Efficient remote axial-to-central chirality transfer in enantioselective SmI2-mediated reductive coupling of aldehydes with crotonates of atropisomeric 1-naphthamides

Article abstract of DOI:10.1021/jo0526486

Control of enantioselectivity by remote amide conformation has been studied in SmI₂-mediated reductive coupling of aldehydes with the crotonates possessing different 2-substituted 8-methoxy-1-naphthamides. The enantiomers of atropisomeric 8-met

Full text of DOI:10.1021/jo0526486

Efficient Remote Axial-to-Central Chirality Transfer in
Enantioselective SmI2-Mediated Reductive Coupling of Aldehydes
with Crotonates of Atropisomeric 1-Naphthamides
Yan Zhang, Yongqiang Wang, and Wei-Min Dai*
Department of Chemistry, The Hong Kong UniVersity of Science and Technology, Clear Water Bay,
Kowloon, Hong Kong SAR, China
chdai@ust.hk
ReceiVed December 24, 2005
Control of enantioselectivity by remote amide conformation has been studied in SmI2-mediated reductive
coupling of aldehydes with the crotonates possessing different 2-substituted 8-methoxy-1-naphthamides.
The enantiomers of atropisomeric 8-methoxy-1-naphthamides were prepared through a chemical resolution
process, and their absolute stereochemistry was determined by X-ray crystal structural analysis. It was
found that the linkage between crotonate and the C2 position of 8-methoxy-1-naphthamides remarkably
influenced the efficiency of remote chirality transfer originated from the amide conformation. Among
the four crotonates examined, the one derived from 2-hydroxy-8-methoxy-1-naphthamide reacted with
pentanal to afford the highest ee of >99% for the cis-γ-butyrolactone and in 90% combined yield with
a cis/trans ratio of 90:10. We developed a new procedure for attaching the chiral crotonate via the C8
oxygen to a Rink amide resin under mild conditions and obtained the same level of highly remote axial-
to-central chirality transfer in the solid-phase reaction.
Introduction
used to induce stereogenic center(s) in reactions taking place
at close proximity, which are normally separated by two bond
lengths.3-5 However, in a system such as the propionates rac-1
(Chart 1), where the R-carbon of the ester is four bond lengths
away from the ipso position of the amide subunit, Clayden and
co-workers reported poor stereocontrol in aldol reactions, giving
31:69 (for X ) H) and 59:41 (for X ) SiMe3) mixtures of anti/
syn aldols, respectively.6 It seems that the amide conformation
of 1 could not efficiently communicate with the enolate reaction
site, although a successful example exists for a similar reaction
on the basis of the Fuji et al. binol derivative which gave anti-
Chirality transfer or asymmetric induction from chiral cata-
lysts or chiral auxiliaries is the basis for asymmetric synthesis
of enantiomerically enriched chiral molecules. The efficiency
of the chirality transfer is largely dependent on how tight the
interaction is between the chirality source and the reacting site.
A short distance is normally considered being favorable for
highly efficient chirality transfer or asymmetric induction.1 It
is of interest to study stereocontrol among remote sites.2,3 One
recent example reported by Clayden and co-workers illustrated
the state of art in achieving remote stereocontrol in two sites
separated by more than 20 bond lengths or a linear distance of
>2.5 nm.3 The system in the work of Clayden and co-workers
features chiral relay of rotationally restricted tertiary amides
through the space,3,4 and the axially chiral amide unit is then
(4) (a) Clayden, J. Angew. Chem., Int. Ed. Engl. 1997, 36, 949-951.
(b) Clayden, J. Synlett 1998, 810-816. (c) Clayden, J. Chem. Commun.
2004, 127-135.
(5) Selected examples of asymmetric induction using enantio-enriched
atropisomeric amides, see: (a) Hughes, A. D.; Simpkins, N. S. Synlett 1998,
967-968. (b) Hughes, A. D.; Price, D. A.; Simpkins, N. S. J. Chem. Soc.,
Perkin Trans. 1 1999, 1295-1304. (c) Kitagawa, O.; Izawa, H.; Sato, K.;
Dobashi, A.; Taguchi, T. J. Org. Chem. 1998, 63, 2634-2540. (d) Clayden,
J.; McCarthy, C.; Cumming, J. G. Tetrahedron Lett. 2000, 41, 3279-3283.
(e) Clayden, J.; Lund, A.; Youssef, L. H. Org. Lett. 2001, 3, 4133-4136.
(6) Clayden, J.; Helliwell, M.; McCarthy, C.; Westlund, N. J. Chem.
Soc., Perkin Trans. 1 2000, 3232-3249.
(1) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds;
Wiley: New York, 1994.
(2) (a) Magnus, N.; Magnus, P. Tetrahedron Lett. 1997, 38, 3491-3494.
(b) Linnane, P.; Magnus, N.; Magnus, P. Nature 1997, 385, 799-801.
(3) Clayden, J.; Lund, A.; Vallverdu, L.; Helliwell, M. Nature 2004, 431,
966-971.
10.1021/jo0526486 CCC: $33.50 © 2006 American Chemical Society
Published on Web 02/11/2006
J. Org. Chem. 2006, 71, 2445-2455
2445

Zhang et al.
CHART 1. Structures of Conformationally Restricted Benzamides, 1-Naphthamides, and Chiral Crotonates
SCHEME 1. Synthesis of Chiral Crotonates of 2-Hydroxy-8-methoxy-1-naphthamide
selective aldols.7 In our previous studies on asymmetric reactions
and catalysis using enantiomerically pure atropisomeric 1-naph-
thamides, we have reported highly diastereoselective desym-
metrization of meso-anhydrides with (-)-(aR,S)-2,8 Pd-catalyzed
asymmetric allylic alkylation with the atropisomeric amide-
derived phosphine (A2phos) (+)-(aS)-3a,9a asymmetric Heck
reaction with A2phos (+)-(aS)-3c,9b and asymmetric Suzuki-
Miyaura coupling with A2phos (+)-(aS)-3b.9c We report here
our results on SmI2-mediated reductive coupling of aldehydes
with the chiral crotonates 5-8 (Chart 1),10 possessing atropi-
someric 8-methoxy-1-naphthamide scaffolds. By comparison
with the reactions of (1S,2R)-4, derived from N-methylephe-
drine,11 we planned to determine the structural elements essential
for highly efficient axial-to-central chirality transfer from the
amide moiety to remote centers separated at least by five bond
lengths.
Results and Discussion
Synthesis and Stereochemistry Determination of Chiral
Crotonates 5-8. In our previous study, we obtained (+)-(aS)-5
in 94.3% ee via kinetic resolution under asymmetric dihydroxy-
lation conditions by using (DHQD)2-PHAL [1,4-bis(9-O-
dihydroquinidine)phthalazine] as the chiral ligand.10,12 The
absolute stereochemistry of (+)-(aS)-5 was established by
correlation to a compound whose absolute stereochemistry was
determined by X-ray crystallographic analysis.10 To prepare
enantiomerically pure crotonate 5, we turned our attention to
the chemical resolution approach as shown in Scheme 1. Starting
from the known 8-silyloxy compound rac-9,10 the 8-hydroxy-
(7) Ahn, M.; Tanaka, K.; Fuji, K. J. Chem. Soc., Perkin Trans. 1 1998,
185-192.
(8) Dai, W.-M.; Yeung, K. K. Y.; Chow, C. W.; Williams, I. D.
Tetrahedron: Asymmetry 2001, 12, 1603-1613.
(9) (a) Dai, W.-M.; Yeung, K. K. Y.; Liu, J.-T.; Zhang, Y.; Williams, I.
D. Org. Lett. 2002, 4, 1615-1618. (b) Dai, W.-M.; Yeung, K. K. Y.; Wang,
Y. Tetrahedron 2004, 60, 4425-4430. (c) Zhang, Y. Ph.D. Thesis, The
Hong Kong University of Science and Technology, Clear Water Bay,
Kowloon, Hong Kong SAR, China, 2005.
(10) The chiral crotonate (+)-(aS)-5 was prepared previously by kinetic
resolution via asymmetric dihydroxylation, see: Dai, W.-M.; Zhang, Y.;
Zhang, Y. Tetrahedron: Asymmetry 2004, 15, 525-535.
(11) (a) Fukuzawa, S.; Seki, K.; Tastuzawa, M.; Mutoh, K. J. Am. Chem.
Soc. 1997, 119, 1482-1483. For a review on sequencing reactions with
SmI2, see: (b) Molander, G. A.; Harris, C. R. Chem. ReV. 1996, 96, 307-
338. For a recent study on the role of proton donors in SmI2-mediated ketone
reduction, see: (c) Chopade, P. R.; Prasad, E.; Flowers, R. A., II. J. Am.
Chem. Soc. 2004, 126, 44-45.
(12) VanNieuwenhze, M. S.; Sharpless, K. B. J. Am. Chem. Soc. 1993,
115, 7864-7865.
2446 J. Org. Chem., Vol. 71, No. 6, 2006

EnantioselectiVe ReductiVe Coupling of Aldehydes
SCHEME 2. Synthesis of Chiral Crotonates of 2-Hydroxymethyl-8-methoxy-1-naphthamide
1-naphthamide rac-10 was obtained in 99% yield after desilyl-
ation with n-Bu4NF in THF. Esterification of rac-10 with (S)-
camphanic chloride in the presence of DMAP in CH2Cl2
afforded a pair of diastereomers (+)-(aS,S)-11 (49%) and (-)-
(aR,S)-12 (48%), which were separated by column chromatog-
raphy on silica gel. The stereochemistries of (+)-(aS,S)-11 and
(-)-(aR,S)-12 were assigned after conversion to the known
8-methoxy derivatives (+)-(aS)-5 and (-)-(aR)-5, respectively.
Because we observed slow racemization of axially chiral
8-hydroxy-1-naphthamide (aS)-10 (not shown) at room tem-
perature after removal of the camphanyl group from (+)-(aS)-
11, we applied a one-pot transformation of (+)-(aS,S)-11 and
(-)-(aR,S)-12 to (+)-(aS)-5 and (-)-(aR)-5 (Scheme 1) in an
overall yield of 63%, without isolation of 8-hydroxy-1-naph-
thamide (aS)-10 and (aR)-10.
