Asymmetric synthesis of anti-aldol segments via a nonaldol route: Synthetic applications to statines and (-)-tetrahydrolipstatin

Article abstract of DOI:10.1021/jo900642f

(Chemical Equation Presented) An asymmetric synthesis of anti-aldol segments via a nonaldol route is described. The strategy involves a highly diastereoselective synthesis of functionalized tetrahydrofuran derivatives from optically active 4-phenylbutyrolactone. Treatment of the tetrahydrofuran derivatives with a Lewis acid and acetic anhydride provided the corresponding ring-opened styrene derivatives. Oxidative cleavage of the styrene derivatives provided access to the anti-aldol segments. The utility of this methodology was demonstrated by the synthesis of statine derivatives and pancreatic lipase inhibitor, (-)-tetrahydrolipstatin.

Full text of DOI:10.1021/jo900642f

Asymmetric Synthesis of anti-Aldol Segments via a Nonaldol Route:
Synthetic Applications to Statines and (-)-Tetrahydrolipstatin
Arun K. Ghosh,* Khriesto Shurrush, and Sarang Kulkarni
Departments of Chemistry and Medicinal Chemistry, Purdue UniVersity, West Lafayette, Indiana 47907
akghosh@purdue.edu
ReceiVed March 26, 2009
An asymmetric synthesis of anti-aldol segments via a nonaldol route is described. The strategy involves
a highly diastereoselective synthesis of functionalized tetrahydrofuran derivatives from optically active
4-phenylbutyrolactone. Treatment of the tetrahydrofuran derivatives with a Lewis acid and acetic anhydride
provided the corresponding ring-opened styrene derivatives. Oxidative cleavage of the styrene derivatives
provided access to the anti-aldol segments. The utility of this methodology was demonstrated by the
synthesis of statine derivatives and pancreatic lipase inhibitor, (-)-tetrahydrolipstatin.
Introduction
tion as the key step.5 Opening of the tetrahydrofuran ring via
an acyloxonium ion intermediate afforded functionalized ꢀ-hy-
droxy ester 3a, which was converted to cryptophycin 52 (4).
The overall process is practical and may provide convenient
access to a variety of γ-substituted ester derivatives. Of
particular interest, this functionalized hexenoate derivative can
The anti-R-alkyl-ꢀ-hydroxycarbonyl motifs are prevalent in
a wide variety of natural and unnatural bioactive organic
molecules.1 An asymmetric aldol addition of a suitable carbonyl
derivative to an aldehyde stands out as the most straightforward
approach to their synthesis. Consequently, a number of asym-
metric methodologies have been developed over the years.
Particularly, a number of chiral auxiliary-controlled highly
diastereoselective anti-aldol additions have been reported.2
However, issues related to limited reaction scope, functional
group compatibility, ready availability of reagents and auxil-
iaries, and operation complexity continue to attract much interest
for alternative approaches. One notable nonaldol process has
been developed by Jung and co-workers.3 Recently, in the
context of the synthesis of cryptophycin 52, optically active
phenylbutyrolactone 1 was efficiently converted to functional-
ized tetrahydrofuran derivative 2a (Figure 1).4 Both new
stereogenic centers in 2a were created based upon the chirality
of 4-phenylbutyrolactone, which in turn was prepared on a
multigram scale by using Corey-Bakshi-Shibata (CBS) reduc-
* To whom correspondence should be addressed. Phone: 765-494-5323. Fax:
765-496-1612.
(1) (a) Staunton, J.; Weissman, K. J. Nat. Prod. Rep. 2001, 18, 380. (b)
Hoffmann, R. W. Angew Chem., Int. Ed. 1987, 26, 489. (c) Heathcock, C. H.
Asymmetric Synthesis. Morrison, J. D., Ed. Academic Press: New York, 1984;
Vol. 3, p 111. (d) Masamune, S.; Choy, W.; Peterson, J. S.; Sita, L. R. Angew.
Chem., Int. Ed. 1985, 24, 1. (e) Franklin, A. S.; Paterson, I. Contemp. Org.
Synth. 1994, 317.
FIGURE 1. Nonaldol route to key anti-aldol precursor 3.
4508 J. Org. Chem. 2009, 74, 4508–4518
10.1021/jo900642f CCC: $40.75 2009 American Chemical Society
Published on Web 05/13/2009

Synthesis of anti-Aldol Segments Via a Nonaldol Route
SCHEME 1. Synthesis of anti-Aldol Segments
TABLE 2. Synthesis of Substituted Tetrahydrofurans
entry
R
product
% yield
dra
1
2
3
4
5
6
7
-CH3
2a
2b
2c
2d
2e
2f
70
91
82
91
70
86
55
11:1
60:1
11:1
49:1
14:1
100:1
1:1
-CH2CH3
-CH2CN
-CH2-C6H5
-CH2-C6H5-pNO2
-CH2CH2CHCH2
-H
2g
a
1
The dr was determined by H NMR of the crude reaction mixture.
furnished tetrahydrofuran derivatives 2a-g. As shown in Table
2, these tetrahydrofuran derivatives were formed in excellent
yield and diastereoselectivity.
Having made the requisite tetrahydrofurans 2a-g, we then
explored the key ring-opening reaction. Previously, we have
carried out a ring-opening reaction of the methyl-substituted
derivative 2a by using a catalytic amount (6 mol %) of ZnCl2
in the presence of acetic anhydride.4,6 However, these conditions
were not optimal for tetrahydrofuran derivatives containing
electron-rich substituents at C-3. After surveying a number of
Lewis acids, we found that a catalytic amount of Zn(OTf)2
provided the best results. Thus, exposure of furans 2a-g to
Zn(OTf)2 (5 mol %) and acetic anhydride in refluxing toluene
gave rise to the anti-aldol precursors 3a-g as shown in Table
3.
TABLE 1. The Alkylation of Lactone 1 with Various Electrophiles
entry
R
X
product
% yield
dra
1
2
3
4
5
6
-CH3
I
I
Br
Br
Br
Br
5a
5b
5c
5d
5e
5f
75
67
76
63
71
32
16:1
17:1
17:1
99:1
99:1
20:1
-CH2CH3
-CH2CN
-CH2C6H5
-CH2-C6H5-pNO2
-CH2CH2CHCH2
Initially, we explored the ring-opening reaction of unsubsti-
tuted tetrahydrofuran 2g (R ) H), which proceeded smoothly
in the presence of a catalytic amount (5 mol %) of Zn(OTf)2
a
1
The dr was determined by H NMR of the crude reaction mixture.
(2) (a) Meyers, A. I.; Yamamoto, Y. Tetrahedron. 1984, 40, 2309. (b)
Helmchen, G.; Leikauf, U.; Taufer-Knopfel, I. Angew. Chem., Int. Ed. 1985,
24, 874. (c) Gennari, C.; Bernardi, A.; Colombo, L.; Scolastico, C. J. Am. Chem.
Soc. 1985, 107, 5812. (d) Masamune, S.; Sato, T.; Kim, B. M.; Wollman, T. A.
J. Am. Chem. Soc. 1986, 108, 8279. (e) Corey, E. J.; Kim, S. S. J. Am. Chem.
Soc. 1990, 112, 4976. (f) Meyers, A. G.; Widdowson, K. L. J. Am. Chem. Soc.
1990, 112, 9672. (g) Walker, M. A.; Heathcock, C. H. J. Org. Chem. 1991, 56,
5747. (h) Braun, M.; Sacha, H. Angew. Chem., Int. Ed. 1991, 30, 1318. (i)
Oppolzer, W.; Lienard, P. Tetrahedron Lett. 1993, 34, 4321. (j) Paterson, I.;
Wren, S. P. J. Chem. Soc., Chem. Commun. 1993, 1790. (k) Abiko, A.; Liu,
J.-F.; Masamune, S. J. Am. Chem. Soc. 1997, 119, 2586. (l) Ghosh, A. K.; Onishi,
M. J. Am. Chem. Soc. 1996, 118, 2527. (m) Ghosh, A. K.; Fidanze, S.; Onishi,
M.; Hussain, K. A. Tetrahedron Lett. 1997, 38, 7171. (n) Kurosu, M.; Lorca,
M. J. Org. Chem. 2001, 66, 1209. (o) Evans, D. A.; Tedrow, J. S.; Shaw, J. T.;
Downey, C. W. J. Am. Chem. Soc. 2002, 124, 392. (p) Denmark, S. E.; Wynn,
T.; Beutner, G. L. J. Am. Chem. Soc. 2002, 124, 13405. (q) Ghosh, A. K.; Kim,
J.-H. Org. Lett. 2003, 5, 1063. (r) Crimmins, M. T.; McDougall, P. J. Org. Lett.
2003, 5, 591. (s) Fanjul, S.; Hulme, A. N.; White, J. W. Org. Lett. 2006, 8,
4219. (t) Gnas, Y.; Glorius, F. Synthesis 2006, 1899.
serve as a useful anti-aldol surrogate since olefin cleavage would
provide the anti-aldol product. Generation of such anti-aldol
products would not be straightforward with the use of a direct
aldol reaction. Encouraged by the good diastereoselectivity and
overall efficiency of the route, we have now investigated the
generality of this “nonaldol anti-aldol” strategy. We have applied
this nonaldol strategy to the synthesis of statine derivatives
which are widely utilized in the design and synthesis of aspartyl
protease inhibitors. Also, we have demonstrated the utility of
this method in the synthesis of (-)-tetrahydrolipstatin, a potent
inhibitor of pancreatic lipase.
Results and Discussion
(3) (a) Jung, M. E.; D’Amico, D. C. J. Am. Chem. Soc. 1993, 115, 12208.
(b) Jung, M. E.; D’Amico, D. C. J. Am. Chem. Soc. 1995, 117, 7379. (c) Jung,
M. E.; D’Amico, D. C. J. Am. Chem. Soc. 1997, 119, 12150. (d) Jung, M. E.;
Marquez, R. Tetrahedron Lett. 1999, 40, 3129. (e) Jung, M. E.; Lee, W. S.;
Sun, D. Org. Lett. 1999, 1, 307. (f) Jung, M. E.; Sun, D. Tetrahedron Lett.
1999, 40, 8343. (g) Jung, M. E.; Marquez, R. Org. Lett. 2000, 2, 1669. (h) Jung,
M. E.; Lee, C. P. Tetrahedron Lett. 2000, 41, 9719. (i) Jung, M. E.; Lee, C. P.
Org. Lett. 2001, 3, 333. (j) Jung, M. E.; van den Heuvel, A. Tetrahedron Lett.
2002, 43, 8169. (k) Jung, M. E.; Hoffmann, B.; Rausch, B.; Contreras, J. M.
Org. Lett. 2003, 5, 3159. (l) Jung, M. E.; van den Heuvel, A.; Leach, A. G.;
Houk, K. N. Org. Lett. 2003, 5, 3375. (m) Jung, M. E.; van den Heuvel, A.
Org. Lett. 2003, 5, 4705. (n) Jung, M. E.; Yoo, D. Org. Lett. 2007, 9, 3543. (o)
Jung, M. E.; Zhang, T. Org. Lett. 2008, 10, 137. (p) Jung, M. E.; Yoo, D.
Tetrahedron Lett. 2008, 49, 816. (q) Jung, M. E.; Allen, D. A. Org. Lett. 2008,
10, 2039.
(4) Ghosh, A. K.; Swanson, L. J. Org. Chem. 2003, 68, 9823.
(5) Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C.; Singh, V. K. J. Am.
Chem. Soc. 1987, 109, 7925.
(6) For the zinc-catalyzed ring expansion reaction see: (a) Hori, N.; Nagasawa,
K.; Shimizu, T.; Nakata, T. Tetrahedron Lett. 1999, 40, 2145. (b) Nakata, T.;
Nomura, S.; Matsukura, H. Tetrahedron Lett. 1996, 37, 213.
On the basis of our previous work, we decided to expand
the scope and utility of functionalized tetrahydrofurans in
synthesis.4 In particular, we planned to study the opening of
the tetrahydrofuran ring to unravel the cyclic stereochemistry
into an acyclic form. As shown in Scheme 1, our synthesis
utilized known lactone 1, which was obtained in multigram
quantities by employing CBS reduction as the key step.5
Alkylation of lactone 1 with LDA, and a variety of electrophiles,
provided substituted lactones 5a-f in good diastereoselectivity
(1H NMR analysis) and excellent yields as shown in Table 1.
Reduction of lactones 5a-f and 1 by using DIBAL-H afforded
the corresponding lactols. Wittig olefination of the resulting
lactols gave rise to R,ꢀ-unsaturated esters 6a-g with high
1
E-selectivity as shown by H NMR analysis. Treatment of the
R,ꢀ-unsaturated esters 6a-g with KHMDS in THF at -78 °C
J. Org. Chem. Vol. 74, No. 12, 2009 4509

Ghosh et al.
