Anti and syn glycolate aldol reactions with a readily displaced thiol auxiliary

Article abstract of DOI:10.1021/jo801720v

(Chemical Equation Presented) The TBDPS protected glycolate derivative of thiol auxiliary 1 is readily prepared (3 steps, 80% overall yield) and has been shown to give excellent anti:syn selectivity (>97:3) and high facial selectivity (88:12 to 97:3) in g

Full text of DOI:10.1021/jo801720v

oxazolidinone glycolate precursors5 and the titanium enolate of
oxazolidinethiones.6 More recently, an alternative approach for
the preparation of syn glycolate aldol adducts based on the
reaction of the glycolate esters of the Abiko-Masamune
norephedrine auxiliary 27 has been reported by Andrus.8 There
are fewer known methods for the selective synthesis of anti
aldol adducts from glycolate enolates. Moderately selective anti
aldol reactions of the tin(II) enolates of oxazolidinones and
thiazolidinethiones have been observed by Evans and Koba-
yashi;9 while Crimmins has reported a highly anti-selective aldol
reaction for the titanium enolates of oxazolidinethione glycolate
precursors.10 This latter reaction proceeds via an open transition
state similar to the one described by Heathcock for its propionate
counterpart.11 However, practical difficulties associated with
each of these methods have driven the continued search for
alternative auxiliary-based approaches for the synthesis of anti
glycolate aldol adducts including the development of oxapyrone
boron-enolates,12 titanium enolates of oxazolidin-2-selones,13
and lithium enolates of the butane diacetals of glycolic acid.14
Werecentlyintroducedathiolvariant1oftheAbiko-Masamune
norephedrine-derived chiral auxiliary 2 for use in anti propionate
boron aldol reactions where displacement of the auxiliary under
mild conditions is imperative.15 This auxiliary may be displaced
by a range of nucleophiles (including hydride, hydroxide,
methoxide, thiols, and phosphonate anions) under very mild
conditions. We have demonstrated the synthetic utility of thiol
auxiliary 1 in the synthesis of the fully functionalized backbone
of the marine polyketide octalactin A,16 and believed that it
might be of use in similarly demanding glycolate aldol reactions.
We focused our initial investigations on the boron aldol
reactions of the methyl- and benzyl-protected glycolate thio-
lesters 3 and 4 (Scheme 1). Andrus has reported that aldol
reactions of the corresponding glycolate esters of auxiliary 2
give monoprotected syn diols with a range of aldehydes in high
yields (>75%) but with variable diastereoselectivity (67:33 to
97:3).8b Intriguingly, the optimized conditions for syn diol
Anti and Syn Glycolate Aldol Reactions with a
Readily Displaced Thiol Auxiliary
Sandra Fanjul and Alison N. Hulme*
School of Chemistry, The UniVersity of Edinburgh, West
Mains Road, Edinburgh, EH9 3JJ, United Kingdom
alison.hulme@ed.ac.uk
ReceiVed August 9, 2008
The TBDPS protected glycolate derivative of thiol auxiliary
1 is readily prepared (3 steps, 80% overall yield) and has
been shown to give excellent anti:syn selectivity (>97:3)
and high facial selectivity (88:12 to 97:3) in glycolate aldol
reactions with a range of aldehydes (75-87% isolated yield
major diastereomer). In contrast, its benzyl protected coun-
terpart displays more versatility with respect to the generation
of either anti or syn glycolate aldol adducts, but only modest
facial selectivity. The thiol auxiliary has been shown to be
readily displaced under mild conditions to give alcohol and
ester derivatives of the glycolate aldol adducts.
The glycolate aldol reaction has been used extensively to
generate 1,2-diols in a regio-, diastereo-, and enantiocontrolled
manner in natural product synthesis, where it can provide an
attractive alternative to other synthetic methodologies, e.g. the
syn dihydroxylation of double bonds.1,2 Although a limited
number of catalytic3 and organocatalytic4 approaches to enan-
tioselective glycolate aldol reactions have been published,
stereoselective glycolate aldol reactions are still most commonly
performed by using auxiliary-based methodology.
(5) For recent examples, see: (a) Vincent, G.; Mansfield, D. J.; Vors, J.-P.;
Ciufolini, M. A. Org. Lett. 2006, 8, 2791–2794. (b) Owen, R. M.; Roush, W. R.
Org. Lett. 2005, 7, 3941–3944. (c) Jin, M.; Taylor, R. E. Org. Lett. 2005, 7,
1303–1305. (d) Crimmins, M. T.; Christie, H. S.; Chaudhary, K.; Long, A. J. Am.
