d, J ) 16.1, 1 H), 7.18-7.41 (m, 5 H); 13
C
d l-4,5-Dip h en yl-2-for m yld ioxola n e N,N-Dim eth ylh y-
d r a zon e (d l-14). According to the general procedure for the
preparation of 9, a solution of acetal trans-4,5-diphenyl-2-(2-
phenylethenyl)-1,3-dioxolane18 (6.56 g, 20 mmol) in MeOH (250
mL) was treated at -78 °C with ozone and was quenched with
Me2S (3.10 g, 0.05 mol) to give the residue, which was allowed
to react with H2NNMe2 (2.70 g, 45 mmol) in the presence of
PPTs (0.25 g, 1.0 mmol) in CH2Cl2 (50 mL) to give dl-14 (3.49
NMR (CDCl3, 75 MHz) δ 26.4, 27.4, 63.0, 63.3, 73.1, 73.2, 78.7,
79.3, 108.4, 126.7, 127.7, 128.5, 129.2, 131.5, 136.4; HRMS
calcd for C22H34O4 362.2457, found 362.2448.
4,5-Bis(th exyloxym eth yl)-2-m eth yl-2-(2-ph en yleth en yl)-
1
d ioxola n e (8f): 85%; [R]27 ) +5.7 (c 3.8, CHCl3); H NMR
D
(CDCl3, 300 MHz) δ 0.84 (d, J ) 6.4 Hz, 6 H), 0.86 (d, J ) 6.4
Hz, 6 H), 1.06 (s, 6 H), 1.08 (s, 6 H), 1.55 (s, 3 H), 1.77 (septet,
J ) 6.4 Hz, 1 H), 1.78 (septet, J ) 6.4 Hz, 1 H), 3.37-3.62 (m,
4 H), 3.88-4.01 (m, 2 H), 6.25 (d, J ) 16.1 Hz, 1 H), 6.73 (d,
J ) 16.1 Hz, 1 H), 7.16-7.44 (m, 5 H); 13C NMR (CDCl3, 75
MHz) δ 17.5, 17.5, 21.9, 22.0, 22.0, 22.1, 26.4, 35.3, 35.6, 62.1,
62.4, 78.7, 79.4, 108.2, 126.7, 127.7, 128.5, 129.2, 131.6, 136.5;
HRMS calcd for C26H42O4 418.3083, found 418.3089.
1
g, 59%): mp 94-96 °C; IR (KBr) ν 1595 cm-1; H NMR (200
MHz, CDCl3) δ 2.93 (s, 6 H), 4.81 (d, J ) 7.8 Hz, 1 H), 4.84 (d,
J ) 7.8 Hz, 1 H), 5.89 (d, J ) 6.2 Hz, 1 H), 6.55 (d, J ) 6.2 Hz,
1 H), 7.21-7.35 (m, 10 H); 13C NMR (50 MHz, CDCl3) δ 42.3,
84.9, 86.5, 104.6, 126.3, 126.8, 128.1, 128.3, 128.4, 128.5, 136.7,
138.2; HRMS calcd for C18H20O2N2 296.1525, found 296.1523.
Gen er a l P r oced u r e for th e Ad d ition of Alk yllith iu m
to 9. To a solution of hydrazone (1.0 mmol) in toluene or other
solvent (50 mL) at -78 °C was added alkyllithium dropwise
via syringe. The reaction mixture was stirred at -78 °C for
4-16 h and quenched with saturated NH4Cl at -78 °C. The
reaction mixture was allowed to warm to rt and filtered
through a short column of silica gel. After removal of the
solvent in vacuo, the residue was subjected to 1H NMR analysis
to determine diastereoselectivity. The crude mixture was then
chromatographed on silica gel (10% EtOAc in hexane with 2%
Et3N) to afford purified diastereomeric product 15.
Gen er a l P r oced u r e for th e P r ep a r a tion of 4,5-Bis-
(a lk oxym eth yl)-2-for m yld ioxola n e N,N-Dim eth ylh yd r a -
zon e (9). A methanolic solution (250 mL) of 8 (33 mmol) at
-78 °C was bubbled with ozone. The mixture was stirred at
-78 °C for 8-12 h and quenched by the dropwise addition of
Me2S (0.10 mol). After the reaction was warmed to room
temperature, the solvent was evaporated in vacuo to give the
residue to which was added CH2Cl2 (50 mL), PPTs (1.0 mmol),
and H2NNMe2 (70 mmol). The mixture was then stirred at rt
for 4-6 h, quenched with K2CO3, filtered, evaporated, and
purified by chromatography.