TABLE 3. Synthesis of Substituted ꢀ-Acetoxy Ester
SCHEME 3. Oxidative Cleavage and Synthesis of Statines
entry
R
product
% yield
1
2
3
4
5
6
7
-CH3
3a
3b
3c
3d
3e
3f
76
60
53
-CH2CH3
-CH2CN
a
-CH2-C6H5
-CH2-C6H5-pNO2
-CH2CH2CHCH2
-H
90
86
78
3g
a See Scheme 2 for benzyl example.
SCHEME 2. Lewis Acid Catalyzed Ring-Opening of Benzyl
Derivative 2d
derivative 3d with a diastereomeric mixture (3:1) of tetraline
derivatives 11a and 11b. This mixture was separated by HPLC
and the identity of products 11a and 11b was confirmed by
extensive NMR studies.
The rationale for the ring-opening reaction and the formation
of tetraline derivatives 11a and 11b is shown in Scheme 2.
Activation of acetic anhydride by Zn(OTf)2 leads to the
formation of acyloxonium ion 8. The ring-opening by cleavage
of the C-O bond at C-5 would give rise to a more stable
benzylic carbonium ion 9. Cleavage of the C-O bond at C-2,
on the other hand, would provide a less stable carbonium ion.
Also, elimination of an R-proton of the ester followed by
cleavage of the C-O bond may lead to the formation of an
R,ꢀ-unsaturated ester derivative. However, no product corre-
sponding to the cleavage of the C-O bond at C-2 was isolated.
The formation of products 3d, 11a, and 11b can be rationalized
through the formation of benzylic carbonium ion 9. The loss of
a proton from 9 (path a) presumably resulted in the styrene
derivative 3d. The tetraline derivatives 11a and 11b were formed
due to a competing intramolecular trapping of the benzylic
carbonium ion intermediate 9 as shown in path b. The observed
ratio of tetralines 11a and 11b can be rationalized on the basis
of proposed transition states TS-11a and TS-11b shown in
Figure 2. The transition state TS-11a is preferred over TS-11b
because of the developing 1,3-diaxial interaction in TS-11b.
Upon the basis of this insight, we speculated that an electron-
withdrawing group on the aromatic ring would slow down the
and excess acetic anhydride to furnish the styrene 3g in 78%
yield. The reactions with methyl- and ethyl-substituted deriva-
tives 2a and 2b also gave the respective styrene derivatives 3a
and 3b in good yield (Table 3, entries 1 and 2). The ring-opening
reaction of nitrile-substituted derivative 2c failed to furnish any
appreciable amount of the corresponding styrene derivative,
probably due to the strong coordination of the nitrile group with
Zn(OTf)2. When the reaction was carried out in the presence
of 3 equiv of Zn(OTf)2, the desired styrene derivative 3c was
obtained in 53% yield. We then explored the ring-opening
reaction with benzyl- and allyl-substituted tetrahydrofurans. The
ring-opening reaction of the allyl-substituted tetrahydrofuran
provided a complex mixture of products due to cation-olefin
cyclization. The ring-opening reaction with homoallyl derivative
2f (Table 3, entry 6) proceeded smoothly to afford styrene
derivative 3f in 86% yield. Our attempts to open 2d with
Zn(OTf)2 under a variety of reaction conditions provided a
complex mixture of opened ring products as well as substituted
tetraline derivatives. As shown in Scheme 2, exposure of 2d to
5 mol % of Zn(OTf)2 resulted in a 1:4 mixture of styrene
FIGURE 2. Proposed transition state for the intramolecular trapping
of the benzylic carbonium ion.
4510 J. Org. Chem. Vol. 74, No. 12, 2009

Synthesis of anti-Aldol Segments Via a Nonaldol Route
SCHEME 4. Synthesis of Styrene Derivative 21
FIGURE 3. Retrosynthetic analysis for (-)-tetrahydrolipstatin.
the FDA under the trade name Orlistat in 2006, for the treatment
of obesity.12 The ꢀ-lactone moiety present in Orlistat inhibits
gastric and pancreatic lipases, thus slowing the hydrolysis of
triglycerides into free fatty acids and reducing their absorption
in the gut.13 Futhermore, tetrahydrolipstatin was recently shown
to be a potent fatty acid synthase (FAS) inhibitor. FAS is an
enzyme responsible for the synthesis of fatty acids in many
human carcinomas and is required for tumor cell survival,
making FAS inhibitor a promising drug for the treatment of
cancer.14 Tetrahydrolipstatin and its analogues have been of
great interest in the past years, as they have shown many
interesting biological activities. This has provided immense
interest in the chemistry and biology of tetrahydrolipstatin.15
As shown in Figure 3, the structural element of the ꢀ-lactone
functionality can be derived from the styrene derivative 15 by
oxidative cleavage to provide the anti-aldol unit with appropriate
stereochemistry. Styrene derivative 15 can be obtained from
the tetrahydrofuran derivative 16 by a stereoselective reduction
followed by a Lewis acid-catalyzed, acyloxonium ion-mediated
ring-opening reaction. Stereochemically defined tetrahydrofuran
derivative 16 would be derived from optically active lactone 1
by the sequence of reaction steps described above.
competing intramolecular trapping of the benzylic carbonium
ion and would favor the formation of the desired styrene opening
product through pathway a in Scheme 2. Indeed, Lewis acid-
catalyzed reaction with p-NO2 benzyl derivative 2e furnished
styrene derivative 3e in 90% yield.
Various styrene derivatives resulting from the Lewis acid-
catalyzed ring opening are suitable precursors of the anti-aldol
segments. As shown in Scheme 1, oxidative cleavage of styrenes
3a and 3b with RuCl3/NaIO4 gave rise to the corresponding
acids which were subsequently converted to the methyl esters
7a and 7b by treatment with diazomethane. However, better
yields for the cleavage of styrenes were obtained by using OsO4
and oxone in DMF.7 Accordingly, styrenes 3b and 3e were
converted to their respective acids 10b and 10e and then
subjected to Curtius rearrangement.8 The resulting acids without
further purification were exposed to 2.2 equiv of diphenyl
phosphorazidate and 2.2 equiv of triethylamine in toluene at
reflux. Benzyl alcohol was added and the resulting mixture was
heated at reflux for 12 h to provide Cbz derivatives 12 and 13
in 99% and 67% yields, respectively, over two steps (Scheme
4). These statine derivatives have been extensively utilized in
the design of aspartyl protease inhibitors, particularly for renin
and HIV-1 protease inhibitors.9-11 The present methodology
will provide access to substituted statine derivatives in optically
active form.
The synthesis of styrene 21 is shown in Scheme 4. Alkylation
of lactone 1 with iodohexane using LDA in the presence of
(12) Weibel, E. K.; Hadvary, P.; Hochuli, E.; Kupfer, E.; Lengsfeld, H. J.
Antibiot. 1987, 40, 1081.
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K. J. Antibiot. 1987, 40, 1086.
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L. M.; Cieplak, P.; Romo, D.; Jeffrey, W.; Smith, J. W. J. Med. Chem. 2008,
51, 5285. (b) Ortar, G.; Bisogno, T.; Ligresti, A.; Morera, E.; Nalli, M.; Di
Marzo, V. J. Med. Chem. 2008, 51, 6970, and references cited therein.
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327. (b) Yadav, J. S.; Rao, K. V.; Prasad, A. R. Synthesis 2006, 3888. (c)
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45, 3873. (d) Yadav, J. S.; Vishweahwar Rao, K.; Sridhar Reddy, M.; Prasad,
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Lett. 2000, 2, 2405. (j) Dirat, O.; Kouklovsky, C.; Langlois, Y. Org. Lett. 1999,
1, 753. (k) Ghosh, A. K.; Liu, C. Chem. Commun. 1999, 1743. (l) Paterson, I.;
Doughty, V. A. Tetrahedron Lett. 1999, 40, 393. (m) Fleming, I.; Lawrence,
N. J. J. Chem. Soc., Perkin Trans. 1. 1998, 2679. (n) Giese, B.; Roth, M. J. J.
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Chem. 1993, 58, 7768. (q) Case-Green, S. C.; Davies, S. G.; Hedgecock, C. J. R.
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Widmer, U. HelV. Chim. Acta 1987, 70, 1412. (w) Barbier, P.; Schneider, F.
HelV. Chim. Acta 1987, 70, 196.
We have utilized this methodology in the total synthesis of
(-)-tetrahydrolipstatin (14). This natural product was isolated
from Streptomyces toxytricini in 1987, and was approved by
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K.; Lindberg, J.; Nystroem, S.; Hallberg, A.; Rosenquist, A.; Samuelsson, B.
Bioorg. Med. Chem. 2008, 16, 9471. (c) Barazza, A.; Gotz, M.; Cadamuro, S. A.;
Goettig, P.; Willem, M.; Steuber, H.; Kohler, T.; Jestel, A.; Reinemer, P.; Renner,
C.; Bode, W.; Moroder, L. ChemBioChem. 2007, 8, 2078.
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J. Org. Chem. Vol. 74, No. 12, 2009 4511

Ghosh et al.
SCHEME 5. Synthesis of (-)-Tetrahydrolipstatin 14
utilize conditions reported by Adam and co-workers (PhSO2Cl/
pyridine, p-NO2PhSO2Cl/pyridine).19 Our many attempts to form
the ꢀ-lactone using acid 23 under the same conditions resulted
in low yields (10-15%). Ortar and co-workers have reported a
similar poor yield during their synthesis of tetrahydrolipstatin.14b
Interestingly, in an earlier synthesis of (-)-tetrahydrolipstatin
from our laboratory, we employed the above Adam’s conditions
to the C-5 epimer of acid 23 and obtained the corresponding
C-5 epimeric ꢀ-lactone in 74% yield.15i Presumably, the steric
hindrance of the TIPS-protected syn-diol 23 is responsible for
the sluggish reaction and poor yield of the corresponding
ꢀ-lactone under Adam’s conditions. We then utilized Yamaguchi
conditions and formed the desired ꢀ-lactone in 55% yield.20
Removal of the TIPS protecting group was achieved by using
TBAF and acetic acid to give alcohol 24 in 62% yield. To
complete the synthesis, we attempted the esterification of 24
with N-formyl leucine in the presence of DCC/DMAP. These
conditions resulted in substantial epimerization of tetrahydro-
lipstatin (1:1 ratio). Reduction of DMAP concentration to 0.2
equiv suppressed the formation of the epimer to 1.4:1. To
circumvent this problem, we carried out a three-step procedure
as described by Uskokovic and co-workers.21 This involved (1)
esterification with Cbz-Leu-OH 25, using DCC and DMAP,22
(2) removal of the Cbz protection by hydrogenolysis, and (3)
formylation of the amine by using the mixed anhydride at 23
HMPA furnished the requisite lactone 17 in 84% yield with an
1
excellent diastereomeric ratio (99:1 by H NMR). DIBAL-H
reduction of lactone 17 afforded the corresponding lactol in
quantitative yield. A Horner-Wadsworth-Emmons reaction of
the resulting lactol with phosphonate 18 in the presence of
Ba(OH)2 resulted in the formation of tetrahydrofuran derivative
16 in 83% yield with an excellent diastereomeric ratio (33:1
°C to provide (-)-tetrahydrolipstatin (14, [R]20 -32 (c 0.05,
D
CHCl3); lit.15v ([R]23D -33 (c 0.36, CHCl3)) in 48% yield over
2 steps. Spectral data (1H and 13C NMR) of synthetic (-)-
tetrahydrolipstatin are identical with those reported for the
natural product.
16,17
1
by H NMR).
At this point, our attempt at the ring-opening reaction of
substituted tetrahydrofuran 16 was unsuccessful resulting in
recovery of the starting material. This was possibly due to the
sequestering of the Lewis acid through the formation of a stable
six-membered complex with the ketone. We therefore planned
to reduce the ketone stereoselectively and then carry out the
ring-opening reaction. For the stereoselective reduction of the
ketone, we elected to carry out a chelation-controlled reduction
described by us previously.18 Thus, reduction of ketone 16 with
LAH in the presence of LiI resulted in the formation of alcohol
20 in 88% yield with excellent diastereoselectivity (17:1 dr).
The high degree of diastereoselectivity can be explained by
formation of a chelated rigid intermediate 19. Hydride attack
presumably proceeded from the less hindered bottom face,
providing the syn-alcohol 20 selectively. Subsequent ring-
opening reaction of alcohol 20 with 5 mol % of Zn(OTf)2 and
an excess of Ac2O in refluxing toluene proceeded smoothly,
providing diacetoxy styrene derivative 21 in 85% yield.