Chem. Soc. 2005, 127, 13810–13812. (e) Hulme, A. N.; Rosser, E. M. Org.
Lett. 2002, 4, 265–267.
(6) Crimmins, M. T.; Ellis, J. M. J. Org. Chem. 2008, 73, 1649–1660.
(7) (a) Abiko, A. Acc. Chem. Res. 2004, 37, 387–395. (b) Abiko, A.; Liu,
J.-F.; Masamune, S. J. Am. Chem. Soc. 1997, 119, 2586–2587.
(8) (a) Andrus, M. B.; Meredith, E. L.; Simmons, B. L.; Sekhar, B. B. V. S.;
Hicken, E. J. Org. Lett. 2002, 4, 3549–3552. (b) Andrus, M. B.; Sekhar,
B. B. V. S.; Turner, T. M.; Meredith, E. L. Tetrahedron Lett. 2001, 42, 7197–
7201.
(9) (a) Evans, D. A.; Gage, J. R.; Leighton, J. L.; Kim, A. S. J. Org. Chem.
1992, 57, 1961–1963. (b) Mukaiyama, T.; Uchiro, H.; Shiina, I.; Kobayashi, S.
Chem. Lett. 1990, 6, 1019–1022.
(10) (a) Crimmins, M. T.; McDougall, P. J.; Emmitte, K. A. Org. Lett. 2005,
7, 4033–4036. (b) Crimmins, M. T.; McDougall, P. J. Org. Lett. 2003, 5, 591–
594.
(11) Walker, M. A.; Heathcock, C. H. J. Org. Chem. 1991, 56, 5747–5750.
(12) (a) Andrus, M. B.; Meredith, E. L.; Sekhar, B. B. V. S. Org. Lett. 2001,
3, 259–262. (b) Andrus, M. B.; Sekhar, B. B. V. S.; Meredith, E. L.; Dalley,
N. K. Org. Lett. 2000, 2, 3035–3037.
(13) Li, Z.; Wu, R.; Michalczyk, R.; Dunlap, R. B.; Odom, J. D.; Silks, L. A.
J. Am. Chem. Soc. 2000, 122, 386–387.
(14) Ley, S. V.; Polara, A. J. Org. Chem. 2007, 72, 5943–5959.
(15) Fanjul, S.; Hulme, A. N.; White, J. W. Org. Lett. 2006, 8, 4219–4222.
(16) Aird, J. I.; Hulme, A. N.; White, J. W. Org. Lett. 2007, 9, 631–634.
Of the various auxiliary-based approaches that have been
reported to date, syn glycolate aldol adducts have been obtained
mostly through reaction of the boron enolate of Evans’
(1) For recent examples, see: (a) Crimmins, M. T.; Ellis, J. M. J. Org. Chem.
2008, 73, 1649–1660. (b) Crimmins, M. T.; Zhang, Y.; Diaz, F. A. Org. Lett.
2006, 8, 2369–2372. (c) Khartulyari, A. S.; Kapur, M.; Maier, M. E. Org. Lett.
2006, 8, 5833–5836. (d) Davies, S. G.; Nicholson, R. L.; Smith, A. D. Org.
Biomol. Chem. 2005, 3, 348–359.
(2) Ley, S. V.; Sheppard, T. D.; Myers, R. M.; Chorghade, M. S. Bull. Chem.
Soc. Jpn. 2007, 80, 1451–1472.
(3) (a) Denmark, S. E.; Chung, W.-J. J. Org. Chem. 2008, 73, 4582–4595.
(b) Trost, B. M.; Ito, H.; Silcoff, E. R. J. Am. Chem. Soc., 2001, 123, 3367–
3368. (c) Kobayashi, S.; Horibe, M. J. Am. Chem. Soc. 1994, 116, 9805–9806.
(4) (a) Andrus, M. B.; Liu, J.; Ye, Z.; Cannon, J. F. Org. Lett. 2005, 7, 3861–
3864. (b) Northrup, A. B.; Mangion, I. K.; Hettche, F.; MacMillan, D. W. C.
Angew. Chem., Int. Ed. 2004, 43, 2152–2154.
9788 J. Org. Chem. 2008, 73, 9788–9791
10.1021/jo801720v CCC: $40.75 2008 American Chemical Society
Published on Web 11/07/2008

TABLE 2. Anti Glycolate Aldol Reactions of Bn-Protected
SCHEME 1. Preparation of Me- and Bn-Protected
Glycolate Thiolesters of Thiol Auxiliary 1
Thiolester 4a
entry
base
solvent
yield (%)b
anti:sync
9a:10ac
1
2
3
Et3N
CH2Cl2
CH2Cl2
Et2O
98
49
92
98:2
94:6
>98:2
77:23
71:29
77:23
iPr2NEt
Et3N
TABLE 1. Syn Glycolate Aldol Reactions of Me- and
Bn-Protected Thiolesters 3 and 4a
a Reagents and Conditions: (i) c-Hex2BCl (3.0 equiv), base (2.5
equiv), solvent, -78 °C, 1 h; (ii) PhCHO (3.0 equiv), -78 °C, 2 h; then
0 °C, 1.5 h. b Combined yield. c Determined by NMR and HPLC.