15a (88%, 2S/2R ) 91/9); (2S)-15a : [R]24 ) +1.9 (c 11.0,
4,5-Bis(isop r op oxym eth yl)-2-for m yld ioxola n e N,N-Di-
D
CHCl3); IR (neat) ν 3390 cm-1; H NMR (300 MHz, CDCl3) δ
1
m eth ylh yd r a zon e (9a ): 88%; [R]27 ) +0.8 (c 4.5, CHCl3);
D
IR (neat) ν 1666 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.12 (d, J
) 6.1 Hz, 6 H), 1.14 (d, J ) 6.0 Hz, 6 H), 2.81 (s, 6 H), 3.45-
3.67 (m, 6 H), 3.90-4.02 (m, 2 H), 5.40 (d, J ) 6.3 Hz, 1 H),
6.28 (d, J ) 6.3 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ 21.8,
21.8, 42.0, 68.3, 68.6, 72.0, 72.1, 77.7, 78.3, 103.6, 128.7; HRMS
calcd for C14H28O4N2 288.2049, found 288.2049.
1.05 (d, J ) 6.2 Hz, 3 H), 1.11 (d, J ) 5.9 Hz, 6 H), 1.13 (d, J
) 5.9 Hz, 6 H), 1.90-2.10 (br s, 1 H), 2.38 (s, 6 H), 2.95 (dq, J
) 4.2, 6.2 Hz, 1 H), 3.42-3.65 (m, 6 H), 3.84 (dt, J ) 5.0, 6.6
Hz, 1 H), 3.95 (dt, J ) 5.3, 6.6 Hz, 1 H), 4.95 (d, J ) 4.2 Hz,
1 H); 13C NMR (75 MHz, CDCl3) δ 14.0, 21.9, 22.0, 48.1, 55.2,
68.3, 68.6, 72.1, 72.2, 77.6, 78.6, 105.1; HRMS calcd for
C
15H32O4N2 304.2362, found 304.2355.
4,5-Bis(ter t-bu toxym eth yl)-2-for m yld ioxola n e N,N-Di-
15b (75%, 2S/2R ) 89/11); (2S)-15b: [R]24 ) -11.3 (c 5.6,
m eth ylh yd r a zon e (9b); 95%; [R]27 ) +7.9 (c 2.8, CHCl3);
D
D
CHCl3); IR (neat) ν 3392 cm-1; H NMR (300 MHz, CDCl3) δ
0.88 (t, J ) 6.7 Hz, 3 H), 1.14 (d, J ) 5.6 Hz, 6 H), 1.15 (d, J
) 6.0 Hz, 6 H), 1.25-1.48 (m, 5 H), 1.49-1.64 (m, 1 H), 1.70-
1.95 (br s, 1 H), 2.40 (s, 6 H), 2.71-2.86 (m, 1 H), 3.47-3.67
(m, 6 H), 3.86 (dt, J ) 5.1, 6.5 Hz, 1 H), 3.97 (dt, J ) 5.2, 6.5
Hz, 1 H), 5.08 (d, J ) 3.1 Hz, 1 H); 13C NMR (75 MHz, CDCl3)
δ 14.1, 21.9, 22.0, 23.1, 28.2, 28.4, 48.1, 59.6, 68.4, 68.6, 72.2,
72.3, 77.5, 78.6, 104.5; HRMS calcd for C18H38O4N2 346.2832,
found 346.2858.
1
IR (neat) ν 1600 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.15 (s, 9
H), 1.16 (s, 9 H), 2.80, (s, 6 H), 3.38-3.57 (m, 4 H), 3.84-3.95
(m, 2 H), 5.39 (d, J ) 6.0 Hz; 1 H), 6.27 (d, J ) 6.0 Hz, 1 H);
13C NMR (75 MHz, CDCl3) δ 27.4, 42.2, 62.6, 63.0, 73.1, 73.2,
78.3, 79.0, 103.6, 129.1; HRMS calcd for C16H32O4N2 316.2362,
found 316.2354.
4,5-Bis(t h exyloxym et h yl)-2-for m yld ioxola n e N,N-Di-
m eth ylh yd r a zon e (9c): 95%; [R]24 ) +10.9 (c 2.9, CHCl3);
D
IR (neat) ν 1601 cm-1; 1H NMR (300 MHz, CDCl3) δ 0.83 (d, J
) 6.8 Hz, 12 H), 1.03 (s, 6 H), 1.04 (s, 6 H), 1.74 (septet, J )
6.8 Hz, 1 H), 1.75 (septet, J ) 6.8 Hz, 1 H), 2.80 (s, 6 H), 3.37-
3.58 (m, 4 H), 3.90-4.02 (m, 2 H), 5.38 (d, J ) 6.0 Hz, 1 H),
(18) Campi, E. M.; J ackson, W. R.; Perlmutter, P.; Tasdelen, E. E.