The completion of the total synthesis of tetrahydrolipstatin
is shown in Scheme 5. Treatment of diacetate 21 with DIBAL-H
at -78 °C gave the corresponding diol. Selective protection of
this diol with TIPSOTf in the presence of 2,6-lutidine at -78
°C gave silyl ether 22.15i Oxidative cleavage of the styrene
moiety with OsO4 and NaIO4 resulted in an aldehyde that was
oxidized to the acid by using sodium chlorite in 50% yield over
three steps. For the formation of the ꢀ-lactone, we planned to
In conclusion, we have developed an alternative strategy to
the formation of anti-aldol segments in optically active form
via a nonaldol route. The strategy utilizes optically active
4-phenylbutyrolactone as the key starting material. Both ste-
reogenic centers of the anti-aldol segments are derived from
the 4-phenyltetrahydrofuran. The scope and utility of this
methodology was demonstrated by the asymmetric synthesis
of statine derivatives which are important scaffolds for aspartyl
protease inhibitors. Furthermore, the methodology was utilized
in the stereoselective synthesis of (-)-tetrahydrolipstatin. The
key steps involved a highly diastereoselective chelation-
controlled syn-reduction of a ketone, a catalytic asymmetric ring-
opening reaction, and the formation of the ꢀ-lactone under
Yamaguchi conditions. Further application of this methodology
is in progress.
Experimental Section
General Experimental Methods. 1H NMR and 13C NMR
spectra were recorded on Bruker Avance ARX- 400 and DRX-
500 spectrometers. IR spectra were recorded on a Mattason Genesis
II FT-IR spectrometer. Optical rotations were recorded on a Perkin-
Elmer 341 polarimeter. Anhydrous solvents were obtained as
follows: THF and diethyl ether by distillation from sodium and
benzophenone; pyridine and dichloromethane from CaH2. All other
solvents were reagent grade. All moisture-sensitive reactions were
carried out in a flame-dried flask under argon atmosphere. Column
(16) (a) Grimes, K. D.; Lu, Y.-J.; Zhang, Y.-M.; Luna, V. A.; Hurdle, J. G.;
Carson, E. I.; Qi, J.; Kudrimoti, S.; Rock, C. O.; Lee, R. E. ChemMedChem.
2008, 3, 1936. (b) Gurjar, M. K.; Pramanik, C.; Bhattasali, D.; Ramana, C. V.;
Mohapatra, D. K. J. Org. Chem. 2007, 72, 6591–6594.
(17) Paterson, I.; Yeung, K. S.; Smaill, J. B. Synlett 1993, 774.
(18) (a) Ghosh, A. K.; Lei, H. J. Org. Chem. 2002, 67, 8783. (b) Mori, Y.;
Kuhara, M.; Takeuchi, A.; Suzuki, M. Tetrahedron Lett. 1988, 29, 5419. (c)
Mori, Y.; Takeuchi, A.; Kageyama, H.; Suzuki, M. Tetrahedron Lett. 1988, 29,
5423.
(19) Adam, W.; Baeza, J.; Liu, J.-C. J. Am. Chem. Soc. 1972, 94, 2000.
(20) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989.
(21) Chadha, N. K.; Batcho, A. D.; Tang, P. C.; Courtney, L. F.; Cook, C. M.;
Wovkulich, P. M.; Uskokovic, M. R. J. Org. Chem. 1991, 56, 4714.
(22) Frelek, J.; Fryszkowska, A.; Kwit, M.; Ostaszewski, R. Tetrahedron:
Asymmetry 2006, 17, 2469.
4512 J. Org. Chem. Vol. 74, No. 12, 2009

Synthesis of anti-Aldol Segments Via a Nonaldol Route
chromatography was performed with Whatman 240-400 mesh
silica gel under a low pressure of 3-5 psi. TLC was carried out
with E. Merck silica gel 60-F-254 plates. HPLC data were collected
using a system composed of an Agilent 1100 series degasser,
quaternary pump, thermostatable column compartment, variable
wavelength detector, and Agilent 1200 series auto sampler and
fraction collector controlled by Chemstation software. All chro-
matographic reagents used were HPLC grade.
(m, 10H), 5.39 (dd, J ) 7.8, 4.7 Hz, 1H), 3.25 (dd, J ) 13.6, 4.3
Hz, 1H), 3.02-2.95 (m, 1H), 2.90-2.85 (m, 1H), 2.50-2.43 (m,
1H), 2.31-2.24 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 178.5,
139.6, 138.0, 128.8, 128.6, 128.6, 128.1, 126.8, 124.8, 78.6, 40.4,
36.1, 35.5; IR (NaCl) 3033, 2926, 1764, 1495, 1451, 1132, and
1011 cm-1; EI-HRMS (m/z) calcd for C17H16O2 ([M]+) 252.1150,
found 252.1147.
(3S,5S)-3-(4-Nitrophenyl)-5-phenyldihydrofuran-2(3H)-one (5e).
The title compound was prepared from γ-lactone 1 following the
same procedure that was used for the synthesis of 5a, using
p-nitrobenzyl bromide. Purification by flash chromatography (95:5
(3R,5S)-3-Methyl-5-phenyldihydrofuran-2(3H)-one (5a). To
a stirring solution of THF (5 mL) and diisopropylamine (490 µL,
3.7 mmol) at 0 °C under argon was added n-BuLi (2.1 mL, 1.6 M
solution in hexanes, 3.39 mmol) dropwise; the mixture was then
stirred for 15 min and cooled to -78 °C. Then lactone 1 (500 mg,
3.08 mmol) was dissolved in 15 mL of THF and added dropwise
over a 0.5 h period. The reaction mixture was stirred for an
additional 0.5 h at -78 °C. Iodomethane (210 µL, 3.4 mmol) was
added dropwise and the reaction mixture was stirred for 1 h at -78
°C. The reaction was quenched with saturated aqueous NH4Cl and
warmed to room temperature, then the aqueous layer was extracted
with EtOAc (3×) and the organic layer was washed with water
and brine and dried over anhydrous Na2SO4. The residue was
chromatographed on silica gel (85:15 hexanes/EtOAc) to give 5a
toluene/MeOH) afforded 5e (917 mg, 71% yield) as an oil; dr (99:
1
1); [R]20 +29.6 (c 1.1, CHCl3); H NMR (400 MHz, CDCl3) δ
D
8.19 (d, J ) 8 Hz, 2H), 7.41-7.31 (m, 5H), 7.26-7.24 (m, 2H),
5.50 (dd, J ) 12, 5 Hz, 1H), 3.32 (m, 1H), 3.04-2.95 (m, 2H),
2.48-2.41 (m, 1H), 2.35-2.30 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 177.6, 146.9, 145.7, 139.2, 129.8, 128.8, 128.3, 124.7,
123.9, 78.3, 39.7, 35.8, 35.4; IR (NaCl) 2998, 2885, 2837, 2362,
1776, 1602, 1516, and 1346 cm-1; EI-HRMS (m/z) calcd for
C17H15NO4 ([M]+) 297.1001, found 297.1004.
(3R,5S)-3-(But-3-enyl)-5-phenyldihydrofuran-2(3H)-one (5f).
To a stirring solution of THF (5 mL) and diisopropylamine (485
µL, 3.71 mmol) at 0 °C under argon was added n-BuLi (2.2 mL,
1.6 M solution in hexanes, 3.54 mmol) dropwise; the mixture was
stirred for 15 min, then HMPA (3 mL) was added dropwise and
the reaction mixture was stirred at 0 °C for 15 min and then cooled
to -78 °C. Then lactone 1 (546 mg, 3.37 mmol) was dissolved in
15 mL of THF and added dropwise over a 0.5 h period. The reaction
mixture was stirred for another 0.5 h at -78 °C. Then a catalytic
amount of TBAI (190 mg, 0.51 mmol) was added in one portion,
and then 1-bromo-3-butene (380 µL, 3.71 mmol) was added
dropwise; next the reaction mixture was stirred for 1 h at -78 °C
and then warmed to 0 °C and stirred for 3 h. The reaction was
quenched with saturated aqueous NH4Cl and warmed to room
temperature. The aqueous layer was extracted with EtOAc (3×),
then the combined organic layers were washed with water and brine
and dried over anhydrous Na2SO4. The residue was chromato-
(407 mg, 75% yield) as an oil; dr (16:1), [R]20 -19.5 (c 1.1,
D
1
CHCl3); H NMR (400 MHz, CDCl3) δ 7.43-7.18 (m, 5H), 5.55
(dd, J ) 8, 5 Hz, 1H), 2.71 (m, 1H), 2.46-2.31 (m, 2H), 1.33 (d,
J ) 4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 179.6, 139.8, 128.6,
128.0, 124.9, 78.2, 38.2, 33.5, 15.3; IR (NaCl) 3066, 1773, 1450,
and 1171 cm-1
.
(3R,5S)-3-Ethyl-5-phenyldihydrofuran-2(3H)-one (5b). To a
stirring solution of THF (5 mL) and diisopropylamine (450 µL,
3.39 mmol) at 0 °C under argon was added n-BuLi (2 mL, 1.6 M
solution in hexanes, 3.24 mmol) dropwise, the mixture was stirred
for 15 min, then DMPU (3 mL) was added dropwise and the
reaction mixture was stirred at 0 °C for 15 min and then cooled to
-78 °C. Lactone 1 (500 mg, 3.08 mmol) was dissolved in 15 mL
of THF and added dropwise over a 0.5 h period. The reaction
mixture was stirred for an additional 0.5 h at -78 °C. Then
iodoethane (370 µL, 4.62 mmol) was added dropwise and the
reaction mixture was stirred for 1 h at -78 °C. The reaction was
quenched with saturated aqueous NH4Cl and warmed to room
temperature. The aqueous layer was extracted with EtOAc (3×),
then the combined organic layers were washed with water and brine
and dried over anhydrous Na2SO4. The residue was chromato-
graphed on silca gel (90:10 hexanes/EtOAc) to give 5f (233 mg,
1
32% yield) as an oil; dr (20:1); [R]20 -11.9 (c 0.9, CHCl3); H
D
NMR (400 MHz, CDCl3) δ 7.40-7.29 (m, 5H), 5.84-5.74 (m,
1H), 5.56 (t, J ) 6 Hz, 1H), 5.08-4.99 (m, 2H), 2.71-2.63 (m,
1H) 2.41-2.38 (m, 2H), 2.25-2.13 (m, 2H), 2.05-1.96 (m, 1H),
1.68-1.59 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 179.0, 139.7,
136.9, 128.6, 128.1, 124.8, 115.7, 78.5, 38.0, 36.5, 31.2, 29.5; IR
(NaCl) 2969, 1775, and 1167 cm-1; EI-HRMS (m/z) calcd for
C14H16O2 ([M]+) 216.1150, found 216.1152.
graphed on silica gel (80:20 hexanes/EtOAc) to give 5b (393 mg,
1
67% yield) as an oil; dr (17:1); [R]20 -28.5 (c 2.1, CHCl3); H
D
NMR (400 MHz, CDCl3) δ 7.40-7.26 (m, 5H), 5.55 (t, J ) 4 Hz,
1H), 2.64-2.56 (m, 1H), 2.45-2.34 (m, 2H), 1.95-1.87 (m, 1H),
1.64-1.55 (m, 1H), 1.03 (t, J ) 8 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 179.1, 139.9, 128.6, 128.1, 124.9, 78.5, 40.1, 35.9, 23.5,
11.6; IR (NaCl) 2955, 2872, 1773, 1453, and 1171 cm-1; CI-HRMS
(m/z) calcd for C12H14O2 ([M]+) 190.0994, found 190.0992.
(E,S)-Ethyl 6-Hydroxy-6-phenylhex-2-enoate (6g). To a solu-
tion of 1 (307 mg, 1.89 mmol) in 15 mL of CH2Cl2 under argon at
-78 °C was added DIBAL-H (2.3 mL, 1 M solution in CH2Cl2,
2.28 mmol) dropwise. The reaction was stirred for 0.5 h at -78
°C and then quenched with 2 mL of methanol then warmed to room
temperature, 15 mL of K-Na tartrate was added, and once the
emulsion had separated, the aqueous layer was extracted with
CH2Cl2 (3×) and the combined organic layers were washed with
brine and dried over anhydrous Na2SO4. Without further purification
the crude oil was dissolved in 20 mL of CH2Cl2 then Ph3PCHCO2Et
(835 mg, 2.39 mmol) was added and the reaction mixture was
refluxed for 12 h at 40 °C. The reaction mixture was then
concentrated and chromatographed (90:10 hexanes/EtOAc) to give
2-((3R,5S)-2-Oxo-5-phenyltetrahydrofuran-3-yl)acetonitrile (5c).
The title compound was prepared from 1 following the same
procedure that was used for the synthesis of 5a, using bromoac-
etonitrile. Purification by flash chromatography (80:20 hexanes/
EtOAc) afforded 5c as an oil (471 mg, 76% yield); dr (17:1); [R]20
D
1
+2.60 (c 1.2, CHCl3); H NMR (400 MHz, CDCl3) δ 7.43-7.28
(m, 5H), 5.73 (dd, J ) 7, 4 Hz, 1H), 3.04-2.97 (m, 1H), 2.87 (dd,
J ) 17, 5 Hz, 1H), 2.73-2.65 (m, 3H); 13C NMR (100 MHz,
CDCl3) δ 175.4, 138.5, 128.9, 128.6, 124.6, 116.7, 78.3, 35.2, 35.2,
18.4; IR (NaCl) 3032, 2925, 2854, 2251, 1777, 1451, and 1171
cm-1; EI-HRMS (m/z) calcd for C12H11NO2 ([M + H]+) 202.9888,
found 202.0866.