Our preparation of (+)-(aR)-6 and (-)-(aS)-6 was straight-
forward, starting from the known racemic aldehyde rac-135d,6
(Scheme 2). Clayden and co-workers used a dynamic resolution
by using a chiral diamine to obtain (-)-(aR)-13 in 99% ee and
in 56% yield from rac-13 through a three-step operation.5d,6
We obtained both enantiomeric alcohols (+)-(aR)-14 and (-)-
(aS)-14 from the reduction of rac-13, followed by the semi-
preparative HPLC separation of the racemic alcohol over a chiral
stationary phase (Chiralpak AD). The absolute stereochemistry
of (-)-(aS)-14 was assigned by oxidation to the known aldehyde
(-)-(aR)-13 with a change in priority of the substituents.5d,6 In
the reactions of (+)-(aR)-14 with (E)-crotonyl chloride in the
presence of Et3N as the base, we found a byproduct (aR)-6′
(60%), featured with a monosubstituted olefin moiety in the
1H NMR spectrum, which suggests a 3-butenoate unit. Use of
n-BuLi as the base could suppress the byproduct to afford the
desired crotonate (+)-(aR)-6 or (-)-(aS)-6 in 71% yield.
Initially, we planned to use racemic 8-methoxy-1-naphtha-
mide syn-17 for the synthesis of the chiral crotonates (+)-
(aR,R)-7 and (-)-(aS,S)-7 (Scheme 3). The addition of MeMgCl
with rac-13 gave a mixture of two diastereomers whose ratio
is 78:22 (syn/anti)13 in favor of the syn isomer.14 Unfortunately,
the diastereomeric camphanic esters of (-)-(aR,R,S)-21 and (-)-
(aS,S,S)-22 formed from syn-17 could not be separated on a
silica gel column. Then, we adopted the chemical resolution of
8-silyloxy analogue syn-18. Starting from the known amide rac-
15,9a,10 the aldehyde rac-16 was prepared in 79% yield via the
amide-directed ortho lithiation, followed by quenching with
DMF. The addition of MeMgCl with rac-16 gave a 56:44
mixture of syn-18 and anti-18 in 91% combined yield. It is
interesting to note the diminished atroposelectivity due to the
bulky 8-silyloxy group in rac-16 as compared to that of the
8-methoxy analogue rac-13. We secured the relative stereo-
chemistry of anti-18 by X-ray crystal structural analysis, and
the structural drawing is given in Figure S1 of the Supporting
Information. Condensation of syn-18 with (S)-camphanic chlo-
ride in the presence of DMAP in CH2Cl2 afforded the pure
diastereomers (+)-(aR,R,S)-19 and (-)-(aS,S,S)-20 after separa-
tion by column chromatography on silica gel. To eliminate the
possibility of racemization after desilylation, we developed a
one-pot conversion of (+)-(aR,R,S)-19 and (-)-(aS,S,S)-20 into
the corresponding 8-methoxy derivatives (-)-(aR,R,S)-21 and
(-)-(aS,S,S)-22, respectively, via a high-yielding in situ de-
silylation and methylation process (n-Bu4NF, MeI, THF; Scheme
3). The absolute stereochemistry of (-)-(aS,S,S)-22 was estab-
lished again by X-ray crystallographic analysis as illustrated in
Figure S2 of the Supporting Information. It in turn confirmed
the stereochemistry assignment of the diastereomer (-)-(aR,R,S)-
21. Finally, removal of the camphanyl group in the esters (-)-
(aR,R,S)-21 and (-)-(aS,S,S)-22 formed the enantiomerically
pure (+)-(aR,R)-17 and (-)-(aS,S)-17, which were converted
into the chiral crotonates (+)-(aR,R)-7 and (-)-(aS,S)-7, re-
spectively, after deprotonation with n-BuLi and a reaction with
(E)-crotonyl chloride.
By following a similar approach as described above, we
synthesized the chiral crotonates (+)-(aR,R)-8 and (-)-(aS,S)-
8, as depicted in Scheme 4. The addition of PhMgCl with rac-
13 provided syn-23 as the single isomer in 96% yield. The
increased atroposelectivity with PhMgCl is in agreement with
the early observation in a similar reaction of the aldehyde
lacking the 8-methoxy group.14 Ester bond formation between
racemic syn-23 and (S)-camphanic chloride was carried out in
(13) The syn and anti isomers are defined as follows. With an orthogonal
orientation of the naphthalene ring and amide moiety in 1-naphthamides,
the syn and anti isomers may be viewed by placing the small group (H) of
the C2 tetrahedral substituent on the naphthalene plane and pointing toward
the C1 amide moiety. Thus, the syn isomer has the amide carbonyl oxygen
atom on the same side with the oxygen atom (or functional group) of the
tetrahedral substituent.
(14) (a) Clayden, J.; Westlund, N.; Wilson, F. X. Tetrahedron Lett. 1996,
37, 5577-5580. (b) Clayden, J.; McCarthy, C.; Westlund, N.; Frampton,
C. S. J. Chem. Soc., Perkin Trans. 1 2000, 1363-1378.
J. Org. Chem, Vol. 71, No. 6, 2006 2447

Zhang et al.
SCHEME 3. Synthesis of Chiral Crotonates of 2-(1′-Hydroxyethyl)-8-methoxy-1-naphthamide
CH2Cl2 in the presence of DMAP to afford pure diastereomers
(+)-(aR,R,S)-24 and (-)-(aS,S,S)-25 after column chromato-
graphic separation over silica gel. The absolute stereochemistry
of (-)-(aS,S,S)-25 was deduced by X-ray crystal structural
analysis and the structural drawing is given in Figure S3 of the
Supporting Information. Alkaline hydrolysis of (+)-(aR,R,S)-
24 and (-)-(aS,S,S)-25 gave the enantiomeric alcohols (+)-
(aR,R)-23 and (-)-(aS,S)-23 in 89% yields. The latter were
treated with n-BuLi and (E)-crotonyl chloride to furnish the
chiral crotonates (+)-(aR,R)-8 and (-)-(aS,S)-8, respectively,
in 70% yield.
SmI2-Mediated Reductive Coupling of Aldehydes with
Chiral Crotonates. In 1997, Fukuzawa and co-workers first
reported the SmI2-mediated reductive coupling of aldehydes with
chiral acrylates and crotonates derived from N-methylephedrine
to form chiral γ-butyrolactones in high enantioselectivity.11a
Recently, Lin and co-workers reported the synthesis of chiral
γ-butyrolactones from the SmI2-mediated reductive coupling of
ketones with both achiral and chiral acrylates in the presence
of a chiral proton donor.15 We performed the SmI2-mediated
reductive coupling of aldehydes with our chiral crotonates 5-8
prepared above for investigating remote axial-to-central chirality
transfer. The results are summarized in Table 1. Reactions of
both (-)-(aR)-5 and (+)-(aS)-5 with pentanal gave the γ-bu-
tyrolactone 36a in 90% yield with 90:10 cis/trans isomer ratio
(Table 1, entries 1 and 2). The enantioselectivities for both cis-
and trans-36a are >99 and g95%, respectively. However, the
same reactions using chiral crotonates 6-8 afforded lower yields
of 36a and lower enantiomer excess in the range of 14-63%
for the cis isomer (Table 1, entries 6, 8, and 10), although the
cis/trans isomer ratios remained high (83:17-95:5). A similar
efficiency in chirality transfer was observed in the reactions of
2,2,2-trimethylacetaldehyde with the chiral crotonates 5-7
(entries 4, 7, and 9), while the cis-γ-butyrolactone 36c was
obtained in 96% ee from the reaction of (+)-(aS)-5. We carried
out the SmI2-mediated reductive coupling of isobutyraldehyde
and cyclohexanecarboxaldehyde with (+)-(aS)-5 and (-)-(aR)-5
(15) (a) Xu, M.-H.; Lin, G.-Q.; Xia, L.-J. Chin. J. Chem. 1998, 16, 561-
564. (b) Xu, M.-H.; Wang, W.; Lin, G.-Q. Org. Lett. 2000, 2, 2229-2232.
(c) Wang, W.; Xu, M.-H.; Lei, X.-S.; Lin, G.-Q. Org. Lett. 2000, 2, 3773-
3776. (d) Xu, M.-H.; Wang, W.; Xia, L.-J.; Lin, G.-Q. J. Org. Chem. 2001,
66, 3952-3962. (e) Wang, W.; Zhong, Y.-W.; Lin, G.-Q. Tetrahedron Lett.
2003, 44, 4613-4616. (f) Huang, L.-L.; Xu, M.-H.; Lin, G.-Q. J. Org.
Chem. 2005, 70, 529-532.
2448 J. Org. Chem., Vol. 71, No. 6, 2006

EnantioselectiVe ReductiVe Coupling of Aldehydes
SCHEME 4. Synthesis of Chiral Crotonates of 2-(1′-Hydroxybenzyl)-8-methoxy-1-naphthamide
TABLE 1. SmI2-Mediated Reductive Coupling of Aldehydes with Chiral Crotonates
entry
I
RCHO
yielda (%)
cis/transb
eec (%, cis; trans)
cis [R]23D;e config.