Aust. J . Chem. 1993, 46, 995.

1,4-Di-O-tert-alkyl-L-threitols as Chiral Auxiliaries
J . Org. Chem., Vol. 63, No. 5, 1998 1489
15c (71%, 2S/2R ) 98/2); (2S)-15c: [R]26 ) +16.2 (c 5.1,
47.9, 61.6, 62.1, 65.1, 77.4, 77.4, 78.0, 79.0, 105.3, 127.3, 127.9,
128.5, 139.4; HRMS calcd for C26H46O4N2 450.3458, found
450.3463.
D
CHCl3); IR (neat) ν 3481 cm-1; H NMR (300 MHz, CDCl3) δ
1
1.08 (d, J ) 6.0 Hz, 6 H), 1.13 (d, J ) 6.4 Hz, 3 H), 1.14 (d, J
) 6.4 Hz, 3 H), 1.60-1.95 (br s, 1 H), 2.40 (s, 6 H), 3.36-3.63
(m, 6 H), 3.76 (q, J ) 5.7 Hz, 1 H), 3.92 (q, J ) 5.7 Hz, 1 H),
3.98 (d, J ) 4.4 Hz, 1 H), 5.11 (d, J ) 4.4 Hz, 1 H), 7.18-7.35
(m, 3 H), 7.36-7.44 (m, 2 H); 13C NMR (75 MHz, CDCl3) δ
21.8, 21.9, 22.0, 47.8, 65.0, 68.1, 68.5, 72.1, 72.2, 77.6, 78.5,
105.3, 127.3, 127.9, 128.5, 139.2; HRMS calcd for C20H34O4N2
366.2519, found 366.2508.
15j (84%, 2S/2R >99/1); (2S)-15j: [R]25 ) +38.3 (c 3.6,
D
CHCl3); IR (neat) ν 3441 cm-1; H NMR (300 MHz, CDCl3) δ
1
1.06 (d, J ) 6.4 Hz, 3 H), 1.12 (d, J ) 6.2 Hz, 6 H), 1.13 (d, J
) 6.2 Hz, 6 H), 1.30 (s, 3 H), 1.85-2.20 (br s, 1 H), 2.37 (s, 6
H), 2.88 (q, J ) 6.4 Hz, 1 H), 3.39-3.63 (m, 6 H), 3.86 (dt, J )
5.0, 8.1 Hz, 1 H), 3.97 (dt, J ) 5.0, 8.1 Hz, 1 H); 13C NMR (75
MHz, CDCl3) δ 15.3, 21.1, 21.8, 21.9, 47.9, 59.2, 68.7, 68.7,
72.1, 72.1, 78.2, 111.6; HRMS calcd for C16H34O4N2 318.2519,
found 318.2524.
20
15d (90%, 2S/2R ) 95/5); (2S)-15d : [R]D ) +0.2 (c 11.2,
1
CHCl3); IR (neat) ν 3400 cm-1; H NMR (300 MHz, CDCl3) δ
15k (68%, 2S/2R ) 98/2); (2S)-15k : [R]28 ) +8.1 (c 9.4,
D
1.06 (d, J ) 6.2 Hz, 3 H), 1.16 (s, 9 H), 1.17 (s, 9 H), 2.68-2.90
(br s, 1 H), 2.39 (s, 6 H), 2.96 (dq, J ) 4.2, 6.2 Hz, 1 H), 3.35-
3.56 (m, 4 H), 3.80 (q, J ) 5.8 Hz, 1 H), 3.90 (q, J ) 5.8 Hz, 1
H), 4.95 (d, J ) 4.2 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ
14.2, 27.4, 48.0, 55.2, 62.5, 63.7, 73.2, 73.2, 78.0, 79.3, 105.0;
HRMS calcd for C17H36O4N2 332.2675, found 332.2672.