SCHEME 2. Preparation of TBDPS-Protected Glycolate
Thiolester 12
P
L
base
Me c-Hex Et3N
Bn c-Hex Et3N
Me c-Hex iPr2NEt
Bn
c-Hex iPr2NEt
Me Bu
Bn Bu
Me Bu
Bn Bu
yield (%)b syn:antic 5a:6a or 7a:8ac
1
2
3
4
5
6
7
8
90
90
85
84
84
82
78
74
91:9
>98:2
95:5
>98:2
91:9
>98:2
98:2
94:6
66:34
74:26
68:32
65:35
26:74
36:64
31:69
28:72
Et3N
TABLE 3. Anti Glycolate Aldol Reactions of TBDPS-Protected
Et3N
Thiolester 12a
iPr2NEt
iPr2NEt
a Reagents and Conditions: (i) L2BOTf (3.0 equiv), base (2.5 equiv),
CH2Cl2, -78 °C, 1 h; (ii) PhCHO (3.0 equiv), -78 °C, 2 h; then 0 °C,
1.5 h. b Combined yield. c Determined by NMR and HPLC.
entry
R
yield (%)b
anti:sync
13:14c
production determined by Andrus (c-Hex2BOTf/Et3N/CH2Cl2)
concurred with those reported by Abiko,7 and ourselves,15 as
affording anti propionate aldol adducts with high selectivity.
Using benzaldehyde as our model substrate, we rapidly
determined that high levels of syn:anti selectivity (generally
>93:7) could be achieved with both thiolester substrates 3 and
4, independent of the base used (Et3N or iPr2NEt) for enolization
(Table 1). But the observed facial selectivity of these aldol
reactions as reflected in the ratios 5a:6a17 or 7a:8a was modest.18
When c-Hex ligands were used on the boron triflate the facial
selectivity reflected that observed by Andrus (Table 1, entries
1-4).8b But the use of less sterically demanding ligands, e.g.
Bu or 9-BBN, resulted in a switch in facial selectivity, such
that the other syn diastereomer was favored (Table 1, entries
5-8).
When thiolester 4 was subjected to enolization in the presence
of c-Hex2BCl, high anti:syn selectivities were observed, but
again only disappointing facial selectivity (9a:10a,19 Table 2).
A number of alternative enolization conditions were explored,
including the use of MgBr2 ·OEt2/iPr2NEt/CH2Cl2 as reported
by Coltart,20 and TiCl4/sparteine/CH2Cl2 as reported by
Crimmins;10b but while some anti selectivity was observed there
was no improvement in the facial selectivity. On the basis of
preliminary computational studies of the E and Z boron-enolates
of the glycolate thiolesters of 1 using different ligands and
1
2
3
4
5
Ph
a
b
c
d
e
75
85
77
87
89e
97:3
>98:2
>98:2
>98:2
>98:2
92:8
94:6
88:12
97:3
93:7
(OCH2O)Phd
CH(CH3)2
CH2CH(CH3)2
C(CH3))CH2
a Reagents and Conditions: (i) c-Hex2BOTf (3.0 equiv), Et3N (3.0
equiv), CH2Cl2, -78 °C, 1 h; (ii) RCHO (3.0 equiv), -78 °C, 2 h; then
0 °C, 2 h. b Isolated yield of major diastereomer 13. c Determined by
NMR and HPLC. d Piperonal. e Isolated as a 93:7 mixture of anti
diasteromers.
protecting groups, we decided to investigate the reactions of
TBDPS-protected thiolester 12 as a means to enhance the facial
selectivity. We anticipated that this protecting group might offer
the further synthetic advantage that it would be readily removed
to reveal the parent diol. A number of approaches to the
preparation of TBDPS-protected glycolate thiolester 12 were
thus investigated; the most practical approach, which could be
carried out on gram-scale, made use of a DIC/DMAP-mediated
coupling of TBDPS-protected glycolic acid 11 to thiol 1
(Scheme 2).21
The glycolate aldol reaction conditions were once again
optimized by using benzaldehyde as the substrate, and then
applied to a range of aldehydes (Table 3). In sharp contrast to
results obtained with Me- and Bn-protected thiolesters 3 and 4,
for thiolester 12 both c-Hex2BOTf and c-Hex2BCl were found
to give the same major diastereomer. Conversion of this
diastereomer to the corresponding known diol methyl ester 15
(17) The absolute stereochemistry of syn adduct 5a was determined by X-ray
crystallography.