+80.8; (3R,4R)
1
2
(-)-(aR)-5
(+)-(aS)-5
(+)-(aS)-5
(+)-(aS)-5
(-)-(aR)-5
(-)-(aS)-6
(-)-(aS)-6
(+)-(aR,R)-7
(+)-(aR,R)-7
(-)-(aS,S)-8
(aS)-35
n-BuCHO
n-BuCHO
i-PrCHO
t-BuCHO
CyCHO
n-BuCHO
t-BuCHO
n-BuCHO
t-BuCHO
n-BuCHO
t-BuCHO
CyCHO
36a: 90
36a: 90
36b: 81
36c: 85
36d: 87
36a: 55
36c: 67
36a: 48
36c: 45
36a: 40
36c: 58
36d: 66
90:10
90:10
91:9
72:28
88:12
95:5
100:0
84:16
84:16
83:17
71:29
89:11
>99; 96
>99; 95
>99; 75
96; 61
80d
32; 46
5
63; 76
36; >95
14; 83
94; 89
88d
3
4
5
+46.5
(3R,4R)
6
7
8
(3S,4S)
(3R,4R)
+50.9
9
10
11
12
(aR)-35
a Isolated yield of both isomers. b The isomer ratio was determined by the 1H NMR of the crude product mixture. c The ee values were determined by GC
analysis of the purified product mixture over a chiral stationary phase. The conditions are as follows: column, Cyclosil B (30 m × 0.25 mm i.d. and 0.25
µm film); oven temperature, starting at 120 °C for 2 min and increasing to 220 °C at 0.2-2.5 °C/min; carrier, He at 19 cm/sec; sample injection, 1.5 µL of
a sample solution in CH2Cl2 (10 mg/mL). d The enantiomers of 36d could not be separated by GC. The ee value was estimated by optical rotation data.
e Measured in MeOH (c ) 0.20-0.65). Reported values in ref 11a for (3R,4R)-36a, +73.8 (94% ee); for (3S,4S)-36a, -74.3 (96% ee); for (+)-36d, +55.7
(96% ee); and for (-)-36d, -56.8 (97% ee).
to furnish the γ-butyrolactones 36b and 36d in 81 and 87%
yields and in 91:9 and 88:12 ratios for the cis and trans isomers
(Table 1, entries 3 and 5). The enantioselectivity is >99% and
80% for cis-36b and cis-36d, respectively. The results clearly
indicate that the bridging group “G” [-O-, -CH2O-, -CH-
(Me)O-, or -CH(Ph)O-] in the substrates I significantly
influences the efficiency of remote axial-to-central chirality
transfer.
γ-butyrolactones16,17 by engineering the Fukuzawa et al. N-
methylephedrinyl acrylate and crotonate11 onto a solid support.
The ephedrine unit serves as a “chiral linker”,18 which is a tether
to bridge the resin and the substrate and acts as a chiral auxiliary
for inducing chirality during the solid-phase asymmetric trans-
formation. For the reactions of aliphatic aldehydes with the
(16) (a) Kerrigan, N. J.; Hutchison, P. C.; Heightman, T. D.; Procter, D.
J. Chem. Commun. 2003, 1402-1403. (b) Kerrigan, N. J.; Hutchison, P.
C.; Heightman, T. D.; Procter, D. J. Org. Biomol. Chem. 2004, 2, 2476-
2482.
Solid-Phase Synthesis. In 2003, Procter and co-workers
reported an elegant “asymmetric catch-release” approach to
J. Org. Chem, Vol. 71, No. 6, 2006 2449

Zhang et al.
SCHEME 5. Synthesis of Resin-Bound Chiral Crotonates of 2-Hydroxy-8-methoxy-1-naphthamide
ephedrine-modified resin-bound crotonate in the presence of
SmI2 at -15 °C, the cis-γ-butyrolactones 36a-d were obtained
in 50-66% yields and in 91-93% ee.16 We envisioned that
the axially chiral crotonate (+)-(aS)-5 and its antipodal may be
attached to a resin through the C8 oxygen to produce a new
type of resin-bound chiral auxiliary, where the 2,8-dioxygenated
N,N-diisopropyl-1-naphthamide unit functions as an “atropiso-
meric chiral linker”. As a proof-of-concept study, we designed
the chiral crotonate (aR)-35 and (aS)-35 bound to the Rink amide
resin (Scheme 5). To cope with the acid- and base-sensitive
nature of the crotonate, we developed a strategy for attachment
of the linker via an aryl ether bond with the resin-bound phenols
34. We obtained the tailor-made benzyl chloride 30 in good
overall yield through a five-step sequence. Coupling the 1-alkyne
26 with 4-bromobenzaldehyde (27) in the presence of Pd(0)
and Cu(I), followed by hydrogenation of the alkyne, gave the
hydroxy aldehyde 29. The hydroxy group in 29 was protected
as the silyl ether, and the aldehyde was reduced by NaBH4 to
form the benzyl alcohol. The latter was treated with MeSO2Cl
and 2,6-lutidine in the presence of LiCl to afford directly the
benzyl chloride 30. The reaction of rac-10 at the C8 -OH with
30 in the presence of KI and K2CO3 furnished racemic 31, which
was then resolved by semipreparative HPLC over a chiral
stationary phase (Chiralpak AD) to give (+)-(aR)-31 and (-)-
(aS)-31. The silyl group in (-)-(aS)-31 was removed under mild
acidic conditions to afford the alcohol (-)-(aS)-32 in 99% yield.
We initially prepared the resin-bound phenol 34a from Rink
amide resin and 4-hydroxybenzoic acid (33a) in DMF, at 120
°C for 5 min under controlled microwave heating.19 However,
coupling of 34a with the alcohol (+)-(aR)-32 failed at room
temperature for 48 h by using PPh3 and DEAD. We considered
(17) For a pseudoephedrine linker, see: (a) Hutchison, P. C.; Heightman,
T. D.; Procter, D. J. Org. Lett. 2002, 4, 4583-4585. (b) Hutchison, P. C.;
Heightman, T. D.; Procter, D. J. J. Org. Chem. 2004, 69, 790-801.
(18) For a recent review on polymer-supported chiral auxiliaries in
asymmetric synthesis, see: (a) Chung, C. W. Y.; Toy, P. H. Tetrahedron:
Asymmetry 2004, 15, 387-399. Also see some recent examples of using
chiral linkers: (b) Gais, H.-J.; Babu, G. S.; Gu¨nter, M.; Das, P. Eur. J.
Org. Chem. 2004, 1464-1473. (c) Gaertner, P.; Schuster, C.; Knollmueller,
M. Lett. Org. Chem. 2004, 1, 249-253. (d) Schuster, C.; Knollmueller,
M.; Gaertner, P. Tetrahedron: Asymmetry 2005, 16, 3211-3223.
2450 J. Org. Chem., Vol. 71, No. 6, 2006

EnantioselectiVe ReductiVe Coupling of Aldehydes
CHART 2. Proposed Orientation of Substrates for the
Observed Axial-to-Central Chirality Transfer
smaller degree of preference as a result of the unfavorable ring
strain. Therefore, the addition reaction of the ketyl radical with
the crotonates might occur through the species without com-
plexation of the atropisomeric naphthamide carbonyl oxygen,
resulting in a remarkably diminished efficiency in remote
chirality transfer. These results are consistent with the impor-
tance of chelation observed by Fukuzawa and co-workers,11a
because only the racemic product was obtained from the reaction
of 4 in the presence of HMPA.
Conclusion
We have examined the structural elements in four chiral
crotonates for efficient remote axial-to-central chirality transfer
in the SmI2-mediated enantioselective reductive coupling of
aldehydes to form chiral γ-butyrolactones. For accessing to both
enantiomers of the chiral crotonates, we used a chemical
resolution method in the synthesis, and the stereochemistry of
the compounds was carefully established with the help of X-ray
crystal structural analysis. We found that the linkage between
crotonate and the C2 position of atropisomeric 8-methoxy-1-
naphthamides plays a determinant role in the enantioselective
reactions. The best substrate for high axial-to-central chirality
transfer is the crotonate of atropisomeric 2-hydroxy-8-methoxy-
1-naphthamide, affording >96% ee for the cis-γ-butyrolactones
36a-c, formed from pentanal, isobutyraldehyde, and 2,2,2-
trimethylacetaldehyde, except for 80% ee for the cis-γ-butyro-
lactone 36d, obtained from the reaction of cyclohexanecarbox-
aldehyde. A similar level of efficiency in remote axial-to-central
chirality transfer has been demonstrated on solid-phase reactions
with the resin-bound version of the atropisomeric crotonate. A
mechanism was proposed for the remote chiral transfer, featuring
a cage-like complex with coordinations to Sm(III) through both
amide and ester carbonyl oxygen atoms of the crotonate, along
with the ketyl radical generated from the reduction of aldehydes.
Our results demonstrate that a remote axial-to-central chirality
transfer can be achieved at the remote centers separated at least
by five bond lengths.
that the phenol 34a might be deactivated by the conjugated
amide moiety at C4. We synthesized the resin-bound phenol
34b from 4-hydroxyphenylacetic acid (33b) in DMF-CH2Cl2
at 30 °C for 1 h. The latter was successfully coupled with (-)-
(aS)-32 to give the resin-bound chiral crotonate (aS)-35. The
enantiomer (aR)-35 was prepared similarly from (+)-(aR)-32
and 34b. We were delighted to find that the SmI2-mediated
reductive coupling of 2,2,2-trimethylacetaldehyde with (aS)-35
gave the γ-butyrolactone 36c in 58% yield with a 71:29 ratio
of cis and trans isomers (Table 1, entry 11). The enantioselec-
tivity is 94 and 89% ee, respectively, for cis-36c and trans-
36c. Under similar reaction conditions, the resin-bound chiral
crotonate (aR)-35 reacted with cyclohexanecarboxaldehyde to
give 36d in 66% yield and with an 89:11 ratio of cis and trans
isomers (Table 1, entry 12). The enantioselectivity for cis-36d
is 88% ee, which is slightly higher than the 80% ee obtained in
the solution reaction of (-)-(aR)-5 (Table 1, entry 5).