CHCl3); IR (neat) ν 3446 cm-1;1H NMR (300 MHz, CDCl3) δ
0.86 (t, J ) 7.1 Hz, 3 H), 1.11 (d, J ) 6.3 Hz, 6 H), 1.12 (d, J
) 5.8 Hz, 6 H), 1.20-1.59 [(m, 9 H), embodied a singlet at δ
1.32 (s, 3 H)], 2.10-2.28 (br s, 1 H), 2.36 (s, 6 H), 2.68 (dd, J
) 4.5, 6.5 Hz, 1 H), 3.45-3.63 (m, 6 H), 3.83 (dt, J ) 5.0, 8.2
Hz, 1 H), 3.98 (ddd, J ) 3.9, 5.2, 8.2 Hz, 1 H); 13C NMR (75
MHz, CDCl3) δ 14.1, 21.9, 22.0, 22.2, 23.2, 29.4, 30.1, 47.9,
64.1, 68.7, 68.8, 72.1, 72.2, 78.0, 78.2, 112.0; HRMS calcd for
C19H40O4N2 360.2988, found 360.2979.
15e (83%, 2S/2R ) 92/8); (2S)-15e: [R]24 ) -13.4 (c 6.5,
D
CHCl3); IR (neat) ν 3481 cm-1; H NMR (200 MHz, CDCl3) δ
1
0.86 (t, J ) 6.5 Hz, 3 H), 1.14 (s, 9 H), 1.16 (s, 9 H), 1.17-1.62
(m, 6 H), 2.29-2.40 (br s, 1 H), 2.38 (s, 6 H), 2.71-2.80 (m, 1
H), 3.35-3.55 (m, 4 H), 3.79 (dt, J ) 5.1, 6.5 Hz, 1 H), 3.89
(dt, J ) 5.3, 6.5 Hz, 1 H), 5.06 (d, J ) 3.2 Hz, 1 H); 13C NMR
(50 MHz, CDCl3) δ 14.1, 23.1, 27.4, 27.4, 28.2, 28.4, 48.1, 59.6,
62.6, 62.9, 73.2, 79.1, 81.9, 104.4; HRMS calcd for C20H42O4N2
374.3145, found 374.3147. (2R)-15e: 1H NMR (200 MHz,
CDCl3) δ 0.84 (t, J ) 6.5 Hz, 3 H), 1.13 (s, 9 H), 1.14 (s, 9 H),
1.15-1.65 (m, 6 H), 2.29-2.39 (br s, 1 H), 2.37 (s, 6 H), 2.71-
2.80 (m, 1 H), 3.35-3.52 (m, 4 H), 3.83 (dt, J ) 5.0, 6.3 Hz, 1
H), 3.88 (dt, J ) 5.1, 6.3 Hz, 1 H), 5.02 (d, J ) 3.2 Hz, 1 H);
13C NMR (50 MHz, CDCl3) δ 14.0, 23.0, 27.4, 27.4, 28.3, 28.7,
48.1, 59.5, 62.6, 62.7, 73.1, 77.9, 78.7, 104.3.
15l (82%, 2S/2R > 99/1); (2S)-15l: [R]23 ) +29.2 (c 18.9,
D
CHCl3); IR (neat) ν 3438 cm-1; H NMR (300 MHz, CDCl3) δ
1
1.05 (d, J ) 6.3 Hz, 3 H), 1.14 (s, 9 H), 1.15 (s, 9 H), 1.28 (s, 3
H), 2.29-2.35 (br s, 1 H), 2.36 (s, 6 H), 2.86 (q, J ) 6.3 Hz, 1
H), 3.39-3.56 (m, 4 H), 3.81 (dt, J ) 5.3, 8.1 Hz, 1 H), 3.91
(dt, J ) 5.2, 8.1 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ 15.3,
21.2, 27.3, 27.3, 47.9, 59.2, 62.9, 63.0, 72.9, 78.4, 78.9, 111.4;
HRMS calcd for C18H38O4N2 346.2832, found 346.2832.
15m (70%, 2S/2R ) 98/2); (2S)-15m : [R]27 ) +8.9 (c 2.2,
D
CHCl3); IR (neat) ν 3435 cm-1; H NMR (300 MHz, CDCl3) δ
1
0.86 (t, J ) 6.9 Hz, 3 H), 1.13 (s, 9 H), 1.15 (s, 9 H), 1.18-1.60
[(m, 9 H), embodied a singlet at δ 1.32 (s, 3 H)], 2.15-2.30 (br
s, 1 H), 2.36 (s, 6 H), 2.68 (dd, J ) 4.6, 6.5 Hz, 1 H), 3.36-3.58
(m, 4 H), 3.79 (ddd, J ) 4.8, 5.9, 8.3 Hz, 1 H), 3.93 (ddd, J )
4.8, 5.9, 8.3 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ 14.1, 22.3,
23.2, 27.4, 27.4, 29.4, 30.1, 47.9, 62.9, 63.1, 64.1, 73.0, 73.1,
78.2, 79.0, 111.9; HRMS calcd for C21H44O4N2 388.3301, found
388.3304.