(18) This facial selectivity was consistent across a range of different
aldehydes.
(19) The absolute stereochemistry of anti adduct 9a was determined through
NaBH4 reduction of the thiolester, and conversion to known protected triol 16
(Scheme 3b).
(21) For optimum yields in the subsequent glycolate aldol coupling,
purification of 12 by HPLC was found to be essential.
(22) Partial migration of the TBDPS protecting group was observed under
these conditions.
(20) Yost, J. M.; Zhou, G.; Coltart, D. M. Org. Lett. 2006, 8, 591–594.
J. Org. Chem. Vol. 73, No. 24, 2008 9789

SCHEME 3. Facile Displacement of Thiol Auxiliary 1 from
Anti Aldol Adducts (a) 13a, and (b) 9a
δ (62.9 MHz, CDCl3) 176.2 (C), 135.3 (4CH), 131.6 (2C), 129.4
(2CH), 127.5 (4CH), 61.6 (CH2), 26.5 (3CH3), 19.0 (C).
To a stirred solution of freshly prepared TBDPS-protected
glycolic acid 11 (1.70 g, 5.41 mmol) in CH2Cl2 (5 mL) was added
a solution of thiol 115 (1.01 g, 2.30 mmol) in CH2Cl2 (5 mL), then
DMAP (28 mg, 0.23 mmol) and DIC (0.73 mL, 4.6 mmol). The
reaction mixture was stirred at rt for 14 h. The diisopropylurea
formed was removed by filtration and the filtrate was concentrated.
NaCl (20 mL, sat aq) was added and the mixture was extracted
with CH2Cl2 (3 × 10 mL) and washed with NaCl (10 mL, sat aq),
HCl (10 mL, 1 N aq), NaCl (10 mL, sat aq), NaHCO3 (10 mL, sat
aq), and NaCl (10 mL, sat aq). The organics were dried (MgSO4)
and the volatiles removed under reduced pressure. Purification by
flash chromatography (10% EtOAc in hexane) gave a waxy solid
that was further purified by HPLC to give thiolester 12 (1.65 g,
98%); HPLC Rt 16 min (10% EtOAc in hexane); Rf (10% EtOAc
in hexane) 0.35; [R]D +40.0 (c 4.40, CHCl3); νmax (neat)/cm-1 1694,
through transesterification22 and subsequent TBDPS deprotection
(Scheme 3) showed conclusively that it correlated with the anti
glycolate aldol adduct 13a as shown. Hence, use of the bulky,
nonchelating TBDPS protecting group has caused a reversion
in selectivity to that observed in the propionate thiolester series
where both L2BOTf15 and L2BCl23 give the anti diastereomer
with the same relative stereochemistry as the major adduct 13.
In conclusion, in contrast to literature precedent Me- and Bn-
protected glycolate aldol reactions mediated by thiol auxiliary
1 display excellent anti:syn or syn:anti selectivity (91:9 to 98:
2) and high yields, but only modest facial selectivity 5a:6a, 7a:
8a, or 9a:10a (typically 2:1 to 3:1). However, it was found to
be possible in each case to isolate the major diastereomer by
HPLC. When subjected to a simple protecting group switch to
the TBDPS group, auxiliary 1 induces anti selectivity exclu-
sively. The resultant major anti diastereomer 13 may be isolated
in good to excellent yields (75-87%) across a range of aldehyde
substrates. In confirming the stereochemical assignments of 9a
and 13a, the thiol auxiliary has been shown to be readily
displaced to give alcohol and ester derivatives of the glycolate
aldol adducts.