1
6g (393 mg, 89% yield over two steps) as an oil; H NMR (400
MHz, CDCl3) δ 7.35-7.27 (m, 5H), 6.98-6.94 (m, 1H), 5.82 (d,
J ) 15 Hz, 1H), 4.70-4.66 (m, 1H), 4.18 (q, J ) 7 Hz, 2H),
2.30-2.25 (m, 2H), 2.06 (s, 1H), 1.96-1.84 (m, 2H), 1.27 (t, J )
7 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.6, 148.4, 144.1,
128.5, 127.7, 125.8, 121.6, 73.6, 60.1, 37.0, 28.4, 14.2; IR (NaCl)
3300, 2982, 1716, 1652, 1451, and 1193 cm-1; EI-HRMS (m/z)
calcd for C14H18O3 ([M]+) 234.1256, found 234.1255.
(3R,5S)-3-Benzyl-5-phenyldihydrofuran-2(3H)-one (5d). The
title compound was prepared from γ-lactone 1 following the same
procedure that was used for the synthesis of 5a, using benzyl
bromide. Purification by flash chromatography (90:10, hexanes/
EtOAc) afforded 5d (116 mg, 63% yield) as an oil; dr (99:1); [R]20
(4R,6S,E)-Ethyl 6-Hydroxy-4-methyl-6-phenylhex-2-enoate
(6a). The title compound was prepared from γ-lactone 5a following
D
+135.3 (c 0.5, CHCl3); 1H NMR (CDCl3; 400 MHz) δ 7.38-7.16
J. Org. Chem. Vol. 74, No. 12, 2009 4513

Ghosh et al.
the same procedure that was used for the synthesis of 6g.
Purification by flash chromatography (90:10 hexanes/EtOAc) af-
(R,E)-Ethyl 4-((S)-2-Hydroxy-2-phenylethyl)octa-2,7-dienoate
(6f). The title compound was prepared from γ-lactone 5f following
the same procedure that was used for the synthesis of 6g.
Purification by flash chromatography (90:10 hexanes/EtOAc) af-
forded 6f (95 mg, quantitative yield over two steps) as a single
forded 6a (502 mg, 94% yield over two steps) as a single
1
diastereomer; [R]20 -21.8 (c 1.1, CHCl3); H NMR (400 MHz,
D
CDCl3) δ 7.35-7.28 (m, 5H), 6.86 (dd, J ) 16, 8 Hz, 1H), 5.86
(d, J ) 16 Hz, 1H), 4.64-4.61 (m, 1H), 4.18 (q, J ) 7 Hz, 2H),
2.63-2.60 (m, 1H), 2.03 (s, 1H), 1.89-1.82 (m, 1H), 1.70-1.63
(m, 1H), 1.29 (t, J ) 7 Hz, 3H), 1.08 (d, J ) 7 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 166.8, 153.4, 144.6, 128.5, 127.6, 125.6,
120.4, 72.1, 60.2, 45.3, 33.4, 20.1, 14.2; IR (NaCl) 3300, 2958,
diastereomer; [R]20 +1.6 (c 1, CHCl3); 1H NMR (400 MHz,
D
CDCl3) δ 7.39-7.23 (m, 5H), 6.74 (dd, J ) 16, 10 Hz, 1H), 5.89
(d, J ) 16 Hz, 1H), 5.81-5.71 (m, 1H), 5.01-4.90 (m, 2H),
4.59-4.55 (m, 1H), 4.18 (q, J ) 7 Hz, 2H), 2.64-2.55 (m, 1H),
2.25 (s, 1H), 2.07-1.93 (m, 2H), 1.91-1.85 (m, 1H), 1.64-1.57
(m, 1H), 1.55-1.42 (m, 1H), 1.30 (t, J ) 7 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 166.5, 152.0, 144.9, 138.0, 128.4, 127.4,
125.5, 122.2, 114.8, 71.7, 60.3, 43.9, 38.8, 33.9, 31.2, 14.1; IR
(NaCl) 3265, 2852, 1709, 1641, 1303, and 1161 cm-1; EI-HRMS
(m/z) calcd for C18H24O3 ([M]+) 287.1725, found 288.1722.
Ethyl 2-((5S)-5-Phenyltetrahydrofuran-2-yl)acetate (2g). To
a stirred solution of KHMDS (4.0 mL, 0.5 M solution in toluene,
2.01 mmol) in THF (5 mL) was added 6g (392 mg, 1.67 mmol) in
THF (15 mL) at -78 °C dropwise over a 30 min period and the
mixture was then stirred at -78 °C for an additional 1 h. Then the
reaction was quenched with saturated aqueous NH4Cl (10 mL) and
warmed to room temperature. The aqueous layer was extracted with
EtOAc (3×), then the organic layer was washed with brine and
dried over anhydrous Na2SO4. The organic layer was then concen-
trated and chromatographed (90:10 hexanes/EtOAc) to give 2g as
1717, 1652, 1455, and 1272 cm-1
.
(4R,6S,E)-Ethyl 4-Ethyl-6-hydroxy-6-phenylhex-2-enoate (6b).
The title compound was prepared from γ-lactone 5b following the
same procedure that was used for the synthesis of 6g. Purification
by flash chromatography (90:10 hexanes/EtOAc) afforded 6b (482
mg, 89% yield over two steps) as a single diastereomer; [R]20D -6.6
1
(c 2, CHCl3); H NMR (400 MHz, CDCl3) δ 7.34-7.23 (m, 5H),
6.75 (dd, J ) 16, 10 Hz, 1H), 5.88 (d, J ) 16 Hz, 1H), 4.59-4.55
(m, 1H), 4.18 (q, J ) 7 Hz, 2H), 2.49-2.44 (m, 1H), 2.25 (s, 1H),
1.92-1.85 (m, 1H), 1.63-1.56 (m, 1H), 1.51-1.46 (m, 1H),
1.41-1.36 (m, 3H), 1.30 (t, J ) 7 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 166.6, 152.3, 144.9, 128.4, 128.2, 127.4, 125.5, 122.1,
60.2, 43.6, 40.9, 27.7, 14.1, 11.5; IR (NaCl) 3136, 2961, 1719,
1649, 1452, and 1199 cm-1; CI-HRMS (m/z) calcd for C16H22O3
([M]+) 262.1569, found 262.1570.
1
a mixture of diastereomers (216 mg, 55% yield); H NMR (400
(4R,6S,E)-Ethyl 4-(Cyanomethyl)-6-hydroxy-6-phenylhex-2-
enoate (6c). The title compound was prepared from γ-lactone 5c
following the same procedure that was used for the synthesis of
6g. Purification by flash chromatography (90:10 hexanes/EtOAc)
MHz, CDCl3) δ 7.40-7.22 (m, 10H), 5.04 (t, J ) 7 Hz, 1H), 4.92
(t, J ) 7 Hz, 1H), 4.65-4.59 (m, 1H), 4.51-4.44 (m, 1H),
4.21-4.14 (m, 4H), 2.81-2.71 (m, 2H), 2.62-2.52 (m, 2H),
2.42-2.09 (m, 4H), 1.95-1.72 (m, 4H), 1.28 (t, J ) 7 Hz, 6H);
13C NMR (100 MHz, CDCl3) δ 171.1, 143.3, 142.8, 128.2, 128.2,
127.1, 125.6, 125.4, 81.1, 80.3, 75.9, 75.8, 60.4, 41.0, 40.9, 35.0,
34.2, 32.0, 31.1, 14.1; IR (NaCl) 2977, 1734, and 1188 cm-1; EI-
HRMS (m/z) calcd for C14H18O3 ([M]+) 234.1256, found 234.1254.
Ethyl 2-((2S,3R,5S)-3-Methyl-5-phenyltetrahydrofuran-2-
yl)acetate (2a). The title compound was prepared from alcohol 6a
following the same procedure that was used for the synthesis of
2g. Purification by flash chromatography (90:10 hexanes/EtOAc)
afforded 2a (354 mg, 70% yield) as an oil; dr (11:1); [R]20D +53.3
(c 1.3, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.34-7.22 (m, 5H),
5.03 (t, J ) 7 Hz, 1H), 4.22-4.16 (m, 2H), 4.05-4.00 (m, 1H),
2.72-2.61 (m, 2H), 2.09-1.99 (m, 3H), 1.29 (t, J ) 7 Hz, 3H),
1.10 (d, J ) 6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 171.3,
143.4, 128.1, 126.9, 125.1, 82.5, 79.3, 60.4, 42.6, 39.8, 38.1, 17.1,
14.1; IR (NaCl) 2961, 1736, 1029, and 699 cm-1; ESI-HRMS
(m/z) calcd for C15H20O3Na ([M + Na]+) 271.1310, found 271.1303.
Ethyl 2-((2S,3R,5S)-3-Ethyl-5-phenyltetrahydrofuran-2-yl)ac-
etate (2b). The title compound was prepared from alcohol 6b
following the same procedure that was used for the synthesis of
2g. Purification by flash chromatography (90:10 hexanes/EtOAc)
afforded 2b (379 mg, 91% yield) as an oil; dr (60:1); [R]20D -39.2
(c 1.5, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.40-7.22 (m, 5H),
5.55 (t, J ) 7 Hz, 1H), 4.23-4.15 (m, 2H), 4.14-4.10 (m, 1H),
2.72-2.62 (m, 2H), 2.10-2.00 (m, 2H), 1.96-1.87 (m, 1H),
1.61-1.53 (m, 1H), 1.44-1.33 (m, 1H), 1.29 (t, J ) 7 Hz, 3H),
0.96 (t, J ) 7 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 171.2,
143.3, 128.0, 126.9, 125.5, 81.0, 79.6, 60.3, 45.5, 40.3, 40.3, 25.4,
14.0, 12.4; IR (NaCl) 3011, 1736, and 1274 cm-1; CI-HRMS
(m/z) calcd for C16H22O3 ([M]+) 262.1569, found 262.1568.
Ethyl 2-((2S,3R,5S)-3-(Cyanomethyl)-5-phenyltetrahydrofu-
ran-2-yl)acetate (2c). The title compound was prepared from
alcohol 6c following the same procedure that was used for the
synthesis of 2g. Purification by flash chromatography (80:20
afforded 6c (110 mg, 83% yield over two steps) as a single
1
diastereomer; [R]20 -25.7 (c 0.5, CHCl3); H NMR (400 MHz,
D
CDCl3) δ 7.39-7.27 (m, 5H), 6.81 (dd, J ) 16, 9 Hz, 1H), 6.03
(d, J ) 16 Hz, 1H), 4.65-4.62 (m, 1H), 4.21 (q, J ) 7 Hz, 2H,),
3.03-2.97 (m, 1H), 2.52-2.49 (m, 2H), 2.19 (s, 1H), 2.03-1.95
(m, 1H), 1.81-1.74 (m, 1H), 1.31 (t, J ) 7 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 165.8, 146.7, 143.9, 128.6, 127.9, 125.5,
124.1, 117.5, 71.5, 60.6, 42.5, 35.8, 22.8, 14.1; IR (NaCl) 3146,
3053, 2249, 1712, 1657, 1451, 1306, and 1223 cm-1; EI-HRMS
(m/z) calcd for C16H19NO3 ([M]+) 273.1365, found 273.1370.
(4R,6S,E)-Ethyl 4-Benzyl-6-hydroxy-6-phenylhex-2-enoate (6d).
The title compound was prepared from γ-lactone 5d following the
same procedure that was used for the synthesis of 6g. Purification
by flash chromatography (80:20 hexanes:EtOAc) afforded 6d (944
mg, 84% yield over two steps) as a single diastereomer; oil; [R]20
D
1
+13.1 (c 0.9, CHCl3); H NMR (400 MHz, CDCl3) δ 7.35-7.11
(m, 10H), 6.84 (dd, J ) 15.5, 9.4 Hz, 1H), 5.79 (d, J ) 15.7 Hz,
1H), 4.61 (dd, J ) 10.3, 3.1 Hz, 1H), 4.21-4.14 (m, 2H), 2.96-2.87
(m, 1H), 2.75-2.72 (m, 2H), 1.99-1.87 (m, 2H), 1.69-1.62 (m,
1H), 1.29 (t, J ) 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
166.4, 151.3, 144.7, 138.9, 129.1, 128.4, 128.2, 127.5, 126.1, 125.5,
122.2, 71.7, 60.2, 43.1, 41.3, 40.8, 14.1; IR (NaCl) 3447, 3062,
1716, 1651, 1494, 1453, 1370, 1305, 1217, and 1030 cm-1; ESI-
HRMS (m/z) calcd for C21H24O3 ([M]+) 324.1725, found 324.1728.