15f (85%, 2S/2R ) 98/2); (2S)-15f: [R]26 ) +17.0 (c 5.4,
D
CHCl3); IR (neat) ν 3478 cm-1; H NMR (200 MHz, CDCl3) δ
1
1.10 (s, 9 H), 1.16 (s, 9 H), 1.55-1.79 (br s, 1 H), 2.40 (s, 6 H),
3.24-3.48 (m, 4 H), 3.71 (q, J ) 5.7 Hz, 1 H), 3.87 (q, J ) 5.7
Hz, 1 H), 3.99 (d, J ) 4.4 Hz, 1 H), 5.10 (d, J ) 4.4 Hz, 1 H),
7.21-7.45 (m, 5 H); 13C NMR (50 MHz, CDCl3) δ 27.4, 27.5,
47.9, 62.4, 62.9, 65.0, 73.2, 78.0, 79.1, 105.3, 127.4, 127.9, 128.6,
139.4; HRMS calcd for C22H38O4N2 394.2832, found 394.2838.
23b (79%, de 56%); 1H NMR (300 MHz, CDCl3) δ 0.98 (t, J
) 6.9 Hz, 3 H), 1.34-1.85 (m, 7 H), 2.48 (s, 6 H), 3.02-3.15
(m, 1 H), 4.70 (d, J ) 8.1 Hz, 1 H), 4.74 (d, J ) 8.1 Hz, 1 H),
5.51 (d, J ) 3.9 Hz, 1 H), 7.18-7.35 (m, 10 H); 13C NMR (75
MHz, CDCl3) δ 14.1, 23.1, 28.1, 28.3, 48.2, 60.3, 85.0, 86.9,
105.6, 126.4, 126.8, 128.1, 128.4, 128.5, 139.6.
Gen er a l P r oced u r e for th e Red u ctive Clea va ge of th e
N-N bon d of 15. A mixture of hydrazine (1.0 mmol) and
excess W2 Raney nickel in methanol (50 mL) was refluxed for
1-2 h and then filtered through a short column of flash silica
gel. The filtrate was evaporated in vacuo, and the residue was
chromatographed (25% EtOAc in hexane with 2% Et3N) to give
amine 16. In certain cases, 16 was used directly for the next
transformation into 17.
15g (86%, 2S/2R ) 91/9); (2S)-15g: [R]25 ) -0.8 (c 3.8,
D
CHCl3); IR (neat) ν 3443 cm-1; H NMR (CDCl3, 300 MHz) δ
1
0.83 (d, J ) 6.7 Hz, 9 H), 0.84 (d, J ) 6.7 Hz, 3 H), 1.01-1.07
[(m, 15 H), embodied a singlet at δ 1.04 (s, 6 H), a singlet at
δ 1.06 (s, 6 H)], 1.73 (septet, J ) 6.7 Hz, 1 H), 1.75 (septet, J
) 6.7 Hz, 1 H), 2.00-2.20 (br s, 1 H), 2.38 (s, 6 H), 2.93 (dq, J
) 4.2, 6.5 Hz, 1 H), 3.33-3.51 (m, 4 H), 3.83 (q, J ) 5.7 Hz, 1
H), 3.95 (q, J ) 5.7 Hz, 1 H), 4.93 (d, J ) 4.2 Hz, 1 H); 13C
NMR (CDCl3, 50 MHz) δ 14.1, 17.4, 17.5, 17.5, 21.9, 22.0, 22.1,
35.6, 35.8, 48.2, 55.4, 61.7, 62.2, 77.3, 78.1, 79.0, 105.0; HRMS
calcd for C21H44O4N2 388.3301, found 388.3301.
15h (73%, 2S/2R ) 92/8); (2S)-15h : [R]24 ) -10.6 (c 9.9,
D
(2S)-16a : 77%; [R]30D ) -4.7 (c 4.3, CHCl3); IR (neat) ν 3374
cm -1; 1H NMR (CDCl3, 300 MHz) δ 1.01 (d, J ) 6.9 Hz, 3 H),
1.15 (s, 18 H), 1.28 (s, 3 H), 1.55-1.69 (br s, 2 H), 2.84 (q, J )
6.6 Hz, 1 H), 3.39-3.56 (m, 4 H), 3.87 (dt, J ) 4.7, 8.2 Hz, 1
H), 3.95 (dt, J ) 4.5, 8.2 Hz, 1 H); 13C NMR (CDCl3, 75 MHz)
δ 17.8, 21.7, 27.4, 53.6, 62.4, 63.3, 73.1, 78.3, 79.0, 112.1.