1
1603, 1495; H NMR δ (250 MHz, CDCl3) 7.61-7.55 (4H, m),
7.43-7.24 (11H, m), 7.15 (1H, t, J ) 7.3 Hz), 7.04 (2H, t, J ) 7.6
Hz), 6.84 (2H, s), 6.75 (2H, d, J ) 7.1 Hz), 4.84 (1H, d, JA-B
)
16.3 Hz), 4.80 (1H, d, J ) 8.7 Hz), 4.50 (1H, d, JA-B ) 16.3 Hz),
4.21 (1H, dq, J ) 8.7 and 6.8 Hz), 4.15 (2H, d, J ) 1.5 Hz), 2.32
(6H, s), 2.30 (3H, s), 1.24 (3H, d, J ) 6.8 Hz) 1.08 (9H, s); 13C
NMR δ (62.9 MHz, CDCl3) 199.0 (C), 142.2 (C), 140.4 (2C), 140.2
(C), 138.5 (C), 135.4 (4C), 134.7 (C), 132.9 (C), 132.0 (3CH), 129.9
(CH), 128.5 (3CH), 128.2 (3CH), 127.8 (C), 127.7 (3CH), 127.6
(3CH), 127.2 (CH), 127.0 (CH), 69.1 (CH2), 56.5 (CH), 50.1 (CH),
47.5 (CH2), 26.5 (3CH3), 23.5 (2CH3), 20.8 (CH3), 19.1 (C), 17.3
(CH3); m/z (ESI+) 1493 ([2M + Na]+, 100), 1198 (23), 758 ([M +
Na]+, 45), 463 (7); HRMS (ESI+) [M + H]+ found 736.2955,
C43H50NO4S2Si requires 736.2945.
TBDPS-Protected Anti Glycolate Aldol Adducts (Table 3). To
a stirred solution of TBDPS-protected thiolester 12 (100 mg, 0.136
mmol) in CH2Cl2 (3 mL) at -78 °C was added dicyclohexylboron
triflate (1.0 M in hexane, 0.41 mL, 0.41 mmol) then triethylamine
(58 µL, 0.41 mmol). The reaction mixture was stirred at -78 °C
for 1 h, then aldehyde (0.41 mmol) was added. The reaction was
stirred at -78 °C for 2 h and then at 0 °C for 2 h. The mixture was
quenched by the addition of pH 7 buffer and methanol (1:1, 4 mL)
and diluted with methanol (4 mL) to make a homogeneous solution.
After careful addition of H2O2 (30% aq, 1 mL) the mixture was
stirred at rt for 15 min. NaCl (10 mL, sat aq) was added and the
mixture was extracted with CH2Cl2 (3 × 10 mL). The combined
organics were washed with NaCl (10 mL, sat aq), dried (MgSO4),
and concentrated under reduced pressure to give the crude aldol
product as a mixture of diastereomers (13:14 as determined by 1H
NMR). Purification by flash chromatography (10% EtOAc in
hexane) then HPLC gave the desired anti aldol adduct 13.
Experimental Section
(1′S,2′R)-2′-(N-Benzyl-N-mesitylenesulfonylamino)-1′-phenylpro-
pyl 2-(tert-Butyldiphenylsilyloxy)thiolacetate, 12. To a stirred solu-
tion of glycolic acid (550 mg, 7.23 mmol) in pyridine (20 mL)
was added TBDPSCl (7.7 mL, 29 mmol). The reaction mixture
was stirred at rt for 3.5 h. NaCl (20 mL, sat aq) was added and the
mixture was extracted with CH2Cl2 (3 × 20 mL) and washed with
HCl (3 × 20 mL, 1 N aq) and NaCl (20 mL, sat aq). The organics
were dried (MgSO4) and the volatiles removed under reduced
pressure. Purification by flash chromatography (10% EtOAc in
hexane) gave the TBDPS-protected silylester as a colorless oil (3.81
g, 95%), which was used immediately in the following reaction;
1H NMR δ (250 MHz, CDCl3) 7.61 (4H, d, J ) 7.7 Hz), 7.53 (4H,
d, J ) 7.7 Hz), 7.34-7.15 (12H, m), 4.28 (2H, s), 0.97 (9H, s),
0.96 (9H, s); 13C NMR δ (62.9 MHz, CDCl3) 169.9 (C), 135.4
(4CH), 135.1 (4CH), 132.7 (2C), 131.5 (2C), 129.9 (2CH), 129.7
(2CH), 127.7 (4CH), 127.6 (4CH), 62.8 (CH2), 26.7 (3CH3), 26.5
(3CH3), 19.0 (2C).