(4R,6S,E)-Ethyl 6-Hydroxy-4-(4-nitrobenzyl)-6-phenylhex-2-
enoate (6e). The title compound was prepared from γ-lactone 5e
following the same procedure that was used for the synthesis of
6g. Purification by flash chromatography (80:20 hexanes/EtOAc)
afforded 6e (531 mg, 96% yield over two steps) as a single
1
diastereomer; [R]20 +21.04 (c 1.9, CHCl3); H NMR (400 MHz,
D
CDCl3) δ 8.10 (d, J ) 9 Hz, 2H), 7.34-7.24 (m, 7H), 6.76 (dd,
J ) 16, 10 Hz, 1H), 5.75 (d, J ) 16 Hz, 1H), 4.62-4.59 (m, 1H),
4.18-4.12 (m, 2H), 2.99-2.94 (m, 1H), 2.89-2.84 (m, 1H),
2.79-2.74 (m, 1H), 2.20-2.19 (m, 1H), 1.96-1.89 (m, 1H),
1.69-1.63 (m, 1H), 1.26 (t, J ) 7 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 166.1, 149.9, 146.9, 146.4, 144.5, 129.8, 128.5, 127.7,
125.4, 123.5, 122.9, 71.5, 60.4, 43.3, 41.1, 40.7, 14.1; IR (NaCl)
2900, 1709, 1516, and 1345 cm-1; EI-HRMS (m/z) calcd for
C21H23NO5 ([M + H]+) 370.1654, found 370.1657.
hexanes/EtOAc) afforded 2c (62 mg, 82% yield) as an oil; dr (11:
1
1); [R]20 -36.9 (c 3.1, CHCl3); H NMR (400 MHz, CDCl3) δ
D
7.36-7.24 (m, 5H), 5.02 (t, J ) 7 Hz, 1H), 4.21-4.14 (m, 3H),
2.84-2.40 (m, 6H), 2.29-2.13 (m, 2H), 1.28 (t, J ) 7 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 170.5, 141.4, 128.3, 127.5, 125.5,
118.2, 79.8, 79.4, 60.7, 40.2, 39.9, 39.6, 20.4, 14.0; IR (NaCl) 2872,
4514 J. Org. Chem. Vol. 74, No. 12, 2009

Synthesis of anti-Aldol Segments Via a Nonaldol Route
2400, 1729, and 1240 cm-1; EI-HRMS (m/z) calcd for C16H19NO3
([M]+) 273.1365, found 273.1369.
MHz, CDCl3) δ 7.37-7.20 (m, 5H), 6.44 (d, J ) 16 Hz, 1H), 6.09
(dd, J ) 16, 8 Hz, 1H), 5.36-5.32 (m, 1H), 4.14-4.08 (m, 2H),
2.68-2.56 (m, 3H), 2.04 (s, 3H), 1.23 (t, J ) 7 Hz, 3H), 1.12 (d,
J ) 7 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 170.5, 170.2, 137.0,
131.4, 130.1, 128.4, 127.3, 126.1, 73.0, 60.6, 40.8, 36.9, 20.9, 16.0,
14.0; IR (NaCl) 2949, 2875, 1740, 1371, 1237, 1179, and 1028
cm-1; CI-HRMS (m/z) calcd for C17H22O4 ([M - H]+) 289.1440,
found 289.1437.
(3S,4R,E)-Ethyl 3-Acetoxy-4-ethyl-6-phenylhex-5-enoate (3b).
The title compound was prepared from furan 2b following the same
procedure that was used for the synthesis of 3g. Purification by
flash chromatography (90:10 hexanes/EtOAc) afforded 3b (251 mg,
60% yield) as an oil; [R]20D -19.4 (c 2.7, CHCl3); 1H NMR (CDCl3
400 MHz) δ 7.37-7.19 (m, 5H), 6.41 (d, J ) 16 Hz, 1H), 6.00
(dd, J ) 16, 9 Hz, 1H), 5.42-5.38 (m, 1H), 4.15-4.05 (m, 2H),
2.63-2.52 (m, 2H), 2.34-2.28 (m, 1H), 2.03 (m, 3H), 1.61-1.55
(m, 1H), 1.40-1.36 (m, 1H) 1.23 (t, J ) 7 Hz, 3H), 0.91 (t, J )
7 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 170.4, 170.1, 136.9,
133.1, 128.5, 128.3, 127.2, 126.0, 72.0, 60.4, 48.9, 37.5, 24.0, 20.8,
13.9, 11.7; IR (NaCl) 3097, 1742, 1640, 1370, 1236, and 1028
cm-1; ESI-HRMS (m/z) calcd for C18H24O4 ([M + Na]+) 327.1572,
found 327.1569.
Ethyl 2-((2S,3R,5S)-3-Benzyl-5-phenyltetrahydrofuran-2-
yl)acetate (2d). The title compound was prepared from alcohol 6d
following the same procedure that was used for the synthesis of
2g. Purification by flash chromatography (90:10 hexanes/EtOAc)
afforded 2d (435 mg, 91% yield) as an oil; dr (49:1); [R]20D -32.7
(c 1.3, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.39-7.20 (m, 10H)
5.08 (t, J ) 7.2 Hz, 1H), 4.28-4.22 (m, 1H), 4.18 (q, J ) 7.1 Hz,
2H), 2.87 (dd, J ) 13.7, 6.3 Hz, 1H), 2.76-2.62 (m, 2H), 2.53
(dd, J ) 15.1, 4.9 Hz, 1H), 2.40-2.34 (m, 1H), 2.21-2.14 (m,
1H), 2.03-1.96 (m, 1H), 1.29 (t, J ) 7.2 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 171.1, 143.1, 139.8, 128.7, 128.4, 128.1,127.1,
126.2, 125.5, 81.0, 79.5, 60.5, 45.3, 40.3, 40.3, 38.8, 14.1; IR (NaCl)
3027, 2978, 2928, 1734, 1603, 1494, 1453, 1368, 1304, 1158, and
1029 cm-1; ESI-HRMS (m/z) calcd for C21H24O3 ([M]+) 324.1725,
found 324.1724.
Ethyl 2-((2S,3R,5S)-3-(4-Nitrobenzyl)-5-phenyltetrahydrofu-
ran-2-yl)acetate (2e). The title compound was prepared from
alcohol 6e following the same procedure that was used for the
synthesis of 2g. Purification by flash chromatography (80:20
hexanes/EtOAc) afforded 2e (344 mg, 70% yield) as an oil; dr (14:
1); [R]20D -20.1 (c 1, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.15
(d, J ) 8 Hz, 2H), 7.37-7.17 (m, 7H), 5.06 (t, J ) 7 Hz, 1H),
4.24-4.13 (m, 3H), 3.01-2.96 (m, 1H), 2.82-2.77 (m,1H),
2.71-2.65 (m, 1H), 2.58-2.53 (m, 1H), 2.42-2.37 (m, 1H),
2.14-2.08 (m, 1H), 2.04-1.92 (m, 1H), 1.27 (t, J ) 7 Hz, 3H);
13C NMR (CDCl3; 100 MHz) δ 170.9, 147.7, 146.5, 142.5, 129.5,
128.2, 127.2, 125.4, 125.0, 123.7, 80.7, 79.4, 60.6, 44.9, 40.0, 38.6,
14.1; IR (NaCl) 2926, 1727, 1517, and 1346 cm-1; EI-HRMS
(m/z) calcd for C21H23NO5 ([M]+) 369.1576, found 369.1573.
Ethyl 2-((2S,3R,5S)-3-(But-3-enyl)-5-phenyltetrahydrofuran-
2-yl)acetate (2f). The title compound was prepared from alcohol
6f following the same procedure that was used for the synthesis of
2g. Purification by flash chromatography (80:20 hexanes/EtOAc)
afforded 2f (63 mg, 86% yield) as an oil; dr (100:1); [R]20D -51.2
(c 0.7, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.40-7.22 (m, 5H),
5.88-5.74 (m, 1H), 5.05-4.97 (m, 3H), 4.23-4.10 (m, 3H),
2.68-2.65 (m, 2H), 2.15-1.99 (m, 6H), 1.67-1.61 (m, 1H),
1.50-1.45 (m, 1H), 1.30-1.27 (m, 4H); 13C NMR (100 MHz,
CDCl3) δ 171.2, 143.2,138.0, 128.1, 127.0, 125.5, 114.8, 81.2, 79.7,
60.5, 43.4, 40.5, 40.3, 32.1, 31.9, 14.1; IR (NaCl) 2898, 1736, 1658,
1549, and 1449 cm-1; EI-HRMS (m/z) calcd for C18H24O3 ([M]+)
288.1725, found 288.1725.
(3S,4R,E)-Ethyl 3-Acetoxy-4-(cyanomethyl)-6-phenylhex-5-
enoate (3c). The title compound was prepared from furan 2c
following the same procedure that was used for the synthesis of
3g, using 3 equiv of Zn(OTf)2. Purification by flash chromatography
(85:15 hexanes/EtOAc) afforded 3c (116 mg, 53% yield) as an oil;
[R]20 -24.6 (c 1.1, CHCl3); 1H NMR (400 MHz, CDCl3) δ
D
7.41-7.28 (m, 5H), 6.60 (d, J ) 16 Hz, 1H), 6.10 (dd, J ) 16, 9
Hz, 1H), 5.47-5.43 (m, 1H), 4.20-4.06 (m, 2H), 2.68-2.49 (m,
5H), 2.12 (s, 3H), 1.30-1.17 (m, 3H); 13C NMR (100 MHz, CDCl3)
δ 170.2, 169.7, 135.9, 128.6, 128.2, 126.5, 123.5, 117.7, 71.1, 60.9,
43.0, 37.0, 29.6, 20.9, 20.7, 14.0; IR (NaCl) 2876, 2130, 1544,
1370, and 1231 cm-1; CI-HRMS (m/z) calcd for C18H22NO4
([M + H]+) 316.1549, found 316.1544.
(3S,4R,E)-Ethyl 3-Acetoxy-4-benzyl-6-phenylhex-5-enoate (3d).
To a stirred suspension of Zn(OTf)2 (3 mg, 0.008 mmol), 2d (50
mg, 0.15 mmol), and CH3CN (400 µL, 7.71 mmol) in toluene (3
mL) under argon was added Ac2O (730 µL, 7.71 mmol) then the
reaction mixture was refluxed for 4 h. The reaction was then cooled
to room temperature and saturated aqueous NaHCO3 was added.
The aqueous layer was extracted with EtOAc (3×), then the
combined organic layers were washed with saturated solution
NaHCO3 brine and dried over Na2SO4. The organic layer was then
concentrated and chromatographed (90:10 hexanes/EtOAc) to give
3d, 11a, and 11b (55.8 mg) as a complex mixture. The following
mixture was separated by HPLC by using the following conditions:
column, YMC-Pack ODS-A 250 × 10 mm, 5 µm coupled to Luna
(R,E)-Ethyl 3-Acetoxy-6-phenylhex-5-enoate (3g). To a stirred
suspension of Zn(OTf)2 (15 mg, 0.042 mmol) in toluene (2 mL)
under argon was added 2g (197 mg, 0.84 mmol) dissolved in toluene
(10 mL). Then Ac2O (1.58 mL, 16.7 mmol) was added and the
reaction mixture was refluxed for 4 h until TLC indicated complete
consumption of the starting material. The reaction was then cooled
to room temperature and saturated aqueous NaHCO3 was added.
The aqueous layer was extracted with EtOAc (3×), then the
combined organic layers were washed with saturated aqueous
NaHCO3 and brine and dried over anhydrous Na2SO4. The organic
layer was then concentrated and chromatographed (90:10 hexane/
C
18 250 × 10 mm, 5 µm; flow rate, 2.75 mL/min; solvents, isocratic
80:20 MeOH:H2O; UV, 210 nm; temperature, 25 °C. The yield
was 9 mg (16% yield). [R]20 -102.28 (c 0.4, CHCl3); H NMR
1
D
(500 MHz, CDCl3) δ 7.36-7.16 (m, 10H), 6.28 (d, J ) 16 Hz,
1H), 6.13 (dd, J ) 16, 9.1 Hz, 1H), 5.43 (m, 1H), 4.14 (m, 2H),
2.92 (dd, J ) 13, 5.2 Hz, 1H), 2.84-2.78 (m, 1H), 2.76-2.57 (m,
3H), 2.12 (s, 3H), 1.25 (t, J ) 7.1 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 170.3, 170.2, 139.2, 137.0, 133.6, 129.2, 128.4, 128.2,
127.7, 127.4, 126.2, 126.1, 72.0, 60.6, 48.6, 37.9, 37.5, 29.7, 21.0,
14.1; IR (NaCl) 3026, 2929, 2956, 1741, 1601, 1495, 1453, 1370,
1235, 1179, and 1029 cm-1; ESI-HRMS (m/z) calcd for C23H26O4
([M + H]+) 367.1909, found 367.1913.