(2S)-16b: 80%; IR (neat) ν 3383 cm-1; 1H NMR (CDCl3, 300
MHz) δ 0.83 (t, J ) 7.0 Hz, 3 H), 0.95-1.59 [(m, 29 H),
embodied a singlet at δ 1.12 (s, 18 H), a singlet at δ 1.26 (s, 3
H)], 2.59 (dd, J ) 2.2, 10.1 Hz, 1 H), 3.40-3.56 (m, 4 H), 3.87
(dt, J ) 5.0, 8.1 Hz, 1 H), 3.95 (dt, J ) 4.5, 8.1 Hz, 1 H); 13C
NMR (CDCl3, 75 MHz) δ 13.9, 21.3, 22.7, 27.3, 29.1, 31.5, 58.1,
62.3, 63.1, 72.9, 78.4, 78.6, 112.1; HRMS calcd for C19H40O4N
(M++1) 346.2957, found 346.2957.
Gen er a l P r oced u r e for th e Syn th esis of P h th a lim id e
17. A mixture of 16 (1.0 mmol) and phthalic anhydride (1.0
mmol) in ether (50 mL) was stirred at rt for 2 h. Solvent was
removed in vacuo to give the residue to which were added
excess NaOAc (10.0 mmol) and acetic anhydride (60 mL). The
mixture was refluxed for 1 h. Water was added and the
mixture was extracted with ether (50 mL × 3), dried (MgSO4),
CHCl3); IR (neat) ν 3481 cm-1; H NMR (CDCl3, 300 MHz) δ
1
0.83 (d, J ) 6.7 Hz, 12 H), 0.86 (t, J ) 6.9 Hz, 3 H), 1.03 (s, 6
H), 1.05 (s, 6 H), 1.20-1.61 (m, 7 H), 1.73 (septet, J ) 6.7 Hz,
1 H), 1.75 (septet, J ) 6.7 Hz, 1 H), 2.38 (s, 6 H), 2.71-2.79
(m, 1 H), 3.36-3.50 (m, 4 H), 3.83 (q, J ) 5.7 Hz, 1 H), 3.95
(q, J ) 5.7 Hz, 1 H), 5.05 (d, J ) 3.3 Hz, 1 H); 13C NMR (CDCl3,
75 MHz) δ 14.1, 17.4, 17.5, 17.5, 21.9, 22.0, 23.1, 28.2, 28.4,
35.6, 35.8, 48.1, 59.7, 61.8, 62.0, 77.3, 77.4, 78.0, 78.7, 104.3;
HRMS calcd for C24H50O4N2 430.3771, found 430.3772.
15i (70%, 2S/2R ) 98/2); (2S)-15i: [R]26 ) +5.4 (c 5.3,
D
CHCl3); IR (neat) ν 3337 cm-1; H NMR (CDCl3, 300 MHz) δ
1
0.79 (d, J ) 7.0 Hz, 6 H), 0.85 (d, J ) 7.0 Hz, 3 H), 0.86 (d, J
) 7.0 Hz, 3 H), 0.99 (s, 6 H), 1.04 (s, 6 H), 1.73 (septet, J ) 6.7
Hz, 1 H), 1.75 (septet, J ) 6.7 Hz, 1 H), 1.62-1.80 (br s, 1 H),
2.40 (s, 6 H), 3.26 (dd, J ) 5.6, 9.3 Hz, 1 H), 3.32 (dd, J ) 5.2,
9.3 Hz, 1 H), 3.33 (dd, J ) 5.6, 9.3 Hz, 1 H), 3.39 (dd, J ) 5.0,
9.3 Hz, 1 H), 3.76 (dt, J ) 5.0, 5.6 Hz, 1 H), 3.90 (dt, J ) 5.2,
5.6 Hz, 1 H), 3.96 (d, J ) 4.7 Hz, 1 H), 5.08 (d, J ) 4.7 Hz, 1
H), 7.18-7.33 (m, 3 H), 7.37-7.44 (m, 2 H); 13C NMR (CDCl3,
75 MHz) δ 17.4, 17.4, 17.5, 21.9, 21.9, 22.0, 22.1, 35.5, 35.8,

1490 J . Org. Chem., Vol. 63, No. 5, 1998
Hsieh et al.
and concentrated to give the residue which was chromato-
13C NMR (75 MHz, CDCl3) δ 13.9, 22.2, 23.2, 25.1, 27.3, 28.7,
58.6, 62.7, 62.8, 73.0, 73.1, 78.9, 79.3, 110.7, 123.0, 123.1, 131.4,
132.2, 133.6, 133.8, 168.3, 169.0; HRMS calcd for C27H41O6N
475.2934, found 475.2938.
graphed on silica gel (25% EtOAc in hexane) to give 17.