Proposed Mechanism of Chirality Transfer. We propose
a chelation-control model III as illustrated in Chart 2 for the
reaction of (+)-(aS)-5 with aldehydes, leading to the formation
of (3S,4S)-36 as the major products. Chelation of both carbonyl
oxygen atoms of the atropisomeric naphthamide unit and the
crotonate moiety within the substrate forms an eight-membered
ring complex, which seems to play a key role for the remote
axial-to-central chirality transfer as depicted in IIIa. The ketyl
radical generated from the reduction of aldehydes can coordinate
with the Sm(III) cation only from the same side of the amide
unit as a result of the unique cage-like complex. Both s-cis20
and s-trans16b conformations of the crotonate moiety were
proposed in the reaction mechanisms; we use the s-cis confor-
mation in III with the ketyl radical approaching the â carbon
of the crotonate from the si-face. After careful examination of
molecular models, only a nearly eclipsed arrangement is possible
for the reactants, as shown in IIIb. This model predicts the
formation of (3S,4S)-36 from (+)-(aS)-5, being consistent with
the experimental results. The other possible model built on the
s-trans conformation of the crotonate is found in Chart S1 of
the Supporting Information. It is energetically less favored and
leads to the formation of the antipodal product. In the cases of
the chiral crotonates 6-8, the nine-membered ring of the Sm-
(III) complexes similar to IIIa would be formed but to a much
Experimental Section
General Procedure A. Preparation of Esters of (-)-(1S)-
Camphanic Acid. (+)-(aS,1′S,4′R)-N,N-Diisopropyl-2-[2′-(E)-
butenoyloxy]-8-{4′,7′,7′-trimethyl-3′-oxo-2′-oxabicyclo[2.2.1]-
heptanecarbonyloxy}-1-naphthamide, (+)-(aS,S)-11, and (-)-
(aR,1′S,4′R)-N,N-Diisopropyl-2-[2′-(E)-butenoyloxy]-8-{4′,7′,7′-
trimethyl-3′-oxo-2′-oxabicyclo[2.2.1]heptanecarbonyloxy}-1-
naphthamide, (-)-(aR,S)-12. To a solution of N,N-diisopropyl-
2-[2′-(E)-butenoyl]-8-hydroxy-1-naphthamide rac-10 (178.0 mg,
0.50 mmol) and DMAP (183.0 mg, 1.50 mmol) in dry CH2Cl2 (2
mL) under a nitrogen atmosphere was added a solution of (1S)-
(-)-camphanic chloride (217.0 mg, 1.00 mmol) in dry CH2Cl2 (3
mL), followed by stirring at room temperature for 12 h. The reaction
mixture was filtered though a plug of Celite and silica gel by rinsing
with EtOAc. The filtrate was concentrated under reduced pressure
to give a solid diastereomeric mixture that was separated by flash
column chromatography (silica gel, 3% EtOAc-CH2Cl2) to give
(+)-(aS,S)-11 (131.0 mg, 49%, dr > 99.5:0.5 by HPLC) and (-)-
(aR,S)-12 (130.0 mg, 48%, dr > 99.5:0.5 by HPLC). HPLC
conditions are as follows: Chiralpak AD column eluted with 95:5
ratio of hexane-2-propanol at 1.0 mL/min and by UV detection at
254 nm.
(19) (a) Olivos, H. J.; Alluri, P. G.; Reddy, M. M.; Salony, D.; Kodadek,
T. Org. Lett. 2002, 4, 4057-4059. For microwave-assisted solid-phase
organic synthesis (MASPOS), see: (b) Dai, W.-M.; Guo, D.-S.; Sun, L.-
P.; Huang, X.-H. Org. Lett. 2003, 5, 2919-2922.
(20) Kawatsura, M.; Dekura, F.; Shirahama, H.; Matsuda, F. Synlett 1996,
373-376.
(+)-(aS,S)-11: a white solid; mp 88-89 °C (CH2Cl2-hexane);
[R]20 +85.6 (c 1.22, CHCl3); Rf ) 0.30 (9% EtOAc-CH2Cl2);
D
IR (CHCl3) 2973, 1790, 1739, 1635, 1312, 1211, 1151, 1094, 1033
J. Org. Chem, Vol. 71, No. 6, 2006 2451

Zhang et al.
1
cm-1; H NMR (300 MHz, CDCl3) δ 7.87 (d, J ) 8.4 Hz, 1H),
(silica gel, 15% EtOAc-hexane) to afford syn-18 (493.0 mg, 51%)
and anti-18 (387.0 mg, 40%).
7.79 (d, J ) 8.1 Hz, 1H), 7.46 (t, J ) 7.8 Hz, 1H), 7.39 (d, J ) 9.0
Hz, 1H), 7.28-7.18 (m, 1H), 7.07 (d, J ) 7.8 Hz, 1H), 6.02 (d, J
) 15.6 Hz, 1H), 4.31-4.15 (m, 1H), 3.47-3.33 (m, 1H), 2.60-
2.40 (m, 1H), 2.39-2.25 (m, 1H), 1.95 (d, J ) 6.9 Hz, 3H), 1.84-
1.72 (m, 2H), 1.54 (d, J ) 6.9 Hz, 3H), 1.49 (d, J ) 6.6 Hz, 3H),
1.28-1.12 (m, 9H), 1.09 (d, J ) 6.6 Hz, 3H), 0.98 (d, J ) 6.9 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 178.5, 168.7, 166.4, 164.8,
148.8, 147.5, 146.3, 133.6, 129.9, 127.9, 126.2, 124.9, 124.2, 123.4,
122.1, 121.1, 91.0, 55.6, 54.7, 51.4, 46.9, 33.6, 29.8, 23.4, 22.8,
21.5 (× 2), 19.1, 18.0 (× 2), 10.4; MS (+ESI) m/z 536 (M + H+,
100). Anal. Calcd for C31H37NO7: C, 69.51; H, 6.96; N, 2.62.
Found: C, 68.94; H, 6.91; N, 2.51.
syn-18: a white solid; mp 73-74 °C (CH2Cl2-hexane); Rf )
0.50 (33% EtOAc-hexane); IR (CHCl3) 3391, 2963, 2932, 1614,
1256, 1102 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.80 (d, J ) 8.4
Hz, 1H), 7.63 (d, J ) 8.4 Hz, 1H), 7.44 (d, J ) 8.1 Hz, 1H), 7.31
(t, J ) 7.8 Hz, 1H), 6.98 (d, J ) 7.5 Hz, 1H), 5.11 (q, J ) 6.9 Hz,
1H), 3.75 (septet, J ) 6.6 Hz, 1H), 3.10 (septet, J ) 6.6 Hz, 1H),
3.10-2.75 (br s, 1H), 1.69 (d, J ) 6.9 Hz, 3H), 1.63 (d, J ) 6.3
Hz, 3H), 1.61 (d, J ) 6.9 Hz, 3H), 1.02 (d, J ) 6.6 Hz, 3H), 0.97
(s, 9H), 0.81 (d, J ) 6.6 Hz, 3H), 0.45 (s, 3H), 0.09 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 171.6, 152.8, 140.6, 134.9, 131.5, 129.5,
126.5, 124.6, 124.1, 122.4, 116.8, 65.6, 51.3, 47.0, 27.9 (× 3), 23.1,
21.2, 21.1 (× 2), 21.0, 20.2, -1.55, -3.05; MS (+CI) m/z 430 (M
+ H+, 3), 412 (M+ - OH, 25), 372 (M+ - t-Bu, 100).
anti-18: a white solid; mp 189-190 °C (CH2Cl2-hexane); Rf
) 0.40 (33% EtOAc-hexane); IR (CHCl3) 3414, 2962, 2931, 1616,
1600, 1104 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.81 (d, J ) 8.4
Hz, 1H), 7.70 (d, J ) 8.7 Hz, 1H), 7.43 (d, J ) 8.4 Hz, 1H), 7.30
(t, J ) 7.8 Hz, 1H), 6.97 (d, J ) 7.5 Hz, 1H), 5.21 (q, J ) 6.3 Hz,
1H), 3.77 (septet, J ) 6.6 Hz, 1H), 3.14 (septet, J ) 6.6 Hz, 1H),
1.95 (br s, 1H), 1.68 (d, J ) 6.9 Hz, 3H), 1.62 (d, J ) 6.0 Hz, 3H),
1.60 (d, J ) 6.9 Hz, 3H), 1.00 (d, J ) 7.5 Hz, 3H), 0.99 (s, 9H),
0.90 (d, J ) 6.3 Hz, 3H), 0.46 (s, 3H), 0.14 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 170.0, 153.0, 140.5, 135.1, 130.3, 129.5, 126.3,
124.3, 124.0, 122.3, 116.7, 68.1, 51.1, 46.6, 28.0 (× 3), 26.9, 23.3,
21.4, 21.2, 21.1, 20.4, -1.52, -3.00; MS (+CI) m/z 430 (M +
H+, 3), 412 (M+ - OH, 12), 372 (M+ - t-Bu, 100). Anal. Calcd
for C25H39NO3Si: C, 69.88; H, 9.15; N, 3.26. Found: C, 69.85;
H, 9.12; N, 3.16. The relative stereochemistry of anti-18 was
confirmed by X-ray crystal structural analysis, as depicted in Figure
S1 (see Supporting Information).
(-)-(aR,S)-12: a white solid; mp 95-96 °C (CH2Cl2-hexane);
[R]20 -90.0 (c 0.74, CHCl3); Rf ) 0.40 (9% EtOAc-CH2Cl2);
D
IR (CHCl3) 2972, 1790, 1760, 1739, 1635, 1312, 1211, 1150, 1096,
1036 cm-1; H NMR (300 MHz, CDCl3) δ 7.87 (d, J ) 8.7 Hz,
1
1H), 7.80 (d, J ) 7.8 Hz, 1H), 7.48 (t, J ) 7.8 Hz, 1H), 7.39 (d,
J ) 8.4 Hz, 1H), 7.28-7.18 (m, 1H), 7.08 (d, J ) 7.5 Hz, 1H),
6.01 (dd, J ) 15.6, 2.1 Hz, 1H), 4.12-3.96 (m, 1H), 3.41-3.26
(m, 1H), 2.67-2.45 (m, 2H), 1.95 (dd, J ) 7.2, 1.5 Hz, 3H), 1.79-
1.66 (m, 2H), 1.59 (d, J ) 6.6 Hz, 3H), 1.50 (d, J ) 6.6 Hz, 3H),
1.19-1.07 (m, 12H), 0.96 (d, J ) 6.9 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 178.8, 168.3, 166.8, 164.8, 148.7, 146.8, 146.3, 133.5,
130.0, 127.9, 126.2, 124.9, 124.0, 123.4, 122.1, 121.4, 91.3, 56.7,
55.7, 51.5, 47.0, 31.5, 29.9, 23.6, 22.5, 21.3, 21.2, 19.0, 17.6, 17.5,
10.6; MS (+ESI) m/z 536 (M + H+, 100).