1
EtOAc) to give 3g (181 mg, 78% yield) as an oil; H NMR (400
MHz, CDCl3) δ 7.35-7.20 (m, 5H), 6.45 (d, J ) 16 Hz, 1H),
6.17-6.09 (m, 1H), 5.38-5.35 (m, 1H), 4.12 (q, J ) 7 Hz, 2H),
2.61 (d, J ) 7 Hz, 2H), 2.56-2.53 (m, 2H), 2.03 (s, 3H), 1.24 (t,
J ) 7 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 170.2, 170.1, 136.9,
133.5, 128.4, 127.3, 126.0, 124.1, 69.7, 60.5, 38.5, 37.5, 21.0, 14.0;
(R)-Ethyl 3-Acetoxy-3-((2S,4S)-4-phenyl-1,2,3,4-tetrahydro-
IR (NaCl) 2933, 2857, 1739, 1455, 1372, 1237, and 1030 cm-1
;
naphthalen-2-yl)propanoate (11a). The title compound was
CI-HRMS (m/z) calcd for C16H21O4 ([M + H]+) 277.1440, found
277.1442.
1
obtained in 47% yield (26 mg); [R]20 -25.7 (c 0.7, CHCl3); H
D
NMR (500 MHz, CDCl3) δ 7.37-7.04 (m, 8H), 6.79 (d, J ) 7.8
Hz, 1H), 5.35 (dt, J ) 7.3, 5.8 Hz, 1H), 4.21-4.15 (m, 2H), 4.09
(dd, J ) 12.2, 5.5 Hz, 1H), 2.97-2.91 (m, 1H), 2.86-2.78 (m,
1H), 2.72-2.70 (m, 2H), 2.35-2.21 (m, 2H), 2.09 (s, 3H), 1.66
(dd, J ) 25.3, 12.8 Hz, 1H), 1.29 (t, J ) 7.2 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ 170.4, 170.3, 146.4, 139.5, 135.6, 129.4,
(3S,4R,E)-Ethyl 3-Acetoxy-4-methyl-6-phenylhex-5-enoate (3a).
The title compound was prepared from furan 2a following the same
procedure that was used for the synthesis of 3g. Purification by
flash chromatography (90:10 hexanes/EtOAc) afforded 3a (323 mg,
1
76% yield) as an oil; [R]20 +27.3 (c 1.9, CHCl3); H NMR (400
D
J. Org. Chem. Vol. 74, No. 12, 2009 4515

Ghosh et al.
128.9, 128.7, 128.5, 126,4, 126.0, 125.9, 73.0, 60.7, 46.8, 38.1,
36.7, 35.6, 32.5, 20.9, 14.1; IR (NaCl) 3061, 1735, 1599, 1493,
1371, 1178, and 1028 cm-1; ESI-HRMS (m/z) calcd for C23H26O4
([M]+) 366.1831, found 366.1833.
13.8, 12.1; IR (NaCl) 1739, 1463, 1373, and 1200 cm-1; ESI-HRMS
(m/z) calcd for C11H18 O6 ([M + H]+) 247.1182, found 247.1185.
(2S,3S)-5-Ethyl 1-Methyl 3-acetoxy-2-ethylpentanedioate (7b).
The title compound was obtained from 3b (216 mg, 0.71 mmol)
as described for 7a after flash chromatography (1:4 EtOAc/hexanes)
as a colorless oil (144 mg, 87% yield over 2 steps); [R]20D +1.4 (c
(R)-Ethyl 3-Acetoxy-3-((2S,4R)-4-phenyl-1,2,3,4-tetrahydro-
naphthalen-2-yl)propanoate (11b). The title compound was
1
1
obtained in 20% yield (11 mg); [R]20 -60.9 (c 0.5, CHCl3); H
2.1, CHCl3); H NMR (400 MHz, CDCl3) δ 5.37-5.43 (m, 1H),
D
4.06-4.12 (m, 2H), 3.65 (s, 3H), 2.63-2.69 (m, 2H), 2.55 (dd,
J ) 15.8, 7.7 Hz, 1H), 1.98 (s, 3H), 1.51-1.68 (m, 2H), 1.20 (t, J
) 7.3 Hz, 3H), 0.86 (t, J ) 7.3 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 172.7, 169.9, 169.7, 70.0, 60.7, 51.6, 50.3, 36.6, 20.9,
20.7, 14.0, 11.7; IR (NaCl) 1743, 1370, 1233, and 1177 cm-1; ESI-
HRMS (m/z) calcd for C12H20O6 ([M + H]+) 261.1338, found
261.1339.
(3S,4S)-Ethyl 3-Acetoxy-4 (benzyloxycarbonylamino)-5-(4-
nitrophenyl)pentanoate (13). To a stirred solution of 3e (50 mg,
0.12 mmol) in DMF (0.6 mL) was added OsO4 in 2.5% tert-butyl
alcohol (1 µL) and the mixture was stirred for 5 min. Then Oxone
(300 mg, 0.48 mmol) was added and the reaction mixture was stirred
for 3 h. After 3 h, Na2SO3 was added and the reaction was stirred
until the mixture turned brown, then 1 M HCl was added, the
aqueous layer was extracted with EtOAc (3×), and the combined
organic layers were washed with 1 M HCl (3×) and brine, dried
over anhydrous Na2SO4, and concentrated under reduced pressure
to give a mixture of the crude acid and benzoic acid.
To a stirred solution of the crude and benzoic acid (58 mg, 0.12
mmol) in PhMe (2.5 mL) under argon was added Et3N (38 µL,
0.27 mmol) and diphenylphosphoryl azide (59 µL, 0.27 mmol).
The resulting mixture was heated at reflux for 3 h and then benzyl
alcohol (51 µL, 0.49 mmol) was added. Stirring and refluxing were
continued for an additional 12 h. After this period the reaction
mixture was cooled to room temperature and concentrated under
reduced pressure. The resulting residue was partitioned between
EtOAc and saturated aqueous NaHCO3. The organic layer was then
washed with brine, dried over anhydrous Na2SO4, concentrated
under reduced pressure, and chromatographed (70:30 hexanes/
EtOAc) to give protected amine 13 (37 mg, 67% yield over 2 steps)
as an oil; [R]20D -47.2 (c 6, CHCl3); 1H NMR (400 MHz, CDCl3)
δ 8.07 (d, J ) 8.6 Hz, 2H), 7.34-7.21 (m, 7H), 5.35-5.31 (m,
1H), 5.10-4.93 (m, 3H), 4.26-4.20 (m, 1H), 4.09 (q, J ) 7.1 Hz,
2H), 2.90 (dd, J ) 6.2, 14 Hz, 1H), 2.78 (dd, J ) 8.6, 13.9 Hz,
1H), 2.62 (t, J ) 7.2 Hz, 2H), 2.07 (s, 3H), 1.20 (t, J ) 7.1 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 169.7, 169.6, 155.8, 146.6,
144.7, 135.9, 129.9, 128.4, 128.2, 128.0, 123.5, 70.5, 66.8, 60.8,
54.0, 38.7, 36.45, 20.7, 13.9; IR (NaCl) 3344, 3034, 3066, 2981,
1740, 1604, 1520, 1347, 1228, and 1045 cm-1; EI-HRMS (m/z)
calcd for C23H26N2O8 ([M + H]+) 459.1767, found 459.1765.
(3S,4S)-Ethyl 3-Acetoxy-4-(benzyloxycarbonylamino)hex-
anoate (12). The title compound was prepared from styrene 3b
following the same procedure that was used for the synthesis of
13. Purification by flash chromatography (80:20 to 70:30 hexanes/
NMR (500 MHz, CDCl3) δ 7.30-7.12 (m, 6H), 7.02-6.98 (m,
3H), 5.32 (dt, J ) 5.6, 3.7 Hz, 1H), 4.37 (t, J ) 4.3 Hz, 1H),
4.10-4.03(m, 2H), 2.96 (dd, J ) 16.1, 5.1 Hz, 1H), 2.72-2.50
(m, 3H), 2.12-2.06 (m, 1H), 2.04 (s, 3H), 2.04-2.00 (m, 2H),
1.21 (t, J ) 7.2 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 170.4,
170.3, 146.7, 137.6, 136.1, 130.3, 129.0, 128.5, 128.1, 126.3, 126.1,
125.9, 72.6, 60.6, 43.7, 37.1, 32.8, 32.7, 31.9, 20.9, 14.0; IR (NaCl)
3059, 1741, 1601, 1493, 1448, 1370, 1236, 1176, and 1028 cm-1
;
ESI-HRMS (m/z) calcd for C23H26O4 ([M + H]+) 367.1909, found
367.1904.
(3S,4R,E)-Ethyl 3-Acetoxy-4-(4-nitrobenzyl)-6-phenylhex-5-
enoate (3e). The title compound was prepared from furan 2e
following the same procedure that was used for the synthesis of
3g. Purification by flash chromatography (90:10 hexanes/EtOAc)
afforded 3e in 90% yield; [R]20D -142.8 (c 1.7, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 8.10 (d, J ) 9 Hz, 2H), 7.31-7.21 (m, 7H),
6.22 (d, J ) 16 Hz, 1H), 6.06 (dd, J ) 16, 9 Hz, 1H), 5.49-5.32
(m, 1H), 4.15-4.04 (m, 2H), 3.05-2.98 (m, 1H), 2.85-2.79 (m,
2H), 2.69-2.55 (m, 2H), 2.11 (s, 3H), 1.22 (t, J ) 7 Hz, 3H); 13
C
NMR (100 MHz, CDCl3) δ 170.1, 170.1, 147.2, 146.4, 136.3, 134.4,
129.9, 128.5, 127.7, 126.3, 126.1, 123.5, 71.8, 60.7, 48.4, 37.9,
37.3, 20.9, 14.0; IR (NaCl) 2918, 1740, 1600, 1345, and 1235 cm-1
;
ESI-HRMS (m/z) calcd for C23H25NO6Na ([M + Na]+) 434.1580,
found 434.1577.
(3S,4R)-Ethyl 3-Acetoxy-4-styryloct-7-enoate (3f). The title
compound was prepared from furan 2f following the same procedure
that was used for the synthesis of 3g. Purification by flash
chromatography (95:5 hexanes/EtOAc) afforded 3f in 86% yield;
dr (50:1); [R]20D -37.8 (c 2.4, CHCl3); 1H NMR (400 MHz, CDCl3)
δ 7.39-7.24 (m, 5H), 6.41 (d, J ) 16 Hz, 1H), 6.00 (dd, J ) 16,
9 Hz, 1H), 5.83-5.73 (m, 1H), 5.41-5.37 (m, 1H), 5.03-4.96 (m,
2H), 4.18-4.06 (m, 2H), 2.63-2.52 (m, 2H), 2.51-2.43 (m, 1H),
2.17-2.11 (m, 1H), 2.06-1.98 (m, 4H), 1.65-159 (m, 1H),
1.54-1.45 (m, 1H), 1.24 (t, J ) 7 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 170.4, 170.2, 138.0, 136.9, 133.4, 128.4, 128.3, 127.3,
126.1, 114.9, 72.3, 60.5, 46.4, 37.6, 31.2, 30.2, 20.9, 14.0; IR (NaCl)
3039, 2884, 1742, 1597,1449, 1369, and 1234 cm-1; ESI-HRMS
(m/z) calcd for C20H27O4 ([M + H]+) 331.1909, found 331.1906.
(2S,3S)-5-Ethyl 1-Methyl 3-acetoxy-2-methylpentanedioate
(7a). To a stirring solution of 3a (113 mg, 0.62 mmol) in a mixture
of CH3CN:CCl4:H2O (1:1:1.5, 3.5 mL) was added RuCl3 ·H2O (13
mg, 0.062 mmol) followed by NaIO4 (663 mg, 3.1 mmol). The
resulting solution was allowed to stir overnight; after this time the
solvents were evaporated under reduced pressure and saturated
aqueous NaHCO3 was added and the mixture was washed with
Et2O (2×). The layers were then separated and the aqueous layer
was acidified with 1 N HCl to pH 3. The aqueous layer was then
extracted with EtOAc (3×) and the combined organic layers were
dried on anhydrous Na2SO4 and concentrated under reduced
pressure to give a mixture of acids.