(2S)-17a : 91%; mp 95-97 °C; [R]24 ) +4.1 (c 5.4, CHCl3);
D
IR (KBr) ν 1713, 1699 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.10
(s, 9 H), 1.17 (s, 9 H), 1.50 (d, J ) 7.2 Hz, 3 H), 3.34 (dd, J )
5.6, 9.3 Hz, 1 H), 3.39-3.54 (m, 3 H), 3.85 (q, J ) 6.2 Hz, 1
H), 3.94 (dt, J ) 5.2, 6.2 Hz, 1 H), 4.24 (quint, J ) 7.2 Hz, 1
H), 5.58 (d, J ) 7.2 Hz, 1 H), 7.63-7.83 (m, 4 H); 13C NMR (75
MHz, CDCl3) δ 14.2, 27.3, 27.4, 50.6, 62.4, 63.1, 73.1, 73.2,
78.7, 79.1, 103.1, 123.1, 132.0, 133.7, 168.1; HRMS calcd for
P h th a lim id e 25. In a manner similar to that described
above, a mixture of dl-14 (0.59 g, 2.0 mmol) and MeLi (6 mL
of a 1.6 M solution in ether, 9.6 mmol) in toluene (60 mL) was
stirred at -78 °C for 16 h. After usual workup, the crude 23
(dr ) 32/68) was taken up into methanol (50 mL) to which
was added excess Raney nickel (W2). The mixture was
refluxed for 1h and filtered through a short column of flash
silica gel to yield crude 24. Without further purification, a
mixture of crude 24, phthalic anhydride (0.30 g, 2.0 mmol),
and NaOAc (1.96 g, 20.0 mmol) in acetic anhydride (60 mL)
was refluxed for 1 h. The mixture was worked up to give 25
(0.22 g, 27%). The diastereomeric mixture was separated by
flash column chromatography (silica gel, 25% EtOAc in hex-
C
23H33O6N 419.2308, found 419.2294.
(2S)-17b: 85%; [R]24D ) -5.6 (c 7.8, CHCl3); IR (neat) ν 1716
cm-1; H NMR (200 MHz, CDCl3) δ 0.81 (t, J ) 6.7 Hz, 3 H),
1.09 (s, 9 H), 1.10-1.35 [(m, 13 H), embodied a singlet at δ
1.17 (s, 9 H)], 1.69-1.92 (m, 1 H), 2.01-2.30 (m, 1 H), 3.26-
3.57 (m, 4 H), 3.77-3.99 (m, 2 H), 4.11 (ddd, J ) 4.1, 7.3, 11.4
Hz, 1 H), 5.55 (d, J ) 7.3 Hz, 1 H), 7.63-7.84 (m, 4 H); 13C
NMR (75 MHz, CDCl3) δ 13.9, 22.3, 27.2, 27.3, 27.4, 28.2, 55.6,
62.5, 63.2, 73.1, 78.5, 79.1, 102.8, 123.2, 132.0, 133.8, 168.5;
HRMS calcd for C26H39O6N 461.2777, found 461.2779.