General Procedure B. Preparation of Crotonates by Using
n-BuLi as the Base. (-)-(aS)-N,N-Diisopropyl-2-[(2′-(E)-butenoyl-
oxy)methyl]-8-methoxy-1-naphthamide, (-)-(aS)-6. To a flame
dried flask with a stirring bar was added a solution of the alcohol
(-)-(aS)-14 (64.0 mg, 0.2 mmol) in THF (10 mL) under a nitrogen
atmosphere. To the resultant solution, cooled in a dry ice-acetone
bath (-78 °C), was added n-butyllithium (2.5 M in hexane, 80
µL, 0.2 mmol) dropwise, followed by stirring at -78 °C for 30
min. Crotonyl chloride (24 µL, 0.24 mmol) was added to the
mixture, followed by stirring at -78 °C for 30 min and then at 0
°C for 30 min. The reaction mixture was poured into water (10
mL) and extracted with EtOAc (3 × 20 mL). The combined organic
layer was washed with H2O and brine, dried over anhydrous Na2-
SO4, filtered, and concentrated under reduced pressure to give a
solid residue, which was purified by flash column chromatography
(silica gel, 5% EtOAc-hexane) to afford (-)-(aS)-6 (54.0 mg, 71%)
as a white solid; mp 121-122 °C (CH2Cl2-hexane); [R]20D -108.5
(c 0.95, CHCl3); Rf ) 0.38 (33% EtOAc-hexane); IR (CHCl3)
General Procedure D. One-Pot Conversion of 8-Silyl Ether
to 8-Methyl Ether. (-)-(aR,1′R,1”S,4”R)-N,N-Diisopropyl-8-
methoxy-2-{1′-{4”,7”,7”-trimethyl-3”-oxo-2”-oxabicyclo[2.2.1]-
heptanecarbonyloxy}ethyl}-1-naphthamide, (-)-(aR,R,S)-21. To
a solution of (+)-(aR,R,S)-19 (48.0 mg, 0.08 mmol) in THF (2 mL),
cooled in an ice-water bath (0 °C), was added n-Bu4NF (80 µL,
0.02 mmol) and MeI (50 µL, 0.80 mmol), followed by stirring at
0 °C for 2 h. The reaction mixture was filtered through a plug of
Celite and silica gel. The filtrate was concentrated under reduced
pressure to give a solid crude product, which was purified by flash
column chromatography (silica gel, 5% EtOAc-CH2Cl2) to afford
(-)-(aR,R,S)-21 (32.6 mg, 80%) as a white solid; mp 210-211 °C
(CH2Cl2-hexane); [R]20 -12.6 (c 1.0, CHCl3); Rf ) 0.38 (17%
D
EtOAc-CH2Cl2); IR (CHCl3) 2974, 1789, 1749, 1728, 1632, 1308,
1262, 1105 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.81 (d, J ) 9.0
Hz, 1H), 7.67 (d, J ) 8.4 Hz, 1H), 7.46-7.38 (m, 2H), 6.90-6.81
(m, 1H), 6.37 (q, J ) 6.6 Hz, 1H), 3.91 (s, 3H), 3.64-3.44 (m,
2H), 2.41 (ddd, J ) 13.8, 10.5, 4.2 Hz, 1H), 2.01 (ddd, J ) 13.5,
9.3, 4.5 Hz, 1H), 1.90-1.67 (m, 2H), 1.73 (d, J ) 6.6 Hz, 3H),
1.70 (d, J ) 6.6 Hz, 3H), 1.69 (d, J ) 6.6 Hz, 3H), 1.08 (d, J )
6.6 Hz, 3H), 1.04 (s, 3H), 1.01 (d, J ) 7.2 Hz, 3H), 0.98 (s, 3H),
0.85 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 179.0, 169.5, 166.8,
156.3, 135.7, 133.2, 133.1, 129.2, 127.5, 125.3, 121.6, 121.4, 106.7,
91.8, 70.8, 55.8, 55.5, 54.9, 51.3, 46.8, 31.1, 29.6, 21.7, 21.6, 21.5,
21.1, 20.4, 17.5, 17.3, 10.5; MS (+ESI) m/z 509 (M+, 14), 312
(M+ - camphanyloxy, 90), 212 (100). Anal. Calcd for C30H39-
NO6: C, 70.70; H, 7.71; N, 2.75. Found: C, 70.50; H, 7.75; N,
2.65.
2972, 1720, 1631, 1438, 1316, 1261, 1174 cm-1; H NMR (300
1
MHz, CDCl3) δ 7.77 (d, J ) 8.7 Hz, 1H), 7.51 (d, J ) 8.7 Hz,
1H), 7.44-7.37 (m, 2H), 7.04 (dq, J ) 15.6, 7.2 Hz, 1H), 6.87
(dd, J ) 6.6, 1.8 Hz, 1H), 5.91 (dq, J ) 15.6, 1.6 Hz, 1H), 5.39
and 5.34 (ABq, J ) 12.9 Hz, 2H), 3.93 (s, 3H), 3.60-3.42 (m,
2H), 1.89 (dd, J ) 7.2, 1.8 Hz, 3H), 1.70 (d, J ) 6.6 Hz, 3H), 1.67
(d, J ) 6.9 Hz, 3H), 1.03 (d, J ) 6.6 Hz, 3H), 1.00 (d, J ) 6.3 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 170.1, 166.8, 156.2, 145.8,
135.3, 130.5, 128.8, 127.3, 127.2, 123.0, 123.0, 121.9, 121.5, 106.9,
63.8, 56.0, 51.6, 46.6, 21.3, 21.2, 21.1, 20.4, 18.8; MS (+ESI) m/z
384 (M + H+, 100). Anal. Calcd for C23H29NO4: C, 72.04; H,
7.62; N, 3.65. Found: C, 71.97; H, 7.76; N, 3.62.
General Procedure C. Addition of Grignard Reagents with
Aldehydes. (aR*,R*)- and (aR*,S*)-N,N-Diisopropyl-8-(tert-
butyldimethylsilyloxy)-2-(1′-hydroxyethyl)-1-naphthamide, syn-
18 and anti-18. To a solution of rac-16 (931.0 mg, 2.25 mmol) in
THF (16 mL), cooled in a dry ice-acetone bath (-78 °C), was
added MeMgCl (2.25 mL, 6.75 mmol), followed by stirring at -78
°C for 4 h. The reaction was quenched with NH4Cl (16 mL) and
then extracted with EtOAc (4 × 30 mL). The combined organic
layer was washed with H2O and brine, dried over anhydrous Na2-
SO4, filtered, and concentrated under reduced pressure to give a
solid residue, which was purified by flash column chromatography
General Procedure E. Hydrolysis of Esters of (1S)-Campanic
Acid. (+)-(aR,R)-N,N-Diisopropyl-8-methoxy-2-(1′-hydroxyethyl)-
1-naphthamide, (+)-(aR,R)-17. To a solution of (-)-(aR,R,S)-21
(94.0 mg, 0.18 mmol) in THF (10 mL), cooled in an ice-water
bath (0 °C), was added a solution of KOH (258.0 mg, 4.60 mmol)
in H2O (1 mL), followed by stirring at room temperature for 7 h.
The reaction was quenched with NH4Cl (10 mL) and then extracted
with EtOAc (4 × 30 mL). The combined organic layer was washed
with H2O and brine, dried over anhydrous Na2SO4, filtered, and
2452 J. Org. Chem., Vol. 71, No. 6, 2006

EnantioselectiVe ReductiVe Coupling of Aldehydes
concentrated under reduced pressure to give a solid residue, which
was purified by flash column chromatography (silica gel, 10%
EtOAc-CH2Cl2) to afford (+)-(aR,R)-17 (55.3 mg, 91%) as a white
solid; [R]20D +116.3 (c 0.72, CHCl3). Other physical and spectro-
scopic data are identical to those of syn-17.
(M+ - OH, 100). Anal. Calcd for C19H25NO3: C, 72.35; H, 7.99;
N, 4.44. Found: C, 72.56; H, 7.98; N, 4.37.
(+)-(aR)-14: a white solid; mp 185-186 °C (CH2Cl2-hexane);
[R]20D +125.6 (c 0.93, CHCl3); Rf ) 0.28 (50% EtOAc-hexane).
Other spectroscopic data are identical to those of (-)-(aS)-14.
The stereochemical assignment of (-)-(aS)-14 was confirmed
by PCC oxidation in dry CH2Cl2 to the known (-)-(aR)-13.5d,6
HPLC retention times for (-)-(aR)-13 and (+)-(aS)-13 are 83.4
and 59.4 min, respectively, over a Chiralpak AD column eluted
with 95:5 ratio of hexane-2-propanol at 1.0 mL/min and by UV
detection at 262 nm.