EtOAc) afforded protected amine 12 (48 mg, 99% yield over 2
1
steps) as an oil; [R]20 -22.6 (c 2, CHCl3); H NMR (400 MHz,
D
CDCl3) δ 7.38-7.29 (m, 5H), 5.37 (dt, J ) 8.8, 2.5 Hz, 2H), 5.11
(s, 2H), 4.80 (d, J ) 10.1 Hz, 1H), 4.15-4.09 (m, 2H), 3.82-3.74
(m, 1H), 2.62-2.59 (m, 2H), 2.02 (s, 3H), 1.24 (t, J ) 7.1 Hz,
3H), 0.95 (t, J ) 7.3, 3H); 13C NMR (100 MHz, CDCl3) δ 170.0,
169.8, 156.3, 136.2, 128.5, 128.2, 128.1, 70.9, 66.9, 60.7, 55.0,
36.8, 25.7, 20.7, 14.0, 10.3; IR (NaCl) 3347, 1732, 1531, 1456,
1372, 1229, 1183, 1054, and 1028 cm-1; EI-HRMS (m/z) calcd
for C18H25NO6 ([M]+) 351.1682, found 351.1682.
To the above crude mixture of acids in ether was added CH2N2
in Et2O until a yellow color persisted. The excess CH2N2 was
quenched with AcOH until the solution turned colorless. The
solvents were then evaporated under reduced pressure and the
residue was purified by column chromatography (1:4 EtOAc/
(3R,5S)-3-Hexyl-5-phenyldihydrofuran-2(3H)-one (17). To a
stirring solution of THF (7 mL) and diisopropylamine (0.9 mL,
6.78 mmol) at 0 °C under argon was added n-BuLi (4.1 mL, 1.6
M solution in hexanes, 6.48 mmol) dropwise; the mixture was then
stirred for 15 min, HMPA (4 mL) was added dropwise, and the
reaction mixture was stirred at 0 °C for 15 min and then cooled to
-78 °C. Then lactone 1 (1.0 g, 6.17 mmol) in THF (15 mL) was
added dropwise over a 0.5 h period. The reaction mixture was stirred
hexanes) to give ester 7a (99 mg, 64% yield over 2 steps) as
1
colorless oil; [R]20 +13.4 (c 1, CHCl3); H NMR (CDCl3, 300
D
MHz) δ 5.37-5.43 (m, 1H), 4.02-4.12 (m, 2H), 3.64 (s, 3H),
2.81-2.90 (m, 1H), 2.50-2.66 (m, 2H), 1.97 (s, 3H), 1.19 (t, J )
7.2 Hz, 3H), 1.12 (d, J ) 7.5 Hz, 3H); 13C NMR (CDCl3, 75 MHz)
δ 173.0, 169.7, 169.5, 100.9, 70.5, 60.4, 51.6, 42.1, 35.9, 20.5,
4516 J. Org. Chem. Vol. 74, No. 12, 2009

Synthesis of anti-Aldol Segments Via a Nonaldol Route
for an additional 0.5 h at -78 °C. Then iodohexane (2.7 mL, 7.41
mmol) was added dropwise and the reaction mixture was stirred
for 6 h at -78 °C. The reaction was quenched with saturated
aqueous NH4Cl and warmed to room temperature. The aqueous
layer was extracted with EtOAc (3×), then the combined organic
layers were washed with water, brine, dried over anhydrous Na2SO4,
and concentrated under reduced pressure. The residue was chro-
matographed on silica gel (95:5 to 90:10 hexanes/EtOAc) to give
1643, 1457, and 1092 cm-1; ESI-HRMS (m/z) calcd for C29H51O2
([M + H]+) 431.3889, found 431.3892.
(7R,8S,10S)-7-Styrylhenicosane-8,10-diyl Diacetate (21). To
a stirring suspension of Zn(OTf)2 (19.5 mg, 0.054 mmol) in toluene
(3 mL) under argon was added furan 20 (462 mg, 1.1 mmol)
dissolved in toluene (10 mL). Then Ac2O (2.03 mL, 21.5 mmol)
was added and the reaction mixture was refluxed for 4 h. The
reaction was quenched with a saturated solution of aqueous
NaHCO3. The aqueous layer was extracted with EtOAc (3×), then
the combined organic layers were washed with saturated aqueous
NaHCO3 (2×) and brine and dried over anhydrous Na2SO4. The
organic layer was then concentrated and chromatographed (95:5
17 (1.21 g, 84% yield) as an amorphous solid; [R]20 -11.5 (c 1,
D
1
CHCl3); H NMR (400 MHz, CDCl3) δ 7.40-7.29 (m, 5H), 5.55
(t, J ) 6.3 Hz, 1H), 2.64-2.60 (m, 1H), 2.41-2.37 (m, 2H),
1.92-1.85 (m, 1H), 1.58-1.49 (m, 1H), 1.42-1.23 (m, 9H), 0.88
(t, J ) 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 179.3, 139.9,
128.6, 128.1, 124.9, 78.6, 38.8, 36.4, 31.5, 30.4, 28.9, 27.2, 22.5,
hexanes/EtOAc) to give 21 (460 mg, 85% yield) as an oil; [R]20
D
1
-19.3 (c 1.1, CHCl3); H NMR (400 MHz, CDCl3) δ 7.42-7.20
14.0; IR (NaCl) 2947, 2855, 1865, 1649, 1454, and 1166 cm-1
;
(m, 5H), 6.40 (d, J ) 16 Hz, 1H), 6.00 (dd, J ) 16, 10 Hz, 1H),
5.04-5.00 (m, 1H), 4.95-4.85 (m, 1H), 2.39-2.32 (m, 1H), 2.05
(s, 3H), 2.03 (s, 3H), 1.83-1.79 (m, 2H), 1.52-1.41 (m, 3H),
1.31-1.19 (m, 31H), 0.88 (t, J ) 7 Hz, 6H); 13C NMR (100 MHz,
CDCl3) δ 170.7, 170.6, 137.2, 132.6, 129.4, 128.5, 127.2, 126.1,
73.1, 71.3, 47.0, 36.7, 34.0, 31.8, 31.7, 31.2, 29.5, 29.5, 29.3, 29.3,
29.2, 27.2, 22.6, 22.6, 21.2, 21.1, 14.1, 14.0; IR (NaCl) 2923, 2853,
1737, and 1238 cm-1; ESI-HRMS (m/z) calcd for C33H54O4Na
([M + Na]+) 537.3920, found 537.3921.
CI-HRMS (m/z) calcd for C16H22O2 ([M]+) 246.1620, found
246.1617.
1-((2S,3R,5S)-3-Hexyl-5-phenyltetrahydrofuran-2-yl)tridecan-
2-one (16). To a stirring solution of CH2Cl2 (35 mL) and 17 (1.04
g, 4.22 mmol) at -78 °C under argon was added DIBAL-H (5.10
mL, 1 M solution in dichloromethane, 5.07 mmol) dropwise. The
solution was stirred for a 0.5 h at -78 °C and then quenched with
a saturated solution of Na-K tartrate and allowed to warm to room
temperature. Once the emulsion had separated the aqueous layer
was then extracted with CH2Cl2 (3×), then the combined organic
layers were washed with brine, dried over anhydrous Na2SO4, and
concentrated under reduced pressure. Without further purification
the crude lactol was used in the next reaction.
To a stirring suspension of THF (5 mL) and Ba(OH)2 (1.07 g,
3.38 mmol) at room temperature under argon was added 18 (9.05
g, 29.6 mmol) dissolved in THF (20 mL) dropwise and the mixture
was stirred for 15 min. Then the crude lactol in THF (40 mL) was
added dropwise and the mixture was stirred for 72 h. The reaction
was quenched with H2O and the aqueous layer was extracted with
EtOAc (3×). The combined organic layers were washed with H2O
and brine, dried over anhydrous Na2SO4, and concentrated under
reduced pressure. The residue was chromatographed on silica gel
(7R,8S,10S)-7-Styryl-10-(triisopropylsilyloxy)henicosan-8-ol
(22). To a stirring solution of CH2Cl2 (12 mL) and diacetate 21
(448 mg, 0.87 mmol) at -78 °C under argon was added DIBAL-H
(1.83 mL, 1 M in CH2Cl2, 1.82 mmol) dropwise and then the
reaction mixture was stirred for 0.5 h. The reaction was then
quenched with Na-K tartrate and allowed to warm to room
temperature. Once the emulsion had separated the aqueous layer
was extracted with CH2Cl2 (3×) and the combined organic layers
were washed with brine and dried over Na2SO4. The organic layer
was then concentrated and chromatographed (85:15 hexanes/EtOAc)
to give the diol (303 mg, 81% yield) as an oil; [R]20D -7.2 (c 0.9,
1
CHCl3); H NMR (400 MHz, CDCl3) δ 7.46-7.19 (m, 5H), 6.42
(d, J ) 16 Hz, 1H), 6.07 (dd, J ) 16, 9 Hz, 1H), 3.84-3.81 (m,
2H), 3.13 (s, 1H), 2.93 (s, 1H), 2.24-2.11 (m, 1H), 1.66-1.36
(m, 6H), 1.33-1.19 (m, 29H), 0.90-0.85 (m, 6H); 13C NMR (100
MHz, CDCl3) δ 137.1, 132.8, 130.3, 128.5, 127.2, 126.1, 75.5, 73.0,
50.5, 40.7, 38.1, 31.8, 31.7, 31.0, 29.6, 29.3, 27.4, 25.4, 22.6, 22.6,
14.1, 14.0; IR (NaCl) 3018, 2925, and 1215 cm-1; ESI-HRMS
(m/z) calcd for C29H50O2Na ([M + Na]+) 453.3709, found 453.3706.
To a stirring solution of CH2Cl2 (5 mL) and the diol (138 mg,
0.321 mmol) at -78 °C under argon were added 2,6-lutidine (75
µL, 0.64 mmol) and TIPSOTf (91 µL, 0.34 mmol) dropwise, then
the reaction mixture was stirred at -78 °C for 1 h. The reaction
was then quenched with H2O and allowed to warm to room
temperature, the aqueous layer was extracted with CH2Cl2 (3×),
then the combined organic layers were washed with brine and dried
over anhydrous Na2SO4. The organic layer was then concentrated
(95:5 hexanes/EtOAc) to give 16 (1.5 g, 83% yield over two steps)
1
as an oil; dr (33:1); [R]20 -45.8 (c 1.1, CHCl3); H NMR (400
D
MHz, CDCl3) δ 7.37-7.22 (m, 5H), 4.97 (t, J ) 7 Hz, 1H),
4.08-4.03 (m, 1H), 2.79 (dd, J ) 15, 8 Hz, 1H), 2.65 (dd, J ) 15,
4 Hz, 1H), 2.54-2.51 (m, 2H), 2.02 (t, J ) 7 Hz, 2H), 1.94-1.86
(m, 1H), 1.60 (t, J ) 7 Hz, 2H,), 1.50-1.47 (m, 1H), 1.40-1.11
(m, 30H), 0.89 (t, J ) 7 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ
209.6, 143.5, 128.1, 127.0, 125.5, 125.2, 81.2, 79.5, 48.0, 44.2,
43.8, 40.6, 32.6, 31.8, 31.7, 29.5, 29.4, 29.3, 29.1, 28.1, 23.5, 22.6,
22.5, 14.0, 14.0; IR (NaCl) 2924, 2853, 1715, 1651, and 1457 cm-1
;
ESI-HRMS (m/z) calcd for C29H48O2Na ([M + Na]+) 451.3552,
found 451.3554.
(S)-1-((2S,3R,5S)-3-Hexyl-5-phenyltetrahydrofuran-2-yl)tride-
can-2-ol (20). To a stirring solution of ether (25 mL) and 16 (530
mg, 1.24 mmol) at -40 °C under argon was added LiI (1.66 g,
12.4 mmol). The reaction was stirred for 20 min at -40 °C and
then cooled to -78 °C, then LiAlH4 (469 mg, 12.4 mmol) was
added in three portions and the reaction was then stirred for 30
min. The reaction was quenched with Na-K tartrate and allowed
to warm to room temperature. Once the emulsion had separated
the aqueous layer was extracted with EtOAc (3×). The combined
organic layers were washed with brine, dried over anhydrous
Na2SO4, and concentrated under reduced pressure. The residue was
chromatographed on silica gel (95:5 hexanes/EtOAc) to give 20
and chromatographed (98:2 hexanes/EtOAc) to give 22 (131 mg,
1
70% yield) as an oil; [R]20 +4.5 (c 1.1, CHCl3); H NMR (400
D
MHz, CDCl3) δ 7.44-7.19 (m, 5H), 6.39 (d, J ) 15 Hz, 1H), 6.15
(dd, J ) 15, 9 Hz, 1H), 4.08-4.05 (m, 1H), 3.83-3.80 (m, 1H),
2.99 (s, 1H), 2.17-2.10 (m, 1H), 1.67-1.45 (m, 7H), 1.30-1.02
(m, 33H), 1.19-1.04 (m, 20H), 0.90-0.85 (m, 6H); 13C NMR (100
MHz, CDCl3) δ 137.6, 131.9, 131.0, 128.4, 126.9, 126.1, 73.5, 50.1,
41.0, 37.9, 31.9, 31.8, 31.2, 29.8, 29.6, 29.4, 29.3, 27.5, 24.9, 22.6,
18.3, 18.1, 14.1, 12.9; IR (NaCl) 3018, 2927, and 1215 cm-1; ESI-
HRMS (m/z) calcd for C38H71O2Si ([M + H]+) 587.5223, found
587.5228.