(1′S,2S,2′R,3S)-2′-(N-Benzyl-N-mesitylenesulfonylamino)-1′-phe-
nylpropyl 2-(tert-butyldiphenylsilyloxy)-3-hydroxy-3-phenylthiol-
propionate, 13a: 86 mg, 75%; HPLC Rt (10% EtOAc in hexane)
33 min; Rf (20% EtOAc in hexane) 0.43; [R]D +25.0 (c 1.0, CHCl3);
ν
max (neat)/cm-1 3510, 1684, 1600, 1494, 1321, 1152; 1H NMR δ
(250 MHz, CDCl3) 7.61-6.95 (21H, m), 6.81 (2H, s), 6.76 (2H, d,
J ) 7.0 Hz), 6.62 (2H, d, J ) 7.1 Hz), 4.75 (1H, d, JA-B ) 16.3
Hz), 4.60 (1H, d, J ) 9.6 Hz), 4.59 (1H, d, J ) 4.4 Hz), 4.36 (1H,
d, J ) 4.4 Hz), 4.34 (1H, d, JA-B ) 16.3 Hz), 4.12 (1H, dq, J )
9.6 and 6.8 Hz), 2.30 (3H, s), 2.25 (6H, s), 1.10 (3H, d, J ) 6.8
Hz), 1.08 (9H, s); 13C NMR δ (90.5 MHz, CDCl3) 197.1 (C), 142.1
(C), 140.4 (2C), 139.8 (C), 138.3 (C), 137.7 (C), 135.8 (2CH), 135.7
(2CH), 132.6 (C), 132.2 (C), 132.0 (2CH), 131.7 (C), 130.11 (CH),
130.06 (CH), 128.7 (2CH), 128.2 (2CH), 128.1 (2CH), 127.8 (2CH),
127.7 (2CH), 127.6 (4CH), 127.6 (CH), 127.2 (CH), 126.9 (CH),
126.4 (2CH), 82.5 (CH), 76.1 (CH), 55.9 (CH), 50.7 (CH), 47.2
(CH2), 26.8 (3CH3), 22.7 (2CH3), 20.8 (CH3), 19.2 (C), 17.9 (CH3);
m/z (ESI-) 840 ([M - H]-, 4%), 801 (95), 633 (18), 367 (100);
HRMS (ESI-) [M - H]- found 840.3186, C50H54NO5S2Si requires
840.3207.
To a stirred solution of the silylester (3.63 g, 6.58 mmol) in
THF (2 mL) and MeOH (4 mL) was added a solution of K2CO3
(2.8 g, 20 mmol) in H2O (2 mL) at rt. After stirring at rt for 30
min, the mixture was acidified to pH 3 with HCl (1 N aq) and
the solution was extracted with Et2O (3 × 10 mL). The organics
were washed with NaCl (2 × 10 mL, sat aq) and dried (MgSO4),
and the volatiles were removed under reduced pressure to give
a colorless oil that was purified by flash chromatography (20%
EtOAc in hexane-1% AcOH) to give 11 as a colorless oil (1.78
g, 86%), which was used immediately in the following reaction;
1H NMR δ (250 MHz, CDCl3) 10.90 (1H, br), 7.55 (4H, d, J )
7.3 Hz), 7.32-7.17 (6H, m), 4.14 (2H, s), 0.97 (9H, s); 13C NMR
(23) Fanjul, S. Ph.D. Thesis, The University of Edinburgh, 2008.
9790 J. Org. Chem. Vol. 73, No. 24, 2008

(1′S,2S,2′R,3S)-2′-(N-Benzyl-N-mesitylenesulfonylamino)-1′-phe-
nylpropyl 2-(tert-butyldiphenylsilyloxy)-3-hydroxy-3-piperonylthi-
olpropionate, 13b: 103 mg, 85%; HPLC Rt (20% EtOAc in hexane)
20 min; Rf (20% EtOAc in hexane) 0.34; [R]D +33.8 (c 1.30,
CHCl3); νmax (neat)/cm-1 3519, 1685, 1604, 1319; 1H NMR δ (250
MHz, CDCl3) 7.55-7.45 (4H, m), 7.40-7.20 (11H, m), 7.15 (1H,
t, J ) 8.2 Hz), 7.00 (2H, t, J ) 7.8 Hz), 6.81 (2H, s), 6.62 (2H, d,
J ) 8.4 Hz), 6.45 (1H, d, J ) 8.0 Hz), 6.31 (1H, s), 6.18 (1H, d,
J ) 8.0 Hz), 5.86 (2H, d, J ) 3.5 Hz), 4.75 (1H, d, JA-B ) 16.2
Hz), 4.62 (1H, d, J ) 9.6 Hz), 4.49 (1H, br s), 4.34 (1H, d, JA-B
) 16.2 Hz), 4.29 (1H, d, J ) 4.6 Hz), 4.13 (1H, dq, J ) 9.6 and
6.8 Hz), 2.30 (3H, s), 2.25 (6H, s), 1.13 (3H, d, J ) 6.8 Hz), 1.07
(9H, s); 13C NMR δ (90.5 MHz, CDCl3) 197.3 (C), 147.1 (C), 146.9
(C), 142.2 (C), 140.5 (2C), 139.8 (C), 138.3 (C), 135.8 (2CH), 135.7
(2CH), 132.6 (C), 132.2 (C), 132.0 (2CH), 131.74 (C), 131.68 (C),
130.12 (CH), 130.08 (CH), 128.7 (2CH), 128.2 (2CH), 128.2 (2CH),
127.7 (2CH), 127.64 (2CH), 127.59 (2CH), 127.2 (CH), 127.0 (CH),
120.5 (CH), 107.6 (CH), 107.0 (CH), 100.7 (CH2), 82.5 (CH), 75.9
(CH), 56.0 (CH), 50.7 (CH), 47.2 (CH2), 26.8 (3CH3), 22.7 (2CH3),
20.8 (CH3), 19.1 (C), 17.8 (CH3); m/z (ESI-) 884 ([M - H]-, 92%),
411 (33), 367 (28), 265 (600); HRMS (FAB, 3-NOBA) [M + Na]+
found 908.3107, C51H55NO7S2SiNa requires 908.3087.