(-)-(aR)- and (+)-(aS)-N,N-Diisopropyl-2-[2′-(E)-butenoyl-
oxy]-8-methoxy-1-naphthamide, (-)-(aR)-5 and (+)-(aS)-5. To
a solution of (-)-(aR,S)-12 (27.0 mg, 0.05 mmol) in THF-H2O
(20:1, 2 mL), cooled in an ice-water bath (0 °C), was added 10%
aqueous KOH (56 µL), followed by stirring at 0 °C for 4 h. Then
MeI (34 µL, 0.5 mmol) was added to the mixture, followed by
stirring at 0 °C for 23 h. The reaction was quenched with saturated
aqueous NH4Cl (10 mL) and then extracted with EtOAc (3 × 20
mL). The combined organic layer was washed with H2O and brine,
dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure to give a solid residue, which was purified by
flash column chromatography (silica gel, 3% EtOAc-CH2Cl2) to
afford the known (-)-(aR)-5 (12.0 mg, 63%). The enantiomer (+)-
(aS)-5 was similarly prepared from (+)-(aS,S)-11. The physical and
spectroscopic data of (+)-(aS)-5 and (-)-(aR)-5 are identical to
those reported before.10
N,N-Diisopropyl-2-[2′-(E)-butenoyloxy]-8-hydroxy-1-naph-
thamide, rac-10. To a solution of the known rac-910 (469.0 mg,
1.0 mmol) in THF (10 mL), cooled in an ice-water bath (0 °C),
and under a nitrogen atmosphere was added TBAF (1.0 M in THF
containing 5% H2O, 1 mL, 1.0 mmol), followed by stirring at 0 °C
for 10 min. The reaction mixture was filtered through a plug of
Celite and silica gel. The filtrate was concentrated under reduced
pressure to give a solid crude product that was purified by flash
column chromatography (silica gel, 30% EtOAc-hexane) to afford
rac-10 (353.0 mg, 99%) as a colorless gum; Rf ) 0.31 (50%
EtOAc-hexane); IR (CHCl3) 3056, 2978, 1738, 1608, 1436, 1212,
1152 cm-1; 1H NMR (300 MHz, CDCl3) δ 9.00 (br, 1H), 7.50 (d,
J ) 9.0 Hz, 1H), 7.31-7.17 (m, 1H), 7.13 (d, J ) 9.0 Hz, 1H),
6.79 (t, J ) 8.4 Hz, 1H), 6.55 (t, J ) 7.8 Hz, 1H), 6.36 (d, J ) 7.8
Hz, 1H), 6.06 (dd, J ) 15.6, 1.8 Hz, 1H), 3.61-3.43 (m, 2 H),
1.98 (d, J ) 7.2 Hz, 3H), 1.64 (d, J ) 6.9 Hz, 3H), 1.56 (d, J )
6.9 Hz, 3H), 1.02 (d, J ) 6.6 Hz, 6H); 13C NMR (75 MHz, CDCl3)
δ 170.3, 165.2, 152.8, 147.8, 144.3, 133.2, 129.4, 126.4, 124.7,
122.8, 122.3, 121.5, 119.5, 113.7, 52.2, 46.8, 21.5, 21.2, 20.1 (×
2), 19.0; MS (+CI) m/z 356 (M + H+, 100); HRMS (+ESI) calcd
for C21H25NO4Na (M + Na+), 378.1681; found, 378.1675.
(-)-(aS)- and (+)-(aR)-N,N-Diisopropyl-2-hydroxymethyl-8-
methoxy-1-naphthamide, (-)-(aS)-14 and (+)-(aR)-14. To a
solution of rac-13 (313.0 mg, 1.0 mmol) in MeOH (5 mL), cooled
in an ice-water bath (0 °C), was added NaBH4 (76.0 mg, 2.0
mmol), followed by stirring at 0 °C for 1 h. The reaction was
quenched with H2O (10 mL) and extracted with CH2Cl2 (3 × 20
mL). The combined organic layer was washed with H2O and brine,
dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure to give a solid residue, which was purified by
flash column chromatography (silica gel, 30% EtOAc-CH2Cl2) to
afford rac-14 (274.0 mg, 87%) as a white solid. Semipreparative
HPLC separation of rac-14 over a Chiralpak AD column (eluted
with a 90:10 ratio of hexane-2-propanol at 0.5 mL/min and by
UV detection at 254 nm) gave enantiomerically pure (-)-(aS)-14
and (+)-(aR)-14.
N,N-Diisopropyl-8-(tert-butyldimethylsilyloxy)-2-formyl-1-
naphthamide, rac-16. To a flame-dried flask with a stirring bar
was added a solution of the known rac-159a,10 (386.0 mg, 1.0 mmol)
in THF (10 mL) under a nitrogen atmosphere. To the resultant
solution, cooled in a dry ice-acetone bath (-78 °C), was added
n-butyllithium (1.3 M in hexane, 3.85 mL, 5.0 mmol) dropwise,
followed by stirring at -78 °C for 30 min. Anhydrous DMF (0.54
mL, 7.0 mmol) in THF (1 mL) was added to the mixture, and the
resultant mixture was warmed to room temperature followed by
stirring for 1 h. The reaction mixture was poured into water (10
mL) and extracted with EtOAc (3 × 20 mL). The combined organic
layer was washed with H2O and brine, dried over anhydrous Na2-
SO4, filtered, and concentrated under reduced pressure to give a
solid residue, which was purified by flash column chromatography
(silica gel, 5% EtOAc-hexane) to afford rac-16 (327.0 mg, 79%)
as a white solid; mp 128-129 °C (CH2Cl2-hexane); Rf ) 0.28
(9% EtOAc-hexane); IR (CHCl3) 2963, 1692, 1638, 1310, 1266
1
cm-1; H NMR (300 MHz, CDCl3) δ 10.33 (s, 1H), 7.98 (d, J )
8.7 Hz, 1H), 7.83 (d, J ) 8.7 Hz, 1H), 7.49-7.45 (m, 2H), 7.05
(dd, J ) 6.6, 3.3 Hz, 1H), 3.80 (septet, J ) 6.9 Hz, 1H), 3.02
(septet, J ) 6.9 Hz, 1H), 1.71 (d, J ) 6.9 Hz, 3H), 1.60 (d, J )
6.9 Hz, 3H), 1.03 (s, 9H), 1.02 (d, J ) 6.6 Hz, 3H), 0.83 (d, J )
6.6 Hz, 3H), 0.50 (s, 3H), 0.16 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 191.5, 167.4, 153.7, 139.9, 137.7, 130.1, 129.0, 128.9, 123.3,
122.4, 121.9, 116.7, 50.8, 46.6, 27.2 (× 3), 22.6, 20.6, 20.5, 20.4,
19.6, -2.33, -3.68; MS (+CI) m/z 414 (M + H+, 22), 356 (M+
- t-Bu, 100). Anal. Calcd for C24H35NO3Si: C, 69.69; H, 8.53; N,
3.39. Found: C, 70.05; H, 8.54; N, 3.44.
4-(6′-Hydroxyhexyn-1-yl)benzaldhyde, 28. To a suspension of
4-bromobenzaldhyde (27, 1.850 g, 10.0 mmol), Pd(PPh3)4 (578.0
mg, 0.5 mmol), and CuI (191.0 mg, 1.0 mmol) in degassed CH3-
CN (15 mL) and Et3N (3 mL) was added 1-hexyn-6-ol (26, 1.32
mL, 12.0 mmol) under a nitrogen atmosphere. The resultant mixture
was stirred at 75 °C for 2 h. The reaction mixture was filtered
through a short plug of silica gel with rinsing by EtOAc. The filtrate
was concentrated under reduced pressure, and the residue was
purified by flash column chromatography (silica gel, 10% EtOAc-
CH2Cl2) to give the alkynyl aldehyde (1.740 g, 86%) as a colorless
oil; Rf ) 0.50 (17% EtOAc-CH2Cl2); IR (CHCl3) 3388, 2939,
2230, 1699, 1602, 1208, 830 cm-1; 1H NMR (300 MHz, CDCl3) δ
9.97 (d, J ) 1.8 Hz, 1H), 7.79 (dd, J ) 8.1, 1.8 Hz, 2H), 7.52 (d,
J ) 8.1 Hz, 2H), 3.78-3.70 (m, 2H), 2.57-2.47 (m, 2H), 1.84-
1.66 (m, 4H) (OH is not found); 13C NMR (75 MHz, CDCl3) δ
192.1, 135.5, 132.7 (× 2), 131.0, 130.1 (× 2), 95.2, 81.0, 63.1,
32.7, 25.5, 20.0; MS (+CI) m/z 203 (M + H+, 55), 84 (100); HRMS
(+ESI) calcd for C13H15O2 (M + H+), 203.1072; found, 203.1073.
4-(6′-Hydroxyhexyl)benzaldhyde, 29. A suspension of 28
(202.0 mg, 1.0 mmol) and Pd/C (10%, 10.0 mg) in EtOAc (5 mL)
was stirred under a hydrogen atmosphere (1 atm) at room
temperature for 2 h. The reaction mixture was filtered through a
short plug of silica gel with rinsing by EtOAc. The filtrate was
concentrated under reduced pressure, and the residue was purified
by flash column chromatography (silica gel, 10% EtOAc-CH2-
Cl2) to give 29 (144.0 mg, 70%) as a colorless oil; Rf ) 0.50 (25%
acetone-hexane); IR (CHCl3) 3375, 2932, 2857, 1697, 1606, 1214,
(-)-(aS)-14: a white solid; mp 185-186 °C (CH2Cl2-hexane);
[R]20D -125.6 (c 1.02, CHCl3); Rf ) 0.28 (50% EtOAc-hexane);
1
IR (CHCl3) 3382, 2973, 1608, 1260 cm-1; H NMR (300 MHz,
CDCl3) δ 7.77 (d, J ) 8.4 Hz, 1H), 7.54 (d, J ) 8.7 Hz, 1H),
7.43-7.39 (m, 2H), 6.86 (dd, J ) 7.2, 1.85 Hz, 1H), 4.88 and 4.48
(ABq, J ) 12.3 Hz, 2H), 3.92 (s, 3H), 3.80-3.70 (br s, 1H), 3.58
(septet, J ) 6.6 Hz, 1H), 3.41 (septet, J ) 6.6 Hz, 1H), 1.67 (d, J
) 6.9 Hz, 6H), 1.00 (d, J ) 6.3 Hz, 3H), 0.95 (d, J ) 6.6 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ 172.1, 155.9, 136.0, 135.1, 132.0,
129.4, 128.7, 127.0, 121.9, 121.6, 106.6, 64.1, 56.0, 51.8, 47.0,
21.2, 21.1, 21.0, 20.1; MS (+ESI) m/z 316 (M + H+, 75), 298
1
1169 cm-1; H NMR (300 MHz, CDCl3) δ 9.95 (s, 1H), 7.79 (d,
J ) 8.1 Hz, 2H), 7.33 (d, J ) 8.1 Hz, 2H), 3.64 (t, J ) 6.6 Hz,
2H), 2.70 (t, J ) 7.8 Hz, 2H), 1.74-1.52 (m, 5H), 1.48-1.32 (m,
J. Org. Chem, Vol. 71, No. 6, 2006 2453

Zhang et al.