(464 mg, 88% yield) as an oil; dr (17:1); [R]20 -52.4(c 1.1,
(2S,3S,5S)-2-Hexyl-3-hydroxy-5-(triisopropylsilyloxy)hexade-
canoic Acid (23). To a stirring solution of 22 (1.13 g, 1.92 mmol)
in acetone:H2O (24 mL:3 mL) were added OsO4 (1.21 mL, 2.5%
in tert -butyl alcohol, 0.095 mmol) and NMO (451 mg, 3.84 mmol)
at room temperature, then the reaction was stirred for 48 h. Then
Na2SO3 (500 mg) was added and once the reaction mixture turned
brown H2O (20 mL) was added. The aqueous layer was extracted
with EtOAc (3×), then the combined organic layers were washed
D
1
CHCl3); H NMR (400 MHz, CDCl3) δ 7.39-7.22 (m, 5H), 5.01
(t, J ) 7 Hz, 1H), 3.91-3.84 (m, 2H), 3.77-3.71 (m, 1H),
2.05-1.96 (m, 2H), 1.89-1.82 (m, 2H), 1.69-1.61 (m, 2H),
1.46-1.37 (m, 3H), 1.10-1.40 (m, 30H), 0.88 (t, J ) 7 Hz, 6H);
13C NMR (100 MHz, CDCl3) δ 143.3, 128.2, 127.1, 125.5, 86.3,
80.1, 72.1, 44.9, 41.5, 40.6, 37.5, 32.5, 31.9, 31.7, 29.7, 29.6, 29.4,
29.3, 28.2, 25.5, 22.6, 22.5, 14.1, 14.0; IR (NaCl) 3148, 2924, 2853,
J. Org. Chem. Vol. 74, No. 12, 2009 4517

Ghosh et al.
with H2O and brine, dried over anhydrous Na2SO4, and concentrated
under vacuo to give the crude triol.
was added DCC (38 mg, 0.18 mmol). The reaction mixture was
stirred for 20 min at 0 °C, then the solvent was removed under
vacuum and the reaction mixture was dissolved in DMF (1 mL).
Then the reaction mixture was added dropwise to a solution of
ꢀ-lactone 24 (32 mg, 0.1 mmol) and DMAP (0.13 mg, 0.01 mmol)
in DMF (1 mL) and was stirred for 12 h at room temperature. The
reaction was quenched with H2O (3 mL), the aqueous layer was
extracted with EtOAc (3×), and the combined organic layers were
washed with H2O and brine and dried over anhydrous Na2SO4. The
organic layer was then concentrated under vacuum and chromato-
To a solution of the crude triol in THF:H2O (16 mL:2 mL) was
added NaIO4 (617 mg, 2.88 mmol) at room temperature and the
reaction mixture was stirred for 24 h. Water was added and the
aqueous layer was extracted with EtOAc (3×), then the combined
organic layer was washed with brine, dried over anhydrous Na2SO4,
and concentrated under vacuo to give the crude aldehyde.
To a solution of the crude aldehyde in tert-butyl alcohol:H2O
(10 mL:10 mL) was added NaClO2 (1.74 g, 19.2 mmol), NaH2PO4
(2.65 g, 19.2 mmol), and 2-methyl-2-butene (3 mL, 28.8 mmol) at
room temperature and then the reaction was stirred for 12 h. Then
10 mL of H2O was added and the reaction mixture was acidified
with 1 M HCl to pH 3. The aqueous layer was extracted with EtOAc
(3×) then the combined organic layers were washed with brine
and dried over anhydrous Na2SO4. The organic layer was then
concentrated and chromatographed (90:10 to 80:20 hexanes/EtOAc)
to give acid 23 (507 mg, 50% yield over three steps) as an oil;
graphed (95:5 to 90:10 hexanes/EtOAc) to give the ester (35 mg,
1
63% yield) as an oil; [R]20 -20 (c 1.3, CHCl3); H NMR (400
D
MHz, CDCl3) δ 7.41-7.28 (m, 5H), 5.17-5.06 (m, 3H), 5.02-4.97
(m, 1H), 4.37-4.26 (m, 2H), 3.22-3.18 (m, 1H), 2.17-2.11 (m,
1H), 1.99-1.94 (m, 1H), 1.77-1.44 (m, 10H), 1.36-1.15 (m, 33H),
1.01-0.94 (m, 6H), 0.89-0.85 (m, 6H); 13C NMR (100 MHz,
CDCl3) δ 172.5, 170.8, 155.9, 136.1, 128.5, 128.1, 128.0, 74.5,
72.2, 66.9, 56.9, 52.7, 41.5, 38.6, 34.0, 31.8, 31.5, 31.4, 29.6, 29.5,
29.4, 29.3, 29.2, 29.0, 28.9, 27.6, 26.6, 25.0, 24.7, 24.6, 22.9, 22.8,
22.6, 22.4, 21.6, 14.1, 14.0; IR (NaCl) 3363, 2926, 1824, 1727,
1522, 1467, 1261, and 1048 cm-1; ESI-HRMS (m/z) calcd for
C36H59NO6Na ([M + Na]+) 624.4240, found 624.4244.
[R]20 +3.4 (c 1.3, CHCl3); 1H NMR (400 MHz, CDCl3) δ
D
4.14-4.08 (m, 1H), 4.00-3.97 (m, 1H), 2.42-2.38 (m, 1H),
1.79-1.72 (m, 2H), 1.64-1.52 (m, 4H), 1.36-1.16 (m, 33H),
1.12-1.01 (m, 20H), 0.89-0.82 (m, 6H); 13C NMR (100 MHz,
CDCl3) δ 176.8, 74.1, 71.5, 51.7, 40.4, 37.9, 31.8, 31.5, 29.7, 29.5,
29.5, 29.3, 29.0, 27.2, 24.9, 22.6, 22.5, 18.1, 18.0, 14.0, 14.0, 12.9;
IR (NaCl) 3565, 2924, 1713, 1463, and 1090 cm-1; ESI-HRMS
(m/z) calcd for C31H64O4SiNa ([M + Na]+) 551.4472, found
551.4478.
A stirred solution of the ester (93 mg, 0.15 mmol) in ethanol
(1.5 mL) was hydrogenated in the presence of 10% Pd/C (20 mg)
at room temperature and atmospheric pressure for 4 h. The
suspension was filtered through a short pad of Celite and the filtrate
was evaporated under reduced pressure to give the crude amine,
which was used without further purification in the next reaction.
(3S,4S)-3-Hexyl-4-((S)-2-hydroxytridecyl)oxetan-2-one (24).
To a solution of acid 23 (69 mg, 0.13 mmol) and diisopropylethy-
lamine (57 µL, 0.32 mmol) in THF (2 mL) was added 2,4,6-
trichlorobenzoyl chloride (31 µL, 0.19 mmol) at room temperature,
then the mixture was stirred for 3 h. Then THF was removed under
vacuum and the reaction mixture was dissolved in toluene (2 mL)
and added dropwise over a period of 3 h to a solution of DMAP in
toluene (2 mL) with stirring for 36 h. The reaction mixture was
concentrated in vacuo and purified by column chromatography (98:2
A solution of crude amine was stirred in THF (1 mL) then freshly
generated formic acetic anhydride was added (0.14 mL, 1.85 mmol)
dropwise and the reaction was stirred for 20 min. The reaction was
quenched with saturated aqueous NaHCO3, the aqueous layer was
extracted with EtOAc (3×), and the combined organic layers were
washed with H2O, saturated aqueous NaHCO3, and brine and dried
over anhydrous Na2SO4. The organic layer was then concentrated
under vacuum and chromatographed (7:3 to 1:1 pentanes/ether) to
give (-)-tetrahydrolipstatin (37 mg, 48% yield over two steps) as
an oil; [R]20D -32 (c 0.05, CHCl3); 1H NMR (500 MHz, CDCl3) δ
8.22 (s, 1H), 5.91 (d, J ) 8.1 Hz, 1H), 5.05-5.0 (m, 1H), 4.71-4.66
(m, 1H), 4.29 (dt, J ) 7.3, 4.7 Hz, 1H), 3.22 (dt, J ) 7.1, 3.2 Hz,
1H), 2.15-2.10 (m, 1H), 2.08-2.00 (m, 1H), 1.85-1.51 (m, 7H),
1.41-1.15 (m, 26H), 0.96 (t, J ) 6.3 Hz, 6H), 0.89 (t, J ) 6.5 Hz,
6H); 13C NMR (125 MHz, CDCl3) δ 171.9, 170.7, 160.5, 74.7,
72.7, 57.0, 49.6, 41.5, 38.7, 34.0, 31.8, 31.4, 29.6, 29.4, 29.3, 28.9,
27.6, 26.6, 25.8, 25.0, 24.8, 22.8, 22.6, 22.5, 21.7, 14.1, 14.0; IR
(NaCl) 3328, 2925, 2854, 1825, 1717, 1708, 1457, 1377, 1258,
and 1186 cm-1; ESI-HRMS (m/z) calcd for C29H53NO5Na
([M + Na]+) 518.3821, found 518.3824.
hexanes/EtOAc) to give the lactone (37 mg, 55% yield) as an oil;
1
[R]20 -15.6 (c 0.6, CHCl3); H NMR (400 MHz, CDCl3) δ 4.48
D
(dt, J ) 6.2, 4.3 Hz, 1H), 3.99-3.97 (m, 1H), 3.29-3.24 (m, 1H),
2.10-2.04 (m, 1H), 1.99-1.94 (m, 1H), 1.80-1.72 (m, 2H),
1.58-1.54 (m, 4H), 1.37-1.19 (m, 36H), 1.08-0.99 (m, 26H),
0.93-0.86 (m, 6H); 13C NMR (125 MHz, CDCl3) δ 171.8, 74.7,
69.5, 56.7, 40.5, 36.2, 31.8, 31.4, 29.7, 29.6, 29.5, 29.3, 29.0, 27.7,
26.6, 25.1, 22.6, 22.4, 18.1, 18.1, 14.1, 14.0, 12.5; IR (NaCl) 2924,
2855, 1827, 1464, 1116, and 1062 cm-1; ESI-HRMS (m/z) calcd
for C31H63O3Si ([M + H]+) 511.4547, found 511.4540.
To a solution of lactone (12 mg, 0.024 mmol) and AcOH (10
µL, 0.19 mmol) in THF (2 mL) at 0 °C under argon was added
TBAF (0.26 mL, 1 M in THF, 0.26 mmol) and the resulting mixture
was stirred for 4 h at 0 °C. The reaction was quenched with pH 7
buffer and the aqueous layer was extracted with CH2Cl2 (3×) and
the combined organic layers were washed with brine and dried over
anhydrous Na2SO4. The organic layer was then concentrated and
Formic Acetic Anhydride. To a solution of formic acid 88%
(1 mL) at 0 °C was added acetic anhydride (2 mL) dropwise. The
reaction was then refluxed at 60 °C for 1 h. The resulting solution
was then directly used in the synthesis of 14.
chromatographed (85:15 hexanes/EtOAc) to give ꢀ-lactone 24 (5
1
mg, 62% yield) as an oil; [R]20 -10.4 (c 0.1, CHCl3); H NMR
D
Acknowledgment. Financial support of this work was
provided in part by the National Institutes of Health and Purdue
University. We thank Mr. David D. Anderson of Purdue
University for his help with the HPLC analysis.
(500 MHz, CDCl3) δ 4.48-4.44 (m, 1H), 3.82-3.76 (m, 1H),
3.33-3.29 (m, 1H), 2.05-1.98 (m, 1H), 1.93-1.86 (m, 1H),
1.85-1.79 (m, 1H), 1.78-1.70 (m, 1H), 1.54-1.49 (m, 2H),
1.47-1.38 (m, 2H), 1.35-1.21 (m, 27H), 0.90-0.86 (m, 6H); 13
C
NMR (125 MHz, CDCl3) δ 171.2, 76.2, 69.3, 56.8, 56.8, 41.2, 37.6,
31.9, 31.5, 29.6, 29.5, 29.3, 28.6, 27.7, 26.8, 25.4, 22.6, 22.5, 14.1,
14.0; IR (NaCl) 3325, 2925, 2854, 1817, 1704,1526, 1467, and
1263 cm-1; CI-HRMS (m/z) calcd for C22H43O3 ([M + H]+)
355.3212, found 355.3207.
(-)-Tetrahydrolipstatin (14). To a stirred solution of Cbz-Leu-
OH 25 (48 mg, 0.18 mmol) in CH2Cl2 (1 mL) at 0 °C under argon
1
Supporting Information Available: Copies of H and 13C
NMR spectra of selected compounds and HPLC chromatograms
for 3d, 11a, and 11b. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO900642F
4518 J. Org. Chem. Vol. 74, No. 12, 2009