s), 6.72 (2H, d, J ) 7.8 Hz), 4.84 (1H, d, JA-B ) 16.3 Hz), 4.71
(1H, d, J ) 9.2 Hz), 4.44 (1H, d, JA-B ) 16.3 Hz), 4.25 (1H, d, J
) 3.2 Hz), 4.21 (1H, dq, J ) 9.2 and 6.8 Hz), 3.52-3.45 (1H, m),
2.30 (9H, s), 1.42-1.39 (1H, m), 1.23 (3H, d, J ) 6.8 Hz), 1.15
(9H, s), 1.09 (1H, ddd, J ) 13.8, 9.8, and 4.9 Hz), 0.75 (1H, ddd,
J ) 13.8, 9.2, and 3.3 Hz), 0.62 (3H, d, J ) 6.5 Hz), 0.50 (3H, d,
J ) 6.5 Hz); 13C NMR δ (90.5 MHz, CDCl3) 198.6 (C), 142.2
(C), 140.5 (2C), 139.9 (C), 138.4 (C), 135.8 (2CH), 135.7 (2CH),
132.8 (C), 132.8 (C), 132.0 (2CH), 131.8 (C), 130.2 (CH), 130.1
(CH), 128.5 (2CH), 128.22 (2CH), 128.15 (2CH), 127.9 (2CH),
127.7 (2CH), 127.6 (2CH), 127.2 (CH), 127.0 (CH), 82.3 (CH),
72.3 (CH), 56.2 (CH), 50.7 (CH), 47.5 (CH2), 40.0 (CH2), 26.9
(3CH3), 23.9 (CH), 23.1 (CH3), 22.8 (2CH3), 21.2 (CH3), 20.8
(CH3), 19.3 (C), 17.8 (CH3); m/z (ESI-) 820 ([M - H]-, 100%),
288 (4); HRMS (ESI-) [M - H]- found 820.3540, C48H58NO5S2Si
requires 820.3520.
(1′S,2S,2′R,3S)-2′-(N-Benzyl-N-mesitylenesulfonylamino)-1′-phe-
nylpropyl 2-(tert-butyldiphenylsilyloxy)-3-hydroxy-4-methylthiol-
pent-4-eneoate, 13e: 98 mg, 89%, 93:7 diastereomeric mixture;
HPLC Rt (15% EtOAc in hexane) 18 min; Rf (20% EtOAc in
hexane) 0.45; [R]D +4.6 (c 1.3, CHCl3) (93:7 diastereomeric
mixture); νmax (neat)/cm-1 3521, 1684, 1603, 1495, 1321, 1152;
1H NMR δ (250 MHz, CDCl3) 7.65-7.55 (4H, m), 7.47-7.20
(11H, m), 7.11 (1H, t, J ) 7.7 Hz), 6.98 (2H, t, J ) 7.4 Hz), 6.82
(2H, s), 6.67 (2H, d, J ) 7.8 Hz), 4.81 (1H, d, JA-B ) 16.3 Hz),
4.68 (1H, d, J ) 9.4 Hz), 4.59 (1H, br s), 4.53 (1H, br s), 4.41
(1H, d, JA-B ) 16.3 Hz), 4.28 (1H, d, J ) 4.0 Hz), 4.20 (1H, dq,
J ) 9.4 and 6.7 Hz), 3.90 (1H, br t), 2.29 (3H, s), 2.27 (6H, s),
2.08 (1H, d, J ) 4.0 Hz), 1.25 (3H, s), 1.19 (3H, d, J ) 6.7 Hz),
1.12 (9H, s); 13C NMR δ (90.5 MHz, CDCl3) 196.9 (C), 142.2
(C), 140.7 (C), 140.5 (2C), 139.8 (C), 138.4 (C), 135.8 (2CH), 135.7
(2CH), 132.8 (C), 132.3 (C), 132.0 (2CH), 131.7 (C), 130.2 (CH),
130.1 (CH), 128.6 (2CH), 128.2 (2CH), 128.1 (2CH), 127.8 (2CH),
127.7 (2CH), 127.6 (2CH), 127.2 (CH), 126.9 (CH), 112.8 (CH2),
80.2 (CH), 77.1 (CH), 56.1 (CH), 50.8 (CH), 47.4 (CH2), 26.8
(3CH3), 22.8 (2CH3), 20.8 (CH3), 19.2 (C), 18.5 (CH3), 17.9 (CH3);
m/z (ESI-) 804 ([M - H]-, 100%), 415 (6); HRMS (ESI-) [M -
H]-, found 804.3224, C47H54NO5S2Si requires 804.3207.