4H); 13C NMR (75 MHz, CDCl3) δ 192.5, 150.8, 135.0, 130.5 (×
2), 129.6 (× 2), 63.6, 36.9, 33.4, 31.8, 29.8, 26.3; MS (+CI) m/z
207 (M + H+, 85), 91 (100); HRMS (+ESI) calcd for C13H18O2-
Na (M + Na+), 229.1204; found, 229.1195.
mmol), anhydrous K2CO3 (276.0 mg, 2.00 mmol), and KI (17.0
mg, 0.10 mmol) in dry CH3CN (2 mL) under a nitrogen atmosphere
was added a solution of 30 (340.0 mg, 1.00 mmol) in dry CH3CN
(1 mL), followed by stirring at room temperature for 48 h. The
reaction mixture was filtered off though a plug of Celite and silica
gel with rinsing by EtOAc. The filtrate was concentrated under
reduced pressure. The residue was purified by flash column
chromatography (silica gel, 8% EtOAc-hexane) to give rac-31
(374.0 mg, 70%) as a colorless gum.
4-{6′-[(tert-Butyldimethylsilyl)oxy]hexyl}benzaldhyde. To a
solution of 29 (1.046 g, 5.1 mmol) and imidazole (863.0 mg, 12.8
mmol) in dry DMF (2 mL) was added tert-butyldimethylsilyl
chloride (917.0 mg, 6.1 mmol), followed by stirring at 40 °C for
27 h. The reaction was quenched by saturated NaHCO3 (10 mL)
and then extracted with CH2Cl2 (3 × 10 mL). The combined organic
layer was dried over anhydrous Na2SO4, filtered, and concentrated
under reduced pressure. The residue was purified by flash column
chromatography (silica gel, 10% EtOAc-hexane) to give the silyl
ether (1.491 g, 92%) as a colorless oil; Rf ) 0.50 (9% EtOAc-
hexane); IR (CHCl3) 2930, 2857, 1703, 1606, 1255, 1100, 835
The enantiomerically pure isomers were obtained by HPLC
separation over a chiral stationary phase (Chiralpak AD). The HPLC
separation was done by using a 10:90 mixture of i-PrOH-hexane
at a flow rate of 0.5 mL/min and with UV detection at 254 nm.
Retention times are 34.0 min for (+)-(aR)-31 and 62.5 min for (-)-
(aS)-31. (+)-(aR)-31: a colorless gum; [R]20 +160.9 (c 0.9,
D
1
cm-1; H NMR (300 MHz, CDCl3) δ 9.96 (s, 1H), 7.79 (d, J )
CHCl3); Rf ) 0.32 (20% EtOAc-hexane); IR (CHCl3) 2930, 2857,
1
8.1 Hz, 2H), 7.33 (d, J ) 8.1 Hz, 2H), 3.60 (t, J ) 6.3 Hz, 2H),
2.70 (t, J ) 7.5 Hz, 2H), 1.72-1.60 (m, 2H), 1.58-1.46 (m, 2H),
1.42-1.32 (m, 4H), 0.90 (s, 9H), 0.06 (s, 6H); 13C NMR (75 MHz,
CDCl3) δ 192.5, 150.9, 135.0, 130.5 (× 2), 129.7 (× 2), 63.9, 36.9,
33.5, 31.8, 29.8, 26.8 (× 3), 26.4, 19.2, -4.4 (× 2); MS (+CI)
m/z 321 (M + H+, 40), 263 (100); HRMS (+ESI) calcd for
C19H32O2SiNa (M + Na+), 343.2069; found, 343.2070.
1739, 1638, 1461, 1315, 1212, 1099 cm-1; H NMR (300 MHz,
CDCl3) δ 7.69 (d, J ) 9.0 Hz, 1H), 7.38-7.11 (m, 6H), 7.06 (d,
J ) 7.2 Hz, 2H), 6.74 (d, J ) 7.5 Hz, 1H), 5.98 (d, J ) 15.3 Hz,
1H), 5.25 (s, 2H), 3.71-3.58 (m, 1H), 3.54 (t, J ) 6.6 Hz, 2H),
3.50-3.37 (m, 1H), 2.51 (t, J ) 7.5 Hz, 2H), 1.90 (d, J ) 6.9 Hz,
3H), 1.60-1.39 (m, 10H), 1.36-1.22 (m, 4H), 1.02 (d, J ) 6.3
Hz, 3H), 0.98 (d, J ) 6.3 Hz, 3H), 0.85 (s, 9 H), 0.00 (s, 6 H); 13
C
NMR (75 MHz, CDCl3) δ 167.4, 165.0, 154.7, 148.0, 145.1, 142.8,
134.7, 133.8, 129.3, 129.1 (× 2), 127.6 (× 2), 126.5, 125.7, 123.3,
122.8, 122.3, 121.5, 109.2, 70.9, 63.9, 51.5, 46.4, 36.3, 33.5, 32.1,
29.8, 26.7 (× 3), 26.4, 21.3, 21.3, 21.1, 20.9, 19.1, 19.0, -4.5 (×
2); MS (+ESl) m/z 660 (M + H+, 100); HRMS (+ESI) calcd for
C40H57NO5SiNa (M + Na+), 682.3904; found, 682.3872 (M +
Na+).
4-{6′-[(tert-Butyldimethylsilyl)oxy]hexyl}benzyl Alcohol. To
a solution of 4-{6′-[(tert-butyldimethylsilyl)oxy]hexyl}benzaldhyde
(758.0 mg, 2.4 mmol) in MeOH (10 mL), cooled in an ice-water
bath (0 °C), was added NaBH4 (179.0 mg, 4.8 mmol), followed by
stirring for 1 h at the same temperature. The reaction was quenched
by saturated NH4Cl (10 mL) and then extracted with EtOAc (3 ×
10 mL). The combined organic layer was dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified by flash column chromatography (silica gel,
5% EtOAc-hexane) to give the benzyl alcohol (180.0 mg, 99%)
as a colorless oil; Rf ) 0.43 (20% EtOAc-hexane); IR (CHCl3)
(-)-(aS)-31: a colorless gum; [R]20 -152.3 (c 1.0, CHCl3).
D
Other physical and spectroscopic data are identical to those of (+)-
(aR)-31.
(+)-(aR)-N,N-Diisopropyl-2-[2′-(E)-butenoyloxy]-8-[4′-(6”-hy-
droxyhexyl)benzyloxy]-1-naphthamide, (+)-(aR)-32. A solution
of (+)-(aR)-31 (66.0 mg, 0.10 mmol) in a mixture of AcOH (1.5
mL), THF (0.5 mL), and H2O (0.5 mL) was stirred at room
temperature for 30 min. The reaction mixture was diluted with
EtOAc, washed with H2O and brine, dried over anhydrous MgSO4,
filtered, and concentrated under reduced pressure. The residue was
purified by flash column chromatography (silica gel, 20% EtOAc-
hexane) to give (+)-(aR)-32 (54.0 mg, 99%) as a colorless gum;
1
3342, 2930, 2857, 1463, 1255, 1102, 836 cm-1; H NMR (300
MHz, CDCl3) δ 7.20 (d, J ) 7.5 Hz, 2H), 7.10 (d, J ) 8.1 Hz,
2H), 4.58 (s, 2H), 3.54 (t, J ) 6.3 Hz, 2H), 2.55 (t, J ) 7.5 Hz,
2H), 1.81 (br s, 1H), 1.62-1.52 (m, 2H), 1.50-1.40 (m, 2H), 1.38-
1.22 (m, 4H), 0.85 (s, 9H), 0.01 (s, 6H); 13C NMR (75 MHz, CDCl3)
δ 142.9, 138.7, 129.2 (× 2), 127.7 (× 2), 65.9, 64.0, 36.3, 33.5,
32.3, 29.8, 26.7 (× 3), 26.4, 19.2, -4.4 (× 2); MS (+CI) m/z 323
(M + H+, 4), 191 (100); HRMS (+ESI) calcd for C19H34O2SiNa
(M + Na+), 345.2226; found, 345.2216.
[R]20 +195.7 (c 0.6, CHCl3); Rf ) 0.30 (33% EtOAc-hexane);
D
IR (CHCl3) 3394, 2931, 2857, 1738, 1623, 1461, 1317, 1212, 1151
4-{6′-[(tert-Butyldimethylsilyl)oxy]hexyl}benzyl Chloride, 30.
To a suspension of 4-{6′-[(tert-butyldimethylsilyl)oxy]hexyl}benzyl
alcohol (323.0 mg, 1.0 mmol), 2,6-lutidine (0.47 mL, 4 mmol),
and LiCl (170.0 mg, 4.0 mmol) in DMF (5 mL), cooled in an ice-
water bath (0 °C), was added dropwise MeSO2Cl (0.23 mL, 3.0
mmol). After stirring for 2 h at 0 °C, the reaction was allowed to
warm to room temperature, followed by stirring for another 4 h.