1
1
ane): 25a : mp 106-108 °C; IR (KBr) ν 1771, 1711 cm-1; H
NMR (300 MHz, CDCl3) δ 1.67 (d, J ) 7.2 Hz, 3 H), 4.58 (quint,
J ) 7.2 Hz, 1 H), 4.73 (d, J ) 8.3 Hz, 1 H), 4.79 (d, J ) 8.3 Hz,
1 H), 6.03 (d, J ) 7.2 Hz, 1 H), 7.12-7.35 (m, 10 H); 7.65-
7.70 (m, 2 H), 7.79-7.83 (m, 2 H); 13C NMR (75 MHz, CDCl3)
δ 13.9, 50.5, 84.7, 87.2, 103.6, 123.23, 126.6, 126.7, 128.2, 128.3,
128.4, 128.5, 132.0, 133.9, 136.1, 136.9, 168.3; HRMS calcd
for C25H21O4N 399.1471, found 399.1494. 25b: IR (KBr) ν
(2S)-17c: 93%; [R]30 ) +10.2 (c 1.7, CHCl3); IR (neat) ν
D
1777, 1718 cm-1; 1H NMR (300 MHz, CDCl3) δ 0.81 (t, J ) 7.3
Hz, 3 H), 1.01-1.15 [(m, 15 H), embodied a doublet at δ 1.07
(d, J ) 7.1 Hz, 3 H), a doublet at δ 1.09 (d, J ) 7.4 Hz, 3 H),
a doublet at δ 1.12 (d, J ) 7.1 Hz, 6 H)], 1.20-1.35 (m, 1 H),
1.45 (s, 3 H), 1.64-1.89 (m, 1 H), 2.35-2.53 (m, 1 H), 3.40-
3.65 (m, 6 H), 3.87 (dt, J ) 4.5, 8.7 Hz, 1 H), 3.93 (ddd, J )
4.2, 6.3, 8.7 Hz, 1 H), 4.24 (dd, J ) 3.6, 12.3 Hz, 1 H), 7.63-
7.82 (m, 4 H); 13C NMR (75 MHz, CDCl3) δ 14.1, 21.7, 21.8,
21.9, 22.0, 22.2, 23.2, 25.2, 28.7, 58.6, 68.3, 68.7, 72.0, 72.2,
78.3, 79.1, 110.8, 122.97, 123.1, 131.4, 132.2, 133.6, 133.8,
168.3, 169.0; HRMS calcd for C25H37O6N 447.2621, found
447.2621.
1
1771, 1711 cm-1; H NMR (300 MHz, CDCl3) δ 1.65 (d, J )
6.9 Hz, 3 H), 4.58 (quint, J ) 6.9 Hz, 1 H), 4.70 (d, J ) 8.2 Hz,
1 H), 4.74 (d, J ) 8.2 Hz, 1 H), 6.05 (d, J ) 6.9 Hz, 1 H), 7.12-
7.34 (m, 10 H), 7.65-7.70 (m, 2 H), 7.79-7.85 (m, 2 H); 13C
NMR (75 MHz, CDCl3) δ 14.4, 50.8, 85.3, 87.0, 103.7, 123.3,
126.6, 126.7, 128.3, 128.4, 128.5, 128.6, 132.0, 133.9, 135.8,
136.7, 168.3; HRMS calcd for C25H21O4N 399.1471, found
399.1439.
(2S)-17d : 82%; [R]24 ) +19.4 (c 1.2, CHCl3); IR (neat) ν
D
1
1775, 1717, 1699 cm-1; H NMR (200 MHz, CDCl3) δ 1.13 (s,
Ack n ow led gm en t. This work was supported by the
9 H), 1.15 (s, 9 H), 1.43 (s, 3 H), 1.59 (d, J ) 7.4 Hz, 3 H),
3.39-3.60 (m, 4 H), 3.8-3.96 (m, 2 H), 4.44 (q, J ) 7.4 Hz, 1
H), 7.61-7.82 (m, 4 H); 13C NMR (50 MHz, CDCl3) δ 12.8, 22.9,
27.4, 53.5, 62.7, 62.9, 73.1, 73.2, 79.0, 79.5, 110.9, 123.1, 131.9,
133.7, 168.4; HRMS calcd for C24H36O6N (M+ + 1) 434.2543,
found 434.2538.
National Science Council of the Republic of China.
Su p p or tin g In for m a tion Ava ila ble: The experimental
procedure and data for X-ray crystallography and 1H NMR
spectra for 8a -f, 9a -f, (2S)-15a -m , (2R)-15e, (2S)-16a ,b,
(2S)-17a -e, and 25a ,b (50 pages). This material is contained
in libraries on microfiche, immediately follows this article in
the microfilm version of the journal, and can be ordered from
the ACS; see any current masthead page for ordering
information.
(2S)-17e: 85%; [R]24D ) +7.6 (c 3.0, CHCl3); IR (neat) ν 1775,
1717, 1699 cm-1; 1H NMR (300 MHz, CDCl3) δ 0.81 (t, J ) 7.3
Hz, 3 H), 1.10-1.39 [(m, 22 H), embodied a singlet at δ 1.13
(s, 9 H), a singlet at δ 1.15 (s, 9 H)], 1.43 (s, 3 H), 1.73-1.89
(m, 1 H), 2.35-2.52 (m, 1 H), 3.41-3.58 (m, 4 H), 3.78-3.93
(m, 2 H), 4.25 (dd, J ) 3.6, 12.3 Hz, 1 H), 7.63-7.84 (m, 4 H);
J O971700Y