(1′S,2S,2′R,3S)-2′-(N-Benzyl-N-mesitylenesulfonylamino)-1′-phe-
nylpropyl 2-(tert-butyldiphenylsilyloxy)-3-hydroxy-4-methylthiol-
pentanoate, 13c: 85 mg, 77%; HPLC Rt (10% EtOAc in hexane)
21 min; Rf (20% EtOAc in hexane) 0.52; [R]D -6.0 (c 1.5, CHCl3);
ν
max (neat)/cm-1 3567, 1685, 1603, 1495, 1322, 1153; 1H NMR δ
(250 MHz, CDCl3) 7.64-7.60 (4H, m), 7.47-7.20 (11H, m), 7.13
(1H, t, J ) 7.3 Hz), 7.01 (2H, t, J ) 7.8 Hz), 6.83 (2H, s), 6.71
(2H, d, J ) 7.1 Hz), 4.83 (1H, d, JA-B ) 16.3 Hz), 4.74 (1H, d, J
) 9.2 Hz), 4.45 (1H, d, JA-B ) 16.3 Hz), 4.32 (1H, d, J ) 3.5
Hz), 4.23 (1H, dq, J ) 9.2 and 6.8 Hz), 3.04 (1H, dt, J ) 7.8 and
3.8 Hz), 2.31 (9H, s), 1.60-1.35 (1H, m), 1.24 (3H, d, J ) 6.8
Hz), 1.14 (9H, s), 0.63 (3H, d, J ) 6.6 Hz), 0.50 (3H, d, J ) 6.6
Hz); 13C NMR δ (90.5 MHz, CDCl3) 198.3 (C), 142.2 (C), 140.5
(2C), 139.8 (C), 138.4 (C), 135.8 (2CH), 135.7 (2CH), 132.8 (C),
132.4 (C), 132.0 (2CH), 131.8 (C), 130.2 (CH), 130.1 (CH), 128.5
(2CH), 128.2 (4CH), 127.8 (2CH), 127.7 (2CH), 127.6 (2CH), 127.2
(CH), 126.9 (CH), 79.9 (CH), 79.7 (CH), 56.5 (CH), 50.7 (CH),
47.5 (CH2), 28.7 (CH), 26.9 (3CH3), 22.8 (2CH3), 20.8 (CH3), 19.2
(C), 18.8 (CH3), 18.3 (CH3), 17.6 (CH3); m/z (ESI-) 806 ([M -
H]-, 100%), 367 (7); HRMS (ESI-) [M - H]- found 806.3364,
C47H56NO5S2Si requires 806.3364.
Acknowledgment. We thank the EPSRC (DTA studentship
to S.F.) for financial support of this work.
Supporting Information Available: Preparation of 3 and
4, diagnostic data for glycolate aldol adducts 5a-10a and for
minor glycolate aldol adducts 14a-e, stereochemical assignment
(1′S,2S,2′R,3S)-2′-(N-Benzyl-N-mesitylenesulfonylamino)-1′-phe-
nylpropyl 2-(tert-butyldiphenylsilyloxy)-3-hydroxy-5-methylthiol-
hexanoate, 13d: 97 mg, 87%; HPLC Rt (10% EtOAc in hexane)
23 min; Rf (20% EtOAc in hexane) 0.51; [R]D -2.86 (c 1.75,
CHCl3); νmax (neat)/cm-1 3549, 1686, 1603, 1495, 1323, 1153; 1H
NMR δ (250 MHz, CDCl3) 7.67-7.59 (4H, m), 7.45-7.20 (11H,
m), 7.13 (1H, t, J ) 7.6 Hz), 7.01 (2H, t, J ) 7.3 Hz), 6.83 (2H,
1
data and CIF file for 5a, and H and 13C spectra for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO801720V
J. Org. Chem. Vol. 73, No. 24, 2008 9791