The reaction mixture was diluted with H2O and extracted with
EtOAc, dried over anhydrous MgSO4, filtered, and concentrated
under reduced pressure. The residue was purified by flash column
chromatography (silica gel, 3% EtOAc-hexane) to give 30 (307.0
mg, 90%) as a colorless oil; Rf ) 0.55 (9% EtOAc-hexane); IR
1
cm-1; H NMR (300 MHz, CDCl3) δ 7.75 (d, J ) 9.3 Hz, 1H),
7.40-7.17 (m, 6H), 7.12 (d, J ) 7.8 Hz, 2H), 6.80 (t, J ) 7.5 Hz,
1H), 6.23 (d, J ) 15.6 Hz, 1H), 5.31 (s, 2H), 3.76-3.64 (m, 1H),
3.60 (t, J ) 6.3 Hz, 2H), 3.56-3.44 (m, 1H), 2.57 (t, J ) 8.1 Hz,
2H), 1.97 (dd, J ) 0.9, 7.2 Hz, 3H), 1.70-1.47 (m, 5H), 1.53 (d,
J ) 6.6 Hz, 3H), 1.51 (d, J ) 6.6 Hz, 3H), 1.40-1.30 (m, 4H),
1.08 (d, J ) 6.6 Hz, 3H), 1.04 (d, J ) 6.9 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 167.5, 165.1, 154.7, 148.1, 145.1, 142.7, 134.8,
133.8, 129.3, 129.2 (× 2), 127.6 (× 2), 126.5, 125.6, 123.3, 122.9,
122.3, 121.6, 109.2, 70.9, 63.6, 51.5, 46.4, 36.3, 33.4, 32.1, 29.8,
26.3, 21.4, 21.3, 21.2, 20.9, 19.0; MS (+Cl) m/z 546 (M + H+,
100); HRMS (+ESI) calcd for C34H43NO5Na (M + Na+), 568.3039;
found, 568.3027.
1
(CHCl3) 2930, 2857, 1255, 1101, 836 cm-1; H NMR (300 MHz,
CDCl3) δ 7.30 (d, J ) 8.1 Hz, 2H), 7.17 (d, J ) 8.1 Hz, 2H), 4.59
(s, 2H), 3.61 (t, J ) 6.3 Hz, 2H), 2.62 (t, J ) 7.5 Hz, 2H), 1.69-
1.59 (m, 2H), 1.57-1.47 (m, 2H), 1.41-1.33 (m, 4H), 0.91 (s,
9H), 0.07 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 143.8, 135.3,
129.4 (× 2), 129.1 (× 2), 63.9, 47.1, 36.4, 33.5, 32.1, 29.8, 26.8
(× 3), 26.4, 19.1, -4.4 (× 2); MS (+CI) m/z 285 (M+ + 2-t-Bu,
46), 283 (M+ - t-Bu, 18), 249 (100); HRMS (+ESI) calcd for
C19H33ClOSi (M + H+), 341.2067; found, 341.2070 (M + H+,
100%), 342.2100 (M + 2, 25%), and 343.2041 (M + 2 + H+,
39%).
(aS)-(-)-N,N-Diisopropyl-2-[2′-(E)-butenoyloxy]-8-[4′-(6”-hy-
droxyhexyl)benzyloxy]-1-naphthamide, (aS)-(-)-32. (aS)-(-)-32
was prepared in the same manner as described above for the (aR)-
(+)-enantiomer as a colorless gum; [R]20D -166.2 (c 1.0, CHCl3).
Other physical and spectroscopic data are identical to those of (+)-
(aR)-32.
Preparation of the Resin-Bound Phenol, 34b. Rink amide resin
(0.7 mmol/g) was treated with a solution of 20% piperidine in DMF
for 1 h at room temperature and then washed with DMF and CH2-
Cl2. The washing procedure was repeated five times, and the resin
was dried overnight in vacuo. 4-Hydroxyphenylacetic acid (33b;
5.0 equiv) was coupled to the above pretreated resin by using DIC
(+)-(aR)-N,N-Diisopropyl-2-[2′-(E)-butenoyloxy]-8-{4′-[6”-
((tert-butyldimethylsilyl)oxy)hexyl]-benzyloxy}-1-naph-
thamide, (+)-(aR)-31. To a solution of rac-10 (288.0 mg, 0.81
2454 J. Org. Chem., Vol. 71, No. 6, 2006

EnantioselectiVe ReductiVe Coupling of Aldehydes
(5.0 equiv) and HOBt (5.5 equiv) in DMF-CH2Cl2 (1:1) at room
temperature for 1 h, followed by washing with DMF and CH2Cl2
(repeated five times). The resin-bound phenol was dried overnight
in vacuo. A resin-free sample of the attached phenol (as 4-hydroxy-
phenyl acetamide) was obtained after cleavage from the resin by
treating with 20% CF3CO2H in CH2Cl2. The loading of the resin-
bound phenol 34b is estimated to be 0.45 mmol/g by the increased
weight. 4-Hydroxyphenyl acetamide: 1H NMR (300 MHz, CD3-
OD) δ 7.00 (d, J ) 8.4 Hz, 2H), 6.62 (d, J ) 8.1 Hz, 2H), 3.30 (s,
2H).
and concentrated under reduced pressure. The residue was purified
by column chromatography (silica gel, 5% EtOAc-hexane) to give
the γ-butyrolactones 36. The ratio of cis and trans isomers was
1
estimated by H NMR spectra, and the enantiomeric excess was
determined by GC over a chiral stationary phase. The GC analysis
was carried out with a Cyclosil B column (30 m × 0.25 mm i.d.,
0.25 µm film) with the oven temperature starting at 120 °C for 2
min and then increasing from 120 to 220 °C at 0.2-2.5 °C/min.
The carrier is He at 19 cm/sec with FID detection at 230 °C. A
volume of 1.5 µL of a CH2Cl2 solution of the sample (10 mg/mL)
was prepared and injected for analysis. The results are listed in
Table 1, entries 1-10.
Preparation of the Resin-Bound Phenol, 34a. As a result of
the low reactivity of 4-hydroxybenzoic acid (33a), its coupling with
Rink amide resin was carried out under microwave heating
conditions. The resin and other reactants were charged into a 10
mL pressurized vial containing a magnetic stirrer, and the vial was
sealed with a cap containing a silicon septum. The loaded vial was
then placed into the cavity of a technical microwave reactor (Emrys
creator from Personal Chemistry AB, Uppsala, Sweden) and heated
at 120 °C for 5 min to give the resin-bound phenol 34a with a
loading of 0.40 mmol/g after the workup described for 34b.
However, 34a did not couple with (+)-(aR)-32 in the presence of
PPh3 and DEAD in CH2Cl2 at room temperature for 48 h.
Preparation of the Resin-Bound Chiral Crotonate, (aR)-35.
To a mixture of the resin-bound phenol 34b (1.0 equiv), Ph3P (3.3
equiv), and diethyl azodicarboxylate (DEAD; 3.3 equiv) in CH2-
Cl2 (1 mL) was added a solution of (+)-(aR)-32 (3.0 equiv) in CH2-
Cl2 (1 mL) under a nitrogen atmosphere. The resultant mixture was
shaken at room temperature for 48 h, and then the resin was
collected by filtration and washed with DMF and CH2Cl2 (repeated
five times). After drying overnight in vacuo, the resin-bound chiral
crotonate (aR)-35 was obtained, and the loading (0.45 mmol/g) was
estimated by the increased weight of the resin. A resin-free sample
of the attached chiral crotonate was obtained after cleavage from
the resin. The mass data show an ion at m/z 679 (M + H+, 100),
being consisted with the expected structure. The excess (+)-(aR)-
32 was recovered from the reaction mixture by flash column
chromatography.
The resin-bound chiral crotonate, (aS)-35, was prepared from
(-)-(aS)-32 in the same manner as described above for (aR)-35.
General procedure F. SmI2-Mediated Reductive Coupling of
Aldehydes with Chiral Crotonates. To a solution of a chiral
crotonate (1.2 equiv), an aldehyde (0.2 mmol, 1.0 equiv), and
t-BuOH (1.2 equiv) in THF (1 mL), cooled at -20 °C under a
nitrogen atmosphere, was added a freshly prepared SmI2 (3 equiv)
solution in THF. The resultant mixture was stirred at -20 to -15
°C for 6 h. The reaction was quenched with saturated aqueous NH4-
Cl and extracted with EtOAc (3 × 5 mL). The combined organic
layer was washed with brine, dried over anhydrous MgSO4, filtered,
General Procedure G. Solid-Phase SmI2-Mediated Reductive
Coupling of Aldehydes with Resin-Bound Chiral Crotonates.
A suspension of the resin-bound crotonate (aR)-(35) (0.2 mmol,
1.0 equiv) in THF (1 mL) under a nitrogen atmosphere was gently
stirred for 30 min prior to the addition of an aldehyde (72 µL, 3.0
equiv) and t-BuOH (57 µL, 3.0 equiv). The resultant suspension
was then allowed to stir for another 1 h at room temperature before
being cooled to -15 °C. A precooled solution of freshly prepared
SmI2 (9 equiv) in THF (1 mL) was then added, and the resultant
mixture was allowed to stir at -15 °C for 3 h. The reaction was
then allowed to warm to room temperature over a period of 6 h.
The resin was separated by filtration and washed repeatedly with
THF. The combined filtrate was then washed with saturated brine.
The aqueous layer was separated and extracted with Et2O (3 × 10
mL). The combined organic layer was dried over anhydrous MgSO4,
filtered, and concentrated under reduced pressure. The residue was
purified by flash column chromatography (silica gel, 5% EtOAc-
hexane) to give 36d (24.0 mg, 66%) as an 89:11 mixture of cis
and trans isomers. A pure sample of cis-(+)-36d was obtained by
repeated flash column chromatographic purification. Optical rotation
of the pure cis-(+)-36d is [R]20 +50.9 (c 0.32 MeOH, 88% ee);
D
lit.11a [R]20 +55.7 (c 1.0 MeOH, 95% ee). The results are listed
D
in Table 1, entries 11 and 12.
Acknowledgment. This work is supported by the Depart-
ment of Chemistry, HKUST, and the Research Grants Council
of the Hong Kong Special Administration Region, China
(through a Competitive Earmarked Research Grant, HKUST
6129/01P).
Supporting Information Available: General methods and
1
compound characterization, Chart S1, copies of H and 13C NMR
charts, GC analysis charts, Figures S1-S3, and crystallographic
data. This material is available free of charge via the Internet at
http://pubs.acs.org.
JO0526486
J. Org. Chem, Vol. 71, No. 6, 2006 2455